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[ { "from": "user", "value": "Context: Allelic variations in the vitamin D receptor (VDR) gene were reported to modulate insulin secretion in response to glucose. VDR was investigated as a candidate gene for type 2 diabetes mellitus (T2DM). Four single nucleotide polymorphisms (SNPs) in intron 8 (BsmI, Tru9I, ApaI) and exon 9 (TaqI) of the VDR gene were examined in 309 unrelated French subjects with T2DM and 143 controls. The distribution of alleles and genotypes of the four SNPs was similar in patients and controls. However, in patients whose age at diagnosis of diabetes was < or =45 years, homozygous subjects for the T-allele of the TaqI SNP had a higher body mass index (BMI) (31.7+/-6.7 kg/m2, P=0.0058) and an increased prevalence of obesity (81%, P=0.005) with respect to heterozygous subjects (27.9+/-5.0 kg/m2; 46%) or homozygous subjects for the t-allele (27.7+/-5.0 kg/m2; 52%). Similar results were observed for homozygous subjects for the b-allele of the BsmI SNP. Logistic regression analysis demonstrated that TT homozygosity was independently associated with obesity in these subjects (odds ratio, 4.64; 95% confidence interval (CI), 1.64-14.76; P=0.0056). Question: Are vitamin D receptor gene polymorphisms associated with obesity in type 2 diabetic subjects with early age of onset?" }, { "from": "assistant", "value": "yes. VDR is not a major gene for T2DM in French Caucasians. However, polymorphisms in the VDR gene are associated with the susceptibility to obesity in subjects with early-onset T2DM. The pathophysiological mechanisms of these associations remain unexplained, but they could be related to a direct effect of vitamin D in adypocyte differentiation and metabolism, or to an indirect effect by modulation of insulin secretion." } ]

[ { "from": "user", "value": "Context: Although beneficial roles of hepatocyte growth factor (HGF) and its variants on several hepatic disorders have been reported, their effects on hepatic ischemia-reperfusion (IR) injury remain undetermined. We investigated the action of a deleted form of HGF (dHGF) on hepatic IR injury in rats. dHGF or phosphate-buffered saline was continuously infused intravenously for 20 h prior to a 20-min occlusion of hepatic vessels. Samples were taken before and after IR, for measurement of serum dHGF and released enzymes, liver gamma-glutamylcysteinyl glycine (GSH) level, as well as histological and immunohistochemical examinations. After reperfusion, histological injury, as well as increase in the serum activities of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and creatine kinase-BB were significantly attenuated in the dHGF-treated rats. dHGF maintained a high GSH level and suppressed oxidative stress and intercellular adhesion molecule-1 (ICAM-1) expression on sinusoidal endothelial cells (SECs), on which c-Met was not detected. IR caused activation of c-Met expression, which was milder in the dHGF-treated group, in hepatocytes at the pericentral region. Question: Does continuous intravenous infusion of deleted form of hepatocyte growth factor attenuate hepatic ischemia-reperfusion injury in rats?" }, { "from": "assistant", "value": "yes. dHGF attenuated liver injury after IR. It also maintained a higher GSH level, depressed oxidative stress and inhibited ICAM-1 expression on c-Met negative SECs, suggesting a paracrine effect of dHGF." } ]

[ { "from": "user", "value": "Context: The tolerability and pharmacokinetics of a solvent/detergent-treated intramuscular immunoglobulin were compared with those of the standard product. Single, 750-mg intramuscular (i.m.) injections were administered to a total of 36 healthy individuals: 23 in a double-blind trial and 13 in an open trial. Changes in specific serum hepatitis A and hepatitis B antibodies were monitored for a period of up to 3 months postinjection. No serious adverse reactions were reported, and the bioavailability of the solvent/detergent-treated preparation was equivalent to that of the standard i.m. immunoglobulin. Question: Does solvent/detergent treatment alter the tolerance or uptake of human normal immunoglobulin for intramuscular injection?" }, { "from": "assistant", "value": "no. There is no evidence that solvent/detergent treatment alters the pharmacokinetics or tolerance of human normal immunoglobulin, but it offers additional assurance against potential virus transmission." } ]

[ { "from": "user", "value": "Context: Cardiopulmonary bypass (CPB) increases nitric oxide (NO) production by the activation of NO synthases (NOS). However, the role of NO from inducible NOS (iNOS) in CPB-induced inflammatory response remains unclear. We examined the effect of a selective iNOS inhibitor, aminoguanidine, on CPB-induced inflammatory response in a rat-CPB model. Adult Sprague-Dawley rats underwent 60 minutes of CPB (100 mL x kg(-1) x min(-1), 34 degrees C). Group A (n = 10) received 100 mg/kg of aminoguanidine intraperitoneally 30 minutes before the initiation of CPB, and group B (n = 10) served as controls. There were significant time-dependent changes in plasma interleukin (IL)-6, IL-8, nitrate + nitrite, the percentage ratio of nitrotyrosine to tyrosine (%NO2-Tyr, an indicator of peroxynitrite formation), and respiratory index (RI). Three hours after CPB termination, IL-6, IL-8, and RI were significantly higher in group A (IL-6, 397.5+/-80.6 pg/mL; IL-8, 26.99+/-6.57 ng/mL; RI, 1.87+/-0.31) than in group B (IL-6, 316.5+/-73.9 pg/mL, p <0.05; IL-8, 17.21+/-3.12 ng/mL, p < 0.01; RI, 1.57+/-0.24, p < 0.05) although nitrate + nitrite (31.8+/-4.1 micromol/L) and %NO2-Tyr (1.15%+/-0.20%) were significantly lower in group A than in group B (nitrate + nitrite, 50.2+/-5.0 micromol/L, p < 0.01; %NO2-Tyr, 1.46%+/-0.21%, p < 0.01). Western immunoblot analysis from lung tissue of group A identified marked iNOS inhibition without inhibiting endothelial-constitutive NOS, and neutrophil accumulation in the lung specimens was significantly greater in group A (6.5+/-0.7/alveoli) than in group B (4.4+/-0.4/alveoli, p < 0.01). Question: Is inducible nitric oxide production an adaptation to cardiopulmonary bypass-induced inflammatory response?" }, { "from": "assistant", "value": "yes. These results suggest that NO production from iNOS may be an adaptive response for attenuating the CPB-induced inflammatory response." } ]

[ { "from": "user", "value": "Context: Ankylosing spondylitis (AS) is a chronic disease leading to progressive spinal ankylosis and deformity. The aims of this study were to (1) determine whether infliximab is an effective treatment for AS patients who have failed conventional treatment; (2) identify any baseline clinical variables that can be associated with responsiveness to treatment; and (3) resolve whether the clinical response correlated with changes from baseline inflammatory changes on magnetic resonance imaging (MRI). Twenty-one patients who met the modified New York criteria for AS (M:F 18:3) were enrolled in this open labeled study. The mean age was 37.9+/-7.9 years and mean disease duration was 8.69+/-6.58 years. Patients received infliximab at a dose of 5 mg/kg by intravenous infusion over 2 hours at 0, 2, 6, weeks. Nine functional variables were measured [i.e., Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI) etc.], 6 clinimetrics (chest expansion, finger to floor, etc.), and inflammatory markers in the peripheral blood at baseline and each subsequent visit. Primary response to treatment was defined as a > 20% response in 5/9 functional variables. A subset of 9 consecutive patients was selected for MRI scans before and after infusions. Eighteen patients were available for assessment at week 14 having received 3 infusions (wks 0, 2, 6). There was > 60% improvement in functional variables, i.e., BASDAI, BASFI, Health Assessment Questionnaire, fatigue, and spinal and total body pain. Clinimetric scores selectively improved, e.g., chest expansion (p < 0.021) by 14 weeks. ESR, CRP and haptoglobin all showed significant improvement at 6 weeks and were maintained to the 14 week assessment point. Imaging studies showed improvement in all patients studied including those with advanced disease. Three patients developed headache during the infusions. Infliximab was effective in all, but degree of response varied. Very good responders were distinguished from good responders by shorter duration of disease and better baseline clinimetric scores. Question: Does clinical and imaging correlate of response to treatment with infliximab in patients with ankylosing spondylitis?" }, { "from": "assistant", "value": "yes. Infliximab was an effective treatment for AS in a short term trial. Longterm control of symptoms and potential alteration in clinical course of disease will require longterm assessment." } ]

[ { "from": "user", "value": "Context: We and others reported on the beneficial effects of combined therapy using 8-methoxypsoralen and long wave ultraviolet light (PUVA therapy) in the treatment of scleroderma. We now investigate the mechanism by which PUVA therapy is effective by comparing interleukin 1beta (IL-1beta) mediated signal transduction in scleroderma fibroblasts and those from normal skin. Prostaglandin E2 (PGE2) production and expression of cytosolic phospholipase A2 (cPLA2), cyclooxygenase (COX)-1, and COX-2 (enzymes that regulate PGE2 production) were examined in untreated and IL-1beta treated fibroblasts from scleroderma involved and normal skin. The effect of UVA irradiation on enzyme expression and PGE2 production was examined. PGE2 was measured by a competitive radioimmunoassay and enzyme expression was analyzed by Western immunoblotting and Northern blotting. Constitutive PGE2 production was significantly upregulated and IL-1beta induced PGE2 production was increased by the enhancing expression of both COX-2 mRNA and protein in fibroblasts from scleroderma involved skin; PGE2 production and COX-2 expression were inhibited by UVA irradiation. Question: Are cyclooxygenase-2 expression and prostaglandin E2 biosynthesis enhanced in scleroderma fibroblasts and inhibited by UVA irradiation?" }, { "from": "assistant", "value": "yes. Enhanced PGE2 production regulated by COX-2 expression in scleroderma fibroblasts may contribute to the development of this disorder. PUVA therapy might exhibit its beneficial effect, at least in part, by inhibiting COX-2 expression transcriptionally and translationally, with subsequent inhibition of PGE2 production." } ]

[ { "from": "user", "value": "Context: To investigate whether P-glycoprotein (Pgp) protects the in vitro BBB against the cytotoxic effects of anti-tumour drugs. In an in vitro BBB coculture model the influence of the anti-microtubule drugs vinblastine, colchicine, paclitaxel and the non-anti-microtubule drugs doxorubicin, fluorouracil and etoposide in the absence or presence of Pgp modulators on the trans-endothelial electrical resistance (TEER), which is an indicator for the integrity, was investigated. In the absence of Pgp modulators vinblastine, colchicine and paclitaxel dose dependently decreased TEER values to less than 20% of control. Non-anti-microtubule drugs did not affect TEER values. Following competitive inhibition of Pgp by various Pgp modulators and substrates, even low concentrations of vinblastine, colchicine and paclitaxel substantially decreased TEER. IC50 values of LY 335979, SDZ-PSC 833, cyclosporin A, and verapamil were 0.03, 0.25, 0.46, and 13.7 microM, respectively. Question: Does p-glycoprotein inhibition lead to enhanced disruptive effects by anti-microtubule cytostatics at the in vitro blood-brain barrier?" }, { "from": "assistant", "value": "yes. These results indicate that Pgp normally protects the in vitro BBB against the disruptive effects of anti-microtubule drugs, but its integrity is lost when anti-microtubule drugs are used in combination with potent Pgp modulators. In addition, this procedure offers the possibility to characterize Pgp modulators and substrates with respect to their efficacy and to elucidate drug interactions at the level of Pgp." } ]

[ { "from": "user", "value": "Context: Nonadrenergic noncholinergic (NANC) nerves have important roles in the regulation of the lower esophageal sphincter (LES) motility and function. The effects of thiopental, ketamine, and midazolam on NANC LES relaxation were investigated. The isometric tension of circular muscle strips from Japanese White rabbits was examined. The NANC relaxation was induced by KCl (30 mM) in the presence of atropine (3 x 10(-6) M) and guanethidine (3 x 10(-6) M). The modifications of the NANC and sodium nitroprusside (SNP; 10(-5) M)-induced relaxation by the anesthetics were examined. The content of 3',5'-cyclic guanosine monophosphate (cGMP) was measured by radioimmunoassay. The KCl-induced relaxation was abolished by pretreating with tetrodotoxin (10(-6) M). The NANC relaxation was inhibited in the presence of N(G)-nitro-L-arginine (L-NNA; 3 x 10(-5) M), methylene blue (10(-6) M), apamin (10(-7) M), and glibenclamide (10(-5) M). The SNP-induced relaxation was inhibited by methylene blue but was not affected by tetrodotoxin, L-NNA, apamin, or glibenclamide. Ketamine (EC50 = 8.8 x 10(-5) M) and midazolam (EC50 = 4.8 x 10(-6) M) suppressed the NANC response in a concentration-dependent manner, leaving SNP-induced response unchanged. Thiopental altered neither of the relaxations. cGMP content was decreased in the presence of ketamine and midazolam. Question: Do intravenous anesthetics inhibit nonadrenergic noncholinergic lower esophageal sphincter relaxation via nitric oxide-cyclic guanosine monophosphate pathway modulation in rabbits?" }, { "from": "assistant", "value": "yes. The NANC relaxation was mediated by nitric oxide and by low-conductance calcium- and adenosine triphosphate-sensitive potassium channels of smooth muscle. The modulation of the nitric oxide-cGMP pathway was related, at least in part, to the inhibitory actions of ketamine and midazolam on the NANC LES relaxation." } ]

[ { "from": "user", "value": "Context: Studies show that the sedative and analgesic effects of alpha2 adrenergic agonists decrease over time, which is a form of synaptic plasticity referred to as tolerance. Because both the N-methyl-D-aspartate (NMDA) receptor complex and nitric oxide synthase are pivotal for some forms of synaptic plasticity, their role in tolerance to the hypnotic and analgesic effects of alpha2 agonists was investigated. After institutional approval, rats were made tolerant to the hypnotic or analgesic action of an alpha2 agonist, dexmedetomidine. The hypnotic response to dexmedetomidine was assessed by the duration of loss of righting reflex, and the analgesic response to dexmedetomidine was assessed by the tail-flick assay. In separate cohorts, either the NMDA receptors or nitric oxide synthase was antagonized by coadministration of MK-801, ketamine, or NO2-arginine, respectively, during induction of tolerance. In a separate series of experiments, after tolerance was induced, the hypnotic and analgesic responses to dexmedetomidine were assessed in the presence of acutely administered MK-801 or NO2-arginine. Induction of tolerance to the hypnotic effect of dexmedetomidine is blocked by coadministration of MK-801, ketamine, and NO2-arginine. However, after tolerance developed, acute administration of MK-801, ketamine, or NO2-arginine did not prevent the expression of tolerance. Coadministration of MK-801 or NO2-arginine neither prevents the development nor reverses the expression of tolerance to the analgesic action of dexmedetomidine. Question: Is sedative but not analgesic alpha2 agonist tolerance blocked by NMDA receptor and nitric oxide synthase inhibitors?" }, { "from": "assistant", "value": "yes. The underlying processes responsible for the development of tolerance to the hypnotic and analgesic actions of systemically administered alpha2 agonists were different, with only the sedative tolerance involving the NMDA receptor and nitric oxide synthase system." } ]

[ { "from": "user", "value": "Context: Amplification of the oncogene MYCN in neuroblastoma has been found to correlate with aggressive tumour growth and is used as a predictor of clinical outcome. The MYCN amplicon is known to involve coamplification of extensive DNA regions. Therefore it is possible that other genes are coamplified in this amplicon and that they may play a role in the poor outcome of MYCN amplified tumours. We have implemented an approach for the two-dimensional separation of human genomic restriction fragments to detect and isolate as yet unknown amplified sequences in the MYCN amplicon in neuroblastoma. Using this approach we have recently cloned a novel gene referred to as NAG that is frequently coamplified with MYCN in neuroblastoma. Question: Does two-dimensional DNA electrophoresis identify novel CpG islands frequently coamplified with MYCN in neuroblastoma?" }, { "from": "assistant", "value": "yes. We report here the identification and cloning of two additional CpG islands that are amplified in neuroblastoma. One contains a sequence that is identical to the first intron of DDX1. The other represents a novel CpG island that is associated with an as yet unidentified gene. We show that the novel CpG island is located in close proximity to the MYCN locus on chromosome 2 and is as frequently coamplified with MYCN in neuroblastoma as NAG and DDX1." } ]

[ { "from": "user", "value": "Context: Several in vitro investigations have indicated that the particulate phase of cigarette smoke as nicotine affects many cell types including gingival fibroblasts, but few studies have examined the effect of volatile fraction on cellular structures involved in cell functions such as adhesion and proliferation. Since gingival fibroblast survival and reproduction are fundamental to maintaining the oral connective tissue as well as to wound healing, the effects of acrolein and acetaldehyde, volatile fractions of cigarette smoke, on cytoskeleton were examined in human gingival fibroblasts (HGFs) in vitro. Human gingival fibroblast (HGF) strains from healthy subjects with non-inflamed gingiva were utilized. The cells were incubated in different concentrations of acrolein and acetaldehyde. Cell adhesion was evaluated after 3 hours. The influence of both substances on cytoskeletal structures, tubulin and vimentin intermediate filaments (VIF), was investigated using indirect immunofluorescence technique. The results show that both substances produced similar effects, resulting in a dose-dependent inhibition of HGF adhesion. Disturbance of HGF cytoskeleton consisted of a disruption of microtubules and vimentin microfilaments with alterations in cell shape. Question: Is human gingival fibroblast cytoskeleton a target for volatile smoke components?" }, { "from": "assistant", "value": "yes. Our experimental findings suggest that volatile fractions of cigarette smoke such as acrolein and acetaldehyde, because their ability to bind and interact with the cytoskeleton, prevent HGF adhesion. Consequently the maintenance of the oral connective tissue and integrity and remodeling could be impaired. According to our morphological evidence, these findings confirm other clinical and epidemiological investigations reporting that volatile components of cigarette smoke could lead to the initiation and progression of periodontal disease." } ]

[ { "from": "user", "value": "Context: To determine how magnesium affects human coronary arteries and whether endothelium derived nitric oxide (EDNO) is involved in the coronary arterial response to magnesium. Quantitative coronary angiography and Doppler flow velocity measurements were used to determine the effects of the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) on magnesium induced dilation of the epicardial and resistance coronary arteries. Hiroshima University Hospital a tertiary cardiology centre. 17 patients with angiographically normal coronary arteries. Magnesium sulfate (MgSO(4)) (0.02 mmol/min and 0.2 mmol/min) was infused for two minutes into the left coronary ostium before and after intracoronary infusion of L-NMMA. Diameter of the proximal and distal segments of the epicardial coronary arteries and coronary blood flow. At a dose of 0.02 mmol/min, MgSO(4) did not affect the coronary arteries. At a dose of 0.2 mmol/min, MgSO(4) caused coronary artery dilation (mean (SEM) proximal diameter 3.00 (0.09) to 3.11 (0.09) mm; distal 1.64 (0.06) to 1.77 (0.07) mm) and increased coronary blood flow (79.3 (7.5) to 101.4 (9.9) ml/min, p < 0.001 v baseline for all). MgSO(4) increased the changes in these parameters after the infusion of L-NMMA (p < 0.001 v baseline). Question: Does magnesium cause nitric oxide independent coronary artery vasodilation in humans?" }, { "from": "assistant", "value": "yes. Magnesium dilates both the epicardial and resistance coronary arteries in humans. Furthermore, the coronary arterial response to magnesium is dose dependent and independent of EDNO." } ]

