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Antigenicity of group B Streptococcus strain "M9" and its prevalence in Japan. Serological typing of group B streptococci is important for the epidemiological study of group B streptococcal infections. These days, non typable (NT) strains by conventional serotypes were on an increase. In 1984, strain "M9" was isolated from a pregnant woman in Meijo Hospital, Nagoya City; herein the antigenicity and prevalence of strains typed as "M9" were investigated and discussed. The results obtained were as follows: 1) It was confirmed that strain "M9" had a new polysaccharide antigen, different from conventional types, Ia, Ib, II, III, IV and V, type candidate NT6 and type candidate 7271, as found by precipitation and precipitation absorption reaction. This procedure, moreover, was useful for differentiation type candidate NT6 and 7271 from "M9" because of their provisionality. 2) Group B streptococci typed as "M9" were isolated not only from carriers but from patients who were newborn babies and suffered from sepsis. 3) Strain "M9" was not necessarily located in Nagoya City but in Chiba and in Kyoto, this type was isolated from clinical materials already in 1979. 4) It was observed that polysaccharide "M9" liked to combine with protein "R" and without other proteins, as our collection extends.

Respiration and heart rate variability during sleep in untreated Parkinson patients. Twenty-six patients with untreated mild to moderate Parkinson's disease (PD) lasting 5 years or less, were investigated in the sleep laboratory. Sleep architecture and respiration during sleep did not significantly differ from age-matched controls. PD patients showed defective cardiac autonomic control during sleep, mainly parasympathetic but also sympathetic in nature, although they had normal results in conventional autonomic tests during wakefulness. Therefore, autonomic cardiac involvement seems to be an early sign of PD.

Prospective evaluation of CT-guided HDR brachytherapy as a local ablative treatment for renal masses: a single-arm pilot trial. In this pilot trial, we investigate the safety of CT-guided high-dose-rate brachytherapy (HDR-BT) as a local ablative treatment for renal masses not eligible for resection or nephrectomy. We investigated renal function after irradiation by HDR-BT in 16 patients (11 male, 5 female, mean age 76 years) with 20 renal lesions (renal cell carcinoma n = 18; renal metastases n = 2). Two patients had previous contralateral nephrectomy and two had ipsilateral partial nephrectomy. Six lesions had a hilar localization with proximity to the renal pelvis and would have not been favorable for thermal ablation. Renal function loss was determined within 1 year after HDR-BT by renal scintigraphy and laboratory parameters. Further investigations included CT and MRI every 3 months to observe procedural safety and local tumor control. Renal function tests were analyzed by Wilcoxon's signed rank test with Bonferroni-Holm correction of p-values. Survival and local tumor control underwent a Kaplan-Meier estimation. Median follow-up was 22.5 months. One patient required permanent hemodialysis 32 months after repeated HDR-BT and contralateral radiofrequency ablation of multifocal renal cell carcinoma. No other patient developed a significant worsening in global renal function and no gastrointestinal or urogenital side effects were observed. Only one patient died of renal tumor progression. Local control rate was 95% including repeated HDR-BT of two recurrences. HDR-BT is a feasible and safe technique for the local ablation of renal masses. A phase II study is recruiting to evaluate the efficacy of this novel local ablative treatment in a larger study population.

Infantile idiopathic scoliosis: can it be prevented? The changing incidence of idiopathic scoliosis in 672 patients who attended the Edinburgh Scoliosis Clinic between 1968 and 1982 inclusive is reported. Of these patients, 144 had infantile, 51 juvenile and 477 adolescent idiopathic scoliosis. Thirty-seven of the infantile curves progressed and 107 resolved. The relative frequency of both progressive and resolving infantile idiopathic scoliosis (given as a percentage of the total number of patients with idiopathic scoliosis) declined from 41.75 per cent in the four years from 1968 to 1971, to four per cent in the three years from 1980 to 1982. It is suggested that infantile idiopathic scoliosis is a preventable deformity and that the position in which the infant is laid may be a causative factor.

A phase I study of the metal ionophore clioquinol in patients with advanced hematologic malignancies. Clioquinol is a small-molecule metal ionophore that inhibits the proteasome through a metal-dependent mechanism. Here, we report a phase I study of clioquinol in patients with refractory hematologic malignancies. Neuropathy and abdominal pain were dose-limiting toxicities. Minimal pharmacodynamic effects were observed, and there were no clinical responses. Clioquinol is a small-molecule metal ionophore that inhibits the enzymatic activity of the proteasome and displays preclinical efficacy in hematologic malignancies in vitro and in vivo. Therefore, we conducted a phase I clinical trial of clioquinol in patients with refractory hematologic malignancies to assess its safety and determine its biological activity in this patient population. Patients with refractory hematologic malignancies were treated with increasing doses of oral clioquinol twice daily for 15 doses. Plasma and intracellular levels of clioquinol were measured. Enzymatic activity of the proteasome was measured before and after drug administration. Sixteen cycles of clioquinol were administered to 11 patients with 5 patients reenrolled at the next dose level as per the permitted intrapatient dose escalation. Dose-limiting neurotoxicity and abdominal pain were observed at a dose of 1600 mg twice daily. Intracellular drug levels were low. Minimal inhibition of the proteasome was observed. No clinical responses were observed. In patients with refractory hematologic malignancies, the maximal tolerated dose of clioquinol was determined. Minimal inhibition of the proteasome was observed at tolerable doses, likely due to low intracellular levels of the drug.

Clinical aspects of mitochondrial diabetes. Mitochondrial diabetes is a new nosological entity, the most common form of which is maternally inherited diabetes and deafness (MIDD) syndrome. In this syndrome, delayed insulin dependency is frequently observed, although any form of glucose intolerance is possible. The mechanism of diabetes is localised at the beta-cell level. The participation of an autoimmune process in beta-cell loss is still controversial. An association with macular pattern dystrophy and infraclinical myopathy is common and can facilitate diagnosis. Muscle 31-P MR spectroscopy is a non-invasive tool to detect oxidative and phosphorylative alterations and monitor the reversion of these anomalies through specific treatments. Numerous other mutations, deletions or duplications of mtDNA have been associated with diabetes. The description of mitochondrial diabetes is still in progress. In future, an understanding of the mechanism of glucose intolerance in these diseases should open the way to specific preventive treatments in subjects carrying diabetogeneic mutations of mtDNA.

Incidence and predictors for the development of significant supradiaphragmatic decompressing venous collateral channels following creation of Fontan physiology. The occurrence of supradiaphragmatic decompressing venous collateral channels following construction of a bidirectional cavopulmonary connection or completion of the Fontan operation resulting in abnormal systemic hypoxemia has been infrequently described. In addition, the incidence and predictors of these channels have not been well delineated, especially in those patients without formation of such structures preoperatively. I evaluated, retrospectively, 40 patients who had undergone either construction of a bidirectional cavopulmonary shunt or completion of the Fontan operation, and who had complete pre and postoperative hemodynamic and angiographic data. Of the patients, 17 (43%) had developed a total of 21 decompressing venous collateral channels, of which 7 (18%) were considered to be hemodynamically significant requiring transcatheter coil occlusion. Of all variables examined, seven patients with significant decompressing collaterals had a greater transpulmonary gradient at follow-up catheterization (8 +/- 2 vs 5 +/- 2 mmHg, p=.01) and lower systemic saturations at routine clinical follow-up visits (82 +/- 5 vs 89 +/- 5 mmHg, p =.007) in comparison to the 33 others. When not evident preoperatively, decompressing venous collateral channels develop in a significant number of patients following conversion to Fontan physiology. If sufficiently large, they may produce lower than expected systemic saturations for the observed cardiac physiology. The larger decompressing channels are more likely to occur when a greater transpulmonary gradient exists postoperatively, which may require cardiac catheterization and transcatheter coil occlusion.

Severe liver impairment in a cystic fibrosis-affected child homozygous for the G542X mutation. The clinical and laboratory findings of a cystic fibrosis (CF) patient homozygous for the G542X mutation are described. This is the first case, among the 7 G542X homozygous CF subjects described so far who shows severe liver involvement, associated pancreatic insufficiency, and moderate pulmonary expression of the disease, as demonstrated by laboratory and imaging data. This case adds to the conclusion that genotype/phenotype correlation in cystic fibrosis is more complex than formerly suspected.

Patches and fences: probing for plasma membrane domains. Cell plasma membranes appear to be composed of domains, patches whose composition and function differ from the average for an entire membrane surface. Proteins and lipids may be segregated into domains by different mechanisms. Some of these mechanisms are discussed, followed by a summary of the evidence for membrane domains obtained in my laboratory. This evidence is largely based on measurements of the lateral diffusion of membrane proteins and lipids. Recent new approaches to the interpretation of lateral diffusion measurements, consideration of so-called fractal or long time-tails promise to give new insights into the stability and lifetime of membrane domains.

Endoscopic treatment of patients with bile duct stricture after cholecystectomy: factors predicting recurrence in the long term. Endoscopic treatment is effective in the treatment of patients with bile duct injury after cholecystectomy. We aimed to investigate the long-term results of endoscopic treatment, factors predicting the recurrence of the stricture, and to determine the optimal endoscopic treatment. The study was a retrospective cohort analysis and conducted at a tertiary referral center in patients with major bile duct injury (Strasberg E1-4 and E5 patients with main bile duct injury). Patients with minor injury (Luschka and cystic duct leakage), complete transection, and isolated aberrant bile duct injuries were excluded. The study group included 156 patients. The median follow-up period after stent removal was 6.5 years (range 1-16.5). Recurrence was seen in 18 patients (11 %) after a median duration of 9 months (range 2-96). Multivariate regression analysis revealed that the most important factors predicting the success of endoscopic treatment were: Rome type of treatment (inserting increasing number of stents every 3-4 months) (odds ratio 23.8, 95 % CI 1.46-390.7, p = 0.026) instead of Amsterdam-type treatment (replacing two 10F biliary stents every 3-4 months) and dilation of the stricture diameter to at least 76 % of the common bile duct diameter at the end of stent treatment (odds ratio 25.9, 95 % CI 2.46-272.7, p = 0.007). Endoscopic treatment is an effective method in the treatment of patients with bile duct stricture after cholecystectomy. Inserting multiple stents as much as possible without leaving a scar in the bile ducts should be aimed.

Platelet kinetics in the pulmonary microcirculation in vivo assessed by intravital microscopy. Growing evidence supports the substantial pathophysiological impact of platelets on the development of acute lung injury. Methods for studying these cellular mechanisms in vivo are not present yet. The aim of this study was to develop a model enabling the quantitative analysis of platelet kinetics and platelet-endothelium interaction within consecutive segments of the pulmonary microcirculation in vivo. New Zealand White rabbits were anesthetized and ventilated. Autologous platelets were separated from blood and labeled ex vivo with rhodamine 6G. After implantation of a thoracic window, microhemodynamics and kinetics of platelets were investigated by intravital microscopy. Velocities of red blood cells (RBCs) and platelets were measured in arterioles, capillaries and venules, and the number of platelets adhering to the microvascular endothelium was counted. Kinetics of unstimulated platelets was compared with kinetics of thrombin-activated platelets. Velocity of unstimulated platelets was comparable to RBC velocity in all vessel segments. Unstimulated platelets passed the pulmonary microcirculation without substantial platelet-endothelial interaction. In contrast, velocity of activated platelets was decreased in all vascular segments indicating platelet margination and temporal platelet-endothelium interaction. Thrombin-activated platelets adhered to arteriolar endothelium; in capillaries and venules adherence of platelets was increased 8-fold and 13-fold, respectively. In conclusion, using intravital microscopy platelet kinetics were directly analyzed in the pulmonary microcirculation in vivo for the first time. In contrast to leukocytes, no substantial platelet-endothelium interaction occurs in the pulmonary microcirculation without any further stimulus. In response to platelet activation, molecular mechanisms enable adhesion of platelets in arterioles and venules as well as retention of platelets within capillaries.

Cerebrovascular segmentation of TOF-MRA based on seed point detection and multiple-feature fusion. The accurate extraction of cerebrovascular structures from time-of-flight (TOF) data is important for diagnosis of cerebrovascular diseases and planning and navigation of neurosurgery. In this study, we proposed a cerebrovascular segmentation method based on automatic seed point detection and vascular multiple-feature fusion. First, the brain mask in the T1-MR image is detected to enable the extraction of the TOF brain structure by simultaneously acquiring the TOF image and its corresponding T1-MRI. Second, local maximum points are detected on three maximum-intensity projections of TOF-MRA data and then be traced back in three-dimensional space to detect seed points for the initialization of vascular segmentation. Third, the TOF-MRA image and its corresponding vesselness image are fused to enhance vascular features on the basis of fuzzy inference for the extraction of whole cerebrovascular structures, particularly miniscule cerebral vessels. Finally, detected seed points and multiple-feature fused enhanced images are provided to the procedure of region growing, and cerebrovascular structures are segmented. Experimental results show that compared with traditional methods, the proposed method has higher accuracy for vascular segmentation and can avoid over- and under-segmentations. The proposed cerebrovascular segmentation method is not only effective but also accurate. Therefore, it has potential clinical applications.

Further evidence for masculinization of female rats by males located caudally in utero. The morphology and behavior of female rodents is partially masculinized as a result of residence near males in the same uterine horn (Clemens effect). Two hypothetical mechanisms have been proposed to account for this effect. In the first hypothesis ("contiguity") androgens secreted by males in utero are proposed to diffuse across the amniotic membrane, reaching adjacent fetuses. In the second hypothesis ("caudal male") androgens are transported via the cervical-to-ovarian blood flow and may diffuse directly between closely apposed uterine veins and arteries. This study was designed to test directly which of these mechanisms appears more influential in masculinizing the morphology of female rats. Pregnant Sprague-Dawley rats were decapitated early on Day 22 of gestation and pups were Caesarean delivered. Their anogenital distance and body weight were recorded, location in utero coded by means of footpad tatooing, and each litter fostered to a maternal female. Measurements were taken again when the animals were weaned. Statistical analysis revealed that the presence of one or more males caudal to a female in the uterine horn has a more critical influence on that female's morphology than contiguity per se. Such a mechanism may result in partial masculinization of dimorphic behaviors later in life.

[Recurrence of multicavitating cardiac myxoma]. A 24 years-old female patient with congestive heart failure and clinical, electrocardiographic and radiologic findings compatible with pulmonary stenosis. Angiocardiography study diagnosed a tumor of the right ventricule (RV). Large tumor of the RV and smaller tumors of the left atrium were removed by surgical treatment. Six years later, a 2 cm tumor was identified in the RV. The tumor's growth was accompanied by bidimensional transthoracic echocardiograms. After 6 years a transesophageal echocardiogram showed three tumors, one in the RV and one in each of the right and left atria. These tumors were successful removed by new surgical treatment.