[ { "from": "user", "value": "Context: Maspin (mammary serpin) is a relatively novel serine protease inhibitor with tumor suppressing function in breast cancer. Maspin expression was found in normal breast epithelial cells, but was decreased during tumor progression. Only a few systematic analyses of this phenomenon have been undertaken so far. In this study we developed specific nested reverse transcription polymerase chain reaction (RT-PCR) conditions for the detection of maspin expression in human breast carcinoma and assessed maspin's association with the clinical behavior of primary breast cancers. Tumor specimens obtained from 45 primary breast cancer patients were analyzed for maspin expression by a nested RT-PCR assay. Recurrence free survival was evaluated and correlated to maspin expression. The maspin transcript was detected in 29 (64%) breast cancer specimens whereas no expression was found in 16 (36%) cancer specimens. This expression was unrelated to any of the established prognostic factors. However, 6 out of 8 patients who developed distant metastasis (lymph nodes, lung, liver, bone, pleura) within 3 yr after their initial diagnosis showed no maspin expression of the primary breast cancer (p < 0.05). Question: Is down regulation of the tumor suppressor gene maspin in breast carcinoma associated with a higher risk of distant metastasis?" }, { "from": "assistant", "value": "yes. The lack of maspin expression in breast cancer seems to be associated with a short disease free survival and supports maspin's function as an indicator of tumor aggressiveness and metastatic potential. Nested RT-PCR is a sensitive method to determine maspin expression in human breast cancer tissue." } ]

[ { "from": "user", "value": "Context: The human PrP gene locates at the short-arm of the 20th chromosome. This article is was to map the promoter that transcribes the human PrP gene. The sequence of the human PrP gene Exon I and its upstream segment were amplified using PCR, and inserted into a CAT reporter plasmid pBL-CAT6 after sequence analysis. The values of the relative CAT expression under the control of this fragment were evaluated after transiently transfected into HeLa, COS7 and Sh-sy5y cell lines. The amounts of transcription activator SP1 in these three cell lines were calculated with band-shift assays. Analysis of the human PrP gene Exon I and its upstream segment showed a GC rich sequence, with several potential SP1 binding sites, but without any TATA-box. Under the control of this fragment, the CAT expressions were 2-3 folds increased in transient transfection. Quantity band-shift assays revealed that SP1 was enriched in HeLa cells, but undetectable in COS7 and Sh-sy5y cells. Question: Does [ The sequence of the human PrP gene Exon I and its upstream segment have promoter-like activity ]?" }, { "from": "assistant", "value": "yes. The sequence of the human PrP gene Exon I and its upstream segment functions as a promoter-like sequence, probably being as a weak TATA-less promoter. Cells derived from different tissues contain different amount of SP1. The activity of this promoter-like sequence seems to be independent of SP1 presence." } ]

[ { "from": "user", "value": "Context: Development of recombinant human monoclonal antibody to hepatitis A virus as a emergent measure for prevention of hepatitis A virus infection. Human neutralizing monoclonal antibody Fab fragments to HAV have been developed by using phage display technique. The heavy and light chains of human IgG Fab genes were amplified from a HAV patient in convalescent stage. The combinatorial phage antibody library was established by inserting both heavy and light chains of Fab genes into phage mid-vector pComb3 and followed by help phage infection after 4 rounds of panning with purified HAV as coated antigen. The human Fab fragments to HAV were selected and expressed in bacteria. Question: Do [ Human Fab antibodies derived from phage display library neutralize hepatitis A virus in vitro ]?" }, { "from": "assistant", "value": "yes. The specific binding of Fab antibodies to HAV were demonstrated by their reaction with HAV antigen in ELISA. These results provide the basis for further development of a neutralizing recombinant human whole IgG molecule and hold promise for future use in the prophylaxis of HAV infection." } ]

[ { "from": "user", "value": "Context: MASH1, a transcription factor with basic helix-loop-helix domain, has a pivotal function to promote differentiation of neural crest cells into autonomic neurons. To investigate the functional significance of human MASH1 (hASH1) in the pathogenesis of neuroblastoma, which is originated from autonomic precursor cells, we studied hASH1 gene expression in primary neuroblastomas and human nueroblastoma cell lines. The follovving results were obtained: (i) hASH1 was expressed in 40 out of 61 (66%) primary neuroblastomas, (ii) hASH1 transcripts were downregulated in several cell lines prior to differentiation induced by all-trans retinoic acid (RA), (iii) a neuroblasotma cell line without expression of endogenous hASH1 did not respond to RA at all, and (iv) the analysis of the hASH1 genomic DNA revealed two possible transcription initiation sites, which may correspond to 3.0 kb and 3.5 kb transcripts. Question: Is downregulation of hASH1 associated with the retinoic acid-induced differentiation of human neuroblastoma cell lines?" }, { "from": "assistant", "value": "yes. Our observations suggest that, although hASH1 may not preserve the growth capacity of neuroblastomas, downregulation of hASH1 may be necessary to promote neuronal differentiation of neuroblastoma." } ]

[ { "from": "user", "value": "Context: The CD95/CD95 ligand (CD95L) system is a key regulator of apoptosis. To evaluate a possible role of the CD95/CD95L system in human neuroblastoma (NB) cells, we investigated the constitutive and interferongamma (INFgamma)-induced expression of CD95 and CD95L, and CD95-mediated cell death in the SK-N-BE(2) cell line. Modulation of CD95/CD95L expression and triggering of an autocrine apoptotic mechanism by IFNgamma suggest a potential role for INFgamma as a therapeutic agent for NB. Question: Does apoptosis in neuroblastomas induced by interferon-gamma involve the CD95/CD95L pathway?" }, { "from": "assistant", "value": "yes. The evidence that retinoids induce apoptosis via tissue transglutaminase (tTG) and that N-methyl-D-aspartate (NMDA) and gp120 act through the nitric oxide synthase (NOS) activation pathway, indicates the existence of different molecular mechanisms of action, whose pharmacological exploitation might be used in an additive fashion." } ]

[ { "from": "user", "value": "Context: To determine correlates of clinical outcomes in patients with short bowel syndrome (SBS). Retrospective medical record review of neonates treated between 1986 and 1998 who met our criteria for SBS: dependence on parenteral nutrition (PN) for at least 90 days after surgical therapy for congenital or acquired intestinal diseases. Thirty subjects with complete data were identified; 13 (43%) had necrotizing enterocolitis, and 17 (57%)had intestinal malformations. Mean (SD) residual small bowel length was 83 (67) cm. Enteral feeding with breastmilk (r = -0.821) or an amino acid-based formula (r = -0.793) was associated with a shorter duration of PN, as were longer residual small bowel length (r = -0.475) and percentage of calories received enterally at 6 weeks after surgery(r = -0.527). Shorter time without diverting ileostomy or colostomy (r = 0.400), enteral feeding with a protein hydrolysate formula (r = -0.476), and percentage of calories received enterally at 6 weeks after surgery (r = -0.504) were associated with a lower peak direct bilirubin concentration. Presence of an intact ileocecal valve and frequency of catheter-related infections were not significantly correlated with duration of PN. In multivariate analysis, only residual small bowel length was a significant independent predictor of duration of PN, and only less time with a diverting ostomy was an independent predictor of peak direct bilirubin concentration. Question: Does nutritional and other postoperative management of neonates with short bowel syndrome correlate with clinical outcomes?" }, { "from": "assistant", "value": "yes. Although residual small bowel length remains an important predictor of duration of PN use in infants with SBS, other factors, such as use of breast milk or amino acid-based formula, may also play a role in intestinal adaptation. In addition, prompt restoration of intestinal continuity is associated with lowered risk of cholestatic liver disease. Early enteral feeding after surgery is associated both with reduced duration of PN and less cholestasis." } ]

[ { "from": "user", "value": "Context: The objective was to study the impact of nonadherence on late rejection after pediatric heart transplantation. This was a retrospective cohort study of cardiac transplant recipients surviving >6 months (n = 50). Patients were stratified by episodes of late rejection. End points were defined by cyclosporin A (CSA) level, CSA level variability, and patient admission of nonadherence. In 15 patients there were 49 episodes of late rejection, and 37 (76%) were associated with nonadherence. Of these patients, 7 of 15 died, and 3 of 15 had transplant coronary artery disease. Risk factors for the rejection were single-parent home, non-white, older age, and higher CSA level variability. In 35 nonrejectors there were 4 deaths from sepsis, post-transplant lymphoproliferative disease, renal failure, and encephalomyelitis. Question: Is nonadherence associated with late rejection in pediatric heart transplant recipients?" }, { "from": "assistant", "value": "yes. Late rejection after pediatric heart transplantation is associated with nonadherence, is common during adolescence, and is associated with poor outcome." } ]

[ { "from": "user", "value": "Context: At present, laser therapy of port-wine stains (PWS) using the flashlamp-pumped dye laser (FPDL) at 450 micros is accepted as the optimal approach. A few years ago, a new long-pulsed tunable dye laser (LPTDL, 1.5 ms) was introduced for the treatment of leg veins. To investigate the efficacy and side-effects of FPDL vs. LPTDL therapy of PWS. Sixty-two patients with untreated PWS underwent test treatments with the FPDL (585 nm; 7-mm spot size; 5.75--7.0 J cm(-2) fluence) and LPTDL (585, 590, 595, 600 nm; 5-mm spot size; 11--20 J cm(-2) fluence). With the LPTDL, the epidermis was additionally cooled (Spray cooling device). The fading was evaluated clinically 6 weeks after the test treatments. Optimal fading was achieved by the LPTDL (> or = 585 nm) in 30 patients and by the FPDL in 12 patients. No difference was found in 20 patients. At 585 nm, the lasers worked equally well in 12 (FPDL) and 13 (LPTDL) patients, respectively. Results were independent of the localization of the PWS and of the patient's age. In spite of the longer pulse duration, the LPTDL treatment did not result in more side-effects as long as sufficient cooling was provided. Question: Do both the flashlamp-pumped dye laser and the long-pulsed tunable dye laser can improve results in port-wine stain therapy?" }, { "from": "assistant", "value": "yes. The results provide evidence that wavelengths longer than 585 nm can increase the efficacy of treatment in some PWS. Owing to the reduced light absorption by haemoglobin at longer wavelengths and consequently increased depth of the vascular injury, larger vessels can be damaged more adequately using an increased fluence. The LPTDL at 585 nm seemed to be slightly superior to the FPDL, while accepting that due to technical reasons the laser parameters were not directly comparable. Availability of both lasers increases the therapeutic possibilities in PWS." } ]

[ { "from": "user", "value": "Context: To investigate the effect of repetitive mucosal trauma, anastomosis and intestinal content on experimental colonic carcinogenesis as there is the possibility than non-specific colon lesions can promote cancer. We performed to sixty female Sprague-Dawley rats a 4 cm colon loop defunctionalization with double colostomy (traumatic site). Intestinal continuity was restored with an end-to-end colo-colic silk anastomosis. The surviving 47 rats were divided in 3 groups: Group A: 27 rats treated with DMH. Group B: 10 rats treated with EDTA and Group C: Control of 10 rats. Animals were sacrificed 31-32 weeks after surgery for macro and micropathological studies. In group A appeared 60 tumours: 44 in the functional colon, 20 of them in the anastomotic site; 8 in the non traumatised defunctionalized segment and 18 in the traumatised segment (p < 0.05). Question: Does repetitive mucosal trauma promote colon cancer in experimental rat model?" }, { "from": "assistant", "value": "yes. a) Continuous microtraumas on colonic mucosa in rats are cancer promotional factors; b) silk suture in anastomosis promotes cancer." } ]

[ { "from": "user", "value": "Context: RFI-641, a small dendrimer-like compound, is a potent and selective inhibitor of respiratory syncytial virus (RSV), which is currently a clinical candidate for the treatment of upper and lower respiratory tract infections caused by RSV. RFI-641 inhibits RSV growth with an IC(50) value of 50 nM and prevents syncytia formation in tissue culture. RSV contains of three surface glycoproteins, a small hydrophobic (SH) protein of unknown function, and attachment (G) and fusion (F) proteins that enable binding and fusion of virus, respectively, with target cells. Because of their role in attachment and fusion, the G and F surface proteins are prominent targets for therapeutic intervention. RFI-641 was previously shown to bind purified preparations of RSV fusion protein. Based on this observation, in conjunction with the biological results, it was speculated that the fusion event might be the target of these inhibitors. A fusion assay based upon the relief of self-quenching of octadecyl rhodamine R18 was used to determine effects of the inhibitors on binding and fusion of RSV. The results show that RFI-641 inhibits both RSV-cell binding and fusion events. The inhibition of RSV is mediated via binding to the fusion protein on the viral surface. A closely related analog, WAY-158830, which is much less active in the virus-infectivity assay does not inhibit binding and fusion of RSV with Vero cells. Question: Does rFI-641 inhibit entry of respiratory syncytial virus via interactions with fusion protein?" }, { "from": "assistant", "value": "yes. RFI-641, an in vivo active RSV inhibitor, is shown to inhibit both binding and fusion of RSV with cells, events that are early committed steps in RSV entry and pathogenicity. The results described here demonstrate that a non-peptidic, small molecule can inhibit binding and fusion of enveloped virus specifically via interaction with the viral fusion protein." } ]

[ { "from": "user", "value": "Context: Based on the success of hematopoietic stem-cell transplantation (HSCT) for multiple myeloma, HSCT is being used to treat patients with primary systemic amyloidosis (AL). This article addresses the extent to which eligibility to undergo HSCT is a favorable prognostic feature and explores prognostic factors within the subset of eligible patients. The Mayo Clinic amyloid database was queried for all patients with AL seen at the Mayo Clinic from 1983 through 1997 who would have been eligible for peripheral-blood stem-cell transplantation. Inclusion criteria included biopsy-proven amyloid, symptomatic disease, absence of a clinical diagnosis of multiple myeloma, age < or = 70 years, cardiac interventricular septal thickness < or = 15 mm, cardiac ejection fraction more than 55%, serum creatinine < or = 2 mg/dL, and direct bilirubin < or = 2.0 mg/dL. Median age was 56 years (range, 25 to 70) with 79 (34%) older than 60 years. One hundred patients had early cardiac involvement; 41, hepatic involvement; 167, renal involvement; and 39, nerve involvement. The 229 patients have had a median follow-up of 52 months, and 151 have died. The median survival was 42 months with 5- and 10-year survival rates of 36% and 15%, respectively. Important predictors of survival were size of M-component in 24-hour urine, number of involved organs, alkaline phosphatase, performance score, and weight loss. Question: Is eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis a favorable prognostic factor for survival?" }, { "from": "assistant", "value": "yes. The same patients who are eligible for HSCT are a good-risk population who do relatively well with chemotherapy (median survival, 42 months), substantially better than the expected median survival of 18 months for all patients with AL. A randomized trial is needed to assess the true effect of HSCT." } ]

[ { "from": "user", "value": "Context: We aimed to know which factors are associated with inappropriate stays in an internal medicine department. We included 1,046 hospitalisations and evaluated the justification of the admission using the Appropriateness Evaluation Protocol. 176 (16.8%) stays were considered inappropriate. In a multiple regression model, variables defining an inappropriate stay were the number of days in hospital, diagnosis on admission and the weekly day. Question: Does [ Predictive factors for inappropriate hospital stay in an internal medicine department ]?" }, { "from": "assistant", "value": "yes. There are determining factors for inappropriate stays in an internal medicine department." } ]

[ { "from": "user", "value": "Context: Many randomized clinical trials in trauma have failed to demonstrate a significant improvement in survival rate. Using a trauma patient database, we simulated what could happen in a trial designed to improve survival rate in this setting. The predicted probability of survival was assessed using the TRISS methodology in 350 severely injured trauma patients. Using this probability of survival, the authors simulated the effects of a drug that may increase the probability of survival by 10-50% and calculated the number of patients to be included in a triad, assuming alpha = 0.05 and beta = 0.10 by using the percentage of survivors or the individual probability of survival. Other distributions (Gaussian, J shape, uniform) of the probability of survival were also simulated and tested. The distribution of the probability of survival was bimodal with two peaks (< 0.10 and > 0.90). There were major discrepancies between the number of patients to be included when considering the percentage of survivors or the individual value of the probability of survival: 63,202 versus 2,848 if the drug increases the probability of survival by 20%. This discrepancy also occurred in other types of distribution (uniform, J shape) but to a lesser degree, whereas it was very limited in a Gaussian distribution. Question: Is distribution of the probability of survival a strategic issue for randomized trials in critically ill patients?" }, { "from": "assistant", "value": "yes. The bimodal distribution of the probability of survival in trauma patients has major consequences on hypothesis testing, leading to overestimation of the power. This statistical pitfall may also occur in other critically ill patients." } ]

[ { "from": "user", "value": "Context: Vigabatrin (VGB) has been shown to cause visual field constriction and other forms of mild visual dysfunction. We determined the safety of continuing VGB therapy in patients who had received prolonged treatment (>2 years) with the drug by serially monitoring changes in visual function over a 1-year period of continued therapy. We also followed up patients who discontinued VGB to see whether alternative therapies are effective. Fifteen of 17 patients who continued VGB therapy had visual-function testing (visual acuity, color vision, kinetic and static perimetry) every 3 months for 1 year. Eighteen patients who discontinued VGB were given alternative antiepileptic drugs (AEDs); their seizure responses were measured after > or =3 months of treatment. Patients continuing VGB showed no worsening of visual acuity, color vision, or visual-field constriction beyond that measured in the initial test. Many patients who discontinued VGB had good seizure control with either newer or previously unsuccessful AEDs. Question: Is visual function stable in patients who continue long-term vigabatrin therapy : implications for clinical decision making?" }, { "from": "assistant", "value": "yes. For patients who have an excellent response to VGB and only mild visual changes, continued therapy may be safe with close visual monitoring. Patients who do not have a significant reduction in seizures or who experience considerable visual dysfunction with VGB may respond well to alternative therapies." } ]

[ { "from": "user", "value": "Context: The progressive early changes in cartilage and subchondral bone in an experimental model of osteoarthritis (OA) were investigated with high-resolution magnetic resonance imaging (MRI) and microradiography. Partial medial meniscectomy was performed in the left knee of 16 rabbits. Four normal and four sham-operated additional rabbits were used as controls. Changes in cartilage and subchondral bone were sequentially assessed after surgery with MRI at 0, 2, 4, 6, 8 and 10 weeks, subchondral bone variations quantified postoperatively on microradiographs of sagittal sections at 6 and 10 weeks and the macroscopic alterations graded according to the severity of joint changes. MRI demonstrated a progressive increase in the articular cartilage thickness in the weight-bearing area of the femur at weeks 4, 6 and 8 vs basal. Tibial cartilage thickness only showed a significant increment at week 6. No significant abnormalities were detected on X-rays in subchondral bone when compared to controls. Macroscopically, 4 weeks after the operation OA rabbits had only slight cartilage discoloration. Cartilage eburnation, pitting, superficial erosions and osteophytes were detected at week 6. These abnormalities were more evident at 8 and 10 weeks after meniscectomy. Question: Does high-resolution MRI detect cartilage swelling at the early stages of experimental osteoarthritis?" }, { "from": "assistant", "value": "yes. The focal increase in cartilage thickness is one of the earliest measurable changes in OA and preceeds subchondral bone remodeling. The measurement of cartilage thickness variations with MRI can be used to follow the course of OA and to evaluate the potential beneficial effect of novel therapies." } ]

[ { "from": "user", "value": "Context: Biliary cholesterol supersaturation, gallbladder stasis and delayed intestinal transit are the key events in cholesterol gallstone formation. We studied the effect of cisapride, a prokinetic drug, on gallbladder emptying and bile composition in patients with gallstone disease undergoing cholecystectomy. Gallbladder emptying, cholesterol saturation index (CSI) and nucleation time were studied in 21 patients with gallstone disease. Eleven patients (cisapride group, age 41.9 +/- 2.9 years) received tablet cisapride 10 mg t.i.d. for 2 weeks, while 10 patients (placebo group, age 42.1 +/- 1.9 years) received placebo for the same duration. Gallbladder emptying was repeated in all patients after a 2-week treatment with cisapride or placebo. Gallbladder bile was obtained at the time of surgery for the measurement of CSI and nucleation time. Residual volume of the gallbladder decreased (mean +/- SE, 18.6 +/- 2.5 mL vs 10.0 +/- 1.1 mL, P = 0.007), and the ejection fraction increased (43.5 +/- 5.3% vs 60.0 +/- 3.2%, P = 0.007) in patients in the cisapride group, while no change was observed in placebo group patients. Nucleation time was higher in the cisapride group than in the placebo group (14.9 +/- 1.3 days vs 8.0 +/- 0.9 days, P = 0.003). Patients in the cisapride group had a significantly lower cholesterol concentration (molar percentage, 5.1 +/- 0.3% vs 6.8 +/- 0.8%, P = 0.049) and CSI (1.0 +/- 0.1 vs 1.36 +/- 0.11, P = 0.034) than patients in the placebo group. Question: Does cisapride improve gallbladder emptying and bile lipid composition in patients with gallstones?" }, { "from": "assistant", "value": "yes. Cisapride improves gallbladder emptying and bile lithogenicity in patients with gallstone disease." } ]

[ { "from": "user", "value": "Context: The cardiac renin-angiotensin-aldosterone system is activated in failing hearts in proportion to the severity of the disease. We hypothesized that a positive feedback mechanism might exist within this system and contribute to the progression of the heart failure. Methods and Results-- To test this hypothesis, we examined whether angiotensin II or aldosterone induces the expression of angiotensin-converting-enzyme (ACE) mRNA in cultured neonatal rat ventricular cardiocytes. Expression of ACE mRNA was detected and quantified using real-time reverse transcription-polymerase chain reaction. Exposure to angiotensin II (10(-5) mol/L) for 24 hours had no significant effect on the expression of ACE mRNA (0.7+/-0.5-fold versus control, P=NS), but similar treatment with aldosterone (10(-5) mol/L) induced a 23.3+/-7.9-fold increase (P<0.01) in ACE mRNA expression. The effect of aldosterone was both time- (maximal effect, 24 hours) and dose-dependent (EC(50), 4x10(-7) mol/L), and it was significantly (P<0.01) inhibited by spironolactone, a specific mineralocorticoid receptor antagonist. Question: Does aldosterone induce angiotensin-converting-enzyme gene expression in cultured neonatal rat cardiocytes?" }, { "from": "assistant", "value": "yes. Aldosterone upregulates ACE mRNA expression, which is blocked by spironolactone in neonatal rat cardiocytes. Thus, spironolactone may suppress the progression of heart failure by blocking the effects of aldosterone and angiotensin II." } ]

[ { "from": "user", "value": "Context: Studies investigating the relationship between plasma total homocysteine (tHcy) and vascular disease usually rely on a single measurement. Little information is available, however, on the seasonal variability of plasma tHcy. The aim of this study was to investigate the seasonal variation in fasting plasma tHcy and related B-vitamin intake and status in a group of people who did not consume fortified foods or take B-vitamin supplements. In this longitudinal study, a group of 22 healthy people were followed for 1 year. A fasting blood sample and dietary information were collected from each individual every 3 months, i.e., at the end of each season. There was no significant seasonal variation in plasma tHcy or in B-vitamin intake or status with the exception of red cell folate (significantly lower in spring compared with autumn or winter) and serum folate (significantly lower in spring compared with the other seasons). Although the between-person variation in plasma tHcy was high (47%), the within-person variation was low (11%). This low variation, combined with the low methodologic imprecision of 3.8%, yielded a high reliability coefficient for plasma tHcy (0.97). Question: Is plasma homocysteine subject to seasonal variation?" }, { "from": "assistant", "value": "no. Although there was a small seasonal variation in folate status, there was no corresponding seasonal variation in plasma tHcy. The high reliability coefficient for plasma tHcy suggests that a single measurement is reflective of an individual's average plasma tHcy concentration, thus indicating its usefulness as a potential predictor of disease. This, however, needs to be confirmed in different subgroups of the population." } ]

[ { "from": "user", "value": "Context: Drug discrimination assays can provide important information on receptor selectivity and relative efficacy to guide the classification and characterization of opioid agonists. A three-choice discrimination was established among high efficacy opioid agonist morphine, low efficacy opioid agonist nalbuphine, and saline to examine the conditions under which differences in relative efficacy might serve as a basis for stimulus control. Seven White Carneau pigeons were trained to discriminate among 5.6 mg/kg nalbuphine, 3.2 mg/kg morphine, and saline under fixed ratio 30 (FR30) schedules of food reinforcement. Substitution and antagonism experiments were then conducted with mu, kappa, and delta opioids and naltrexone, respectively and the percent responding appropriate to the training stimuli was determined. Low, intermediate, and high doses of morphine produced > or = 80% saline-, > or = 60% nalbuphine-, and > or = 96% morphine-appropriate responding, respectively. Low and high doses of nalbuphine produced > or = 80% saline- and nalbuphine-appropriate responding, respectively. In substitution tests, low doses of fentanyl and etorphine produced partial nalbuphine-appropriate responding (20-60%) and high doses produced > or = 60-80% morphine-appropriate responding. Intermediate doses of buprenorphine and dezocine produced > or = 60-80% nalbuphine-appropriate responding and high doses produced > or = 80% morphine-appropriate responding. The lower efficacy agonists butorphanol, nalorphine, and levallorphan produced > or = 40-80% nalbuphine-appropriate responding. The kappa agonists spiradoline and U50,488 produced approximately > or = 50% nalbuphine-appropriate responding whereas d-amphetamine, saline, and delta agonists BW373U86 and SNC 80 produced > or = 80% saline-appropriate responding. Naltrexone produced > or = 80% saline-appropriate responding and reversed the stimulus effects of morphine and nalbuphine. Question: Is three-choice discrimination in pigeons based on relative efficacy differences among opioids?" }, { "from": "assistant", "value": "yes. The discrimination between morphine and nalbuphine in pigeons is predominantly based on the relative efficacy differences between morphine, a higher-efficacy mu agonist and nalbuphine, a lower-efficacy mu agonist." } ]

[ { "from": "user", "value": "Context: Dopaminergic compounds have been targeted as potential treatments for cocaine abuse because of the known role of dopamine systems in drug reinforcement. Recent preclinical and human data have focused on the D1/5 antagonist, SCH 39166 (ecopipam), as a potential therapeutic agent. The objective of the present study was to determine whether treatment with chronic ecopipam can blunt or block the subjective effects of cocaine in the absence of significant behavioral impairment or toxic physiological effects. Four doses of ecopipam (0, 10, 25, and 100 mg p.o.) were administered daily for 1 week each in double-blind, random order to inpatient cocaine-dependent volunteers (n = 10). Cocaine challenge doses (0, 25, and 50 mg/70 kg i.v.) were administered on the 7th day in ascending order, 1 h apart. Ecopipam alone produced reliable dose-dependent deficits in performance on the digit symbol substitution task (DSST) and the circular lights task, but not a balance task. Impairment on the DSST waned with repeated dosing suggesting the development of tolerance. Ecopipam resulted in few direct subjective effects. Cocaine alone produced dose-dependent changes in prototypic subjective and physiological measures, however, ecopipam largely failed to alter either cocaine's direct effects or the desire for cocaine. Question: Does repeated administration of the D1/5 antagonist ecopipam fail to attenuate the subjective effects of cocaine?" }, { "from": "assistant", "value": "yes. Although the performance effects verify that these doses of ecopipam were behaviorally active, the absence of an attenuation of cocaine's effects of craving for cocaine in this chronic dosing paradigm suggests this compound is unlikely to be an effective pharmacotherapy for cocaine abuse." } ]

[ { "from": "user", "value": "Context: Low-dose erythromycin therapy improves airflow limitation and airway inflammation in patients with diffuse panbronchiolitis (DPB). However, to our knowledge there has been no study to determine whether physiologic improvement during erythromycin therapy correlates with radiologic findings. To clarify whether improvement in pulmonary function correlates with specific changes on chest CT. The relationship between five CT findings and five pulmonary function parameters was evaluated before and 3 months after low-dose erythromycin therapy in 24 patients with DPB retrospectively. After erythromycin therapy, the predicted percentage of vital capacity (%VC; 87.0 +/- 3.07% vs 98.9 +/- 3.39%; p = 0.00006) and 50% of the maximum midexpiratory flow rate of FVC (1.41 +/- 0.26 L/s vs 1.61 +/- 0.27 L/s; p = 0.03) significantly increased, and the residual volume/total lung capacity ratio (RV/TLC%; 44.5 +/- 1.93% vs 40.7 +/- 1.83%; p = 0.0019) significantly decreased, but the FEV(1) to FVC ratio and 25% of the maximum expiratory flow rate of FVC did not. In five CT findings, centrilobular nodules (3.7 +/- 0.4 vs 1.5 +/- 0.3; p = 0.0001), peripheral bronchiolar wall thickness (3.8 +/- 0.3 vs 2.6 +/- 0.4; p = 0.0007), and peripheral bronchiolectasis (2.8 +/- 0.3 vs 2.2 +/- 0.4; p = 0.0058) had significantly improved, whereas low attenuation area and central bronchiectasis had not. There were positive correlations of improved scores of centrilobular nodules with improved %VC (r = 0.58, p = 0.0062) and RV/TLC% (r = 0.64, p = 0.0022). Question: Do centrilobular nodules correlate with air trapping in diffuse panbronchiolitis during erythromycin therapy?" }, { "from": "assistant", "value": "yes. Decreased air trapping in DPB correlates with an improvement of centrilobular nodules, which reflects the obstructive lesions of bronchioles during the erythromycin therapy." } ]

[ { "from": "user", "value": "Context: Episodes of increased air pollution are associated with increases in hospital admissions for cardiovascular disease. Even modest acute phase responses are associated with increased risk of coronary heart disease. The study investigates whether induction of an acute phase response by exposure to air pollution may contribute to cardiovascular pathology. A prospective cohort study based on a survey in 1984/85 with a 3-year follow-up was conducted in 631 randomly selected men aged 45 to 64 years free of cardiovascular disease at entry 1984/85. Serum C-reactive protein concentrations were determined by a high sensitivity immunoradiometric assay. C-reactive protein concentration was increased in association with the 1985 air pollution episode. In multivariate analyses, elevated concentrations were independently associated with concentrations of total suspended particles and the sulphur dioxide episode. At ambient concentrations of pollution, as noted during the 1985 air pollution episode, the odds of observing C-reactive protein concentrations above 5.7 mg. l(-1)(>90th percentile) tripled, and increases of 26 microg. m(-3)total suspended particles (mean of 5 days) raised the odds of C-reactive protein levels 50% above the 90th percentile. Question: Is particulate air pollution associated with an acute phase response in men ; results from the MONICA-Augsburg Study?" }, { "from": "assistant", "value": "yes. Exposure to current levels of particulate matter in the atmosphere elicits an acute phase response in randomly selected healthy middle-aged men, which may contribute to the increased cardiovascular risk caused by air pollution." } ]

[ { "from": "user", "value": "Context: On the basis of previous reports of an attentional bias for threat-related emotional material in deluded schizophrenics (e.g. Bentall & Kaney, 1989), the present study examined the proposal that a similar bias would be demonstrated by delusion-prone individuals, reflected by longer response latencies for the task of processing threat-related facially displayed affects (e.g. anger, fear). A non-randomized matched group design was employed to examine the performance of delusion-prone individuals in comparison with a control group. 50 psychiatrically healthy participants completed the Peters et al. Delusions Inventory (PDI) as an index of delusional ideation (Peters, Day, & Garety, 1996; Peters, Joseph, & Garety, 1999). Subjects were presented with a standard set of facial stimuli depicting happy, sad, neutral, fearful and angry emotion expressions (Mazurski & Bond, 1993). Reaction times for the task of identifying each type of affect were compared between groups of high and low scorers on the PDI. Highly delusion-prone individuals displayed a significant delay in processing angry facial expressions in comparison with low scorers on the PDI. Question: Is processing of threat-related affect delayed in delusion-prone individuals?" }, { "from": "assistant", "value": "yes. The increased response latency for processing angry expressions was interpreted as evidence of attentional bias for material posing a threat to the self, supporting previous cognitive data in relation to deluded patients. Threatening facial expressions may be regarded with increased significance by delusion-prone individuals, and it is possible that this bias is involved in the formation of delusional beliefs." } ]

[ { "from": "user", "value": "Context: To test (1) whether eye movements during retrieval of emotional memories are followed by less vividness and less emotionality of future recollections, (2) whether this effect, if present, is stronger than the effects of a control activity (finger tapping), (3) whether the alleged effects of tapping and eye movements are stronger than a no-movement, control condition (mere imagery), (4) whether reductions in vividness and emotionality after eye movements (and finger tapping) are specific to negative memories or also occur in the case of positive memories. Sixty healthy volunteers recalled either positive or negative memories and scored the vividness and emotionality of the recollections. Next, memories were recalled whilst the participant was performing rapid eye movements, finger tapping, or not performing a dual task. Then participants were asked to recall the event again and to rate its vividness and emotionality. Compared to finger tapping and the no-dual-task condition, recollections after eye movements made future recollections less vivid. After eye movements, but not after the other interventions, negative memories became less negative, and positive memories became less positive. Question: Do autobiographical memories become less vivid and emotional after eye movements?" }, { "from": "assistant", "value": "yes. The findings show that eye movements not only reduce vividness and emotionality of memories during the eye moving, but also affect future recollections, during which no eye movements are made. Some theoretical explanations are discussed. As to clinical implications, it is suggested that if there is a role for eye-movement-based treatments, it is very limited." } ]

[ { "from": "user", "value": "Context: To investigate the hypothesis that treadmill training will improve peak fitness, while lowering the energy cost of hemiparetic gait in chronic stroke patients. Noncontrolled exercise intervention study with repeated-measures analysis. Hospital-based senior exercise research center. Twenty-three patients (mean age +/- standard deviation [SD] 67 +/- 8 yr) with chronic hemiparetic gait after remote (>6 mo) ischemic stroke. Three 40-minute sessions of treadmill exercise weekly for 6 months. Peak exercise capacity (VO2peak) and rate of oxygen consumption during submaximal effort treadmill walking (economy of gait) by open circuit spirometry and ambulatory workload capacity before and after 3 and 6 months of training. Patients who completed 3 months of training (n = 21) increased their VO2peak +/- SD from 15.4 +/- 2.9 mL x kg(-1) x min(-1) to 17.0 +/- 4.4 mL x kg(-1) x min(-1) (p <.02) and lowered their oxygen demands of submaximal effort ambulation from 9.3 +/- 2 mL x kg(-1) x min(-1) to 7.9 +/- 1.5 mL x kg(-1) x min(-1) (p =.002), which enabled them to perform the same constant-load treadmill task using 20% less of their peak exercise capacity (62.3% +/- 17.2% vs 49.9% +/- 19.3%, p <.002). Gains in VO2peak and economy of gait plateaued by 3 months, while peak ambulatory workload capacity progressively increased by 39% (p <.001) over 6 months. Question: Does treadmill training improve fitness reserve in chronic stroke patients?" }, { "from": "assistant", "value": "yes. Treadmill training improves physiologic fitness reserve in chronic stroke patients by increasing VO2peak while lowering the energy cost of hemiparetic gait, and increases peak ambulatory workload capacity. These improvements may enhance functional mobility in chronic stroke patients." } ]

[ { "from": "user", "value": "Context: To test the efficacy of high-velocity training in healthy older persons. A 12-week randomized trial, with subjects blocked for gender and residence, comparing high-velocity resistance training with a self-paced walking program. Retirement community. Forty-three volunteers over the age of 70 years. Power group: high-velocity leg exercises 3 times weekly with weekly increases in resistance combined with 45 minutes of moderate, nonresistance exercise weekly. Walking group: moderate intensity exercise 30 minutes daily, 6 days weekly. Variables measured included leg press peak power and leg extensor strength. Functional performance outcomes included: 6-minute walk distance, Short Physical Performance Battery, Physical Performance Test, and Medical Outcomes Study Short-Form Health Survey. Peak power improved 22% (p =.004) in the power group (3.7 +/- 1.0 W/kg to 4.5 +/- 1.4 W/kg) but did not change in the walking group (3.99 +/-.76 W/kg to 3.65 +/-.94 W/kg). Leg extensor power at resistance of 50%, 60%, and 70% of body weight increased 50%, 77%, and 141%, respectively, in the power group (p <.0001, repeated-measures analysis of variance). Strength improved 22% in the power-trained individuals and 12% in the walkers (p <.0001). Training did not improve functional task performance in either group. One subject developed a radiculopathy during training. Question: Does velocity training induce power-specific adaptations in highly functioning older adults?" }, { "from": "assistant", "value": "yes. Resistance training focusing on speed of movement improved leg power and maximal strength substantially, but did not improve functional performance in healthy high-functioning older volunteers." } ]

[ { "from": "user", "value": "Context: The inducible nitric oxide synthase (iNOS) is strongly expressed following inflammatory stimuli. Adenosine 3',5'-cyclic monophosphate (cAMP) increases iNOS expression and activity in a number of cell types but decreases cytokine-stimulated iNOS expression in hepatocytes. The mechanisms for this effect are unknown. Rat hepatocytes were stimulated with cytokines to induce iNOS and cultured with cAMP agonists dibutyryl-cAMP (dbcAMP), 8-bromo-cAMP, and forskolin (FSK). Nitric oxide synthesis was assessed by supernatant nitrite levels and iNOS expression was measured by Northern and Western blot analyses. Nuclear factor kappaB binding was assessed by electromobility shift assay. Cyclic AMP dose dependently decreased NO synthesis in response to a combination of proinflammatory cytokines or interleukin-1beta (IL-1beta) alone. The adenylate cyclase inhibitor SQ 22,536 increased cytokine- or IL-1beta-stimulated NO synthesis. dbcAMP decreased iNOS mRNA expression and iNOS protein expression. Both dbcAMP and glucagon decreased iNOS promoter activity in rat hepatocytes transfected with the murine iNOS promoter and decreased DNA binding of the transcription factor NF-kappaB. Question: Does cAMP inhibit inducible nitric oxide synthase expression and NF-kappaB-binding activity in cultured rat hepatocytes?" }, { "from": "assistant", "value": "yes. These data suggest that cAMP is important in hepatocyte iNOS expression and agents that alter cAMP levels may profoundly alter the response of hepatocytes to inflammatory stimuli through effects onthe iNOS promoter region and NF-kappaB." } ]

[ { "from": "user", "value": "Context: Patients with primary Raynaud's phenomenon (PRP) have more severe symptoms in the winter. The aetiology of this is more complex than simply increased vasoconstriction in response to the immediate ambient temperature. The aim of this study was to investigate differences in skin temperature (Tsk), microvascular blood flow and responses to endothelium-dependent and independent vasodilators in healthy controls, and women with PRP under identical environmental temperatures but in different seasons. Ten women with PRP were compared with age matched women (10) and men (10). Finger skin responses were recorded immediately on arrival, after stabilizing in a temperature regulated laboratory at 22-24 degrees C, and at matched warm (35 degrees C) and cold (15 degrees C) Tsk in the winter and summer. Baseline red blood cell flux (r.b.c. flux), and the change in flux in response to iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP) were recorded by laser Doppler fluxmetry at the warm and cold Tsk. Arrival Tsk were significantly cooler for all subjects during the winter (mean seasonal difference -2.6 degrees C, P < 0.0001), and markedly colder in subjects with PRP (mean seasonal difference -3.5 degrees C, P < 0.0005). Statistically significant seasonal differences persisted in all subjects at stable Tsk despite an identical laboratory temperature (mean difference 1.3 degrees C, P < 0.0001). To achieve comparable controlled finger Tsk a significantly colder local environment was required for male controls (mean of -2.1 degrees C, P < 0.0001), and a significantly warmer environment for subjects with PRP (mean of + 2.4 degrees C, P < 0.0001) compared with female controls. This needed to be warmer in the winter, by a mean of 2.4 degrees C, than the summer for all subjects. Vasodilatation in response to ACh, but not SNP, was significantly smaller (P < 0.0001) in the PRP group compared with the female controls for all visits, with most of this difference arising in the winter visits (P < 0.01). Question: Are seasonal differences in finger skin temperature and microvascular blood flow in healthy men and women exaggerated in women with primary Raynaud 's phenomenon?" }, { "from": "assistant", "value": "yes. There is a seasonal and persistent influence on finger Tsk, and microvascular blood flow in healthy men and women, which modifies the observed responses to immediate changes in finger Tsk. The seasonal differences are greater in women than men, and are further exaggerated in women with PRP, in whom this is associated with reduced endothelium-dependent vasodilatation." } ]