Dialysis frequency versus dialysis time, that is the question. We reviewed a number of prospective randomized and multiple retrospective cohort studies of different dialysis prescriptions: longer dialysis time, at a frequency of at least three times a week, or a frequency of daily hemodialysis with a shorter dialysis time. Interestingly, the retrospective analyses have generally found significant survival benefits in the intensive dialysis groups, whereas more modest effects were observed in the prospective randomized controlled trials. The reason for this discrepancy may be related to the retrospective nature of the studies and possible selection bias; for example, the patients who were prescribed more frequent dialysis may have had more difficulties with volume control or high blood pressure. In contrast, the randomized controlled trials of increased dialysis frequency, which have shown indirect and modest benefits in complex coprimary end points, have small sample sizes and are plagued with difficulties in recruitment and compliance with the randomly allocated more frequent dialysis. This review, which attempts to balance the potential benefits of more frequent dialysis with the burden on the patient's lifestyle, an increased risk of access malfunction, as well as societal costs of such intensive dialysis prescriptions, concludes in favor of the conventional three times per week dialysis (at a minimum) but at longer dialysis times than is currently prescribed based on the Kt/Vurea metric alone.

Cytomegalovirus Viremia in HIV-1 Subtype C Positive Women at Delivery in Botswana and Adverse Birth/Infant Health Outcomes. We evaluated the association between maternal cytomegalovirus (CMV) viremia during pregnancy and adverse birth and infant health outcomes in HIV-infected mothers and their HIV-exposed uninfected infants. HIV-positive women and their infants were followed prospectively from pregnancy through 2 years postpartum in the "Tshipidi" study in Botswana. We analyzed the association between detectable CMV DNA in maternal blood at delivery and adverse birth outcomes (stillbirth, preterm delivery, small for gestational age, or birth defect), as well as infant hospitalization and mortality through 24 months. We measured CMV DNA in blood samples from 350 (77.1%) of 454 HIV-positive women from the Tshipidi study. The median maternal CD4 count was 422 cells/mL, and median HIV-1 RNA at entry was 3.2 log10 copies/mL. Fifty-one (14.6%) women had detectable CMV DNA. In unadjusted analyses, detectable CMV DNA was associated with higher maternal HIV-1 RNA [odds ratio (OR) 1.4, 95% confidence interval (CI): 1.1 to 1.9], presence of a birth defect (OR 9.8, 95% CI: 1.6 to 60.3), and occurrence of any adverse birth outcome (OR 2.0, 95% CI: 1.04 to 3.95). In multivariable analysis, we observed a trend toward association between detectable maternal CMV DNA and occurrence of any adverse birth outcome (adjusted OR 1.9, 95% CI: 0.96 to 3.8). Maternal CMV viremia was not associated with infant hospitalization and/or death by 24 months. Approximately 1 in 6 HIV-positive women in Botswana had detectable CMV DNA in blood at delivery. The presence of maternal CMV viremia had a borderline association with adverse birth outcomes but not with 24-month morbidity or mortality in HIV-exposed uninfected children.

Proteomic analysis of excretory secretory products from Clonorchis sinensis adult worms: molecular characterization and serological reactivity of a excretory-secretory antigen-fructose-1,6-bisphosphatase. Clonorchis sinensis is a food-borne zoonotic parasite that resides in bile ducts and causes clonorchiasis, which may result in cholelithiasis, cholecystitis, hepatic fibrosis, and liver tumors. Although total excretory secretory products (ESP) of C. sinensis adults induce hepatic fibrosis in vivo in rats, the causative mechanism is not well understood. To study components of the ESP, C. sinensis culture medium was collected and analyzed using shotgun LC-MS/MS. We identified a total of 110 proteins, including glycometabolic enzymes (such as fructose-1,6-bisphosphatase (FBPase) and enolase), detoxification enzymes (such as glutamate dehydrogenase, dihydrolipoamide dehydrogenase and cathepsin B endopeptidase), and a number of RAB family proteins. To identify a potential causative agent for hepatic fibrosis, we expressed and purified a recombinant FBPase, a 1,041-bp gene product that encodes a 41.7-kDa protein with prototypical FBPase domains and that can form a tetramer with a molecular mass of 166.8 kDa. In addition, we found that FBPase is an antigen present in the ESP and in circulation. Immunofluorescence showed that FBPase localizes to the intestinal cecum and vitellarium in C. sinensis adults. Our results describe the components of the excretory secretory products from C. sinensis adult worms and suggest that FBPase may be an important antigen present in the ESP of C. sinensis and may lay the foundation for additional studies on the development of clonorchiasis-associated hepatic fibrosis.

Assessment of liver iron content in 271 patients: a reevaluation of direct and indirect methods. Two direct methods for hepatic iron assessment (liver iron concentration and stainable liver iron--judged by a new histologic grading) and three indirect methods (serum iron and transferrin saturation, deferoxamine-chelation test, and ferritinemia) were reevaluated in 271 patients. These patients consisted of: 103 with idiopathic hemochromatosis, 39 with alcoholic cirrhosis, 54 with noncirrhotic alcoholic liver diseases, 13 with nonalcoholic liver diseases, and 62 with miscellaneous disorders. The results indicate that: (a) liver iron concentration, well correlated with mobilized excess iron (r = 0.88; p < 0.01), is the method of reference and validates the proposed histologic grading; (b) serum ferritin, which is in good correlation with liver iron concentration (r = 0.80; p < 0.01), is a valuable indirect method for hepatic iron evaluation; (c) regarding the other indirect methods a "boundary zone" may be delimited, thus corresponding to liver iron concentration values of 10.7 mumol/100 mg dry liver weight, beyond which values of serum iron less than 28.6 micrometer or transferrin saturation less than 45% or chelatable iron less than 45 mumol/24 h are rare; and (d) using the various indirect methods, there is a marked risk in idiopathic hemochromatosis to underestimate and in alcoholic liver diseases to overestimate hepatic iron content.

[Essence and significance of surgery. Part I -- Birth of surgery: determining factors and contexts]. The author intends to particularly analyse the origin of Surgery as regards its deterministic factors and contexts, resounding the essence and the meaning of Surgery itself. The primary core of the surgical practice dates back to Prehistoric Times, when, driven by his self-preservation instinct, the cave man, when suffering from some trauma, performed on himself a series of more or less immediate "actions" in order to remain healthy. At the same time, a second meaningful nucleus of the surgical experience rises contiguously to the operations the Prehistoric Man performed on another member of his clan. The third stage of this ongoing process, coincident with the origin of surgery in the strict sense of the word, goes back to the tribal context: in fact, in this social organisation only one member of the group was specifically assigned to treat diseases, based on group regulations. For the mediterranean area, the chronological development of this evolution is likely to have started 250,000 years ago in connection with the experience initially of Neanderthal Man and subsequently Cro-Magnon Man in Pleistocene and Holocene of the Quarternary Era respectively, and it could have finished at the beginning of the Neolithic, when the "ancient civilization" of the Mediterranean Basin arose in approximately 10,000 B.C.

Dialysis with semipermeable membranes as an efficient lipid removal method in the analysis of bioaccumulative chemicals. Herein is a procedure described using a semipermeable membrane (SPM) for enrichment of organic chemicals from lipid-containing samples. Dialysis with SPMs in an organic solvent can separate organochlorine contaminants such as non-, mono-, and di-o-PCBs, PCDDs, PCDFs, PCDTs, PCNs, pesticides, and PAHs from lipids. The method is nondestructive and more than 20 g of lipid can be dialyzed in a single membrane with acceptable recoveries of the internal standards, nearly independent of amount and type of lipid dialyzed. The lipid removal process shows good consistency between subsamples, and the lipid content can be reduced by 90-99%, depending on species and amount lipid. Neither triglycerides nor phospholipids were obtained in the dialysate fraction. The utility and reliability of the method is displayed by good precision for 72 PCBs and 27 organochlorine pesticides in the concentration range 0.05-50 micrograms/sample for triplicate subsamples, by the consistency in PCDD/F levels compared to a classic analytical procedure, and by the analysis of the above listed chemicals in approximately 200 biological samples of a wide variety of types. This technique can also be used as an enrichment device for contaminants when huge amounts of lipids are extracted for toxicological studies. Moreover, it is possible to use SPM to cleanup other samples from molecules with relatively high masses, e.g. sediments, soil, compost, and tar materials.

Hyperprolactinaemic amenorrhoea in Hong Kong. In a retrospective study of 595 patients attending the Menstrual Disorder Clinic from January, 1978 to December, 1981, 92 patients (15.5%) had raised serum prolactin (PRL) levels (greater than 25 ng/ml) on 2 or more separate occasions with a mean (+/- S.E.M.) value of 67.1 +/- 2.5 ng/ml. Galactorrhoea was found in 27.2% of the hyperprolactinaemic patients. Primary amenorrhoea was observed in 1 patient (1.1%) with serum PRL level of 68 ng/ml. Secondary amenorrhoea of longer than 6 months' duration occurred in 61 patients (66.3%) with mean PRL level 84.2 +/- 3.3 ng/ml. The 30 patients (32.6%) with irregular menstruation had a mean PRL level of 47.2 +/- 3.3 ng/ml. Investigations revealed that 43 patients (46.7%) had idiopathic hyperprolactinaemia, 14 patients (15.4%) had drug induced hyperprolactinaemia and 1 patient (1.1%) had hypothyroidism; 18 patients (19.5%) had suspected pituitary microadenoma and 16 patients (17.2%) had abnormal radiographic findings. Bromocriptine treatment was given to 38 patients, 13 with abnormal tomographic findings (mean serum PRL greater than 100ng/ml); 18 with suspected pituitary microadenoma (mean serum PRL 94 +/- 2.7 ng/ml) and 7 with idiopathic hyperprolactinaemia (mean serum PRL 65 +/- 4.7 ng/ml). All patients (38/38) responded to treatment with restoration of menstruation and cessation of galactorrhoea within 1 to 3 months. Mean PRL level was 21.6 +/- 5.2 ng/ml at the time of response. Thirteen patients subsequently became pregnant and all delivered healthy babies.

Blood-derived DNA methylation markers of cancer risk. The importance of somatic epigenetic alterations in tissues targeted for carcinogenesis is now well recognized and considered a key molecular step in the development of a tumor. Particularly, alteration of gene-specific and genomic DNA methylation has been extensively characterized in tumors, and has become an attractive biomarker of risk due to its specificity and stability in human samples. It also is clear that tumors do not develop as isolated phenomenon in their target tissue, but instead result from altered processes affecting not only the surrounding cells and tissues, but other organ systems, including the immune system. Thus, alterations to DNA methylation profiles detectable in peripheral blood may be useful not only in understanding the carcinogenic process and response to environmental insults, but can also provide critical insights in a systems biological view of tumorigenesis. Research to date has generally focused on how environmental exposures alter genomic DNA methylation content in peripheral blood. More recent work has begun to translate these findings to clinically useful endpoints, by defining the relationship between DNA methylation alterations and cancer risk. This chapter highlights the existing research linking the environment, blood-derived DNA methylation alterations, and cancer risk, and points out how these epigenetic alterations may be contributing fundamentally to carcinogenesis.

False alarm rates of statistical methods used in determining increased frequency of reports on adverse drug reaction. Several statistical methods have been proposed or used in the determination of an increase in frequency of reports of adverse drug reactions. Some of the methods are based on large sample approximation or equal sample sizes assumption. The actual type I error may differ significantly from the predetermined nominal level of 5% when the methods are applied to rare adverse events. Simulated false alarm rates of the methods were compared under the assumption of 10 or less expected reports in the reference period.

Effects of Intensive Behavioral Treatment for Children With Varying Levels of Conduct Problems and Callous-Unemotional Traits. The purpose of this study was to examine whether callous-unemotional (CU) traits moderated the effects of intensive behavior therapy in elementary school-age children with varying levels of conduct problems (CP). Both treatment response (magnitude of change between pre- and posttreatment) and treatment outcomes (likelihood of normalization from treatment) were examined. Participants were 67 children (n = 49 boys, Mage = 9.6 years) with varying levels of CP and CU who participated in an intensive 8-week summer treatment program (STP) in which behavior therapy was delivered to children in recreational and classroom settings and to parents via weekly parent training sessions. Effects of treatment were measured using parent and teacher ratings of oppositional defiant disorder (ODD), conduct disorder (CD), callous behavior, and impairment. Results showed that CU moderated treatment effects for CD and callous behavior but not ODD or impairment. The moderating effects showed some evidence that participants with high CP and high CU before treatment had better treatment responses (larger change between pre- and posttreatment) but worse treatment outcomes (lower likelihood of normalization after treatment). These results suggest that intensive treatment, such as the STP, may be necessary but not sufficient for children with CP and CU traits.

European Society of Clinical Microbiology and Infectious Diseases (ESCMID): data review and recommendations for diagnosing Clostridium difficile-infection (CDI). The aim of the present systematic review was to evaluate the available evidence on laboratory diagnosis of CDI and to formulate recommendations to optimize CDI testing. In comparison with cell culture cytotoxicity assay (CCA) and toxigenic culture (TC) of stools, we analyzed the test characteristics of 13 commercial available enzyme immunoasssays (EIA) detecting toxins A and/or B, 4 EIAs detecting Clostridium difficile glutamate dehydrogenase (GDH), and a real-time PCR for C. difficile toxin B gene. In comparison with CCA and TCA and assuming a prevalence of CDI of 5%, PPV and NPV varied between 0.28-0.77, 0.12-0.65 and 0.98-1.00, 0.97-1.00, respectively. Only if the tests were performed in a population with a CDI prevalence of 50 percent, would PPVs be acceptable (ranging from 0.71 to 1.00).To overcome the problem of a low PPV, we propose a two step approach, with a second test or a reference method in case of a positive first test. Further reducing the number of false negative results would require either retesting of all subjects with a negative first test, or re-testing all subjects with a negative second test, after an initially positive test. This approach resulted in non-significant improvements, and emphasizes the need for better diagnostic tests. Further studies to validate the applicability of two-step testing, including assessment of clinical features, are required.

Variations and stability in drinking patterns in a cohort of Swedish males. Information on drinking patterns may make an important contribution to our understanding of the risks and consequences of alcohol consumption. The objective of the present study is to describe variations and stability of patterns of alcohol use at both the aggregate and the individual levels. The reported alcohol consumption was recorded of a normal, representative birth cohort of Swedish male (n = 122) subjects followed from the age of 18 years to early middle age and more extensively scrutinized at the age of 36, using a 28 day time-line follow-back technique. In young middle age a high proportion of total consumption occurred on Fridays and Saturdays (about 60%). In addition, it was possible to classify "standard drinkers", "sporadic binge drinkers", and "frequent drinkers" as separate clusters. While binge drinking was more stable than frequency of drinking from the age of 18 to the age of 36, frequent drinking showed the highest short-term stability at the age of 36 years.