[ { "from": "user", "value": "Context: We investigated whether the injection of 10 mL of normal saline into the subarachnoid space following accidental dural puncture reduced the incidence of postdural puncture headache (PDPH) and the need for epidural blood patch (EBP). Twenty-eight patients who experienced accidental dural puncture with an epidural needle had 10 mL of normal saline injected into the subarachnoid space. In 22 patients, the injection was performed immediately through the epidural needle. In 6 patients who had intrathecal catheters placed through the epidural needle, the saline was injected through the catheter before removal. All other patients who experienced wet taps during the same period that the study was in progress but did not receive the saline injection served as a control group, 26 in number. Patients with severe or persistent PDPHs were treated with EBP. Of those patients who received intrathecal normal saline immediately through the epidural needle, 32% developed a headache compared with 62% of controls. Of these, 1 patient who received saline required EBP compared with nine in the control group (P =.004). Of those patients who had intrathecal catheters placed, there were no headaches in the saline group of 6 compared with 3 in the control group of 5, 1 of whom was treated with EBP (P >.05). Question: Does the injection of intrathecal normal saline reduce the severity of postdural puncture headache?" }, { "from": "assistant", "value": "yes. The immediate injection of 10 mL intrathecal normal saline after a wet tap significantly reduced the incidence of PDPH and the need for EBP. When an intrathecal catheter had been placed following a wet tap, injection of 10 mL of normal saline before its removal effectively prevented PDPH." } ]

[ { "from": "user", "value": "Context: Organic acid anhydrides (OAAs) are highly allergenic compounds used in the chemical industry. The OAAs probably act as haptens but the proteins that form conjugates with OAAs in vivo are still unknown. Conjugates between the anhydrides and serum albumins (SAs) have routinely been used when testing for OAA-specific antibodies. However, the use of SA as the carrier-protein in these tests has never been evaluated. The aim of this study was to identify major and also immunologically relevant protein conjugates of a particularly sensitizing OAA, hexahydrophthalic anhydride (HHPA), in plasma. Plasma was obtained from a HHPA-exposed worker, from a guinea-pig (GP) exposed to HHPA in an exposure chamber for 2 weeks (8 h/day, 5 days/week) and from a GP exposed once, nose-only, to tritium-labelled HHPA for 8 h. The plasma was fractionated using ion exchange chromatography and gel filtration. These fractions and also aliquots of unfractioned plasma were hydrolysed, derivatized and analysed for anhydride adduct content using gas chromatography-mass spectrometry. Further, plasma from the tritium labelled HHPA-exposed GP was separated by SDS gel electrophoresis and analysed by autoradiography. In addition, immunologically relevant proteins were identified through specific IgE and IgG immunoblottings using sera from exposed workers. For humans > 85% and for GPs > 74% of the HHPA-adducts coeluted with SA in plasma. Autoradiography of GP-plasma shows a single 66 kDa protein that binds HHPA. IgE immunoblotting shows a major 66 kDa and a minor 28 kDa protein which could be inhibited by HHPA-SA conjugate. IgG immunoblotting showed a major 66 kDa protein and several minor protein bands. Question: Are serum albumins the major site for in vivo formation of hapten-carrier protein adducts in plasma from humans and guinea-pigs exposed to type-1 allergy inducing hexahydrophthalic anhydride?" }, { "from": "assistant", "value": "yes. This study shows SA to be the major protein in plasma that forms adducts in vivo with HHPA. The results also show that in an in vitro synthesized HHPA plasma protein conjugate, HHPA-specific IgE and IgG antibodies bind preferably to the SA." } ]

[ { "from": "user", "value": "Context: To evaluate the ability of preoperative manometric examinations to predict temporary or permanent dysphagia after antireflux procedures. Retrospective study. Teaching hospital, Sweden. 191 patients who had partial fundoplication. Stationary manometry with a perfused catheter system. Correlation between preoperative manometric examinations and the incidence of dysphagia before and after operation. 98 of 191 patients had dysphagia preoperatively (51%), but 52 of the 98 had no stricture or motor disorder to explain it; 25 of 59 patients with motor disorders shown manometrically (42%) did not complain of dysphagia. The number of patients with dysphagia was reduced to 43 postoperatively. 8 who did not complain of dysphagia preoperatively did so postoperatively; 4 of 8 had defective peristalsis and 4 had normal preoperative tracings. Question: Does preoperative oesophageal motor activity predict postoperative dysphagia?" }, { "from": "assistant", "value": "no. Manometric examination does not help us to understand the mechanism of preoperative dysphagia, nor does it predict who will develop dysphagia postoperatively." } ]

[ { "from": "user", "value": "Context: Studies evaluating osteoarthritis treatment often use increased arthritis activity (\"flare\") as a selection criterion, although no standardized assessments are available to quantify flare intensity and little is known about how this criterion affects treatment comparisons. This study evaluated the reliability of a flare assessment and how pretreatment flare intensity impacts conclusions on treatment efficacy. Using data from a double-blind, randomized, controlled trial (n = 182), we compared 3 osteoarthritis treatments with placebo in patients who met 3 of 4 flare criteria. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire was used to document levels of pain, stiffness, and physical functioning at baseline and at the final visit. Following factor analytic evaluation, the flare items were standardized and summed to create a flare intensity index, which was used to identify patient subgroups. Analysis of covariance was applied to compare change in WOMAC scale scores from baseline to final visit for assessment of treatment differences among the flare intensity subgroups. The flare indicators appeared unidimensional. Analyses were stratified by tertiles of flare intensity. Mean WOMAC scores improved in the patients receiving active treatment who were categorized into the 2 lowest flare intensity subgroups, but mean WOMAC scores improved in patients in all 4 treatment groups (active and placebo) in the most intense flare subgroup. Question: Does stratification of flare intensity identify placebo responders in a treatment efficacy trial of patients with osteoarthritis?" }, { "from": "assistant", "value": "yes. Patients with higher intensity flares may be more likely to report substantial improvement in functional status regardless of treatment. Failure to account for flare intensity in analyses of data from pain trials with flare-based designs may inflate the risk of Type I and Type II errors in the interpretation of study results." } ]

[ { "from": "user", "value": "Context: Mylotarg (Wyeth-Ayerst Laboratories, St. Davids, PA) is the brand name for a calicheamicin-conjugated humanized anti-CD33 monoclonal antibody (gemtuzumab ozogamicin, CMA-676) and has been approved recently for the treatment of a subset of elderly patients who have relapsed acute myeloid leukemia (AML). Mylotarg is associated with an incidence of approximately 20% Grade 3 or 4 hyperbilirubinemia and liver transaminitis in this patient population. Hepatic venoocclusive disease (VOD) has been reported in patients who have undergone stem cell transplantation (SCT) after Mylotarg therapy. Outside of the SCT setting, VOD has been associated very rarely with cytotoxic therapy. The authors assessed the incidence of VOD in 119 patients who were receiving Mylotarg-containing non-SCT regimens. VOD was diagnosed through the use of standard Seattle and Baltimore criteria. A cohort of 119 (61 previously untreated, 58 with relapsed disease) patients with AML (92 patients), advanced myelodysplastic syndrome (25 patients), or chronic myeloid leukemia in blast phase (2 patients), received Mylotarg-based regimens. Fourteen (12%) developed VOD. The diagnosis of VOD was supported by histology in 2 patients and radiologic studies in a further 10 patients. Five (36%) of 14 patients with VOD had received no prior antileukemic cytotoxic therapy, including 2 patients who received single-agent Mylotarg therapy. Question: Is mylotarg ( gemtuzumab ozogamicin ) therapy associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation?" }, { "from": "assistant", "value": "yes. Mylotarg was shown to be associated with the development of potentially fatal VOD in patients with leukemia who had not received SCT. VOD occurred when Mylotarg was used either as a single agent or when it was given with other cytotoxic agents. VOD occurred in Mylotarg-treated patients who had received no prior cytotoxic therapy. The current study concluded that risk factors for VOD should be assessed when considering Mylotarg therapy, and that attempts to avoid and treat VOD are warranted in patients who receive Mylotarg therapy." } ]

[ { "from": "user", "value": "Context: Meningiomas usually are considered to be benign tumors; however, 10-20% of cases recur. Few disease characteristics have proved to have prognostic impact for predicting disease free survival. The objective of the current study was to explore the prognostic value of numeric abnormalities of chromosome 22 for meningioma patients. In this study, the authors prospectively analyzed the incidence of numeric chromosome abnormalities of chromosome 22 by interphase fluorescence in situ hybridization, using a specific probe for the bcr gene located in chromosome 22q11.2, on a total of 88 consecutive meningioma patients. The authors also analyzed its correlation with both the clinicobiologic characteristics at presentation and the patient's outcome. The authors' results show that monosomy 22 was present in 49% of the cases and that this numeric chromosomal abnormality is not associated with other prognostic features of the disease. In contrast, gains (trisomy/tetrasomy) of chromosome 22 were detected in 8 (9%) cases who simultaneously showed gains for other chromosomes and represent an adverse prognostic factor regarding disease free survival (P = 0.001); in addition, trisomy/tetrasomy 22 was more frequently related to younger patients (P = 0.001), aggressive histopathologic features (P < 0.000), a greater incidence of DNA aneuploidy (P =0.006), and a higher proportion of S-phase tumor cells (P = 0.02). Question: Are gains of chromosome 22 by fluorescence in situ hybridization in the context of an hyperdiploid karyotype associated with aggressive clinical features in meningioma patients?" }, { "from": "assistant", "value": "yes. In summary, the authors conclude that loss of a copy of chromosome 22 is a frequent finding in meningioma tumors, but it does not affect the clinical outcome of these patients. In contrast, gains (trisomy/tetrasomy) of chromosome 22, in the context of an hyperdiploid karyotype, although much less frequent, are associated with a more aggressive disease course." } ]

[ { "from": "user", "value": "Context: Endothelial dysfunction is an early feature of atherosclerosis. The relationship between insulin action and hypertriglyceridaemia on endothelial function is still debated. This study was designed to determine the effect of a 3 month treatment with Gemfibrozil (GF) on flow-mediated vasodilatation and insulin sensitivity. Ten type 2 diabetic patients were randomised in crossover, double blind fashion, either to GF, 600 mg b.i.d. or placebo, for 12 weeks. Lipid profile, low-density lipoprotein (LDL) distribution and flotation properties, insulin action and flow-mediated vasodilatation (FMD) by brachial artery ultrasound, were assessed. GF decreased serum triglyceride (TG) concentration with an absolute difference of 1.79 +/- 1.28 mmol L-1 (P < 0.0016) between active treatment and placebo, and significantly increased serum high-density lipoprotein (HDL) cholesterol (P = 0.0233). No differences were observed in total, intermediate-density lipoproteins (IDL), LDL cholesterol concentration and LDL peak buoyancy between treatments. GF also improved SI, an index of insulin action (P = 0.005). The FMD was 7 +/- 3% in the baseline condition, 7 +/- 2% during placebo and 14 +/- 3% after GF (P < 0.006). Question: Does gemfibrozil improve insulin sensitivity and flow-mediated vasodilatation in type 2 diabetic patients?" }, { "from": "assistant", "value": "yes. GF treatment improves both insulin action and flow-mediated vasodilatation in type 2 diabetic patients. The reduction of TG concentration allows the simultaneous correction of two important components of the metabolic syndrome." } ]

[ { "from": "user", "value": "Context: Impaired coronary flow reserve (CFR) can be used to indicate vascular dysfunction before the appearance of angiographic lesions. The hepatic lipase (HL) gene has a functional promoter polymorphism at position C-480T, which affects transcription and leads to high activity (C/C) and low activity (C/T, T/T) genotypes. These genotypes modulate HL activity, but their role in coronary artery disease is controversial and the effect on coronary function has not been studied. We investigated whether HL genotypes are associated with coronary artery function in healthy young men. We studied 49 healthy, mildly hypercholesterolemic men (aged 35 +/- 4 years). Myocardial blood flow was measured at rest and during adenosine induced hyperaemia with positron emission tomography using [15O] H2O. HL genotype was determined by PCR and Nla III enzyme digestion. Resting myocardial blood flow was not statistically different in subjects with high and low activity HL genotypes. However, CFR (the ratio of adenosine flow to resting flow) was 24% higher (4.62 +/- 1.52 vs. 3.73 +/- 1.08 mL g-1 min-1, P = 0.024) in men with the high activity genotype (n = 26) than in those with low activity (n = 23). In multivariate analysis, the HL genotype remained a significant predictor of CFR (P = 0.038) after adjusting for age, body mass index, serum lipids and smoking. Question: Is hepatic lipase gene variation related to coronary reactivity in healthy young men?" }, { "from": "assistant", "value": "yes. The findings of our preliminary study suggest that the C-480T polymorphism of the HL gene may modify coronary reactivity and reflect differences in the early pathogenesis of coronary dysfunction in these healthy young men. If the association between HL polymorphism and impaired CFR is also present in subjects with other dyslipoproteinemias, the HL polymorphism could be a new risk factor for cardiovascular disease." } ]

[ { "from": "user", "value": "Context: Elevated serum homocysteine concentrations have been related to coronary heart disease. However, the association has not indisputably been proven, and the mechanisms by which homocysteine may be atherogenic have only partially been elucidated. The objective of the present study was to investigate whether serum homocysteine is associated with angina pectoris and myocardial infarction. We compared serum homocysteine concentrations in subjects with clinical evidence of angina pectoris or history of myocardial infarction to age-matched controls. The study included 248 males, who participated in a large cross-sectional risk factor survey carried out in five geographic areas in Finland. Serum homocysteine concentration was significantly higher in subjects with a history of myocardial infarction compared to controls (15.3 micromol L-1 and 13.9 micromol L-1 respectively, P = 0.037). In a logistic regression model including several cardiovascular risk factors, serum homocysteine was significantly associated with myocardial infarction (95% CI 1.0157-1.2990, P = 0.027). Serum homocysteine concentrations did not differ between subjects with angina pectoris and age-matched controls (13.9 micromol L-1 and 14.2 micromol L-1 respectively). Question: Does serum homocysteine associate with uncomplicated coronary heart disease?" }, { "from": "assistant", "value": "no. Our results suggest that elevated serum homocysteine is associated with myocardial infarction but not with uncomplicated coronary heart disease." } ]

[ { "from": "user", "value": "Context: The advent of botulinum neurotoxin type A (BoNT/A) gave rise to substantial progress in the treatment of focal dystonias. In the light of the high costs of the toxin and the necessity to establish valid outcome indices for this treatment apart from sheer reduction of dystonic muscle tone and posture, the impact of focal dystonia and its treatment with BoNT/A on patients' health related quality of life (HRQL) was determined. Fifty patients with cranial and cervical dystonia treated long term with BoNT/A were enrolled in a prospective, open labelled cohort study. The HRQL was assessed using the EuroQol (EQ-5D) and the short form 36 health survey questionnaire (SF-36) at baseline before BoNT/A injections and at two follow up visits after 6 and 12 weeks covering one BoNT/A treatment period with maximum effect size at the first follow up. Compared with a general population sample, a considerable negative impact of focal dystonia on HRQL was found in patients under investigation. In both disease types, BoNT/A treatment led to a significant improvement in several HRQL dimensions, in particular providing moderate to marked effect sizes in the fields of mental health and pain. The impairment of HRQL due to pain as well as the BoNT/A induced improvement within this SF-36 subscore were significantly higher in patients with cervical dystonia. Under BoNT/A therapy, no correlation was found between changes of clinical outcome scores and HRQL measures. Question: Is health related quality of life improved by botulinum neurotoxin type A in long term treated patients with focal dystonia?" }, { "from": "assistant", "value": "yes. The data confirm that BoNT/A is able to induce a significant, but temporary amelioration of several aspects of HRQL in both types of focal dystonia. This may substantially contribute to the patients' subjective benefit from the therapy. Moreover, the data provide further arguments to accept high costs of the BoNT/A treatment in these severely handicapped patients, as a consequence of its considerable benefit on quality of life." } ]

[ { "from": "user", "value": "Context: Cerebral cavernous malformations are linked to mutations of the KRIT1 gene at the CCM1 locus and to mutations at two other loci, CCM2 and CCM3, for which genes are not yet identified. There is little information regarding the function of KRIT1. Histological and immunocytochemical analysis of cavernous malformations have not shed much light on their pathophysiology. Morphological analysis of cavernous malformations was extended to the ultrastructural level by examining lesions from two patients by immunocytochemistry and electron microscopy. The lesions consisted of endothelial lined vascular sinusoids embedded in a collagen matrix. Nuclei belonging to cells distinct from endothelial cells were rare. The basal lamina of the endothelial cells consisted focally of multiple layers. No tight junctions at endothelial cell interfaces were found; however, several examined endothelial cell interfaces demonstrated apparent gaps between endothelial cell processes where basal lamina was exposed directly to the lumen of the sinusoids. Heavy hemosiderin deposits were found underlying the vascular channels within microns of the basal lamina without evidence of disrupted vessels. No astrocytic foot processes were seen within lesions. Glial fibrillary acidic protein immunocytochemistry confirmed that astrocyte processes stopped at the border of the lesions. Question: Is ultrastructural and immunocytochemical evidence that an incompetent blood-brain barrier related to the pathophysiology of cavernous malformations?" }, { "from": "assistant", "value": "yes. The absence of blood-brain barrier components may lead to leakage of red blood cells into these lesions and the surrounding brain in the absence of major haemorrhage, thus accounting for the propensity of cavernous malformations to cause seizures. These data also raise the possibility that KRIT1 plays a part in the formation of endothelial cell junctions and expression of a mature vascular phenotype." } ]

[ { "from": "user", "value": "Context: The role of inhaled corticosteroids for the treatment of wheeze in infancy remains unclear. To investigate the effect of inhaled fluticasone on symptoms in a group of wheezy infants who had a high risk of progressing to childhood asthma. A total of 52 infants, under 1 year of age, with a history of wheeze or cough and a history (personal or first degree relative) of atopy were prescribed either 150 microg fluticasone twice daily (group F) or placebo (group P), via metered dose inhaler, for 12 weeks following a two week run in period. Symptoms were scored in a parent held diary and the mean daily symptom score (MDS) and symptom free days (SFD) calculated for each two week period. Thirty seven infants completed the study. Both MDS and SFD improved significantly between the run in and final two week period in group F, but not group P, with a mean difference in change (95% CI) between groups of 1.12 (0.05 to 2.18) for MDS and median difference of 3.0 (0.002 to 8.0) for SFD. Question: Does persistent wheezing in infants with an atopic tendency respond to inhaled fluticasone?" }, { "from": "assistant", "value": "yes. Improvement of clinical symptoms in response to fluticasone can be shown in this high risk group of infants. In the absence of effective alternatives inhaled corticosteroids should be considered in this patient group." } ]