Static and dynamic compression modulate matrix metabolism in tissue engineered cartilage. Static and dynamic compression are known to modulate the metabolism of articular cartilage. The present study focused on determining the effects of compressive loading on the metabolism of sulfated glycosaminoglycans (S-GAG) and protein in tissue engineered cartilage constructs. Cartilage constructs were subjected to static or dynamic compression for 24 h and radiolabeled with 35SO4 and 3H-proline to assess the total synthesis and percentage retention of S-GAG and total protein, respectively. Static compression at an amplitude of 50% suppressed the synthesis of both S-GAG and protein by 35% and 57%, respectively. Dynamic compression at an amplitude of 5% had stimulatory effects on synthesis that were dependent on the static offset compression amplitude (10% or 50%) and dynamic compression frequency (0.001 or 0.1 Hz). Thus, tissue engineered cartilage demonstrated the ability to respond to mechanical loading in a manner similar to that observed with articular cartilage. Mechanical loading may therefore potentially be used to modulate the growth of cartilaginous tissues in vitrd, potentially facilitating the culture of functional cartilage tissues suitable for implantation.

The relevance of genetics and molecular pathology in mesenchymal tumours. Genetic and molecular analyses of soft tissue tumours have provided a great amount of valuable information over the past ten years. One of the most useful diagnostic application is tumour types. Technical advances in techniques such as FISH as well as RT-PCR permit, now, the analysis of archival material, expanding further the practical usefulness of genetic analysis. Genetics has also proved useful as a tool for validating current classification schemes, which still represent a source of endless debate. On the basis of cytogenetic data, relevant subsets of mesenchymal neoplasms are now categorised more rationally. Molecular pathology has greatly contributed to a better understanding of the mechanisms involved in both the pathogenesis and the progression of soft tissue sarcomas. Furthermore, the analysis of distinct subsets of tumours has shown that abberations involving the control of the cell cycle machinery exhibit a certain degree of tumour specificity. This wealth of information provides the necessary scientific background for both innovative therapeutic approaches and epidemiologic strategies for tumour prevention.

The possible combinatory effects of acute consumption of caffeine, creatine, and amino acids on the improvement of anaerobic running performance in humans. Preexercise nutritional investigations have recently become a popular avenue of examining the interaction of multiple ingredients on exercise and training methods. The critical velocity (CV) test is used to quantify the relationship between total running distance and time to exhaustion (TTE), yielding aerobic (CV) and anaerobic parameters (anaerobic running capacity [ARC]). The purpose of this study was to examine the hypothesis that a preexercise supplement containing caffeine, creatine, and amino acids (Game Time; Corr-Jen Laboratories Inc, Aurora, CO) would positively impact CV and ARC in college-aged men and women. In a single-blind crossover design, 10 participants consumed the preexercise supplement (ACT) or placebo (PL) before each testing session. Each participant completed runs to exhaustion on a treadmill at 110%, 90% (day 1), and 105% and 100% (day 2) of the peak velocity (PV) determined from a graded exercise test. The ACT elicited a 10.8% higher ARC (P = .02) compared with the PL, whereas no difference was found in CV (0.6%, P = .38). The TTE was greater for the ACT than the PL at 110% (ACT = 125.7 ± 9.6 seconds, PL = 117.3 ± 12.6 seconds), 105% (ACT = 156.9 ± 11.0 seconds, PL = 143.8 ± 12.9 seconds), and 100% PV (ACT = 185.7 ± 10.7 seconds, PL = 169.7 ± 12.8 seconds) (P = .01-.04); but there was no difference for the TTE at 90% PV (ACT = 353.5 ± 52.7 seconds, PL = 332.7 ± 54.0 seconds) (P = .08). These findings suggest that the acute ingestion of this preexercise supplement may be an effective strategy for improving anaerobic performance, but appears to have no effect on aerobic power.

ADAM10 is upregulated in melanoma metastasis compared with primary melanoma. ADAM10 (a disintegrin and metalloproteinase 10) is involved in the ectodomain shedding of various substrates, including adhesion molecules such as L1 cell adhesion molecule (L1-CAM) and CD44, which are known to have important roles in the development of malignant melanoma. In our study, we characterized the expression of ADAM10 in melanoma cells in vitro and in vivo. Immunohistochemical analysis on tissue microarrays indicated that ADAM10 expression was significantly elevated in melanoma metastasis compared with primary melanomas. In vitro downregulation of ADAM10 with specific small interfering RNA (siRNA) resulted in a suppression of the anchorage-independent cell growth and reduced the migration of melanoma cells. In addition, overexpression of ADAM10 induced the migration of melanoma cells. In cell lines from melanoma patients with metastasis, ADAM10 was significantly overexpressed, and ADAM10 expression correlated with increased cell proliferation. Furthermore, we present evidence that ADAM10 is involved in the release of L1-CAM from melanoma cells. It is important that knockdown of cellular L1-CAM reduced the migration of melanoma cells and abrogated the chemoresistance against cisplatin. In contrast, soluble L1-CAM had no effect on melanoma cell migration or cell survival. Taken together, our data demonstrate that ADAM10 and L1-CAM have important roles during melanoma progression and both molecules represent attractive targets for therapeutical intervention of melanomas.

Prostacyclin release from cultured and ex vivo bovine vascular endothelium. Studies with thrombin, arachidonic acid, and ionophore A23187. Prostacyclin release from systemic and pulmonary endothelium has been evaluated in cultured cell monolayers and in an ex vivo vascular segment model in which the endothelium remains in contact with subendothelial structures. The effect of exposure to arachidonic acid, ionophore A23187, and thrombin on prostacyclin release has been assessed. Arachidonic acid elicited prostacyclin release in a dose-dependent fashion. Ionophore also stimulated bovine systemic endothelium to release prostacyclin. Thrombin-endothelial cell interactions have been examined extensively. Unlike umbilical venous endothelium, systemic and pulmonary bovine endothelium did not release prostacyclin following exposure to thrombin. Exposure to thrombin also failed to evoke the release of tritiated arachidonate metabolites from the bovine endothelial cell preparations. The presence of high affinity binding sites for thrombin (KD = 9.5 X 10(-9) M) on the bovine endothelium suggests that either thrombin binding is causally unrelated to prostacyclin release or that the bovine cells lack mediators required for thrombin to exert its effect.

Surface sliding friction of negatively charged polyelectrolyte gels. The friction between two polyelectrolyte gels carrying the same or opposite sign of charges has been investigated using a rheometer. It is found that the friction was strongly dependent on the interfacial interaction between two gel surfaces. In the repulsive interaction case, especially, the friction was extremely low. The friction behavior is attempted to be described in terms of the hydrodynamic lubrication of the solvent layer between two like-charged gel surfaces, which is formed due to the electrostatic repulsion of the two gel surfaces. From the theoretical analysis (hydrodynamic mechanism), the friction behaviors were explained qualitatively, all of the experimental results, nevertheless, could not be understood well. The viscoelastic feature of the gel and the non-Newtonian behavior of water at the friction interface are considered to be important to elucidate the gel friction.

[Epidemiology of bone and joint disease - the present and future - . The importance of study designs and statistical analysis in epidemiology]. In epidemiological studies where researchers investigate the factors that can affect human health, the theory and methodology of the statistics are a powerful tool to assert findings the data indicate. On the other hand, study designs and data analyses that are made without fully understanding the statistics can easily make it difficult to achieve the study goals or lead to misleading results. In this article, some basics researchers should know in epidemiological studies and some issues they may often misunderstand are addressed, with a particular focus at study designing and data analysis.

Thermogenic capacity in subterranean Ctenomys: Species-specific role of thermogenic mechanisms. One way to understand ecological patterns of species is to determine their physiological diversity on a large geographic and/or temporal scales, in a context of hierarchical biodiversity framework. In particular, macrophysiological studies analyze how environmental factors affect the physiology and therefore the distribution of species. Subterranean species are an excellent model for evaluating the large-scale effects of ambient temperature (Ta) conditions on thermal physiology and distribution, due to their extensive use of burrows that provide a relatively thermal stable environment. Species belonging to the genus Ctenomys are all subterranean and endemic of South America. Cold induced maximum metabolic rate (MMR), basal metabolic rate (BMR) and non shivering thermogenesis (NST) were analyzed, as well as the expression of uncoupled proteins (UCP) in brown adipose tissue (BAT). Biogeographical variables appear to have no effect MMR experimentally induced by cold condition within Ctenomys. Also, mechanisms of heat production are species-specific, varying from a combination of ST and NST to a complete use of shivering mechanisms. This pattern is correlated at tissue level, since species that use only ST show a smaller interscapular BAT patch, not detectable presence of UCP1 and low COX activity. Thus, other factors, including body mass, that constrain cold induced MMR could affect thermogenic variability among Ctenomys. In the evolutionary timescale, if low O2 levels of burrows impose a ceiling in cold induced MMR, and ST is enhanced due to species-specific life history traits, such as digging effort, then the observed differences among Ctenomys species might be explained.

[Endobronchial ultrasonography in postintubation tracheal stenosis]. The correct evaluation of the tracheal wall's structure is necessary for the management of postintubation tracheal stenosis (PTS). Endobronchial ultrasonography (EBUS) is suitable for visualisation of layers of the tracheal wall and the assessment of cartilages' damage. The authors assessed the usefulness of EBUS in the anatomical characterization of PTS and in the decision making in its therapy. Between March 2002, and September 2003, 22 patients with PTS were examined by bronchoscopy together with EBUS. 13 patients had complex stenosis and from them destruction of tracheal cartilage was demonstrated in 5 patients. Of them bronchoscopic intervention resulted in only short term symptom free period in 3 patients. The destruction of tracheal cartilage detected by EBUS might be an indication for an early surgical intervention. According to author's results EBUS can be a useful method in evaluation of PTS.

Exenatide suppresses 1,2-dimethylhydrazine-induced colon cancer in diabetic mice: Effect on tumor angiogenesis and cell proliferation. Colon cancer is the third leading cause of cancer mortality worldwide, which results from interactions of different factors. It is frequently a pathological consequence of persistent inflammation. Diabetes affects several cancers and is positively correlated with the incidence of colon cancer. This study aimed to study the effect of exenatide in ameliorating inflammation, angiogenesis and cell proliferation in 1,2-dimethyl hydrazine (DMH) induced colorectal carcinoma in diabetic mice. Mice were randomly allocated into six groups, 8 mice each. Group 1: vehicle control group. Group 2: diabetic control group. Group 3: DMH control group: diabetic mice treated with DMH (20mg/kg/week,s.c.) for 15 week. Group 4: DMH-cisplatin group: mice received cisplatin (4mg/kg/week, i.p.). Groups 5 & 6: DMH-exenatide (10 and 20μg/kg) group: mice received exenatide (10 or 20μg/kg/day,s.c.), respectively. The present results highlighted an increase in angiogenic markers and cell proliferation in the DMH-diabetic group in comparison with the control group with greater expression of endothelial marker (CD34) and Ki-67 in colon tissue. Monotherapy with cisplatin or exenatide (10 and 20μg/kg) downregulated these markers to different extents. The current results provided evidence that exenatide represents a promising chemopreventive effect against DMH-induced colon carcinogenesis in diabetic mice, at least in part, attributed to its anti-angiogenic and anti-proliferative mechanisms.

A Monte-Carlo-based and GPU-accelerated 4D-dose calculator for a pencil beam scanning proton therapy system. The presence of respiratory motion during radiation treatment leads to degradation of the expected dose distribution, both for target coverage and healthy tissue sparing, particularly for techniques like pencil beam scanning proton therapy which have dynamic delivery systems. While tools exist to estimate this degraded four-dimensional (4D) dose, they typically have one or more deficiencies such as not including the particular effects from a dynamic delivery, using analytical dose calculations, and/or using nonphysical dose-accumulation methods. This work presents a clinically useful 4D-dose calculator that addresses each of these shortcomings. To quickly compute the 4D dose, the three main tasks of the calculator were run on graphics processing units (GPUs). These tasks were (a) simulating the delivery of the plan using measured delivery parameters to distribute the plan amongst 4DCT phases characterizing the patient breathing, (b) using an in-house Monte Carlo simulation (MC) dose calculator to determine the dose delivered to each breathing phase, and (c) accumulating the doses from the various breathing phases onto a single phase for evaluation. The accumulation was performed by individually transferring the energy and mass of dose-grid subvoxels, a technique that models the transfer of dose in a more physically realistic manner. The calculator was run on three test cases, with lung, esophagus, and liver targets, respectively, to assess the various uncertainties in the beam delivery simulation as well as to characterize the dose-accumulation technique. Four-dimensional doses were successfully computed for the three test cases with computation times ranging from 4-6 min on a server with eight NVIDIA Titan X graphics cards; the most time-consuming component was the MC dose engine. The subvoxel-based dose-accumulation technique produced stable 4D-dose distributions at subvoxel scales of 0.5-1.0 mm without impairing the total computation time. The uncertainties in the beam delivery simulation led to moderate variations of the dose-volume histograms for these cases; the variations were reduced by implementing repainting or phase-gating motion mitigation techniques in the calculator. A MC-based and GPU-accelerated 4D-dose calculator was developed to estimate the effects of respiratory motion on pencil beam scanning proton therapy treatments. After future validation, the calculator could be used to assess treatment plans and its quick runtime would make it easily usable in a future 4D-robust optimization system.

On-line removal of volatile fatty acids from CELSS anaerobic bioreactor via nanofiltration. The CELSS resource recovery system, which is a waste-processing system, uses aerobic and anaerobic bioreactors to recover plants nutrients and secondary foods from the inedible biomass. The anaerobic degradation of the inedible biomass, by means of culture of rumen bacteria, generates organic compounds such as volatile fatty acids (VFA) (acetic, propionic, butyric) and ammonia. The presence of VFA in the bioreactor medium at fairly low concentrations decreases the microbial population's metabolic reactions due to end-product inhibition. Technologies to remove VFA continuously from the bioreactor are of high interest. Several candidate technologies were analyzed, such as organic solvent liquid-liquid extraction, adsorption and/or ion exchange, dialysis, electrodialysis, and pressure-driven membrane separation processes. The proposed technique for the on-line removal of VFA from the anaerobic bioreactor was a nanofiltration membrane recycle bioreactor. In order to establish the nanofiltration process performance variables before coupling it to the bioreactor, a series of experiments was carried out using a 10,000 molecular weight cutoff (MWCO) tubular ceramic membrane module. The variables studied were the bioreactor slurry permeation characteristics, such as: the permeate flux, VFA and nutrient removal rates as a function of applied transmembrane pressure, fluid recirculation velocity, suspended matter concentration, and process operating time. Results indicated that the permeate flux, VFA, and nutrients removal rates are directly proportional to the fluid recirculation velocity in the range between 0.6 and 1.0 m/s, applied pressure when these are lower than 1.5 bar, and inversely proportional to the total suspended solids concentration in the range between 23,466 and 34,880 mg/L. At applied pressure higher than 1.5 bar the flux is not more linearly dependent due to concentration polarization and fouling effects over the membrane surface. It was also found that the permeate flux declines rapidly during the first 5-8 h, and then levels off with a diminishing rate of flux decay.