[ { "from": "user", "value": "Context: To test the validity of ambulatory heart rate (HR) assessment with a cuff ambulatory blood pressure (ABP) monitor. Cross-instrument comparison of HR measured intermittently by a cuff ABP monitor (SpaceLabs, Redmond, Washington, USA), with HR derived from continuous electrocardiogram (ECG) recordings (1) in a controlled laboratory experiment and (2) during long-term recording in a true naturalistic setting. Six normotensive subjects participated in the laboratory study. A total of 109 male white-collar workers underwent ambulatory monitoring, of which 30 were mildly hypertensive. Four different laboratory conditions (postures: lying, sitting, standing, walking), repeated twice, were used to assess the short-term effects of cuff inflation on the HR. To test the actual ambulatory validity, participants simultaneously wore a continuous HR recorder and the ABP monitor from early morning to late evening on 2 workdays and one non-workday. Diary and vertical accelerometery information was used to obtain periods of fixed posture and (physical) activity across which HR from both devices was compared. Laboratory results showed that the ABP device reliably detected HR during blood pressure measurement, but that this HR was systematically lower than the HR directly before and after the blood pressure measurement. The ambulatory study confirmed this systematic underestimation of the ongoing HR, but additionally showed that its amount increased when subjects went from sitting to standing to light physical activity (2.9; 4.3 and 9.1 bpm (beats/min), respectively). In spite of this activity-dependent underestimation of HR, the correlation of continuous ECG and intermittent ABP-derived HR was high (median r= 0.81). Also, underestimation was not different for normotensives and mild hypertensives. Question: Is ambulatory heart rate underestimated when measured by an ambulatory blood pressure device?" }, { "from": "assistant", "value": "yes. A direct effect of cuff inflation leads to the underestimation of ongoing HR during cuff-based ABP measurement. Additional underestimation of HR occurs during periods with physical activity, probably due to behavioural freezing during blood pressure measurements. HR underestimation was not affected by hypertensive state. When its limitations are taken into account, ABP-derived ambulatory HR can be considered a reliable and valid measure." } ]

[ { "from": "user", "value": "Context: To compare the volumes of renomedullary interstitial cell (RMIC) lipid droplets (putative source of vasodepressor substance) in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats on high and low salt diets as an indication of whether the renomedullary vasodepressor system of the SHR is defective. Ten-week-old male SHR and WKY rats received a low (0.05% w/w) or high salt (5.0%) diet for 21 days. Conscious mean arterial pressure (MAP) was measured and the renal papilla perfusion fixed with a high osmolarity fixative. Using electron microscopic stereological techniques, the volume density of lipid in RMIC (VVLipid,RMIC) and the total volumes of lipid (VLipid) and RMIC (VRMIC) in papilla were measured. MAP of SHR (high 155 +/- 3 mmHg; low 151 +/- 3 mmHg) was significantly greater than WKY rats (high 126 +/- 2 mmHg; low 129 +/- 2 mmHg; P< 0.001), however salt diet had no significant effect on MAP. The VLipid of rats on the low salt diet was approximately 2.5 times greater than in rats on the high salt diet (P < 0.01). SHR had significantly greater VLipid than WKY rats irrespective of salt diet (P< 0.05; SHR-low 0.245 +/- 0.031 mm3, SHR-high 0.093 +/- 0.007 mm3; WKY-low 0.126 +/- 0.032 mm3, WKY-high 0.051 +/- 0.020 mm3). Similar differences were seen for VVLipid,RMIC, however VRMIC was not different between rat strains or salt diet groups. Question: Is renomedullary interstitial cell lipid droplet content increased in spontaneously hypertensive rats and by low salt diet?" }, { "from": "assistant", "value": "yes. SHR and WKY rats responded similarly to the altered salt diets, and SHR demonstrated greater volumes of stored RMIC lipid droplets irrespective of the level of salt intake. These results indicate that SHR hypertension is not due to a deficiency in the amount of lipid droplets, the putative source of the renomedullary vasodepressor substance and that the renomedullary vasodepressor system of the SHR is capable of responding normally to the physiological stimulus of altered salt intake." } ]

[ { "from": "user", "value": "Context: To examine the relationship between depression, treatment of depression, and interferon gamma (IFN-gamma) production by peripheral blood mononuclear cells in patients with comorbid diagnoses of relapsing-remitting multiple sclerosis (MS) and major depressive disorder. A randomized comparative outcome trial of three 16-week treatments for depression. Assessments were conducted at baseline, week 8, and treatment cessation. An academic outpatient treatment and clinical research center. Fourteen patients who met the criteria for relapsing-remitting MS and major depressive disorder. Individual cognitive behavioral therapy, group psychotherapy, or sertraline therapy. Depression was assessed using the Beck Depression Inventory. Interferon gamma production by peripheral blood mononuclear cells was measured following stimulation with OKT3 or recombinant human myelin oligodendrocyte glycoprotein (MOG). Variability in immune assays was controlled using 8 nondepressed healthy subjects who were enrolled at times corresponding with the enrollment of MS patients. Results of the Beck Depression Inventory were significantly related to IFN-gamma production stimulated with OKT3 or MOG at baseline (P< or = .03 for all). Level of depression, OKT3-stimulated IFN-gamma production, and MOG-stimulated IFN-gamma production all declined significantly over the 16-week treatment period (P< or = .03 for all). Among controls, there were no significant changes over time in OKT3- or MOG-stimulated IFN-gamma, or in depression (P> or = .25 for all). Question: Is treatment of depression associated with suppression of nonspecific and antigen-specific T ( H ) 1 responses in multiple sclerosis?" }, { "from": "assistant", "value": "yes. These findings suggest that the production of the proinflammatory cytokine IFN-gamma by autoaggressive T cells in relapsing-remitting MS is related to depression and that treatment of depression may decrease IFN-gamma production. Thus, treatment of depression may provide a novel disease-modifying therapeutic strategy as well as a symptomatic treatment for patients with MS." } ]

[ { "from": "user", "value": "Context: It has been suggested that dietary fat exacerbates intestinal inflammation. We investigated the effect of fatty acids on interleukin (IL)-8 production in a human intestinal epithelial cell line (Caco-2). The cells were cultured as monolayers on microporous membranes in culture inserts. Oleic acid (OA), capric acid (CA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were applied to the apical compartment of Caco-2 cell monolayers. The concentration of IL-8 in the basolateral medium was measured by using enzyme-linked immunosorbent assay, and the expression of IL-8 mRNA was measured by using competitive reverse transcription--polymerase chain reaction. Protein kinase C inhibitors (GF109203X and calphostin C) and H-7 (a protein kinase inhibitor) were used to study the mechanisms by which IL-8 production is stimulated. Both OA and CA enhanced IL-8 production (approximately fivefold), whereas DHA and EPA did not. Both OA and CA also enhanced IL-1-induced IL-8 production. The onset of OA-induced IL-8 production was delayed compared with that of CA-induced IL-8 production. Both OA and CA enhanced IL-8 mRNA expression (approximately fivefold) after 6 and 3 h, respectively. The protein kinase inhibitor (H-7) reduced both OA- and CA-induced IL-8 production by 88.0 and 85.9%, respectively. The protein kinase C inhibitors (GF109203X and calphostin C) reduced OA-induced IL-8 production by 29.3 and 54.5%, respectively, but showed no effect on CA-induced IL-8 production. Question: Do medium-chain fatty acids stimulate interleukin-8 production in Caco-2 cells with different mechanisms from long-chain fatty acids?" }, { "from": "assistant", "value": "yes. These findings suggest that not only OA but also CA stimulates IL-8 production in intestinal epithelial cells, and the mechanisms of action differ between OA and CA." } ]

[ { "from": "user", "value": "Context: Breast tumors of BRCA1 mutation carriers and those of early onset breast cancer cases share similar histological features, being generally high-grade, highly proliferative, aneuploid tumors that are predominantly estrogen- and progesterone-receptor negative. Because histological features of tumors of premenopausal women differ from those of tumors of older women, we sought to determine whether the immunophenotype of breast tumors of BRCA1 mutation carriers was influenced by age at diagnosis. We examined 31 breast tumors from BRCA1 mutation carriers and compared them with 81 tumors of age-matched (plus or minus 5 years) breast cancer patients unselected for family history. Tumors were further matched for histology, grade, and size. Paraffin-embedded tumor tissues were examined for protein expression of estrogen receptor (ER), PR, Ki-67, cyclin D1, TP53, HER2, beta-catenin, and cyclin E using immunohistochemical approaches. ER (P = 0.01), PR (P = 0.06), and cyclin D1 (P = 0.002) were less frequently expressed and Ki-67 (P = 0.01) and beta-catenin (P = 0.04) were more frequently expressed in tumors of BRCA1 mutation carriers than controls. After age stratification, we found a significant difference in the frequency of tumors of BRCA1 mutation carriers diagnosed before 50 years of age compared with age-matched controls that stained positive for ER (P = 0.01), PR (P = 0.03), Ki-67 (P = 0.008), cyclin D1 (P < 0.001), HER2 (P = 0.04), and beta-catenin (P = 0.05). However, no significant differences were observed in tumors of BRCA1 mutation carriers diagnosed at age 50 or older compared with age-matched controls. Question: Is breast tumor immunophenotype of BRCA1-mutation carriers influenced by age at diagnosis?" }, { "from": "assistant", "value": "yes. These data suggest that age at diagnosis, possibly related to menopausal status, may be an important factor in the expression of specific proteins in breast tumors of BRCA1 mutation carriers." } ]

[ { "from": "user", "value": "Context: Deoxyribonucleic acid oncoviruses can induce neoplastic transformation of cells because their viral proteins interfere with antiproliferative cellular proteins. Simian virus 40 (SV40) is a DNA virus that induces the emergence of ependymomas, choroid plexus tumors, mesotheliomas, osteosarcomas, sarcomas, and various tumors when injected into newborn hamsters. Recently, approximately 60% of human ependymomas, choroid plexus tumors, and mesotheliomas were reported to contain and express SV40 DNA sequences. In this study the presence of SV40 DNA sequences was investigated in human brain tumors. Three of 32 glioblastomas mutiforme (GBMs), but none of two ependymomas and five medulloblastomas, were found to possess SV40 DNA sequences when examined using polymerase chain reaction (PCR). The DNA sequence analysis of PCR-amplified fragments disclosed that the samples were identical to the regulatory region of SV40. All three GBMs, which arose in elderly patients with wild-type p53, were considered to be primary (de novo) tumors. Although each of the three tumors was immunohistochemically negative for SV40 T antigen, in situ hybridization successfully demonstrated the messenger RNA for SV40 T antigen. Question: Do detection of simian virus 40 DNA sequence in human primary glioblastomas multiforme?" }, { "from": "assistant", "value": "yes. The results of this study indicate that latent infection of SV40 in elderly people may be implicated in the tumorigenesis of certain primary GBMs." } ]

[ { "from": "user", "value": "Context: To discuss a potentially powerful approach to safer medication administration on the hospital ward, based on principles of safety developed in other high-risk industries, and consistent with recent national reports on safety in health care released in the United Kingdom (UK) and United States of America (USA). To discuss why punitive approaches to safety on the hospital ward and in the nursing literature do not work. Drug administration error on the hospital ward is an ever-present problem and its occurrence is too frequent. Administering medication is probably the highest-risk task a nurse can perform, and accidents can lead to devastating consequences for the patient and for the nurse's career. Drug errors in nursing are often dealt with by unsystematic, punitive, and ineffective means, with little knowledge of the factors influencing error generation. Typically, individual nurses are simply blamed for their carelessness. By focusing on the individual, the complete set of contributing factors cannot be known. Instead, vain attempts will be made to change human behaviour - one of the most change-resistant aspects of any system. A punitive, person-centred approach therefore, severely hampers effective improvements in safety. By contrast, in other high-risk industries, such as aviation and nuclear power, the systems-centred approach to error reduction is routine. Question: Do a systems approach to the reduction of medication error on the hospital ward?" }, { "from": "assistant", "value": "yes. Accidents or errors are only the tip of the incident iceberg. Through effective, nonpunitive incident reporting, which includes reports of near-misses and system problems in addition to actual accidents, the systems-approach allows the complete set of contributing factors underlying an accident to be understood and addressed. Feedback to participants and targeted improvement in the workplace is also important to demonstrate that incident data are being used appropriately, and to maintain high levels of on-going reporting and enthusiasm for the scheme. Drug administration error is a serious problem, which warrants a well-reasoned approach to its improvement." } ]

[ { "from": "user", "value": "Context: Functional (pharmacodynamic) ethanol tolerance can be evidenced within a single session of exposure to ethanol (acute or within-session tolerance), or after repeated ethanol exposures (chronic or between-session tolerance). To investigate whether acute and chronic tolerance to ethanol are inter-related phenomena, the effect of chronic ethanol exposure was evaluated in mice selectively bred for high (HAFT) or low (LAFT) acute functional tolerance to an ataxic effect of ethanol, i.e., loss of balance on a stationary dowel. Mice were tested for sensitivity (threshold ethanol concentration for loss of balance on the stationary dowel) and acute functional tolerance to ethanol before and after a regimen of chronic ethanol exposure (twice-daily ethanol injections for 6 days). Chronic ethanol treatment did not alter the threshold for ethanol's ataxic effect (i.e., produced no change in sensitivity). However, this treatment, in a dose-dependent manner, resulted in an increase in the magnitude and rate of development of acute functional tolerance. Question: Does chronic ethanol exposure result in increased acute functional tolerance in selected lines of HAFT and LAFT mice?" }, { "from": "assistant", "value": "yes. This finding supports previous postulates that chronic ethanol tolerance can be characterized by a more rapid acquisition or a greater magnitude of acute (within-session) tolerance. However, the increase in acute tolerance that occurred after chronic ethanol exposure was similar in both selected lines of mice, indicating little or no genetic correlation between acute tolerance and chronic tolerance." } ]

[ { "from": "user", "value": "Context: The gold screw of an implant is put under tension during fastening. An increase in operator-induced compressive axial force during fastening may diminish screw tension, lower the friction between the screw threads, and allow for increased tightening torque. This study was undertaken to assess and compare the compressive axial forces and torques placed simultaneously on implant gold screws by persons with varying degrees of expertise. A calibrated electric torque driver was used to fasten implant gold screws. Three groups of operators with various levels of implant experience (faculty [F; n = 4], prosthodontic residents [R; n = 4], and undergraduate dental students [S; n = 6]) were asked to repeatedly tighten and loosen a new gold abutment screw into a standard 3.75-mm diameter Branemark abutment. Compressive axial forces during torquing were assessed over the tightening time by means of a miniature load cell adapted to the electric torque driver. Each operator repeated the experiment 3 times after calibration. Within operator and between operator reliability were evaluated. Loosening compressive axial forces were always higher than tightening compressive axial forces, and peak torque was less on loosening than tightening. Faculty placed a smaller range of forces on the screws (mean = 3.29 N, SD +/- 1.45 N) than did the residents (mean = 2.74 N, SD +/- 1.96) or the students (mean = 3.01 N, SD +/- 2.54). Question: Do operator-induced compressive axial forces during implant gold screw fastening?" }, { "from": "assistant", "value": "yes. The clinical experience of operators seems to influence their application of compressive axial force during gold screw tightening. Less torque during unfastening of gold screws seems to be related to increased axial loading." } ]

[ { "from": "user", "value": "Context: The purpose of this study was a) to compare the effect of three different warm-up protocols upon rowing performance and perception of dyspnea, and b) to identify the functional significance of a respiratory warm-up. A group of well-trained club rowers (N = 14) performed a 6-min all-out rowing simulation (Concept II). We examined differences in mean power output and dyspnea measures (modified CR-Borg scale) under three different conditions: after a submaximal rowing warm-up (SWU), a specific rowing warm-up (RWU), and a specific rowing warm-up with the addition of a respiratory warm-up (RWUplus) protocol. Mean power output during the 6-min all-out rowing effort increased by 1.2% after the RWUplus compared with that obtained after the RWU (P < 0.05) which, in turn, was by 3.2% higher than the performance after the SWU (P < 0.01). Similarly, after the RWUplus, dyspnea was 0.6 +/- 0.1 (P < 0.05) units of the Borg scale lower compared with the dyspnea after the RWU and 0.8 +/- 0.2 (P < 0.05) units lower than the dyspnea after the SWU. Question: Does specific respiratory warm-up improve rowing performance and exertional dyspnea?" }, { "from": "assistant", "value": "yes. These data suggest that a combination of a respiratory warm-up protocol together with a specific rowing warm-up is more effective than a specific rowing warm-up or a submaximal warm-up alone as a preparation for rowing performance." } ]

[ { "from": "user", "value": "Context: To evaluate the safety and efficacy of high-frequency oscillatory ventilation (HFOV) in adult patients with the acute respiratory distress syndrome (ARDS) and oxygenation failure. Prospective, clinical study. Intensive care and burn units of two university teaching hospitals. Twenty-four adults (10 females, 14 males, aged 48.5 +/- 15.2 yrs, Acute Physiology and Chronic Health Evaluation II score 21.5 +/- 6.9) with ARDS (lung injury score 3.4 +/- 0.6, Pao2/Fio2 98.8 +/- 39.0 mm Hg, and oxygenation index 32.5 +/- 19.6) who met one of the following criteria: Pao2 < or =65 mm Hg with Fio2 > or =0.6, or plateau pressure > or =35 cm H2O. HFOV was initiated in patients with ARDS after varying periods of conventional ventilation (CV). Mean airway pressure (Paw) was initially set 5 cm H2O greater than Paw during CV, and was subsequently titrated to maintain oxygen saturation between 88% and 93% and Fio2 < or =0.60. Fio2, Paw, pressure amplitude of oscillation, frequency, blood pressure, heart rate, and arterial blood gases were monitored during the transition from CV to HFOV, and every 8 hrs thereafter for 72 hrs. In 16 patients who had pulmonary artery catheters in place, cardiac hemodynamics were recorded at the same time intervals. Throughout the HFOV trial, Paw was significantly higher than that applied during CV. Within 8 hrs of HFOV application, and for the duration of the trial, Fio2 and Paco2 were lower, and Pao2/Fio2 was higher than baseline values during CV. Significant changes in hemodynamic variables following HFOV initiation included an increase in pulmonary artery occlusion pressure (at 8 and 40 hrs) and central venous pressure (at 16 and 40 hrs), and a reduction in cardiac output throughout the course of the study. There were no significant changes in systemic or pulmonary pressure associated with initiation and maintenance of HFOV. Complications occurring during HFOV included pneumothorax in two patients and desiccation of secretions in one patient. Survival at 30 days was 33%, with survivors having been mechanically ventilated for fewer days before institution of HFOV compared with nonsurvivors (1.6 +/- 1.2 vs. 7.8 +/- 5.8 days; p =.001). Question: Do prospective trial of high-frequency oscillation in adults with acute respiratory distress syndrome?" }, { "from": "assistant", "value": "yes. These findings suggest that HFOV has beneficial effects on oxygenation and ventilation, and may be a safe and effective rescue therapy for patients with severe oxygenation failure. In addition, early institution of HFOV may be advantageous." } ]

[ { "from": "user", "value": "Context: We sought to determine whether trauma patient admission volume to our Level I trauma center was correlated with observable weather or seasonal phenomena. Trauma registry data and national weather service data for the period between September 1, 1992, and August 31, 1998, were combined into a common data set containing trauma admission data and weather data for each day. Sequential linear regression models were constructed to determine relationships between variables in the data set. There is a highly significant relationship (p < 0.00001) between maximum daily temperature and trauma admissions (R = 0.22). Rain is associated with a decrease in overall trauma volume. Rain had no effect on the number of admissions because of motor vehicle crash, however. Neither humidity nor snowfall affects trauma admission volume. Trauma admissions are significantly more frequent in July and August, and on Saturdays and Sundays (p < 0.05). Linear regression analysis identified maximum temperature, precipitation, day of week, and month as independent predictors of trauma admission volume (p < 0.001, R = 0.328). Question: Do relationship between weather and seasonal factors and trauma admission volume at a Level I trauma center?" }, { "from": "assistant", "value": "yes. There is a significant relationship between weather and trauma center activity; temperature and precipitation are independently associated with trauma admission volume at our institution. Statistical models of trauma incidence should consider these phenomena. Evaluation of a larger, population-based data set is needed to confirm these relationships." } ]

[ { "from": "user", "value": "Context: We have previously observed that sympathetic blockade by epidural anesthesia (EA) modifies the cardiovascular response to marked hypercapnic acidosis in dogs. Our objective was to determine whether the combination of marked hypercapnic acidosis and EA reduce left ventricular contractility. We randomly assigned 22 Japanese white rabbits anesthetized with isoflurane (1.0%) to two groups according to the absence (control group, n= 11) or presence (EA group, n= 11) of thoracolumbar EA. After epidural injection (0.5 mL.kg(-1) of 0.9% saline in the control group or 1% mepivacaine in the EA group) and during subsequent hypercapnia (mean arterial CO2 tension 85 mmHg), we measured left ventricular pressure, left ventricular volume by using conductance catheter and plasma catecholamine concentrations. Left ventricular contractility was assessed by the slope of the linear approximation of the left ventricular end-systolic pressure-volume relationship, [i.e., end-systolic elastance (Ees)]. The combination of hypercapnic acidosis and thoracolumbar EA caused a 65% decrease in Ees (P <0.05). Hypercapnic acidosis alone caused a 16% decrease (P <0.05) and thoracolumbar EA alone caused a 49% decrease in Ees (P <0.05). In the EA group, epidural injection caused an 85% decrease in the epinephrine concentration (P <0.05) and a 39% decrease in the norepinephrine concentration (P <0.05), even during hypercapnic acidosis. However, in the control group, hypercapnic acidosis caused no change in the circulating epinephrine concentration but a 74% increase in the circulating norepinephrine concentration (P <0.05). Question: Is left ventricular contractility reduced by hypercapnic acidosis and thoracolumbar epidural anesthesia in rabbits?" }, { "from": "assistant", "value": "yes. Combined hypercapnic acidosis and EA markedly reduce left ventricular contractility in an additive fashion in rabbits receiving general anesthesia." } ]

[ { "from": "user", "value": "Context: We describe two cases in which fiberoptic intubation through the standard laryngeal mask airway (LMA) was successful with large-bore tracheal tubes (TTs) when an intubating LMA (ILMA) could not be used. Patient # 1, with obstructive sleep apnea, underwent elective surgical repair. His mouth opening was just under 25 mm, but difficult intubation was not anticipated. We induced general anesthesia, easily ventilated the patient by mask, and established neuromuscular blockade. Direct laryngoscopy and attempts to insert either a #5 or a #4 ILMA into the mouth failed. A standard #4 LMA, with the connector removed, was inserted, through which a 7.0 mm nasal RAE TT, fiberoptically guided, passed into the trachea at the first attempt. Patient #2, with a loosened implant after left hip arthroplasty, underwent revision prosthesis. Her neck movement was limited. We thus planned awake securing of the airway, but the patient refused. We induced anesthesia and established bag-mask-valve ventilation. The limited neck movement prevented direct laryngoscopy. Visualizing the laryngeal inlet with the fiberoptic bronchoscope (FOB) proved impossible as bloody secretions obscured the FOB's tip. Ventilation by mask was easy. As an ILMA was not available, we removed a #5 LMAs connector and passed an 8.0 mm nasal RAE TT through the LMA. Fiberoptic-guided intubation was easy. In both cases, the remainder of the intraoperative course was uneventful. Question: Does removal of the connector on the laryngeal mask airway provide a useful alternative to the intubating laryngeal mask?" }, { "from": "assistant", "value": "yes. A standard LMA whose connector has been removed to allow passage of TTs of >6.0 mm internal diameter may be substituted for the ILMA when necessary." } ]

[ { "from": "user", "value": "Context: Animal products contribute significantly to the saturated fat and cholesterol content of the American diet. Contrary to dietary advice, consumers have not limited their consumption of animal products. Thus, an alternative approach might be to modify the fatty acid composition of animal products. We tested the hypothesis that modified pork with a high content of polyunsaturated fatty acids (PUFAs) and a low content of saturated fatty acids (SFAs) would lower plasma LDL-cholesterol concentrations in women. Twenty women aged 19-24 y completed a crossover study with 2 diets. Nutritionally complete diets containing 42% of energy from fat differed only in the inclusion of either standard or modified pork. Venous blood samples were collected at weeks 0, 4, and 8. The diet containing modified pork significantly lowered total plasma (P < 0.0076) and LDL (P < 0.0382) cholesterol. The modified diet also resulted in an increase in the PUFA and a decrease in the SFA and monounsaturated fatty acid contents of the cholesteryl ester, free fatty acid, phospholipid, and triacylglycerol lipid classes in both plasma and erythrocytes. Plasma concentrations of glucose, insulin, triacylglycerol, and free fatty acids did not change significantly. Question: Does pork with a high content of polyunsaturated fatty acids lower LDL cholesterol in women?" }, { "from": "assistant", "value": "yes. Consumption of pork with a high PUFA content resulted in a decrease in the subjects' total plasma and LDL cholesterol and shifted the fatty acid composition from SFAs to PUFAs in the plasma and erythrocytes. Modification of the fatty acid composition of animal foods will be a useful approach to lowering the saturated fat consumption of Americans." } ]

[ { "from": "user", "value": "Context: To observe the effect of changes in the pineal sympathetic innervation on the crypt cell proliferation rate in the rat small intestine, and compare these with the effect of pinealectomy to determine the role of the sympathetic innervation in the effect of pinealectomy. The effect of bilateral ablation of the superior cervical ganglion, and that of pinealectomy on the crypt cell proliferation rate in the rat small intestine was determined, using a stathmokinetic technique. Pinealectomy was associated with a considerably increased crypt cell proliferation rate, whereas superior cervical ganglionectomy was associated with a slightly decreased rate. Question: Are changes in pineal sympathetic innervation significant in the hyperproliferative effects of pinealectomy on the intestinal crypts?" }, { "from": "assistant", "value": "no. It appears likely that changes in pineal melatonin production cannot be correlated directly with the effects of pinealectomy on the crypts, although melatonin production was not measured in this case. The role of loss of the non-adrenergic innervation of the pineal in the effect of pinealectomy needs to be examined. There is also other experimental evidence that melatonin-free extracts of the pineal, containing as yet unidentified substances, can influence mitotic activity in some tissues, so the possible role of these substances in the effects of pinealectomy should also be considered. Furthermore, the superior cervical ganglion itself has an extra-pineal role. Changes in pineal sympathetic innervation are not significant in the hyperproliferative effects of pinealectomy on the intestinal crypts." } ]

[ { "from": "user", "value": "Context: Our objective was to study the effects of the macrolide antibiotic clarithromycin on the pharmacokinetics and pharmacodynamics of repaglinide, a novel short-acting antidiabetic drug. In a randomized, double-blind, 2-phase crossover study, 9 healthy volunteers were treated for 4 days with 250 mg oral clarithromycin or placebo twice daily. On day 5 they received a single dose of 250 mg clarithromycin or placebo, and 1 hour later a single dose of 0.25 mg repaglinide was given orally. Plasma repaglinide, serum insulin, and blood glucose concentrations were measured up to 7 hours. Clarithromycin increased the mean total area under the concentration-time curve of repaglinide by 40% (P <.0001) and the peak plasma concentration by 67% (P <.005) compared with placebo. The mean elimination half-life of repaglinide was prolonged from 1.4 to 1.7 hours (P <.05) by clarithromycin. Clarithromycin increased the mean incremental area under the concentration-time curve from 0 to 3 hours of serum insulin by 51% (P <.05) and the maximum increase in the serum insulin concentration by 61% (P <.01) compared with placebo. No statistically significant differences were found in the blood glucose concentrations between the placebo and clarithromycin phases. Question: Does the cytochrome P4503A4 inhibitor clarithromycin increase the plasma concentrations and effects of repaglinide?" }, { "from": "assistant", "value": "yes. Even low doses of the cytochrome P4503A4 (CYP3A4) inhibitor clarithromycin increase the plasma concentrations and effects of repaglinide. Concomitant use of clarithromycin or other potent inhibitors of CYP3A4 with repaglinide may enhance its blood glucose-lowering effect and increase the risk of hypoglycemia." } ]

[ { "from": "user", "value": "Context: The aim of this study is to examine the duration and magnitude of vasodilative effect induced by sympathetic block with the addition of clonidine to mepivacaine. We measured mean arterial pressure (MAP), heart rate (HR), and right and left brachial artery blood flow (BABF) before and after stellate ganglion block (SGB) in dogs. The experimental protocol was designed as follows: (1) left SGB using 1.0 mL 0.5% mepivacaine (n = 6) and (2) left SGB using the addition of clonidine 0.5 microg to 1.0 mL 0.5% mepivacaine (n = 6). MAP and HR did not change significantly throughout the study in either group. Left SGB with mepivacaine increased left BABF significantly from 10 minutes through 50 minutes after SGB (baseline, 100%; peak at 10 minutes after SGB, 176% +/- 28%; P <.01). Left SGB with the addition of clonidine to mepivacaine induced a significant increase of left BABF from 10 minutes through 70 minutes after SGB (baseline, 100%; peak at 10 minutes after SGB, 223% +/- 42%; P <.01). The values of left BABF after SGB with the addition of clonidine to mepivacaine were significantly higher than those of SGB with mepivacaine alone from 10 minutes through 80 minutes after SGB (P <.05). Right BABF decreased significantly after SGB throughout the study in both groups. Question: Does addition of clonidine increase duration and magnitude of vasodilative effect induced by sympathetic block with mepivacaine in dogs?" }, { "from": "assistant", "value": "yes. The addition of clonidine increases both duration and magnitude of the vasodilative effect induced by sympathetic block over that caused by mepivacaine alone." } ]

[ { "from": "user", "value": "Context: The continuous spread of penicillin-resistant pneumococci represents a permanent threat in the treatment of pneumococcal infections, especially when strains show additional resistance to quinolones. The main objective of this study was to determine a treatment modality impeding the emergence of quinolone resistance. Exposure of a penicillin-resistant pneumococcus to increasing concentrations of trovafloxacin or ciprofloxacin selected for mutants resistant to these drugs. In the presence of sub-inhibitory concentrations of vancomycin, development of trovafloxacin-resistance and high-level ciprofloxacin-resistance were prevented. Question: Do sub-inhibitory concentrations of vancomycin prevent quinolone-resistance in a penicillin-resistant isolate of Streptococcus pneumoniae?" }, { "from": "assistant", "value": "yes. Considering the risk of quinolone-resistance in pneumococci, the observation might be of clinical importance." } ]

[ { "from": "user", "value": "Context: The sorting of mRNA is a determinant of cell asymmetry. The cellular signals that direct specific RNA sequences to a particular cellular compartment are unknown. In fibroblasts, beta-actin mRNA has been shown to be localized toward the leading edge, where it plays a role in cell motility and asymmetry. We demonstrate that a signaling pathway initiated by extracellular receptors acting through Rho GTPase and Rho-kinase regulates this spatial aspect of gene expression in fibroblasts by localizing beta-actin mRNA via actomyosin interactions. Consistent with the role of Rho as an activator of myosin, we found that inhibition of myosin ATPase, myosin light chain kinase (MLCK), and the knockout of myosin II-B in mouse embryonic fibroblasts all inhibited beta-actin mRNA from localizing in response to growth factors. Question: Does a Rho-dependent signaling pathway operating through myosin localize beta-actin mRNA in fibroblasts?" }, { "from": "assistant", "value": "yes. We therefore conclude that the sorting of beta-actin mRNA in fibroblasts requires a Rho mediated pathway operating through a myosin II-B-dependent step and postulate that polarized actin bundles direct the mRNA to the leading edge of the cell." } ]

[ { "from": "user", "value": "Context: The aim of the study was to evaluate the risk from calcified atheromas in the ascending aorta, and the extent and topography of the disease in the development of stroke after cardiac surgery. Postoperative stroke constitutes a serious problem in cardiac surgery, and atherosclerosis of the ascending aorta is an important risk factor. Before surgical manipulation epiaortic echocardiographic ultrasound was performed to evaluate the ascending aorta in 921 consecutive patients undergoing cardiac surgery. The presence of calcification, location of atheroma, extent of the disease and clinical variables including postoperative stroke were recorded prospectively. A total of 26.2% of the patients had atherosclerosis of the ascending aorta, and in 44.4% of them more than one of 12 possible segments was involved. Logistic regression showed that atherosclerotic disease in the ascending aorta was the most important predictive factor for postoperative stroke. The incidence of stroke was 1.8% in patients without atherosclerotic disease of the ascending aorta, and 8.7% in patients with the disease (p < 0.0001). Diabetes mellitus was also a predictive factor (p = 0.04). A new and unique finding of this study was that the middle-lateral segment is an independent predictive factor for postoperative stroke, with a relative risk of 26% (p = 0.04). Question: Is postoperative stroke in cardiac surgery related to the location and extent of atherosclerotic disease in the ascending aorta?" }, { "from": "assistant", "value": "yes. Patients with atheromatosis in the ascending aorta had an 8.7% incidence of postoperative stroke, in spite of minor surgical modifications. The risk depended on the presence, location and extent of the disease. Randomized trials evaluating alternative surgical strategies in coronary surgery are urgently needed in high risk patients." } ]

[ { "from": "user", "value": "Context: Certain primary hepatic tumors have been associated with familial adenomatous polyposis (FAP), a condition caused by germline mutations of the adenomatous polyposis coli (APC) gene. However, a genetic association between FAP and hepatocellular carcinoma (HCC) has not been shown. This study tested the hypothesis that biallelic inactivation of the APC gene contributed to the development of HCC in a patient with FAP and a known germline mutation of the APC gene at codon 208, but no other risk factors for HCC. Total RNA and genomic DNA were isolated from the tumor, and in vitro synthesized protein assay and DNA sequencing analysis were used to screen for a somatic mutation in the APC gene. A somatic one-base pair deletion at codon 568 was identified in the wild-type allele of the APC gene. Question: Is biallelic inactivation of the APC gene associated with hepatocellular carcinoma in familial adenomatous polyposis coli?" }, { "from": "assistant", "value": "yes. To the authors' knowledge, this study provides the first evidence that biallelic inactivation of the APC gene may contribute to the development of HCC in patients with FAP." } ]

[ { "from": "user", "value": "Context: To describe socio-economic variations in the treatment and control of hypertension in England. Population based survey. Hypertensives numbering 5019, identified in the Health Survey for England for 1993-1994. Drug treatment and control of hypertension. A total of 1119/2208 (50.7%) hypertensive men, and 1620/2811 (57.6%) hypertensive women, were receiving anti-hypertensive medication. For men, the likelihood of receiving treatment increased with age, widowerhood or divorce, a family history of heart disease, low social support and increasing weight, but was decreased for men who lived alone, owned their own house, smoked or drank heavily. For women, obesity, a family history of heart disease and low social support increased their chance of treatment. A total of 534/1119 (47.7%) men, and 816/1620 (50.4%) of women on treatment, had their hypertension controlled to below 160/90 mmHg. Lack of control was more commonly due to isolated systolic hypertension rather than diastolic hypertension. Increasing age and smoking were associated with poorer control. Men who lived alone and had low social support were less likely to have their hypertension controlled, while those with a family history of heart disease were more likely to be controlled. Question: Are inequalities in the treatment and control of hypertension : age , social isolation and lifestyle more important than economic circumstances?" }, { "from": "assistant", "value": "yes. We found little evidence for socio-economic or geographic differences in the management of hypertension. Variations in treatment rates can be explained by variations in use of primary care and opportunistic screening. Control was poorest among older people who are at the highest risk of cardiovascular events. Socially isolated men and smokers were less likely to be treated or controlled, and need to be targeted by future programmes to detect and treat hypertension." } ]

[ { "from": "user", "value": "Context: Goitre prevalence is dependent on iodine intake and smoking habits, but further risk factors have only been examined briefly. We examined the association between alcohol consumption and the prevalence of thyroid enlargement and nodularity. Cross-sectional population study with ultrasonography of the thyroid gland and assessment of alcohol intake and smoking habits from questionnaires. Four thousand six-hundred and forty-nine men and women aged 18-65 years, randomly selected from the Danish Civil Registration System. Thyroid volume and prevalence of thyroid enlargement, multiple nodules or a solitary nodule in the thyroid. Abstainers and participants with a low alcohol consumption (< 7 drinks/week) had the same prevalence of thyroid enlargement and nodularity, but participants with moderate (8-28 drinks/week for women, 8-42 for men) or high (> 28/42 drinks/week) alcohol consumption had much lower prevalence of thyroid abnormalities. Possible confounding by sex, age, iodine status and smoking was considered in all models. Odds ratios compared to abstainers for thyroid enlargement were 0.74 [95% confidence interval (CI) 0.57-0.96] for moderate- and 0.44 (95% CI 0.22-0.88) for high alcohol consumption. Odds ratios compared to abstainers for a solitary nodule were 0.64 (95% CI 0.42-0.96) for moderate- and 0.41 (95% CI 0.12-1.37) for high alcohol consumption. Mean thyroid volume was 13.5 ml among abstainers compared to 10.9 ml among participants with high alcohol consumption (P < 0.001). Both wine- and beer consumption were associated to lower prevalence of thyroid abnormalities. Question: Is alcohol consumption associated with reduced prevalence of goitre and solitary thyroid nodules?" }, { "from": "assistant", "value": "yes. Increasing levels of alcohol consumption were associated to lower prevalence of thyroid enlargement and to lower prevalence of a solitary nodule in the thyroid, and indications of a causal relationship were found." } ]

[ { "from": "user", "value": "Context: Intense p53 immunostaining may predict for a poor prognosis in central nervous system primitive neuroectodermal tumor of childhood. Medulloblastoma is a common childhood primary brain tumor. Potential prognostic indicators for patients with local disease are age, extent of resection, and gender. However, none of these are well established. Immunohistologic staining is a potentially useful means to identify high-risk patients. The purpose of this clinical pathologic study was to investigate the prognostic significance of GFAP, synaptophysin, Ki-67, and p53 immunostaining in medulloblastoma/central nervous system primitive neuroectodermal tumors (CNS PNETs.) The records of 40 patients with CNS PNETs were reviewed. Their surgical specimens were immunostained for p53, glial fibrillary acidic protein (GFAP), synaptophysin, and Ki-67. The p53 specimens were scored blindly for the intensity of staining of nuclei (intense vs weak) and the quantity of cells stained. The Ki-67, GFAP, and synaptophysin specimens were analyzed for quantity of cells stained. Ten patients' specimens stained intensely for the p53 protein. Eleven had weakly staining nuclei. Nineteen specimens had no staining. The patients with specimens that stained intensely had a statistically significant decreased disease free survival (P = 0.03). Mere presence or quantity of p53 nuclear staining did not correlate with disease free survival. Immunohistochemical staining for Ki-67, GFAP, and synaptophysin did not correlate with disease free survival. Clinical parameters of age, gender, and extent of resection also did not approach statistical significance for disease free survival. Question: Is intense p53 staining a valuable prognostic indicator for poor prognosis in medulloblastoma/central nervous system primitive neuroectodermal tumors?" }, { "from": "assistant", "value": "yes. Intense nuclear staining for p53 was the only variable in this clinical pathologic study that reached statistical significance for disease free survival. This suggests that intense staining for p53 may be the most important prognostic indicator for non-metastatic CNS PNETs. p53 Immunostaining with antibodies against p53 in CNS PNETs should be studied in a multi-institutional setting with larger numbers of patients." } ]