Direct nitric oxide imaging in cultured hippocampal neurons with diaminoanthraquinone and confocal microscopy. A method for the direct measurement of intracellular nitric oxide (NO) production stimulated by penicillin G (PG) in cultured hippocampal neurons with diaminoanthraquinone (DAA) using laser scanning confocal microscopy (LSCM) was developed. Intracellular DAA fluorescence could specifically represent NO production based on two facts: (1) 3-morpholinosydnonimine, a NO donor, could dose-dependently increase DAA fluorescence; and (2) haemoglobin, a NO scavenger, could inhibit the increase of DAA fluorescence. The PG dose-dependently increased the intercellular level of glutamate (Glu, 5 min after stimulation) and the intracellular NO production (30 min throughout stimulation). The increase of NO production could be reversed by N(w)-nitro- l -arginine (a NO synthase inhibitor), and also by d (-)2-amino-5-phosphonovaleric acid, a subtype of Glu receptor antagonist. These results revealed that DAA could be used to indicate real-time and kinetic intracellular NO production of hippocampal neurons with higher sensitivity, specificity and accuracy.

Residual symptoms and functionality in depressed outpatients: A one-year observational study in Switzerland with escitalopram. Residual depressive symptoms are associated with a poor prognosis for relapse or recurrence and are recognized as impeding factors of functionality. Recovery to the pre-depression level of functioning should be the goal of treatment. To evaluate outcomes in depressed outpatients treated with escitalopram regarding response, recovery, residual symptoms, functionality and ability to work over 48 weeks. 3278 outpatients were evaluated at weeks 8, 24 and 48. A simple questionnaire was used to rate severity of illness, impairment of functionality, treatment response, tolerability, presence and severity of residual symptoms, whether remission with residual symptoms or recovery was achieved, and to what degree the patient was able to work. Data over the full 48-week period were available for 75.8% of patients, for whom treatment response was rated as "very good" or "good" in 81%. However, only 42% of the completing patients achieved recovery without residual symptoms, while 41% were rated as remitters with residual symptoms. Lack of energy/motivation was the most common reported residual symptom and was present in 23.5% of patients at study end. Concentration difficulties were present in 15.8% and impaired sleep in 13.9% of patients. Complete inability to work decreased from 36% at baseline to 9% at week 48, while full-time working capacity increased from 37% to 62%. Non-controlled observational real life study using simple ratings rather than established rating scales. <50% of patients completing a one-year antidepressant treatment regimen were rated as being symptomatically fully recovered, and ≈50% still reported functional deficits.

Clinical features and prognosis of heart failure in women. A 5-year prospective study. Although heart failure (HF) is frequent and causes significant morbidity and mortality in women, data on the prognosis of women hospitalized for a first episode of HF are scarce. This study was designed to describe the clinical characteristics and treatment of HF in women and to assess the effect of gender on long-term survival. We prospectively included consecutive patients admitted for a first episode of HF in all healthcare establishments of the Somme department (France) during the year 2000. Baseline characteristics and long-term prognosis were evaluated and compared according to gender. 799 patients were included (389 women and 410 men). Women were older, had a higher prevalence of hypertension and renal insufficiency, and a lower prevalence of coronary artery disease. Prescription of HF medication at discharge was not significantly different between women and men. The prevalence of HF with preserved ejection fraction was higher in women. Five-year overall survival rates were not significantly different between women and men (39% vs. 41%, p=0.58). Cardiovascular mortality in women with HF was comparable with that observed in men. The 5-year survival in women was dramatically lower than the expected 5-year survival of the age-matched general population of women. On multivariable analysis, older age, cancer, stroke, diabetes, renal insufficiency, and lower natraemia were independent predictors of 5-year mortality in women. The prognosis after a first episode of HF in women is severe, comparable to that observed in men, with a 5-year survival rate of 39% and a dramatic excess mortality compared to the general population of women.

Virulence quenching with a prenylated isoflavanone renders the Malagasy legume Dalbergia pervillei resistant to Rhodococcus fascians. The phytopathogenic Actinomycete Rhodococcus fascians induces leafy galls on a wide range of hosts, causing major economical losses in the ornamentals industry. Although differences in the responsivity occur within species, no plant tested so far could be considered resistant to R. fascians strain D188 infection. Here, we observed that members of the genus Dalbergia, which belong to the Fabaceae, did not develop leafy galls when challenged with R. fascians and we set out to unravel the mechanism of this recalcitrance. Whereas organic extracts of Dalbergia tissues exhibited toxicity towards the bacteria, more importantly, dichloromethane bark extracts inhibited the induction of bacterial virulence gene expression without any apparent loss of viability, illustrating that resistance is likely multifactorial. The virulence quencher was identified as a new prenylated isoflavanone, termed perbergin, and specifically targeted the AttR regulon (a LysR-type transcriptional regulator) which is imperative for the switch of R. fascians from an epiphytic to a pathogenic lifestyle. The mode of action of perbergin demonstrated that just like in Gram-negative host-microbe interactions, also in Gram-positive phytopathogens autoregulation is being targeted by the plant as an efficient means of defence. Moreover, the identification of perbergin opens the path to disease control in affected nurseries.

Description and variability of temporal venous vascularization: clinical relevance in temporoparietal free flap technique. The few studies on the venous vascularization of the temporal area indicate a high variability among individuals. The preoperative knowledge of the venous vascularization of the temporal area is critical for microsurgical reconstruction, such as temporoparietal fascia free flap, and especially in understanding the anatomy of the veins for flap survival. Therefore, we conducted an anatomic study to confirm the classification of Legre et al. and a radiologic study to examine the venous network of the temporal area. We found three frequent patterns of the temporal venous network: (1) Type I (the most common), with a predominant temporal vein; (2) Type II, with a predominant posterior auricular vein; (3) Type III, when both veins were equally important. Because of this great variability, the use of a temporal flap for reconstruction of the head and neck should be restricted, and the examination of venous vascularization appears to be necessary before surgery. Here, we report a three-dimensional description of the venous temporal vascularization by computer tomography, which is particularly useful before temporoparietal flaps.

Hemodynamic significance of increased lung uptake of thallium-201. To determine the hemodynamic significance of increased lung thallium-201 uptake, resting thallium images in 23 normal subjects and 90 patients with various cardiac diseases were reviewed. Significant thallium uptake in the lung was observed in 60 cases and was especially frequently in mitral valvular disease (19 of 19 cases) and in myocardial infarction (25 of 37 cases). Chest radiographs of most of these patients showed pulmonary congestion or edema (50 or 69 cases). Pulmonary wedge pressure was measured in 25 of these patients and was significantly higher than in those of normal thallium uptake in the lung. Assessment of lung thallium uptake at the time of myocardial imaging can be used as a noninvasive means for evaluation of pulmonary venous hypertension.

Region-dependent absorption of faropenem shared with foscarnet, a phosphate transporter substrate, in the rat small intestine. Faropenem, a penem antibiotic, is orally active despite its hydrophilic nature. However, its intestinal absorption has not yet been characterised in detail. This study was undertaken to determine the factors regulating faropenem absorption using intestinal loops prepared in the rat duodenum, jejunum and terminal ileum. Faropenem disappearance was much greater than that of cefotaxime and meropenem, and faropenem disappeared more extensively from the terminal ileum than from the jejunum or duodenum. In contrast to faropenem, the disappearance of ceftibuten was much greater from the duodenum and jejunum than from the terminal ileum. As the accumulation and enzymatic degradation of faropenem was minimal in the intestinal mucosa, faropenem was considered to enter the portal vein smoothly after its disappearance from the intestinal loops. Faropenem disappearance was not significantly influenced by the presence of monocarboxylic acids, amino acids or bile acid. Dipeptides such as L-carnosine and glycylglycine slightly but significantly lowered faropenem disappearance from the terminal ileum. On the other hand, foscarnet exerted a marked inhibitory effect on faropenem disappearance, but the antiviral agent did not modulate ceftibuten absorption. The present results suggest that faropenem is in part absorbed via a phosphate transporter present in the rat small intestine.

Cystatin C as biomarker of contrast-induced nephropathy in pediatric cardiac angiography. The purpose of this study is to find the frequency of contrast-induced nephropathy (CIN) and to show the risk factors in the development of CIN and the diagnostic utility of serum cystatin C (CysC) and serum and urine neutrophil gelatinase-associated lipocalin (NGAL) during childhood following cardiac angiography. In this prospective study, we studied 46 children with congenital heart disease. The levels of serum creatinine, serum CysC, and serum NGAL were measured at 4, 24, and 48 h, while levels of urine NGAL and urine creatinine were measured at 4 to 8 and 48 h following cardiac angiography. According to serum creatinine levels, with a cutoff value of 4.1 mL/kg for development of CIN, sensitivity, specificity, area under the receiver-operating characteristic curve, and positive likelihood ratio were calculated as 69%, 70%, 0.67, and 2.29, respectively. The levels of serum CysC and serum creatinine significantly increased at 4, 24, and 48 h after the application of the contrast agent. The results of this study show that according to the definition of CIN, the incidence of CIN is significantly increased in pediatric patients with congenital heart disease. Moreover, the results support that serum CysC levels may allow the detection of CIN after cardiac angiography, like serum creatinine in present study.

The effectiveness of progressive relaxation in chronic hemodialysis patients. An experimental group of 38 patients on chronic hemodialysis were presented a 30-min, self-instructional, color videotape on progressive relaxation (PR) exercises; and a control group of 23 patients viewed a neutral videotape. Both groups were given the State-Trait Anxiety Inventory while on the dialysis machine, before and after the actual viewing. The experimental group significantly reduced its state anxiety level while the control group remained the same. Patients who reported higher levels of state anxiety and experienced tension more frequently tended to achieve the greater benefit from the program. It is postulated that PR can be a useful resource to overcome the sometimes severe anxiety related to the stresses of chronic hemodialysis.

Capillary electromigration techniques for studying interactions between analytes and lipid dispersions. CE has matured into a well-known and much used separation technique, with applications covering more or less all types of samples. EKC, which originally was developed for the separation of uncharged compounds, is still today under much development, with main focus on finding the perfect or ideal carriers (pseudo-stationary phase) for a broad range of analytes. In this review, the use of lipid dispersions as pseudostationary phases in EKC performed in capillaries and microchips, in addition to CE frontal analysis and partial filling EKC using lipid dispersions is discussed. Various types of lipid dispersions including liposomes, PEG-stabilized aggregates, proteoliposomes, lipid-based nanoparticles, and commercial lipid emulsions are described. The purpose of the review is to give the reader an overview of how EKC, CE frontal analysis, and partial filling EKC, have been applied to the study of interactions between analytes and lipid membranes.

Lymphoma in primary chronic cold hemagglutinin disease treated with chlorambucil. Two patients with primary chronic cold hemagglutinin disease (CHAD) were treated with chlorambucil for ten and 7 1/2 years, with cumulative doses of 14 and 6.6 g, respectively. Both responded favorably, and malignant lymphoma eventually developed in both of them. An attempt to assess the incidence of lymphoma as part of the natural course of untreated CHAD failed for want of proof. Literature since 1970 reported no chlorambucil-associated lymphoma. Of 77 responses to a questionnaire mailed to 135 US hematology-oncology programs, 76 reported no examples of chlorambucil-associated lymphoma. One response, however, did relate that diffuse histiocytic lymphoma developed in three of 141 patients receiving prolonged chlorambucil therapy for polycythemia vera. Alkylating-agent therapy for CHAD might be associated with development of lymphoma.

Sequence of the DNA-binding protein gene of a human subgroup B adenovirus (type 7). Comparisons with subgroup C (type 5) and subgroup A (type 12). The adenovirus type 7 (Ad7) single-stranded DNA-binding protein (DBP) structural gene has been sequenced and located between 66.7 and 62.3 map units. This region codes for a protein that contains 517 amino acid residues with a calculated molecular mass of 58,240 daltons. We compared the Ad7 amino acid sequence with those reported for the Ad5 (Kruijer, W., van Schaik, F.M.A., and Sussenbach, J.S. (1981) Nucleic Acids Res. 9, 4439-4457) and Ad12 (Kruijer, W., van Schaik, F.M.A., Speijer, J.G., and Sussenbach, J.S. (1983) Virology 128, 140-153) DNA-binding proteins. A greater amount of amino acid sequence homology was found in the carboxyl-terminal DNA-binding domain of the molecule. This homology is 61% between Ad7 and Ad5 and 49% when Ad12 was included in the comparison. The NH2-terminal domain of DBP retained a 49% homology between Ad7 and Ad5 and a 23% homology for all three serotypes. The greatest difference between the Ad7 and Ad5 DBPs is the absence, in the Ad7 protein, of 12 amino acids located between the two functional domains in the Ad5 protein (amino acids 151-162). In addition, three regions of high amino acid conservation between Ad5, Ad7, and Ad12 consisting of 9 (178-186), 9 (322-330), and 12 (464-475) consecutive amino acids (numbers refer to Ad5) in the DNA-binding portion of the molecule were revealed. These three regions contain a centrally located basic amino acid (183, 326, and 470) as well as an aromatic amino acid residue (181, 324, and 469). Since basic and aromatic amino acids have been implicated in other single-stranded DNA-binding protein/DNA interactions (Anderson, R.A., Nakashima, V., and Coleman, J.E. (1975) Biochemistry 14,907-917; Kowalczykowski, S.C., Lonberg, N., Newport, J.W., and von Hippel, P.H. (1981). J. Mol. Biol. 145, 75-104), these three conserved regions may represent DBP/DNA contact points.

Age, period and cohort models applied to cancer mortality rates. We develop the application of age, period and cohort models to the representation of tables of age- and period-specific rates. A derivation is given by way of a familiar graphical technique. The identifiability problem is discussed, identification techniques are reviewed and a new approach is recommended that is based upon the success of the three two-variable submodels. Other constraints are introduced that enhance interpretation. Examples are given for two sites of cancer. This approach is contrasted with other methods designed to demonstrate trends. Finally, standard errors of the parameters and tests of goodness of fit are discussed.

Coronary perfusion: impact of flow dynamics and geometric design of 2 different aortic prostheses of similar size. Aortic valve replacement leads to improvement of coronary flow but not to complete normalization. Coronary hypoperfusion contributes to higher left ventricular mass persistence, arrhythmias, congestive heart failure and sudden death. This prospective study compares 2 similarly sized aortic prostheses (mechanical and porcine) regarding coronary flow and hemodynamic performances in patients who underwent surgery for pure aortic stenosis. Sixty patients having undergone aortic valve replacement for pure aortic stenosis with Medtronic Mosaic Ultra bioprosthesis 21 mm (n = 30) or St Jude Regent mechanical valve 19 mm (n = 30) were evaluated preoperatively and 12 months postoperatively comparing the coronary flow and the hemodynamic behavior. Echocardiography and cardiac positron emission tomography were performed at rest and during exercise or adenosine maximal stimulation, respectively. The St Jude Regent mechanical valve, compared with the Medtronic Mosaic Ultra bioprosthesis, had reduced coronary flow reserve (2.1 ± 0.3 vs 2.3 ± 0.2; P = .003), less favorable systolic/diastolic time ratio (0.87 ± 0.02 vs 0.78 ± 0.03; P < .001), and higher mean transprosthetic gradient (46 ± 11 vs 38 ± 9; P = .003) during exercise. Multivariate analysis of impaired coronary reserve related indexed effective orifice area less than 0.65 cm/m(2) (risk ratio [RR], 1.9; 95% confidence intervals [CI], 1.5-2.8; P < .001), mechanical valve (RR, 2.5; 95% CI, 1.7-3.3; P < .001), and systolic/diastolic time ratio greater than 0.75 (RR, 2.6; 95% CI, 1.8-3.8; P < .001), as well as high transprosthetic gradient (RR, 1.7; 95% CI, 1.3-2.4; P < .001) ) during exercise with coronary reserve less than 2.2. Improvement of coronary flow and reserve was more evident for bioprostheses than for mechanical valves. The bioprostheses demonstrated superior hemodynamics during exercise, which may have some impact on exercise capability during normal daily life.

The novel DPP-4 inhibitors linagliptin and BI 14361 reduce infarct size after myocardial ischemia/reperfusion in rats. Dipeptidylpeptidase-4 inhibition is reported to have beneficial effects on myocardial ischemia. Mechanisms might include a reduced degradation of stromal cell-derived factor-1 alpha with subsequent increased recruitment of circulating stem cells and/or incretin receptor-dependent pathways. This study evaluated the novel xanthine-based dipeptidylpeptidase-4 inhibitors linagliptin (BI 1356) and BI 14361 in cardiac ischemia. Male Wistar rats were pretreated with linagliptin or BI 14361 and subjected to ligation of the left anterior descending coronary artery for 30 min. Dipeptidylpeptidase-4 inhibition significantly reduced the infarct size after 7 days (-27.7%, p<0.05) and 8 weeks (-18.0%, p<0.05). There was a significantly improved maximum rate of left ventricular pressure decline (dP/dt min) in linagliptin-treated animals 8 weeks after ischemia/reperfusion. Apart from that, treatment did not improve cardiac function as determined by echocardiography and cardiac catheterization. Immunohistological staining revealed an increased number of cells positive for stromal cell-derived factor-1 alpha, CXCR-4 and CD34 within and around the infarcted area of BI 14361-treated animals. Linagliptin and BI 14361 are able to reduce infarct size after myocardial ischemia. The immunohistological findings support the hypothesis that dipeptidylpeptidase-4 inhibition via reduced cleavage of stromal cell-derived factor-1 alpha might lead to an enhanced recruitment of CXCR-4+ circulating progenitor cells.

Regio-defined amino[5]oxa- and thiahelicenes: a dramatic impact of the nature of the heteroatom on the helical shape and racemization barriers. The present approach to heterohelicenes provides original [5]oxa- and thiahelicenes, where both oxygen and sulfur atoms are located at the end of the inner helix. Quantum chemical calculations are carried out to determine the pathway for interconversion between two enantiomers and demonstrate that the energy barrier is strongly dependent on the nature of the heteroatom present on the helical shape.

Methodology for the assessment of lung protection. Human pulmonary artery endothelial cell preservation using haemaccel. This investigation was designed to show an original methodology for the assessment of lung preservation and to analyze the efficacy of a low potassium polygelin solution (haemaccel [HM]) on isolated human pulmonary artery endothelial cells. The effects of HM were compared with those of low potassium dextran (LPD), Belzer (University of Wisconsin [UWS]), and Euro-Collins solutions. The viability of the endothelial cultures was assessed by means of both total protein content and recovery of metabolic cellular function expressed as the protein synthesis rate after 6 hr and 16 hr of incubation at 10 degrees C. Our results failed to show any significant difference in the total protein content for HM, LPD, and UWS, both after 6 and 16 hr of incubation; however, the Euro-Collins-preserved sample revealed a significant drop in this parameter as early as 6 hr after the start. This finding was regarded as a clear indication of cellular cytotoxicity. In contrast, the metabolism recovery capacity of the cells varied significantly between HM and UWS at 6 hr and among HM, LPD, and UWS at 16 hr; at 6 hr, however, no significant difference was observed between HM and LPD. In conclusion, HM appears to exert a more significant effect on human pulmonary artery endothelial cell metabolism recovery than do the other fluids, thus suggesting its suitability as a long-term pulmonary perfusate.

Gambling problem symptom patterns and stability across individual and timeframe. Few studies investigate gambling problems at the symptom level; even fewer investigate how symptom patterns change throughout the course of a gambling disorder. The current study utilized the National Epidemiological Survey on Alcohol and Related Conditions (NESARC; Grant et al., 2004) to investigate how the specific symptoms of disordered gambling relate to its severity and course. Results demonstrated that symptom patterns and stability changed as the number of symptoms endorsed increased. Symptom patterns varied considerably from prior to past year (PPY) to past year (PY) timeframes. Certain symptoms were more stable than others and held predictive value as markers of emerging pathological gambling (PG). In particular, gambling to escape problems was one of the most stable symptoms and also predictive of progression to PG; reliance on others to support gambling was predictive of progression to PG among participants at-risk for PG. The differential diagnostic value of various reported symptoms, as well as their lack of stability, has implications for both researchers and clinicians.

Adalimumab for the treatment of moderate to severe psoriasis: subanalysis of effects on scalp and nails in the BELIEVE study. This post hoc analysis examined the effects of adalimumab in patients with scalp and/or nail psoriasis from BELIEVE (a randomized, controlled, multicentre phase 3 safety and efficacy trial). Efficacy was assessed in the pooled treatment group (adalimumab with or without calcipotriol plus betamethasone dipropionate) by Psoriasis Area and Severity Index (75% improvement; PASI 75), Psoriasis Scalp Severity Index (PSSI), Nail Psoriasis Severity Index (NAPSI), Dermatology Life Quality Index (DLQI) and a visual analog scale (VAS) for pain. Of the 730 enrolled patients, 663 (91.3%), 457 (63.1%) and 433 (60.1%) had psoriasis of the scalp, nails, or both, respectively. Similar proportions of patients with (68.2%) and without (63.5%) scalp involvement achieved a PASI 75 response at week 16 [adjusted odds ratio (OR), 1.34; P = 0.320]. PASI 75 response rates were lower in patients with nail psoriasis compared with patients without nail psoriasis at week 8 (53.0% vs. 62.9%; OR, 0.68; P = 0.019) and week 16 (65.0% vs. 73.0%; OR, 0.70; P = 0.052). PASI 75 response rates were 66.1% in patients with scalp and nail involvement and 70.8% in patients without both scalp and nail involvement at week 16 (OR, 0.87; P = 0.423). Patients in all scalp and nail subgroups reported improvements in DLQI and VAS pain scores throughout the study. Patients with scalp psoriasis exhibited large improvements in scalp symptoms demonstrated by a median (mean ± SD) decrease from baseline PSSI at week 16 of 100% (77.2 ± 96.9%). Patients with nail psoriasis improved, demonstrated by a median (mean ± SD) decrease from baseline NAPSI at week 16 of 39.5% (9.4 ± 164.5%). Our results indicate that adalimumab improves overall psoriasis and scalp and nail symptoms in this patient population with scalp psoriasis and/or nail involvement. In addition, similar PASI 75 response rates are achieved in patients with and without scalp involvement, whereas patients with nail involvement demonstrate a moderate (perhaps delayed) PASI 75 response rate.

Vitreous fluorophotometry and retinal blood flow studies in proliferative retinopathy. The permeability of the blood-retinal barrier and retinal blood flow were evaluated by two new fluorophotometric methods in a series of patients with proliferative retinopathy, due either to retinal vein occlusion or to diabetes. A breakdown of the blood-retinal barrier and a decrease in retinal blood flow were observed in these patients. The breakdown of the blood-retinal barrier could be quantitated by vitreous fluorophotometry, which revealed very high concentrations of fluorescein in the vitreous after intravenous administration. The decrease in retinal blood flow appeared to be due mainly to appreciable narrowing of the retinal arteriolar vessels.

Lung micronodules: automated method for detection at thin-section CT--initial experience. An automated system was developed for detecting lung micronodules on thin-section computed tomographic images and was applied to data from 15 subjects with 77 lung nodules. The automated system, without user interaction, achieved a sensitivity of 100% for nodules (>3 mm in diameter) and 70% for micronodules (<or=3 mm). With the same images, a radiologist detected nodules and micronodules with sensitivities of 91% and 51%, respectively, without system input. With assistance from the automated system, these sensitivities increased to 95% and 74%, respectively. Preliminary results indicate that the automated system considerably improved the radiologist's performance in micronodule detection.

High birthweight was not associated with altered body composition or impaired glucose tolerance in adulthood. To investigate whether a high birthweight was associated with an increased proportion of body fat or with impaired glucose tolerance in adulthood. Our cohort comprised 27 subjects with birthweights of 4500 g or more, and 27 controls with birthweights within ±1 standard deviation scores, born at Uppsala University Hospital 1975-1979. The subjects were 34-40 years old at the time of study. Anthropometric data was collected, and data on body composition was obtained by air plethysmography and bioimpedance and was estimated with a three-compartment model. Indirect calorimetry, blood sampling for fasting insulin and glucose as well as a 75 g oral glucose tolerance test were also performed. Insulin sensitivity was assessed using homoeostasis model assessment 2 and Matsuda index. There were no differences in body mass index, body composition or insulin sensitivity between subjects with a high birthweight and controls. In this cohort of adult subjects, although limited in size, those born with a moderately high birthweight did not differ from those with birthweights within ±1 standard deviation scores, regarding body composition or glucose tolerance.

Benign human enterovirus becomes virulent in selenium-deficient mice. Coxsackieviruses have been implicated as possible co-factors in the etiology of the selenium (Se)-responsive cardiomyopathy known as Keshan disease. Here we report that a cloned and sequenced amyocarditic coxsackievirus B3 (CVB3/0), which causes no pathology in the hearts of Se-adequate mice, induces extensive cardiac pathology in Se-deficient mice. CVB3/0 recovered from the hearts of Se-deficient mice inoculated into Se-adequate mice induced significant heart damage, suggesting mutation of the virus to a virulent genotype. We demonstrate the important role of host nutritional status in determining the severity of a viral infection.

The insulin and glucose responses to meals of glucose plus various proteins in type II diabetic subjects. We previously have shown that ingested beef protein is just as potent as glucose in stimulating a rise in insulin concentration in type II diabetic patients. A synergistic effect was seen when given with glucose. Therefore, we considered it important to determine if other common dietary proteins also strongly stimulate an increase in insulin concentration when given with glucose. Seventeen type II (non-insulin-dependent) untreated diabetic subjects were given single breakfast meals consisting of 50 g glucose, or 50 g glucose plus 25 g protein in the form of lean beef, turkey, gelatin, egg white, cottage cheese, fish, or soy. The peripheral plasma concentrations of glucose, insulin, glucagon, alpha amino nitrogen, urea nitrogen, free fatty acids, and triglycerides were measured. Following ingestion of the meals containing protein, the plasma insulin concentration was increased further and remained elevated longer compared with the meal containing glucose alone. The relative area under the insulin response curve was greatest following ingestion of the meal containing cottage cheese (360%) and was least with egg white (190%) compared with that following glucose alone (100%). The glucose response was diminished following ingestion of the meals containing protein with the exception of the egg white meals. The peripheral glucagon concentration was decreased following ingestion of glucose alone and increased following all the meals containing protein. The alpha amino nitrogen concentration varied considerably. It was decreased after glucose alone, was unchanged after egg white ingestion, and was greatest after ingestion of gelatin. The free fatty acid concentration decrease was 4- to 8-fold greater after the ingestion of protein with glucose compared with ingestion of glucose alone.

Different functional domains of GLUT2 glucose transporter are required for glucose affinity and substrate specificity. GLUT2 is the major glucose transporter in pancreatic beta-cells and hepatocytes. It plays an important role in insulin secretion from beta-cells and glucose metabolism in hepatocytes. To better understand the molecular determinants for GLUT2's distinctive glucose affinity and its ability to transport fructose, we constructed a series of chimeric GLUT2/GLUT3 proteins and analyzed them in both Xenopus oocytes and mammalian cells. The results showed the following. 1) GLUT3/GLUT2 chimera containing a region from transmembrane segment 9 to part of the COOH-terminus of GLUT2 had Km values for 3-O-methylglucose similar to those of wild-type GLUT2. Further narrowing of the GLUT2 component in the chimeric GLUTs lowered the Km values to those of wild-type GLUT3. 2) GLUT3/GLUT2 chimera containing a region from transmembrane segment 7 to part of the COOH-terminus of GLUT2 retained the ability to transport fructose. Further narrowing of this region in the chimeric GLUTs resulted in a complete loss of the fructose transport ability. 3) Chimeric GLUTs with the NH2-terminal portion of GLUT2 were unable to express glucose transporter proteins in either Xenopus oocytes or mammalian RIN 1046-38 cells. These results indicate that amino acid sequences in transmembrane segments 9-12 are primarily responsible for GLUT2's distinctive glucose affinity, whereas amino acid sequences in transmembrane segments 7-8 enable GLUT2 to transport fructose. In addition, certain region(s) of the amino-terminus of GLUT2 impose strict structural requirements on the carboxy-terminus of the glucose transporter protein. Interactions between these regions and the carboxy-terminus of GLUT2 are essential for GLUT2 expression.