[ { "from": "user", "value": "Context: Blood transfusion may adversely affect the prognosis following surgery for non-small cell lung carcinoma (NSCLC). Conventionally by most thoracic surgeons, a perioperative haemoglobin (Hb) less than 10 g/dl has been considered a transfusion trigger. In this prospective trial we have (a) evaluated the overall blood transfusion requirements and factors associated with an increased need for transfusion and (b) in a subsequent subset of patients, tested the hypothesis that elective anaemia after major lung resection may be safely tolerated in the early postoperative period. A total of 198 (M/F 179/10, mean age 61.2, range 32--85 years) patients suffering from NSCLC were submitted to pneumonectomy (n = 89), bilobectomy (n = 19) and lobectomy (n = 90). A rather strict protocol was used as a transfusion strategy. The transfusion requirements were analyzed and seven parameters (gender, age > 65, preoperative Hb < 11.5 g/dl, chest wall resection, history of previous thoracotomy, pneumonectomy and total blood loss) were statistically evaluated by univariate and logistic regression analysis. Subsequently, according to the perioperative Hb level during the first 48 h, patients were divided into group A (n = 49, Hb = 8.5--10) and group B (n = 149, Hb > 10) with a view to estimate the risks of elective perioperative anaemia. Groups were comparable in terms of age, sex, type of operation performed, preoperative Hb, creatinine level, FEV1, arterial blood gases and history of heart disease. The overall transfusion rate was 16%. Univariate analysis revealed that preoperative Hb < 11.5 g/dl (P < 0.01) and total blood loss (P < 0.0001) were associated with increased need for transfusion, but only the total blood loss was identified as an independent variable in multivariate analysis. Statistical analysis between groups A and B showed no significant difference regarding postoperative morbidity and mortality: atelectasis (3 vs. 6), chest infection (2 vs. 9), sputum retention requiring bronchoscopy (5 vs. 12), admission to intensive care unit (5 vs. 7), ARDS (0 vs. 3), postoperative hospital stay (7.7 +/- 2.6 vs. 9.1 +/- 3.8 days) and deaths (1 vs. 3). Question: Does blood use in lung resection for carcinoma : perioperative elective anaemia compromise the early outcome?" }, { "from": "assistant", "value": "no. The use of a strict transfusion strategy could help in reducing overall blood transfusion. Furthermore, a perioperative Hb of 8.5--10 g/dl could be considered safe in elective lung resections for carcinoma." } ]

[ { "from": "user", "value": "Context: The shape of laparoscopic instrument handles can cause physical discomfort. This problem may be ascribed to a lack of standards for instrument design. In this study, new ergonomic requirements for the design of laparoscopic dissection forceps were created. Three representative handles (a Karl Storz [click-line] scissors handle, an Access Plus scissors handle, and an Aesculap cylindrical handle) currently available on the market were evaluated according to the new list of ergonomic criteria. The handles were subjectively (questionnaire) and objectively (video analyses) tested in order to find out whether the new requirements are valid for the evaluation and design of instrument handles. The outcome of the subjective and objective tests matched the predictions by the new criteria list. New criteria were introduced (neutral wrist excursions), and existing general criteria were specified (e.g., a minimal contact area of 10 mm). Significant differences were found among the three handles. The Storz handle met 8 of the 10 requirements, the Access handle met 5, and the Aesculap handle met only 4. Question: Does new ergonomic design criteria for handle of laparoscopic dissection forceps?" }, { "from": "assistant", "value": "yes. The new list of ergonomic requirements is a valid tool to determine the ergonomic value of a handle for laparoscopic dissecting tasks. It gains its strength from its specialized character. Significant differences were found among the three tested handles. Cylindrical handles were inferior to scissors handles." } ]

[ { "from": "user", "value": "Context: Our aim was to determine whether an alteration in splanchnic glucose metabolism could contribute to postprandial hyperglycaemia in people with Type I (insulin-dependent) diabetes mellitus. Splanchnic glucose extraction, hepatic glycogen synthesis and endogenous glucose production were compared in 8 Type I diabetic patients and in 11 control subjects. Endogenous hormone secretion was inhibited with somatostatin while insulin (approximately 550 pmol/l) and glucagon (approximately 130 ng/l) concentrations were matched with exogenous hormone infusions. Glucose containing [3-3H] glucose was infused into the duodenum at a rate of 20 micromol.kg(-1).min(-1). Plasma glucose concentrations were maintained at about 8.5 mmol/l in both groups by means of a separate variable intravenous glucose infusion. Initial splanchnic glucose uptake, calculated by subtracting the systemic rate of appearance of [3-3H] glucose from the rate of infusion of [3-3H] glucose into the duodenum, did not differ in the diabetic and non-diabetic patients (4.1 +/- 0.8 vs 3.0 +/- 1.0 micromol/kg/min). In addition, hepatic glycogen synthesis, measured using the acetaminophen glucuronide method did not differ (10.7 +/- 2.4 vs 10.1 +/- 2.7 micromol.kg(-1).min(-1)). On the other hand, suppression of endogenous glucose production, measured by an intravenous infusion of [6,6-2H2] glucose, was greater (p < 0.05) in the diabetic than in the non-diabetic subjects (1.7 +/- 1.6 vs 5.8 +/- 1.9 micromol.kg(-1).min(-1)). Question: Does type I diabetes mellitus alter initial splanchnic glucose extraction or hepatic UDP-glucose flux during enteral glucose administration?" }, { "from": "assistant", "value": "no. When glucose, insulin and glucagon concentrations are matched in individuals with relatively good chronic glycaemic control, Type I diabetes does not alter initial splanchnic glucose uptake of enterally delivered glucose or hepatic glycogen synthesis. Alterations in splanchnic glucose metabolism are not likely to contribute to postprandial hyperglycaemia in people with well controlled Type I diabetes." } ]

[ { "from": "user", "value": "Context: We sought to test the hypothesis of whether low birth weight rats would have reduced glomerular number, higher systolic blood pressure and an altered acute response to streptozotocin diabetes compared to normal birth weight rats. Female offspring of Wistar rats fed an isocaloric diet containing either 6% casein (LPD) or 18% casein (NPD) in utero were studied. Birth weight, body weight, systolic blood pressure and urine albumin excretion were measured before and after streptozotocin diabetes. Glomerular number and volume were estimated after one week of diabetes. The LPD rats were of low birth weight (5.4 +/- 0.5 g vs 6.4 +/- 0.8 g, p < 0.0001) with higher systolic blood pressure (137 +/- 9mmHg vs 120 +/- 7 mmHg, p < 0.0001) and reduced glomerular number (17,435 +/- 2,074 vs 24,846 +/- 1,864, p < 0.0001). The LPD rats had smaller kidneys (0.925 +/- 0.009 g vs 1.200 +/- 0.173 g, p = 0.041) but similar glomerular volume to NPD control rats (1.11 +/- 0.15 x 10(6) microm3 vs 1.08 +/- 0.17 x 10(6) microm3). After 1 week of diabetes LPD rats had a greater proportional increase in renal size (diabetes 50 +/- 12 % vs control 20 +/- 4%, p = 0.003). Insulin suppressed renal hypertrophy in both LPD and NPD rats but failed to suppress glomerular hypertrophy in LPD rats (1.48 +/- 0.21 x 10(6) microm3 vs 1.03 +/- 0.23 x 10(6) microm3 p = 0.015). Question: Does intra-uterine environment influence glomerular number and the acute renal adaptation to experimental diabetes?" }, { "from": "assistant", "value": "yes. Abnormal intra-uterine environment reduces both renal size and glomerular number and influences the acute renal adaptation to experimental diabetes." } ]

[ { "from": "user", "value": "Context: Alpha-actinin is a ubiquitously expressed protein found in numerous actin structures. It consists of an N-terminal actin binding domain, a central rod domain, and a C-terminal domain and functions as a homodimer to cross-link actin filaments. The rod domain determines the distance between cross-linked actin filaments and also serves as an interaction site for several cytoskeletal and signaling proteins. We report here the crystal structure of the alpha-actinin rod. The structure is a twisted antiparallel dimer that contains a conserved acidic surface. Question: Does crystal structure of the alpha-actinin rod reveal an extensive torsional twist?" }, { "from": "assistant", "value": "yes. The novel features revealed by the structure allow prediction of the orientation of parallel and antiparallel cross-linked actin filaments in relation to alpha-actinin. The conserved acidic surface is a possible interaction site for several cytoplasmic tails of transmembrane proteins involved in the recruitment of alpha-actinin to the plasma membrane." } ]

[ { "from": "user", "value": "Context: To evaluate the reliability of dipstick measurements of urine specific gravity (U-SG). Fresh urine specimens were tested for urine pH and osmolality (U-pH, U-Osm) by a pH meter and an osmometer, and for U-SG by three different methods (refractometry, automatic readout of a dipstick (Clinitek-50), and (visual) change of colour of the dipstick). The correlations between the visual U-SG dipstick measurements and U-SG determined by a refractometer and the comparison of Clinitek((R))-50 dipstick U-SG measurements with U-Osm were less than optimal, showing very wide scatter of values. Only the U-SG refractometer values and U-Osm had a good linear correlation. The tested dipstick was unreliable for the bedside determination of U-SG, even after correction for U-pH, as recommended by the manufacturer. Question: Are dipstick measurements of urine specific gravity unreliable?" }, { "from": "assistant", "value": "yes. Among the bedside determinations, only refractometry gives reliable U-SG results. Dipstick U-SG measurements should be abandoned." } ]

[ { "from": "user", "value": "Context: To determine the prevalence of GB virus-C (GBV-C) RNA and TT virus (TTV) DNA in patients with systemic sclerosis (SSc), rheumatoid arthritis (RA), and osteoarthritis (OA) as well as to compare the autoantibody pattern in patients with SSc with and without evidence of viral infection. The study included 168 patients (84 SSc, 41 RA, and 43 OA) diagnosed according to the American College of Rheumatology criteria and 122 volunteer blood donors. The presence of GBV-C RNA and TTV DNA in serum was assessed by nested reverse transcriptase-polymerase chain reaction (RT-PCR) and semi-nested PCR, respectively. Autoantibodies in patients with SSc were determined by enzyme linked immunosorbent assay (ELISA) and Hep-2 immunofluorescence. TTV-DNA was detected in 10/84 (12%) patients with SSc, 9/41 (22%) patients with RA, 3/43 (7%) patients with OA, and 16/122 (13%) blood donors. GBV-C RNA was present in 4/84 (5%) patients with SSc, 2/43 (5%) patients with OA, and 5/122 (4%) blood donors. No patient with RA was positive for GBV-C RNA. One patient with SSc and one patient with OA showed a double infection with GBV-C and TTV. 74/84 (88%) patients with SSc were positive for at least one autoantibody species tested: 18/84 (21%) showed anticentromeric autoantibodies, 55/84 (66%) a speckled (36/84 (43%) fine, 19/84 (23%) coarse), and 20/84 (24%) a homogeneous nuclear Hep-2 pattern, and 21/84 (25%) had antinucleolar autoantibodies. Anti-Scl-70 antibodies were found in 31/84 (37%) and anti-RNP antibodies in 5/84 (6%) patients with SSc. No differences in the autoantibody pattern in patients with SSc with or without viral infection could be detected. Question: Does prevalence of TTV DNA and GBV-C RNA in patients with systemic sclerosis , rheumatoid arthritis , and osteoarthritis differ from that in healthy blood donors?" }, { "from": "assistant", "value": "no. The prevalence of GBV-C RNA and TTV DNA in serum samples from patients with SSc, RA, and OA was low and comparable with that in blood donors. A continuing infection with TTV and or GBV-C was not associated with a significant change in the autoantibody pattern in patients with SSc. These data provide no evidence for an association between GBV-C and/or TTV infections and SSc and/or arthritis (RA and OA)." } ]

[ { "from": "user", "value": "Context: The Neurologic and Adaptive Capacity Score (NACS) is a multi-item scale that was published in 1982 to measure the effects of intrapartum drugs on the neonate. Although this scoring system has been widely used in obstetric anesthesia research, studies confirming its reliability have not been published. The purpose of this study was to assess the reliability of the NACS. Two teams of observers were trained to perform the NACS on healthy, term neonates born in the vertex presentation. Two examinations were performed on each neonate within the first 2.5 h of life. Simultaneous (or \"split-half\") reliability was assessed using the alpha coefficient. Test-retest reliability was assessed using the intraclass correlation coefficient. The test was considered to be reliable if a was greater than 0.7 and the intraclass correlation coefficient was greater than 0.6. Two hundred babies were studied. The a was 0.47 and the intraclass correlation coefficient was 0.38 (95% confidence interval, 0.24-0.52). Question: Is the neurologic and adaptive capacity score a reliable method of newborn evaluation?" }, { "from": "assistant", "value": "no. The NACS had poor reliability both on simultaneous testing and in the test-retest situation when used to evaluate term, healthy neonates. The authors suggest that other measures need to be developed to evaluate the effect of intrapartum drug administration in the neonate. Health measurement scales should undergo rigorous assessment for reliability and validity before they are used in clinical practice or for research purposes." } ]

[ { "from": "user", "value": "Context: Autologous hematopoietic stem cell transplantation (ASCT) has been recently utilized with encouraging results in patients with poorly controlled MS. To determine in severe cases of MS the effect of ASCT on gadolinium (Gd)-enhanced MRI and to obtain information on clinical course and safety. In a cooperative study, 10 patients with rapidly evolving secondary progressive MS were transplanted, after BEAM conditioning regimen (carmustine, etoposide, cytosine-arabinoside, and melphalan), with unmanipulated autologous peripheral blood SC mobilized with high-dose cyclophosphamide (CY; 4 g/m2) and granulocyte-colony-stimulating factor. Triple-dose Gd-enhanced scans were performed monthly for a pretreatment period of 3 months and compared with serial monthly Gd-enhanced MRI for the following 6 months and then once every 3 months. The median follow-up is now 15 months (range 4 to 30 months). The number of Gd-enhancing lesions decreased immediately after mobilization with CY and finally dropped to zero in all cases after the conditioning regimen. The number of new T2-weighted positive lesions paralleled data obtained for Gd-enhanced MRI. Clinically, patients improved slightly or remained stable. Question: Does autologous hematopoietic stem cell transplantation suppress Gd-enhanced MRI activity in MS?" }, { "from": "assistant", "value": "yes. These results demonstrate that the therapeutic sequence CY-BEAM-ASCT has the capacity to completely suppress MR-enhancing activity, an effect that is sustained with time. The final impact of this procedure on disease course remains to be established." } ]

[ { "from": "user", "value": "Context: Reduced heart rate variability (HRV) is a risk factor for cardiac death. Animal studies have shown increased HRV and reduced mortality after physical training. We evaluated the change in exercise capacity and HRV in cardiac rehabilitation patients, randomised to routine or home-based intensive training. The design was prospective, stratified randomisation with pre-specified subgroup analysis. Maximal bicycle exercise test and 24-h Holter were performed 1 (baseline), 4 and 12 months after myocardial infarction (MI) or coronary artery by-pass surgery (CABG). Patients were randomised to physical training either two (N) or six (I) times per week for 3 months Sixty-two patients (43 MI and 19 CABG patients) were evaluated. Exercise capacity increased significantly more after 3 months of training in group I (mean (S.E.)); 29.0 (3.4) vs. 7.2 (2.6) watts, P<0.001). One year later the difference in exercise capacity remained (26.5 (3.3) vs. 11.8 (3.8) watts, P<0.001). Global HRV measurements SDNN and SDANN increased significantly more in group I after training (17.1 (5.6) vs. 1.7 (3.7) and 16.2 (4.9) vs. 2.8 (3.1) ms, P<0.05) and 1 year later the differences were still significant. Subgroup analysis showed more pronounced HRV response in CABG than MI patients. Question: Does intensive home-based exercise training in cardiac rehabilitation increase exercise capacity and heart rate variability?" }, { "from": "assistant", "value": "yes. Intensive exercise training in cardiac rehabilitation increases exercise capacity and global HRV, which could be of prognostic significance." } ]

[ { "from": "user", "value": "Context: Previous investigators have shown that systemic markers of inflammation may be increased in patients with acute ischemic syndromes or after percutaneous coronary revascularization and that persistent elevation in these markers is predictive of excess risk of subsequent adverse cardiac events. By virtue of its cross-reactivity with the glycoprotein IIb/IIIa, avbeta3, and alphaMbeta2 receptors, abciximab may reduce inflammatory processes. Methods and Results-- Assays for the inflammatory markers C-reactive protein, interleukin-6, and tumor necrosis factor-alpha were performed on serum samples obtained from 160 patients in a placebo-controlled, randomized trial of abciximab during angioplasty. Eighty patients each had received a placebo or abciximab bolus plus a 12-hour infusion. Serum samples were drawn at baseline (before revascularization), 24 to 48 hours after study drug administration, and 4 weeks after study drug administration. Between baseline and 24 to 48 hours, the increase in C-reactive protein was 32% less in patients receiving abciximab than placebo (P=0.025); the rise in interleukin-6 levels was 76% less in the abciximab group (P<0.001); and the rise in tumor necrosis factor-alpha levels was 100% less with abciximab therapy (P=0.112). By 4 weeks, most marker levels had returned to baseline, with no significant differences between placebo and abciximab groups. Question: Does abciximab suppress the rise in levels of circulating inflammatory markers after percutaneous coronary revascularization?" }, { "from": "assistant", "value": "yes. Systemic markers of inflammation increase in the first 24 to 48 hours after angioplasty, but the magnitude of that rise is diminished by periprocedural abciximab. Some of the long-term clinical benefit derived from this agent may be related to an anti-inflammatory effect." } ]

[ { "from": "user", "value": "Context: A chronic immune response involving proinflammatory T helper cell 1 (Th1) lymphocyte activation occurs in the atherosclerotic lesion, but whether this activation is protective or deleterious remains unclear. Methods and Results-- We modulated the immune response of the atherosclerosis-prone apolipoprotein E-deficient (apoE(-/-)) mouse. Eight-week-old apoE(-/-) mice were treated daily with pentoxifylline (PTX), a known inhibitor of the Th1 differentiation pathway, or PBS (control) for 4 weeks or 12 weeks. Twelve-week PTX treatment reduced atherosclerotic lesion size by 60% (P<0.01). PTX-treated mice developed lesions that were limited to the degree of fatty streaks. In contrast, control mice developed mature fibrofatty atherosclerotic lesions. In parallel, the proportion of interferon (IFN)-gamma-producing Th1 splenic lymphocytes was significantly reduced by PTX, and lesion size was correlated to the proportion of IFN-gamma(+) T cells. In vitro addition of PTX to cultured spleen cells did not modify the production of IFN-gamma but increased the production of IL-10 by T cells, indicating that PTX does not suppress IFN-gamma production but rather blocks Th1 polarization while promoting Th2 polarization. Question: Does in vivo downregulation of T helper cell 1 immune responses reduce atherogenesis in apolipoprotein E-knockout mice?" }, { "from": "assistant", "value": "yes. Thus, PTX protected mice from atherosclerosis by reducing the Th1 polarization of T helper lymphocytes. This study demonstrates that the Th1 immune response associated with atherosclerosis is deleterious and that a modulation of the Th1 differentiation pathway may provide a new pharmacological tool to treat this disease." } ]