Molecular and serological evidence for Anaplasma platys and Babesia sp. infection in a dog, imported in Belgium, from Southern Spain. This case report describes a dog suffering from a co-infection with Babesia and Anaplasma parasites. Anaplasma platys was found to be responsible for the anaplasmosis by molecular biology techniques, while microscopical and serological evidence was found for a coexistent babesiosis, although this could not be confirmed by polymerase chain reaction. Moreover, the possible risk of import of exotic pathogens is highlighted.

Intentional replantation of a molar with several endodontic complications. When non-surgical and surgical endodontic retreatments are impractical, intentional replantation (IR) might be employed as an accepted endodontic treatment procedure. This report describes an IR and root amputation of a tooth with several endodontic complications. A 28-year-old woman was referred for management of tooth #37. The tooth had a history of root canal therapy by a general dentist. Clinically the tooth was sensitive to palpation/percussion. Radiographic evaluation showed concurrent root/furcal perforations associated with radiolucent lesions, an inadequate root canal treatment and massive gutta-percha overextensions via perforation sites. The tooth was atraumatically extracted. After mesial root amputation and root-end/furcal preparations, the cavities were filled with calcium-enriched mixture cement. The tooth was then quickly replanted. During one-year clinical follow-ups, the tooth was functional and free of signs/symptoms; radiographic evaluation revealed complete bone healing. This case highlights that IR in hopeless teeth with several endodontic complications might be a successful approach.

Knowledge of rare diseases among health care students – the effect of targeted education Poor knowledge on rare diseases (RD) results in a significant delay in their diagnosis and treatment. So far there are no standards of university education in RD. We assessed knowledge on RD among healthcare students and the effectiveness of targeted education. We conducted an internet-based survey among students of the faculty of medicine, pharmacy and health sciences. Questions regarded personal information, definition and epidemic data on RD. The survey was used to assess the effect of targeted education about RD in an additional group of students. We enrolled 270 students (females: n=181; 67%), aged 22±1.7 years. Most of them (87.8%) declared to be familiar with the term RD. However only 20.7% knew the correct definition of RD, 14% knew that RD affect a significant (6-8%) proportion of population, 21.4% that there are 5-8 thousands of different RD’ entities, 73.7% recognized the most common cause of RD. 12.6% knew, that the RD most frequently occur in the adulthood. Targeted education applied in the additional group of 18 students resulted in a significant improvement of students’ knowledge on RD: definition (by 33%; p=0.007), percentage of population affected by RD (by 67%; p=0.001 ), total number of different RD (by 61%; p=0.003), time of onset of RD (by 61% p=0.003). Despite the declared recognition of the term: RD, knowledge on RD among medical students is poor independently on the year of study. However it can be improved with use of targeted education.

Reduced retinal nerve fiber layer (RNFL) thickness in ALS patients: a window to disease progression. To assess RNFL thickness in ALS patients and compare it to healthy controls, and to detect possible correlations between RNFL thickness in ALS patients and disease severity and duration. Study population consisted of ALS patients and age- and sex-matched controls. We used the revised ALS functional rating scale (ALSFRS-R) as a measure of disease severity. RNFL thickness in the four quadrants were measured with a spectral domain OCT (Topcon 3D, 2015). We evaluated 20 ALS patients (40 eyes) and 25 healthy matched controls. Average RNFL thickness in ALS patients was significantly reduced compared to controls (102.57 ± 13.46 compared to 97.11 ± 10.76, p 0.04). There was a significant positive correlation between the functional abilities of the patients based on the ALSFRS-R and average RNFL thickness and also RNFL thickness in most quadrants. A linear regression analysis proved that this correlation was independent of age. In ALS patients, RNFL thickness in the nasal quadrant of the left eyes was significantly reduced compared to the corresponding quadrant in the right eyes even after adjustment for multiplicity (85.80 ± 23.20 compared to 96.80 ± 16.96, p = 0.008). RNFL thickness in ALS patients is reduced compared to healthy controls. OCT probably could serve as a marker of neurodegeneration and progression of the disease in ALS patients. RNFL thickness is different among the right and left eyes of ALS patients pointing to the fact that asymmetric CNS involvement in ALS is not confined to the motor system.

Effects of interleukin 2 therapy on lymphocyte magnesium levels. Interleukin 2 (IL-2) can cause partial or complete tumor regression in approximately 20% of patients with renal cell carcinoma. Among the many physiologic effects of IL-2, decreased serum levels of the divalent cations magnesium (Mg) and calcium have been demonstrated, with corresponding decreases in their urinary excretion. We investigated the effect of IL-2 on lymphocyte Mg levels among patients receiving three different dosing regimens. Twenty-eight patients with metastatic renal cell carcinoma were treated with high-dose intravenous, low-dose intravenous, or subcutaneous IL-2 therapy. Serum ionized Mg, urinary Mg, and peripheral blood mononuclear cell Mg levels were measured in samples from patients during treatment and compared with pretreatment levels. Serum Mg and ionized Mg levels decreased for all patients within 12 hours of treatment (P <.005) and remained low for the duration of therapy. Urinary Mg decreased in parallel with serum levels in all patients (P <.005). The peripheral blood mononuclear cell Mg content per cell increased within 24 hours of treatment (P <.005). The magnitude of these changes was similar during the first week of treatment for patients receiving intravenous or subcutaneous administration of IL-2. During IL-2 therapy, lymphocyte Mg increases coincident with serum Mg depletion. Mg availability may have functional implications for lymphocyte proliferation and integrin function.

Effects of clopidogrel on the pharmacokinetics of sibutramine and its active metabolites. Sibutramine is metabolized by the enzymes CYP2B6 and CYP2C19 into 2 active metabolites, M1 (mono-desmethyl sibutramine) and M2 (di-desmethyl sibutramine). Clopidogrel is a mechanism-based inhibitor of CYP2B6 and CYP2C19. In this study, 13 extensive metabolizers of CYP2B6 and CYP2C19 were evaluated to clarify whether clopidogrel inhibits the formation of the active metabolites of sibutramine. In the control phase, each subject received a 15-mg oral dose of sibutramine. After a washout period of 2 weeks, in the clopidogrel phase, the subjects received 300 mg of clopidogrel on the first day and then 75-mg once daily for 6 days. One hour after the last dosing of clopidogrel, all subjects received 15-mg of sibutramine. Compared with the control phase, the mean sibutramine and M1 plasma concentrations were higher after clopidogrel treatment. Clopidogrel significantly increased the half-life (242% of control phase) and area under the plasma concentration-time curve from 0 to infinity (AUC(inf)) (227% of control phase) of sibutramine and decreased the apparent oral clearance (31% of control phase) of sibutramine. Pharmacokinetic analysis showed significant increases in the AUC(inf) (162% of control phase) of M1. The CYP2B6 and CYP2C19 inhibitor clopidogrel significantly inhibited the formations of M1 from sibutramine and M2 from sibutramine by 37% and 64%, respectively. Therefore, CYP2B6 and CYP2C19 are in vivo catalysts for the formation of the 2 active metabolites of sibutramine.

Alcohol-use patterns through medical school. A longitudinal study of one class. We describe the patterns of alcohol use of one medical school class assessed repeatedly over time from the first day of medical school to a point several months short of graduation. Although male students consistently drank more than their female counterparts during the preclinical years, the men reduced their alcohol intake during the clinical years to converge on the lower, more consistent intake rates of their female classmates. Over the four years of medical school, 11% of the students met criteria for excessive drinking for at least one six-month period and 18% were identified as alcohol abusers by Research Diagnostic Criteria during the first two years. More than half of the excessive drinkers met abuse criteria, whereas only one third of the alcohol abusers were also excessive drinkers. Alcohol abusers had better first-year grades and better overall scores on the National Board of Medical Examiners, part I, test than their classmates. The implications of these findings for designing and implementing alcoholism intervention/prevention programs in medical schools are discussed herein.

Optimising the ISAR-HP to screen efficiently for functional decline in older patients. The Identification of Seniors At Risk-Hospitalised Patients (ISAR-HP) has recently been included in guidelines as a frailty indicator to identify patients for comprehensive geriatric assessment. Previous studies showed that the conventional cut-off score incorrectly classifies a high percentage of patients as high risk. We aimed to optimise the predictive value of ISAR-HP by using different cut-offs in older acutely hospitalised patients. A prospective follow-up study was performed in two Dutch hospitals. Acutely hospitalised patients aged ≥ 70 years were included. Demographics, illness severity parameters, geriatric measurements and the ISAR-HP scores were obtained at baseline. The primary outcome was a combined end point of functional decline or mortality during 90-day follow-up. In total 765 acutely hospitalised older patients were included, with a median age of 79 years, of whom 276 (36.1%) experienced functional decline or mortality. The conventional ISAR-HP cut-off of ≥ 2 assigned 432/765 patients (56.5%) as high risk, with a positive predictive value (PPV) of 0.49 (95%CI 0.45-0.54) and a negative predictive value of 0.81 (95%CI 0.76-0.85). Thus, 51% of those whom the ISAR-HP denoted as high risk did not experience the outcome of interest. Raising the cut-off to ≥ 4 assigned 205/765 patients (26.8%) as high risk, with a marginally increased PPV to 0.55 (95%CI 0.48-0.62). The ISAR-HP with the conventional cut-off of ≥ 2 incorrectly identifies a large group of patients at high risk for functional decline or mortality and raising the cut-off to 4 only marginally improved performance. Caution is warranted to ensure efficient screening and follow-up interventions.

Children's differential performance on deductive and inductive syllogisms. At what age and in what ways do children distinguish deductive and inductive problems? In Experiment 1, students from kindergarten and from Grades 2, 4, and 6 were presented with deductive or inductive inference problems and asked to draw an inference and rate their confidence. By 4th grade, confidence ratings for deductive problems were higher than those for inductive problems, and responses were faster for deductive than for inductive items. In Experiment 2, students from Grades 2, 3, 4, and 5 responded to the same problems used in Experiment 1 but were asked to provide explanations for their responses. Again, confidence was higher with deductive than with inductive problems, and latency to respond was faster for deductive than for inductive items. Further, explanations differed as a function of the type of problem. These findings help fill in gaps in the emerging picture of the development of children's reasoning skills.

[Histogenesis of the immune system of the "nude" mouse. Postnatal development of the thymus: a light microscopical study (author's transl)]. Mice homozygous for the mutation "nude" display a dysgenetic thymus (Pantelouris, 1968). The anterior mediastinum of these animals contains a rudimentary epithelial organ (pantelouris and Hair, 1970), which has been assumed to represent not a maldeveloped thymus, but rather a remnant of the parathyroid gland or of the ultimobranchial body (Wortis et al., 1971). We have investigated the development of the thymus in homo- and heterozygous nude by both light and electron microscopy. This paper describes the light microscopical findings in embryos and fetuses from the 11th up to the 18th day post conceptionem (pc). Homo- and heterozygous nude (nu/nu + nu/+) mice with the genetic background BALB/c were kept under specific pathogen-free (spf) conditions. Virgin nu/+ females were mated with nu/nu males. In addition, homozygous females were mated with homozygous males in order to investigate 11-day-old homozygous embryos. The embryos and fetuses were fixed in Bouin's solution and embedded in paraffin wax. Serial frontal sections (5mu) were stained with hematoxylin and eosin. Up to the 12th day pc, the thymus anlage of the n/nu embryo is indistinguishable from that of the nu/+ animal. The paired anlage develops from the epithelium of the ventral and dorsal diverticles of the 3rd pharyngeal pouch, and from the ectodermal vesicula cervicalis. In the nu/+ embryo, the thymic epithelium begins to proliferate between the 12th day and 13th day pc. In the central part of the anlage, the epithelial cells dissociate and begin to form a reticulum. At the same time, blood vessels from the surrounding mesenchyme invade the anlage. From the 14th day onwards, lymphoblasts are recognizable..

TPA for ischemic stroke in patients ≥80 years. Although patients >80 years were excluded in RCTs for tPA treatment of acute ischemic stroke (AIS), many centers treat old patients. We wanted to examine whether age ≥80 years is an independent predictor of outcome after tPA. We included 77 consecutive patients ≥80 years and 83 patients <80 years treated with tPA within 4.5 h after onset of AIS. Baseline variables were analyzed by multiple stepwise logistic regression analyses against three outcomes: symptomatic intracerebral hemorrhage (sICH), death and good functional outcome (mRS, 0-1) at 3-month follow-up. Age ≥80 years was associated with increased risk of sICH (OR, 18.2 [95% CI, 1.0-324.1], P = 0.048), and death (OR, 3.3 [95% CI, 1.2-9.1], P = 0.018), but not with functional outcome at 3 months. Other factors associated with death were longer onset to treatment time (OTT) (OR, 1.007/min increase [95% CI, 1.00-1.015], P = 0.047), higher NIHSS (OR, 1.12 per point increase [95% CI, 1.04-1.19], P = 0.001), and previous stroke (OR, 4.0 [95% CI, 1.2-13.7], P = 0.03). Predictors of good functional outcome were shorter OTT (OR, 0.99 [95% CI, 0.98-1.00], P = 0.02) and lower NIHSS (OR, 0.80 [95% CI, 0.74-0.87] P ≤ 0.001). Age ≥80 years might be an independent risk factor for sICH and death the first 3 months after treatment with tPA for AIS, but does not influence the chance of a good functional outcome. We suggest to treat patients over 80 years with tPA, but be cautious if the time from onset (OTT) is long.

Running for your life: A review of physical activity and cardiovascular disease risk reduction in individuals with schizophrenia. Individuals with schizophrenia have a greater risk for cardiometabolic risk factors (e.g. central obesity, insulin resistance, hypertension and dyslipidaemia), cardiovascular diseases and mortality. This risky profile may be explained by the adverse effects of antipsychotic medications and an unhealthy lifestyle (e.g. smoking, poor nutrition and low physical activity). In the general population, physical activity has been shown to be the optimal strategy to improve both cardiometabolic parameters and cardiorespiratory fitness levels. Accordingly, an emerging literature of non-pharmacological interventions (e.g. cognitive behavioural therapy, diet and physical activity) has been studied in individuals with schizophrenia. Therefore, the purpose of this review was 1) to conduct a critical literature review of non-pharmacological interventions that included some kind of physical activity (including supervised and unsupervised exercise training) and target cardiometabolic risk factors in individuals with schizophrenia. 2) To describe the contribution of physical activity alone by reviewing trials of supervised exercise training programmes only. A literature review via systematic keyword search for publications in Medline, PubMed, Embase and PsycINFO was performed. Many non-pharmacological interventions are efficient in reducing cardiovascular disease risk factors when combined with physical activity. Supervised physical activity has been successful in decreasing cardiovascular disease risk, and aerobic interval training appears to provide more benefits by specifically targeting cardiorespiratory fitness levels. In conclusion, physical activity is an effective strategy for addressing cardiovascular disease risk in individuals with schizophrenia. Long-term studies are needed to evaluate the feasibility and impact of exercise training programmes in individuals with schizophrenia.