[ { "from": "user", "value": "Context: Genotype 1b of hepatitis C virus (HCV) comprises mainly three subtypes, each named for its geographic prevalence (worldwide, W; Japan, J; and not in Japan, NJ). To characterise the newly identified subtypes of genotype 1b and to review factors associated with response to interferon (IFN) for each subtype. Chronic hepatitis patients (80 men and 41 women; mean age 48.5 years, range 20.7--69.3) with HCV genotype 1b (W type, n=41; J type, n=38) or genotype 2a (n=42) were treated according to the same IFN protocol. Forty four patients (36.4%) negative for serum HCV RNA six months after cessation of treatment were considered complete responders. Factors associated with complete response were investigated. Genotype 2a patients had lower viral loads (odds ratio 0.11 (95% confidence intervals (CI) 0.049--0.256)) and a better IFN response (odds ratio 0.25 (95% CI 0.117--0.552)) than genotype 1b patients whereas W type and J type patients had similar viral loads and responses to IFN. IFN response in W type patients was associated with female sex (odds ratio 0.23 (95% CI 0.055--0.983)) and low viral load (odds ratio 84.00 (95% CI 14.04--502.6)) whereas response in J type patients was related to transfusion history (odds ratio 7.20 (95% CI 1.443--35.91)), low viral load (odds ratio 117.0 (95% CI 17.82--768.3)), and genetic mutation in the interferon sensitivity determining region of the virus (odds ratio 0.08 (95% CI 0.013--0.553)). Multivariate analysis found low viral load (odds ratio 64.19 (95% CI 14.66--281.06)) to be the only significant independent factor associated with IFN response. Question: Does interferon responsiveness in patients infected with hepatitis C virus 1b differ depending on viral subtype?" }, { "from": "assistant", "value": "yes. Factors associated with IFN responsiveness in HCV infection differ with viral subtype." } ]

[ { "from": "user", "value": "Context: Metabolic interventions that promote glucose use during ischemia have been shown to protect the myocardium and improve functional recovery on reperfusion. In this study we evaluated if cardioprotection can be accomplished by inhibiting fatty acid uptake, which would be expected to increase glycolytic metabolism. Diisothiocyanostilbene sulfonic acid (DIDS), commonly used to inhibit Band-3 mediated anion exchanger, and has also been demonstrated to inhibit fatty acid transport in adipocytes, was used to inhibit fatty acid uptake prior to ischemia. Isolated rat hearts were perfused with buffer containing 5 mM glucose, 70 mU/l insulin, 0.4 mM palmitate, and 0.4 mM albumin, paced at 300 beats/min, and subjected to 50 min of low-flow ischemia followed by 60 min of reperfusion. Ischemic injury, as assessed by creatine kinase release, was diminished in hearts perfused with DIDS (334+/-72 in DIDS vs. 565+/-314 IU/g dry wt in controls, P<0.04). Increases in LVEDP during ischemia were attenuated (8+/-3 mmHg in DIDS vs. 15+/-18 mmHg in controls, P<0.03) and the % recovery of LV function with reperfusion was enhanced in DIDS-treated hearts (78+/-10% of baseline in DIDS vs. 62+/-19% of baseline in controls, P<0.04). These beneficial effects of DIDS were associated with increased glucose metabolism and ATP content during ischemia and reperfusion. Furthermore, treatment with DIDS lowered the accumulation of long chain acyl carnitines. Question: Is protection of ischemic hearts perfused with an anion exchange inhibitor , DIDS , associated with beneficial changes in substrate metabolism?" }, { "from": "assistant", "value": "yes. This study demonstrates that DIDS protects ischemic myocardium, and is associated with inhibition of fatty acid uptake, improved glucose metabolism, and enhanced functional recovery on reperfusion. The data presented here suggest a potential role for therapeutic agents that lower fatty acid uptake as a metabolic adjunct in the treatment of myocardial ischemia." } ]

[ { "from": "user", "value": "Context: A finite-element study to investigate the amount of trabecular bone at risk of fracture and the distribution of load between trabecular core and cortical shell, for healthy, osteopenic, and osteoporotic vertebrae. To determine differences between healthy, osteopenic, and osteoporotic vertebrae with regard to the risk of fracture and the load distribution. The literature contains no reports on the effects of osteopenia and osteoporosis on load distribution in vertebral bodies, nor any reports on the amount of trabecular bone at risk of fracture. Computed tomography data of vertebral bodies were used to construct patient-specific finite-element models. These models were then used in finite-element analyses to determine the physiologic stresses and strains in the vertebrae. For all three classes of vertebrae the contribution of the trabecular core to the total load transfer decreased from about 70% near the endplates to about 50% in the midtransverse region. The amount of trabecular bone that is at risk of fracture was about 1% for healthy vertebrae, about 3% for osteopenic vertebrae, and about 16% for osteoporotic vertebrae. Question: Does osteoporosis change the amount of vertebral trabecular bone at risk of fracture but not the vertebral load distribution?" }, { "from": "assistant", "value": "yes. Our finite-element models indicated that neither osteopenia nor osteoporosis had any effect on the contribution of the trabecular core to the total load placed on the vertebra. The trabecular core carried about half the load. Our finite-element models indicated that osteoporosis had a significant effect on the amount of trabecular bone at risk of fracture, which increased from about 1% in healthy vertebrae to about 16% for osteoporotic vertebrae." } ]

[ { "from": "user", "value": "Context: Electrophysiologic recordings from muscle spindle afferents innervating the lumbar multifidus muscle of the cat while loading the L6 vertebra at its spinous process and while exposing the segmentally adjacent lumbar multifidus muscles to algesic and inflammatory mediators. The purpose of this study was to investigate a possible mechanism underlying muscle spasm and pain in the lumbar spine. The hypothesis was tested that stimulation of chemosensitive afferents with receptive endings in the paraspinal muscle increases the discharge of paraspinal muscle spindle afferents during loading of a lumbar vertebra. The presence of such a phenomenon would provide a mechanism by which pain or inflammation could alter segmental lumbar biomechanics and contribute to lumbar spine dysfunction. Muscle pain, tenderness, and altered muscle tone are often associated with musculoskeletal disorders. The literature suggests that stimulation of Group III and IV muscle afferents sensitive to algesic or inflammatory metabolites increases the stretch sensitivity of muscle spindles via a reflex pathway involving gamma-motoneurons. The reflex increase in muscle spindle activity, in turn, reflexly increases the excitability of alpha-motoneurons leading to enhanced muscle tone and the further accumulation of muscle metabolites and subsequent pain. Studies in the cervical spine support this hypothesis. It has not been investigated in the lumbar spine. Single unit activity from muscle spindles in the L6 multifidus muscle were recorded from the cut peripheral end of the L6 dorsal root in alpha-chloralose-anesthetized cats and in decerebrate unanesthetized cats. The L6 vertebra was loaded at its spinous process using a force-feedback motor. Ramp and hold loads were delivered at 25%, 50%, 75%, and 100% body weight. Chemosensitive afferents in the L5 and L7 multifidus muscle were stimulated by bathing (subfascial injection) or infiltrating (intramuscular injection) the L5 and L7 multifidus muscles with bradykinin or capsaicin. Loading the L6 vertebra stimulated muscle spindles in the L6 multifidus muscle. Neither the saline volume control nor bradykinin nor capsaicin injected subfascially or intramuscularly affected the response of L6 multifidus muscle spindles to ramp and hold vertebral loads in the alpha-chloralose-anesthetized cat. In addition, neither saline nor bradykinin nor capsaicin injected intramuscularly affected the activity of L6 multifidus muscle spindles to ramp and hold vertebral loads in the unanesthetized decerebrate cat. Question: Does stimulation of chemosensitive afferents from multifidus muscle sensitize multifidus muscle spindles to vertebral loads in the lumbar spine of the cat?" }, { "from": "assistant", "value": "no. These results indicate that stimulation of small diameter muscle afferents in a deep muscle of the lumbar spine does not sensitize muscle spindles to vertebral loads. These data do not support the hypothesis that fusimotor reflexes evoked by chemosensitive muscle afferents contribute to muscle spasm or to changes in muscle tone in the lumbar spine. In addition, the present results do not provide evidence for the pain-spasm-pain cycle in the lumbar spine." } ]

[ { "from": "user", "value": "Context: The differential time to positivity (DTTP), defined as the difference in time necessary for the blood cultures taken by a peripheral puncture and through the catheter to become positive has been suggested to be useful in differentiating between catheter-related bloodstream infection (CR-BSI) and other sources of bacteremia. A DTTP of >120 mins was found predominantly in CR-BSI. The objective of our study was to investigate whether DTTP is useful for the diagnosis of CR-BSI in a medical-surgical intensive care unit. Prospective clinical study. A 60-bed medical-surgical intensive care unit of a university hospital. One hundred consecutive adult patients from whom catheter(s) were to be removed for suspected CR-BSI were studied. A blood culture (using aerobic and anaerobic culture bottles) was first taken from a new puncture site. Next, a blood culture was taken through every intravascular catheter in place. DTTP was calculated using the automated BacT/Alert blood culture system. Three patients had CR-BSI and nine patients had noncatheter-related bacteremia. Five patients had catheter-related sepsis without proven bacteremia. There was no significant difference in median DTTP between patients with CR-BSI and noncatheter-related bacteremia (2.1 hrs and 3.3 hrs, respectively; p =.6). Moreover, catheter-related sepsis in patients without bacteremia could not be detected using DTTP. Question: Is difference in time to positivity of hub-blood versus nonhub-blood cultures useful for the diagnosis of catheter-related bloodstream infection in critically ill patients?" }, { "from": "assistant", "value": "no. DTTP seems not to be useful for the diagnosis of CR-BSI in a medical-surgical intensive care unit." } ]

[ { "from": "user", "value": "Context: To evaluate the recently discovered long pentraxin PTX3 in plasma of critically ill patients and to compare it with the classic short pentraxin C-reactive protein and with other indicators of inflammation. A cohort study on plasma samples. Medical intensive care unit (ICU) of the University Hospital of Basel. A total of 101 consecutive critically ill patients admitted to the medical ICU. Venous blood samples were routinely obtained at entry, on day 2, and at discharge or before death. Plasma samples were obtained from 101 consecutive critically ill patients admitted to the ICU with systemic inflammatory response syndrome, sepsis, or septic shock. PTX3 plasma levels were measured by enzyme-linked immunosorbent assay. PTX3 was elevated in critically ill patients, with a gradient from systemic inflammatory response syndrome to septic shock. PTX3 levels correlated with clinical scores reflecting severity of disease (e.g., Acute Physiology and Chronic Health Evaluation II: p =.00097). In addition, high levels of PTX3 were associated with unfavorable outcome. Question: Do circulating levels of the long pentraxin PTX3 correlate with severity of infection in critically ill patients?" }, { "from": "assistant", "value": "yes. The long pentraxin PTX3 is elevated in critically ill patients and correlates with severity of disease and infection. Compared with the short pentraxin C-reactive protein, PTX3 may be a more direct indicator of tissue involvement by inflammatory and infectious processes." } ]

[ { "from": "user", "value": "Context: To investigate the dose response relationships of methotrexate (MTX) therapy in rat adjuvant arthritis (AA), an animal model of rheumatoid arthritis (RA). Female Lewis rats were fed a defined diet and were treated with 0, 0.3, 1, 2, 3, 5, and 10 mg MTX per week beginning 3 days after adjuvant injection and lasting 6 weeks. The presence or absence of arthritis, and its degree were measured by hindpaw edema scores, ankle widths, and radiographic and histopathologic scores. The 2, 3, 5, and 10 mg MTX per week doses resulted in deaths before the end of the protocol and suppressed normal body weight gain. Tissue destruction, measured by radiographic and histopathologic scores, was reduced in a dose dependent manner with increasing MTX dose. Suppression of inflammation, measured by ankle widths and radiographic and histopathologic scores, reached a maximum at the 1 mg MTX dose and declined at higher doses. Question: Does mTX affect inflammation and tissue destruction differently in the rat AA model?" }, { "from": "assistant", "value": "yes. Suppression of tissue destruction and inflammation in rat AA does not occur in a concerted fashion as the dose of MTX increases. The implications of these findings to human disease remain to be determined." } ]

[ { "from": "user", "value": "Context: A lower inflection point, an upper inflection (or deflection) point, and respiratory system compliance can be estimated from an inspiratory static pressure-volume (SPV) curve of the respiratory system. Such data are often used to guide selection of positive end-expiratory pressure (PEEP)/tidal volume combinations. Dynamic pressure-volume (DPV) curves obtained during tidal ventilation are effortlessly displayed on modern mechanical ventilator monitors and bear a theoretical but unproven relationship to the more labor-intensive SPV curves. Attempting to relate the SPV and DPV curves, we assessed both curves under a range of conditions in a canine oleic acid lung injury model. Five mongrel dogs were anesthetized, paralyzed, and monitored to assure a stable preparation. Acute lung injury was induced by infusing oleic acid. SPV curves were constructed by the super-syringe method. DPV curves were constructed for a range of PEEP and inspiratory constant flow settings while ventilating at a frequency of 15 breaths/min and tidal volume of 350 mL. Functional residual capacity at PEEP = 0 cm H2O was measured by helium dilution. The change in lung volume by PEEP at 8, 16, and 24 cm H2O was measured by respiratory inductance plethysmography. The slope of the second portion of the DPV curve did not parallel the corresponding slope of the SPV curve. The mean lower inflection point of the SPV curve was 13.2 cm H2O, whereas the lower inflection point of the DPV curve was related to the prevailing flow and PEEP settings. The absolute lung volume during the DPV recordings exceeded (p < 0.05) that anticipated from the SPV curves by (values are mean +/- SEM) 267 +/- 86 mL, 425 +/- 129 mL, and 494 +/- 129 mL at end expiration for PEEP = 8, 16, and 24 cm H2O, respectively. Question: Do static and dynamic pressure-volume curves reflect different aspects of respiratory system mechanics in experimental acute respiratory distress syndrome?" }, { "from": "assistant", "value": "yes. The contours of the SPV curve are not reflected by those of the DPV curve in this model of acute lung injury. Therefore, this study indicates that DPV curve should not be used to guide the selection of PEEP/tidal volume combinations. Furthermore, an increase in end-expiratory lung volume occurs during tidal ventilation that is not reflected by the classical SPV curve, suggesting a stable component of lung volume recruitment attributable to tidal ventilation, independent of PEEP." } ]

[ { "from": "user", "value": "Context: Lengthened ventricular repolarization, as assessed by the QT interval on electrocardiogram (ECG), can predispose to an increased risk of cardiac dysrhythmias; no data are available on QT corrected for heart rate (QTc) in hyperthyroidism in vivo. QT and RR intervals from 24 h ambulatory ECG Holter recording were measured in patients with hyperthyroidism and again following pharmacological achievement of stable euthyroidism for at least 2 months. We enrolled a total of 16 hyperthyroid patients with Graves' disease, six males and 10 females (mean age 47 +/- 4 years, mean +/- SEM); 13 healthy age- and sex-matched subjects were utilized as a control group. The QT analysis was carried out by a computerized algorithm (QTc was corrected by the heart rate by Bazett's formula). Serum total T4, total T3, free T4, free T3 and TSH concentrations were measured by a fully automated immunoenzymometric assay; plasma norepinephrine by automatized high-pressure liquid chromatography, potassium and chloride by a potentiometric method, magnesium and calcium by a colourimetric method. The 24-h average QTc in the hyperthyroid patients was significantly prolonged compared to controls (458 +/- 7 vs. 431 +/- 6 ms, P = 0.01) and it returned to normal after treatment of thyrotoxicosis (432 +/- 6 ms, P < 0.05 vs. time H, NS vs. controls). QTc positively correlated with FT3 (r = 0.63, P < 0.001) and with FT4 (r = 0.481, P < 0.02). Conversely, QTc did not correlate with plasma basal norepinephrine levels, nor with electrolytes. Question: Is hyperthyroidism associated with lengthening of ventricular repolarization?" }, { "from": "assistant", "value": "yes. Hyperthyroidism is associated with prolonged QTc that normalizes once the patient becomes euthyroid. The strong positive correlation between FT3 and QTc supports the hypothesis of an important role of thyroid hormone on modulation of QTc lengthening." } ]

[ { "from": "user", "value": "Context: Human immunodeficiency virus protease inhibitors (HIV PIs) are associated with hyperlipidemia, hyperglycemia, and obesity; however, it is not known whether they increase risk of atherosclerotic vascular disease. The purposes of this study were to characterize the lipoprotein abnormalities associated with use of HIV PIs in individuals with HIV infection and to determine the pathophysiological significance of these changes by assessing their effect on endothelial dysfunction. This was a cross-sectional study of 37 adults with HIV-1 infection who were receiving antiretroviral therapy. Twenty-two were taking HIV PIs (group 1); 15 were not (group 2). Lipids and lipoproteins were measured by enzymatic techniques and nuclear magnetic resonance spectroscopic analysis. Flow-mediated vasodilation (FMD) of the brachial artery was measured by high-resolution ultrasound. Subjects in both groups were similar in regard to age, time since diagnosis of HIV infection, and CD4 cell count. Group 1 subjects had higher total cholesterol (5.68 versus 4.42 mmol/L, P=0.007) and triglyceride (4.43 versus 1.98 mmol/L, P=0.009) levels, characterized by elevated levels of IDL and VLDL. Subjects in group 1 had impaired FMD (2.6+/-4.6%), indicative of significant endothelial dysfunction. Group 2 subjects had normal FMD (8.1+/-6.7%, P=0.005). In group 1, chylomicron, VLDL, IDL, and HDL cholesterol levels predicted FMD. Question: Is use of human immunodeficiency virus-1 protease inhibitors associated with atherogenic lipoprotein changes and endothelial dysfunction?" }, { "from": "assistant", "value": "yes. Use of HIV PIs is associated with atherogenic lipoprotein changes and endothelial dysfunction. Because these metabolic and vascular changes predispose to atherosclerosis, monitoring and treatment of dyslipidemia in patients taking these medications is warranted." } ]

[ { "from": "user", "value": "Context: Apoptosis contributes to cell loss after ischemia/reperfusion injury in the heart. This study describes the time course and level of apoptosis in different cell types in the intact heart during ischemia/reperfusion injury. Isolated Langendorff-perfused rat hearts were subjected to perfusion alone (control) or to 35 minutes of regional ischemia, either alone or followed by 5, 60, or 120 minutes of reperfusion. Sections were stained by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and propidium iodide and with anti-von Willebrand factor, anti-desmin, or anti-active caspase 3 antibodies; they were then visualized by confocal microscopy. Sections were also examined by electron microscopy. No TUNEL-positive cells were seen in control hearts or hearts exposed to ischemia alone. Early in reperfusion, TUNEL staining was colocalized with endothelial cells from small coronary vessels. Endothelial apoptosis peaked at 1 hour of reperfusion and, at this time, there was clear perivascular localization of apoptotic cardiac myocytes, whose number was inversely proportional to their distance from a positive vessel. After 2 hours of reperfusion, apoptotic cardiac myocytes assumed a more homogeneous distribution. Active caspase 3 labeling was seen independent of DNA fragmentation during ischemia alone, but it colocalized with TUNEL staining over the 3 time points of reperfusion. Immunocytochemical findings were confirmed by electron microscopy and Western blotting. Question: Does apoptosis of endothelial cells precede myocyte cell apoptosis in ischemia/reperfusion injury?" }, { "from": "assistant", "value": "yes. In the very early stages of reperfusion, apoptosis is first seen in the endothelial cells from small coronary vessels. The radial spread of apoptosis to surrounding cardiac myocytes suggests that reperfusion induces the release of soluble pro-apoptotic mediators from endothelial cells that promote myocyte apoptosis." } ]