The synthesized novel fluorinated compound (LJJ-10) induces death receptor- and mitochondria-dependent apoptotic cell death in the human osteogenic sarcoma U-2 OS cells. We designed the 6-fluoro-2-(3-fluorophenyl)-4-substituted anilinoquinazoline derivatives as less toxic anti-cancer candidates. Our result demonstrated that LJJ-10 has greater cytotoxicity than that of the other compounds in human osteogenic sarcoma U-2 OS cells. LJJ-10-induced apoptosis was associated with enhancing ROS generation, DNA damage, and an increase of the protein levels of Fas, FasL, FADD, caspase-8, cytochrome c, Apaf-1, AIF, Endo G, caspase-9 and caspase-3 in U-2 OS cells. LJJ-10-triggered growth inhibition was significantly attenuated by N-acetylcysteine, cyclosporine A, anti-FasL monoclonal antibody, and caspase-8, -9 and -3 specific inhibitors in U-2 OS cells. We suggest that LJJ-10-induced apoptotic cell death in U-2 OS cells through death receptor- and mitochondria-dependent apoptotic signaling pathways.

1,1'-Bis(N-benzimidazolylidene)ferrocene: synthesis and study of a novel ditopic ligand and its transition metal complexes. Diiridum complexes containing 1,1'-bis(N-benzimidazolylidene)ferrocene, a novel ditopic ligand comprised of two N-heterocyclic carbenes (NHCs) linked directly via their N-substituents to each cyclopentadienyl ring of a ferrocene moiety, were synthesized. Crystallographic analyses of these C(2)-symmetric bimetallic complexes revealed the benzimidazolylidene moieties were intramolecularly stacked in nearly opposing orientations, effectively forming Janus-type bis(NHC) structures in the solid state. Using a variety of electrochemical techniques, the oxidation potentials of the ferrocenyl groups in these complexes were found to depend on the auxillary ligands coordinated to the Ir centers (i.e., 1,5-cyclooctadiene vs. carbonyl). Similarly, the nu(CO) of carbonyls ligated to the Ir centers varied in accord with the oxidation state of the ferrocene contained with the bis(NHC) ligand. These results suggest that the Ir and Fe centers in these complexes are electronically coupled and that the electron donating ability of the bis(NHC) ligand reported herein can be tuned electrochemically.

Raw beef, pork and chicken in Japan contaminated with Salmonella sp., Campylobacter sp., Yersinia enterocolitica, and Clostridium perfringens--a comparative study. One hundred and twenty samples each of raw ground beef, pork and chicken from ten local grocery stores in Shimane Prefecture, Japan, were examined for the presence of Salmonella sp. (Sal), Campylobacter jejuni (Cj), Campylobacter coli (Cc), Yersinia enterocolitica (Ye), and Clostridium perfringens (Cp) from April 1984 to March 1985. A total of 205 isolates of Sal (112 strains), Cj (64 strains), Cc (one strain), Ye (7 strains) and Cp (21 strains) were recovered from 17 beef (14.2%), 31 pork (25.8%) and 94 chicken (78.3%) of 120 samples each. Sal biogroup 1 was found in 8.3% of beef, 13.3% of pork and 35.0% of chicken, Sal biogroup 2 in 0.8% of beef, 4.2% of pork and 14.2% of chicken, Cj in 1.7% of beef and pork and 50.0% of chicken, Cc in 0.8% of pork, Ye serotype 03 was found in 5.0% of pork, and Cp in 1.7% of beef and pork and 10.8% of chicken. These enteropathogens were recovered concomitantly from two pork and 31 chicken samples, especially Sal and Cj. Sal was counted at less than or equal to 10(2)/100 g of beef and pork and at less than or equal to 10(3)/100 g of chicken, Cj was counted at less than or equal to 10(1)/g of beef and pork and at less than or equal to 10(2)/g of chicken, Ye serotype 03 was counted at less than or equal to 10(3)/g of pork, Cp was counted at less than or equal to 10(2)/g of pork and at less than or equal to 10(2)g of chicken, and Cc from pork and Cp from beef were recovered by using enrichment culture. This investigation showed that a second-contamination of Sal and Cj from chicken to beef and pork frequently occurred during the warm months of the year. It was suggested that chicken may become a source of infection with plural organisms of enteric pathogens, especially Sal and Cj, at the same time all the year round, and that pork may be an important source of infection with Ye during the cold months.

Sulphurous mud-bath therapy for treatment of chronic low back pain caused by lumbar spine osteoarthritis.

Comparative analysis of dynamic proteomic profiles between in vivo and in vitro produced mouse embryos during postimplantation period. Assisted reproductive technology (ART) increasingly is associated with long-term side-effects on postnatal development and behaviors. High-throughput gene expression analysis has been extensively used to explore mechanisms responsible for these disorders. Our study, for the first time, provides a comparative proteomic analysis between embryos after in vivo fertilization and development (IVO, control) and in vitro fertilization and culture (IVP). By comparing the dynamic proteome during the postimplantation period, we identified 300 and 262 differentially expressed proteins (DEPs) between IVO and IVP embryos at embryonic day 7.5 (E7.5) and E10.5, respectively. Bioinformatic analysis showed many DEPs functionally associated with post-transcriptional, translational, and post-translational regulation, and these observations were consistent with correlation analysis between mRNA and protein abundance. In addition to altered gene expression due to IVP procedures, our findings suggest that aberrant processes at these various levels also contributed to proteomic alterations. In addition, numerous DEPs were involved in energy and amino acid metabolism, as well as neural and sensory development. These DEPs are potential candidates for further exploring the mechanism(s) of ART-induced intrauterine growth restriction and neurodevelopmental disorders. Moreover, significant enrichment of DEPs in pathways of neurodegenerative diseases implies the potentially increased susceptibility of ART offspring to these conditions as adults.

Clinical comparison between the retromandibular approach for reduction and fixation and endoscope-assisted open reduction and internal fixation for mandibular condyle fractures. Endoscope-assisted transoral open reduction and internal fixation (EAORIF) for mandibular condyle fractures has recently become popular because it is minimally invasive, provides excellent visibility without a large incision, and reduces surgical scarring and the risk of facial nerve injury. This report describes a retrospective clinical study that compared certain clinical parameters, including postoperative function, between the retromandibular (RM) approach and EAORIF. Fifteen patients were treated by the RM approach, whereas 15 underwent EAORIF between July 2006 and September 2011 at Kyushu Dental College, Japan. Clinical indices comprised fracture line, fracture type, number of plates used, surgical duration, bleeding amount, and functional items, including maximum interincisal opening, mandibular deviation on the opening pathway, malocclusion, facial paresthesia, and temporomandibular joint pain and clicking. The areas subjected to either approach included lower neck and subcondyle. The RM approach was used for mandibular condyle fractures with dislocation of a small bone segment. Both groups used 2 plates in all cases. Surgical duration, maximum interincisal opening, mandibular deviation, occlusion, and temporomandibular joint function at 6 months after surgery were comparable between groups. The average bleeding amount in the EAORIF group was greater than in the RM group. One patient from the RM group developed facial paresthesia that persisted for 6 months after surgery. It was concluded that surgical treatment was suitable for fractures of the lower neck and subcondylar. Both procedures showed good results in the functional items of this study.

In Vivo Voltage-Sensitive Dye Imaging of Mammalian Cortex Using "Blue" Dyes. Optical recording of membrane potential allows simultaneous measurements to be taken from many different locations in the nervous system. This is important in studies of the nervous system in which simultaneous activity can occur at the regional, cellular, and subcellular levels. New "blue" dyes, developed by Amiram Grinvald's group, are a great advance for in vivo voltage-sensitive dye imaging of mammalian cortex. The blue dyes are excited by red light (630 nm) that does not overlap with light absorption of hemoglobin (510-590 nm). This virtually eliminates the heart pulsation artifact.

Selective clamping under the usage of near-infrared fluorescence imaging with indocyanine green in robot-assisted partial nephrectomy: a single-surgeon matched-pair study. To present a single-surgeon matched-pair analysis to show the feasibility of combining the technique of selective clamping with usage of near-infrared fluorescence imaging in robot-assisted partial nephrectomy and to investigate short-term renal function outcomes. Twenty-two patients underwent selective clamping partial nephrectomy with the application of indocyanine green (ICG). Out of this cohort, a matched-pair analysis for R.E.N.A.L. nephrometry parameter was employed for 15 exactly matching partners. Demographic, surgical, pathological and kidney function data were collected for the initial cohort, and matched-pair comparison was made between the subgroups retrospectively. Robot-assisted partial nephrectomy without clamping of the hilum was possible in 21 patients; in one patient, main artery clamping was necessary due to bleeding. Mean clinical tumor size was 37.7 mm. Mean selective clamping ischemia time was 11.6 min with an estimated blood loss of 347 ml. No intraoperative complications occurred, and postoperative complications (n = 4), including two major urological (urinoma, late-onset acute hemorrhage) complications, were found. There were no side effects of ICG administration. Matched-pair analysis for 15 patients showed similar demographic and surgical data without any significant differences in tumor characteristics. Comparing short-term renal function outcomes, significantly decreased estimated glomerular filtration rate reduction in the selective clamping group with an absolute loss of 5.1 versus 16.1 ml/min in the global ischemia cohort (p = 0.045) could be observed. Robot-assisted partial nephrectomy with selective clamping of the tumor feeding vascular branches is a promising technique for reduced ischemic renal trauma. This may lead to improved kidney function preservation.

Antimicrobial resistance and prevalence of virulence factor genes in fecal Escherichia coli of Holstein calves fed milk with and without antimicrobials. Diarrhea in calves has a significant effect on the dairy industry. A common management practice for preventing or decreasing the effects of such disease in preweaned calves is by the use of antimicrobials in milk or milk replacer. In this study, Escherichia coli antimicrobial resistance in fecal samples collected from calves 2 to 8 d of age that had or had not received antimicrobials in the milk and that had or had not signs of diarrhea by inspection of fecal consistency were investigated. Specifically, resistance of E. coli isolates to individual antimicrobials, multiresistance patterns, and presence of virulence factors were analyzed. Escherichia coli isolates were tested for susceptibility to 12 antimicrobials by use of a Kirby-Bauer disk diffusion assay. The study was conducted at 3 farms, 1 administering growth-promoting antimicrobials (GPA) in the milk and 2 not using GPA in the milk (NGPA). All isolates were susceptible to ciprofloxacin and cefepime. From the total isolates tested, 84% (n=251) were resistant to at least 2 antimicrobials and 81% (n=251) were resistant to 3 or more antimicrobials. When antimicrobial resistance was compared between GPA and NGPA, it was observed that the GPA group had higher odds of antimicrobial resistance for most of the individual antimicrobials tested. No significant correlation of virulence factors in GPA or NGPA and diarrheic or non-diarrheic (control) fecal samples was found. Of the 32 virulence factors evaluated, 21 were detected in the study population; the incidence of only 1 virulence factor was statistically significant in each of the diarrheic status (diarrheic or non-diarrheic) and treatment status (NGPA or GPA) groups. Phylogenetic analysis based on the nucleotide sequence of the DNA gyrase gene (gyrB) from 31 fecal E. coli isolates revealed 3 main clades.

Adipose Recruitment and Activation of Plasmacytoid Dendritic Cells Fuel Metaflammation. In obese individuals, visceral adipose tissue (VAT) is the seat of chronic low-grade inflammation (metaflammation), but the mechanistic link between increased adiposity and metaflammation largely remains unclear. In obese individuals, deregulation of a specific adipokine, chemerin, contributes to innate initiation of metaflammation by recruiting circulating plasmacytoid dendritic cells (pDCs) into VAT through chemokine-like receptor 1 (CMKLR1). Adipose tissue-derived high-mobility group B1 (HMGB1) protein activates Toll-like receptor 9 (TLR9) in the adipose-recruited pDCs by transporting extracellular DNA through receptor for advanced glycation end products (RAGE) and induces production of type I interferons (IFNs). Type I IFNs in turn help in proinflammatory polarization of adipose-resident macrophages. IFN signature gene expression in VAT correlates with both adipose tissue and systemic insulin resistance (IR) in obese individuals, which is represented by ADIPO-IR and HOMA2-IR, respectively, and defines two subgroups with different susceptibility to IR. Thus, this study reveals a pathway that drives adipose tissue inflammation and consequent IR in obesity.

Human cytomegalovirus hyperimmune globulin not only neutralizes HCMV infectivity, but also inhibits HCMV-induced intracellular NF-kappaB, Sp1, and PI3-K signaling pathways. Inhibition of virus-induced intracellular signaling pathways and viral infectivity are our ultimate goals in the development of effective antiviral agents to control human cytomegalovirus (HCMV) infections. The HCMV hyperimmune globulin may meet such criteria. In a human embryonic lung (HEL) fibroblast culture model, pretreatment of Towne strain HCMV with HCMV hyperimmune globulin was shown to inhibit viral infectivity successfully, as measured by a standard plaque assay. The extracellular viral titers and extracellular viral DNA, as measured by plaque assay and PCR, respectively, were also decreased. In addition, the HCMV hyperimmune globulin prevented HCMV from inducing the intracellular activation of NF-kappaB, Sp-1, and PI3-K signaling pathways. The PI3-K pathway was examined by following phosphorylation (activation) of two of its downstream kinases, Akt and p70S6K. HCMV hyperimmune globulin also prevented the production of immediate early, early, and late viral proteins. These studies show that HCMV hyperimmune globulin neutralization of HCMV prevents the earliest known events observed after viral envelope glycoproteins bind their cell membrane receptors, i.e., NF-kappaB, Sp-1 and PI3-K activation. This suggests that HCMV hyperimmune globulin not only can inhibit viral infectivity, but can also prevent the abnormal cellular signaling that may induce unwanted cellular proliferation or cytokine synthesis.

Standardized error severity score (ESS) ratings to quantify risk associated with child restraint system (CRS) and booster seat misuse. Although numerous research studies have reported high levels of error and misuse of child restraint systems (CRS) and booster seats in experimental and real-world scenarios, conclusions are limited because they provide little information regarding which installation issues pose the highest risk and thus should be targeted for change. Beneficial to legislating bodies and researchers alike would be a standardized, globally relevant assessment of the potential injury risk associated with more common forms of CRS and booster seat misuse, which could be applied with observed error frequency-for example, in car seat clinics or during prototype user testing-to better identify and characterize the installation issues of greatest risk to safety. A group of 8 leading world experts in CRS and injury biomechanics, who were members of an international child safety project, estimated the potential injury severity associated with common forms of CRS and booster seat misuse. These injury risk error severity score (ESS) ratings were compiled and compared to scores from previous research that had used a similar procedure but with fewer respondents. To illustrate their application, and as part of a larger study examining CRS and booster seat labeling requirements, the new standardized ESS ratings were applied to objective installation performance data from 26 adult participants who installed a convertible (rear- vs. forward-facing) CRS and booster seat in a vehicle, and a child test dummy in the CRS and booster seat, using labels that only just met minimal regulatory requirements. The outcome measure, the risk priority number (RPN), represented the composite scores of injury risk and observed installation error frequency. Variability within the sample of ESS ratings in the present study was smaller than that generated in previous studies, indicating better agreement among experts on what constituted injury risk. Application of the new standardized ESS ratings to installation performance data revealed several areas of misuse of the CRS/booster seat associated with high potential injury risk. Collectively, findings indicate that standardized ESS ratings are useful for estimating injury risk potential associated with real-world CRS and booster seat installation errors.

Maxillofacial trauma and the GDP--specialty recognition and patterns of referral. To investigate New Zealand GDPs' awareness of maxillofacial trauma and to identify their associated referral patterns. Cross-sectional survey of a random sample of GDPs. A nationwide postal questionnaire survey was sent to GDPs on the New Zealand Dental Register, maintained by the Dental Council of New Zealand. The questionnaire requested socio-demographic details, together with information on the availability of specialist services and their need for continuing professional development in oral and maxillofacial surgery (OMS). The questionnaire also asked the GDPs to indicate which specialty (plastic surgery, ear nose and throat (ENT) surgery, OMS and Other) they expected to manage--and to which specialty they would refer-seven types of maxillofacial injury. Some 377 GDPs responded (76.6%). The majority of GDPs expected OMS to manage maxillofacial trauma, except for facial lacerations and isolated nasal fractures which were expected to be managed by plastic surgery (83.0%) and ENT surgery (79.7%), respectively. Most GDPs (48.0% to 87.9%) referred maxillofacial trauma to OMS, except for isolated nasal fractures, for which there were similar proportions referred to ENT surgery and OMS (45.8% and 41.4%, respectively). Differences in awareness of and referral patterns for maxillofacial trauma were identified by dentist characteristics. Most GDPs (96.0%) felt there was a need for continuing professional development in OMS, and most (84.1%) preferred this to be in the form of lectures and seminars. The first-ever study of GDP referral patterns for maxillofacial trauma in New Zealand has revealed that most GDPs in New Zealand referred maxillofacial trauma appropriately to OMS.

Guide RNA molecules not engaged in RNA editing form ribonucleoprotein complexes free of mRNA. Mitochondrial pre-mRNAs in kinetoplastid organisms undergo uridine additions and deletions after transcription, a phenomenon termed kRNA editing. The reaction involves small, mitochondrial DNA transcripts, so called guide RNAs which provide the editing information via base pairing to the pre-mRNAs and furthermore may act as the U-nucleotide donors. Guide RNAs are not maintained as free molecules within the mitochondrial organelle, instead form several high molecular weight ribonucleoprotein complexes. Here we report the identification of two new gRNA containing RNP complexes, 8S and 15S in size, that only assemble with upstream gRNA molecules which require editing of their cognate pre-mRNA before they can base pair. The two complexes do not contain pre-mRNA molecules and the 8S RNP can be assembled in vitro. It contains two polypeptides under these conditions with apparent molecular weights of 90 and 21 kDa that can be cross-linked to the gRNA molecule. Our observation suggests the existence of structurally simple gRNA/protein complexes that might function as building blocks for the assembly of a high molecular weight editing machinery.

Comparative Cluster Analysis Of Social Areas. Three demographic dimensions previously isolated by cluster analysis procedures (using BC TRY System computer analyses) were compared in different metropolitan areas for their stability over time and place. Also, the social areas discovered within the communities were studied for their stability over time and place. The three demographic dimensions (socio-economic independence, family life, and assimilation) accounted for the generality of 33 census tract (1940) characteristics in two communities. It was also shown that the three basic dimensions were essentially unchanged during the decade which included World War 11. The stability of these dimensions was retained even though there was considerable change in residents in each metropolitan area during the decade. The validity of cluster-search procedures is demonstrated by the stability of the three demographic dimensions.

Concordance levels of PD-L1 expression by immunohistochemistry, mRNA in situ hybridization, and outcome in lung carcinomas. Targeted inhibition of programmed cell death-1 (PD-1) and its ligand (PD-L1) has emerged as first-line therapy for advanced non-small cell lung cancer. Although patients with high PD-L1 expression have improved outcomes with anti-PD-1/PD-L1-directed therapies, use as a predictive biomarker is complicated by robust responses in some patients with low-level expression. Furthermore, reported PD-L1 levels in lung cancers vary widely, and discrepancies exist with different antibodies. PD-L1 expression was thus compared by immunohistochemistry (IHC) versus RNA in situ hybridization (ISH) in 112 lung cancers by tissue microarray: 51 adenocarcinoma, 42 squamous cell carcinoma, 9 adenosquamous carcinoma, 5 carcinoid, 3 undifferentiated large cell carcinoma, 1 large cell neuroendocrine carcinoma, and 1 small cell carcinoma. At least 1% tumor cell staining was considered positive in each modality. A positive concordance of only 60% (67/112) was found between IHC and ISH. Fifty percent (56/112) were positive by IHC and 50% (56/112) by ISH; however, 20% (22/112) were ISH positive but IHC negative. Conversely, 21% (23/112) were IHC positive but ISH negative. There was no significant stratification of PD-L1 positivity by histologic subtype. A trend of more PD-L1-positive stage I cancers identified by ISH versus IHC was observed but was not statistically significant (50% [27/54] by IHC and 64% [35/55] by ISH, P = .18). No significant difference in survival was identified, with an average of 5.3 months in IHC versus 5.2 months in ISH-positive cases. The results demonstrate discordance between PD-L1 RNA levels and protein expression in non-small cell lung cancers, warranting comparison as predictive biomarkers.

Quantitative and ultrastructural study of ascending projections to the medial mammillary nucleus in the rat. We analyzed the termination pattern of axons from the superior central nucleus and the ventral tegmental nucleus of Gudden within the medial mammillary nucleus (MM) in the rat. The neuropil of the MM consists of two classes of terminals, that is, terminals containing round synaptic vesicles and forming asymmetric synaptic contact, and terminals containing pleomorphic synaptic vesicles and forming symmetric synaptic contact. The number of axodendritic terminals with round vesicles is almost equal to that of terminals with pleomorphic vesicles. Almost all axosomatic terminals contain pleomorphic vesicles with symmetric synaptic contact. Injection of WGA-HRP into the central part of the superior central nucleus permitted ultrastructural recognition of many anterogradely labeled terminals within the median region of MM. The labeled terminals contacted mainly intermediate (1-2 microns diameter) and proximal dendrites (more than 2 microns diameter) as well as the neuronal somata. Serial ultrathin sections of neurons of the median region of the MM revealed that 37% of the axosomatic terminals were labeled anterogradely. The pars compacta of the superior central nucleus had reciprocal connections with the median region of MM. The axon terminals from this nucleus occupied 53% of axosomatic terminals, and contacted mainly intermediate dendrites. Following injection of WGA-HRP into the ventral tegmental nucleus, many labeled terminals were found in the medial and lateral regions of MM. They contacted mainly intermediate dendrites as well as neuronal somata. In the medial region, 78% of axosomatic terminals contacting retrogradely labeled neurons were labeled anterogradely. All labeled terminals from these nuclei contained pleomorphic vesicles, and made symmetric synaptic contact.

Striatal dopamine in Parkinson disease: A meta-analysis of imaging studies. A meta-analysis of 142 positron emission tomography and single photon emission computed tomography studies that have investigated striatal presynaptic dopamine function in Parkinson disease (PD) was performed. Subregional estimates of striatal dopamine metabolism are presented. The aromatic L-amino-acid decarboxylase (AADC) defect appears to be consistently smaller than the dopamine transporter and vesicular monoamine transporter 2 defects, suggesting upregulation of AADC function in PD. The correlation between disease severity and dopamine loss appears linear, but the majority of longitudinal studies point to a negative exponential progression pattern of dopamine loss in PD. Ann Neurol 2017;82:873-882.

Immune- and stress-related transcriptomic responses of Solea senegalensis stimulated with lipopolysaccharide and copper sulphate using heterologous cDNA microarrays. The sole, Solea senegalensis, is a common flatfish of Atlantic and Mediterranean waters with a high potential for aquaculture. However, its cultivation is hampered by high sensitivity to different stresses and several infectious diseases. Improving protection from pathogens and stressors is thus a key step in reaching a standardized production. Fish were exposed to lipopolysaccharide (LPS), a mimetic of bacterial infections, and copper sulphate (CuSO(4)), used in aquaculture to control algae and outbreaks of infectious diseases. We employed a European flounder cDNA microarray to determine the transcriptomic responses of Senegalese sole to these exposures. Microarray analyses showed that many genes were altered in expression following both LPS and copper treatments in comparison to vehicle controls. Gene ontology analysis highlighted copper-specific induction of genes related to cellular adhesion and cell signalling, LPS-specific induction of genes related to the immune response, and a common induction of genes related to unfolded protein binding, intracellular transport/secretion and proteasome. Additionally transcripts for glutathione-S-transferases were down-regulated by LPS, and those for digestive enzymes were down-regulated by both treatments. We selected nine changing genes for absolute quantification of transcript copy numbers by real-time RT-PCR to validate microarray differential expression and to assess inter-individual variability in individual fishes. The quantitative RT-PCR data correlated highly with the microarray results. Overall, data reported provide novel insights into the molecular pathways that could mediate the immune and heavy metal stress responses in Senegalese sole and thus might have biotechnological applications in the culture of this important fish species.

Patients with Helicobacter pylori negative gastric marginal zone b-cell lymphoma (MZBCL) of MALT have a good prognosis. In current guidelines H. pylori eradication is recommended as first-line therapy in patients with gastric MALT lymphoma irrespective of stage and H. pylori status. However, data on treatment and clinical course of patients with H. pylori negative MALT lymphoma are rare. To evaluate therapeutical results in patients with H. pylori negative gastric MALT lymphoma. 21 patients (13 male and 8 female; 63.9 years, range 43 - 80) with gastric MALT lymphoma were analysed retrospectively on the basis of medical reports in all cases and repeated outpatient visits at our center in 17 cases. H. pylori infection was excluded by negative histology, rapid urease test, or C13 urease breath test, and serology in all cases. Follow-up was 56.4 (5 - 142) months. Ten of 21 patients were treated with H. pylori eradication, and four of them received no further therapy. The other six patients underwent surgery, chemotherapy, and radiation, after eradication therapy. Those eleven patients without H. pylori eradication received radiation (n = 3), chemotherapy (n = 1), PPIs (n = 2), no treatment (n = 4) as first-line and radiation (n = 2) as second-line therapy while initial therapy remained unknown in one case. 13 patients (61.9 %) reached complete remission of lymphoma, and seven patients (33.3 %) showed minimal histological residuals. Overall and disease-free survival was found in 95 % and 90 %, respectively. Patients with H. pylori negative gastric MALT lymphoma have a good prognosis. We favor initial H. pylori eradication therapy and a watch-and-wait strategy in case of minimal histological residuals of MALT lymphoma. Non-responders to eradication therapy can be successfully treated by radiation and chemotherapy.

A review on the preparation of chitosan oligosaccharides and application to human health, animal husbandry and agricultural production. Chitosan oligosaccharides (COS) are the degraded products of chitin or chitosan prepared by chemical or enzymatic hydrolysis. As compared to chitosan, COS not only exhibit some specific physicochemical properties such as excellent water solubility, biodegradability and biocompatibility, but also have a variety of functionally biological activities including anti-inflammation, anti-bacteria, immunomodulation, neuroprotection and so on. This review aims to summarize the preparation and structural characterization methods of COS, and will discuss the application of COS or their derivatives to human health, animal husbandry and agricultural production. COS have been demonstrated to prevent the occurrence of human health-related diseases, enhance the resistance to diseases of livestock and poultry, and improve the growth and quality of crops in plant cultivation. Overall, COS have presented a broad developmental potential and application prospect in the healthy field that deserves further exploration.

Embryotoxic activity and differential binding of plant-derived carbohydrate-recognizing proteins towards the sea urchin embryo cells. The embryotoxic activity and differential binding of plant-derived carbohydrate-recognizing proteins on sea urchin (Lytechinus variegatus) embryo cells was investigated. IC50 doses for toxicity on larvae development varied from 0.6 up to 96.3 microg ml(-1) and these effects were largely reversed by previously heating the proteins. Changes in the glycoconjungate status of the cell surface were assessed by time-course binding of the proteins during embryogenesis according to their carbohydrate-binding specificity. Glucose/mannose binding-proteins bound embryo cells at the same stage of development, at a similar stage to the N-acetylglucosamine/N-acetylneuraminic acid binding-protein (WGA) and earlier than galactose specific ones. FITC-conjugates of these proteins confirmed the above results and revealed the presence of specific and differential receptors for them. Inhibition assays using inhibitory glycoproteins significantly diminished the labelled patterns of FITC-conjugates. In conclusion, the assayed proteins exhibited embryotoxicity and their binding requirements were useful for following changes in the pattern of cell surface glycoconjugates on embryo cells of sea urchin. This property could be useful in analyzing other cell types.

Dioxygen Sensitivity of [Fe]-Hydrogenase in the Presence of Reducing Substrates. Mono-iron hydrogenase ([Fe]-hydrogenase) reversibly catalyzes the transfer of a hydride ion from H2 to methenyltetrahydromethanopterin (methenyl-H4 MPT+ ) to form methylene-H4 MPT. Its iron guanylylpyridinol (FeGP) cofactor plays a key role in H2 activation. Evidence is presented for O2 sensitivity of [Fe]-hydrogenase under turnover conditions in the presence of reducing substrates, methylene-H4 MPT or methenyl-H4 MPT+ /H2 . Only then, H2 O2 is generated, which decomposes the FeGP cofactor; as demonstrated by spectroscopic analyses and the crystal structure of the deactivated enzyme. O2 reduction to H2 O2 requires a reductant, which can be a catalytic intermediate transiently formed during the [Fe]-hydrogenase reaction. The most probable candidate is an iron hydride species; its presence has already been predicted by theoretical studies of the catalytic reaction. The findings support predictions because the same type of reduction reaction is described for ruthenium hydride complexes that hydrogenate polar compounds.

Population pharmacokinetics of docetaxel during phase I studies using nonlinear mixed-effect modeling and nonparametric maximum-likelihood estimation. Docetaxel, a novel anticancer agent, was given to 26 patients by short i.v. infusion (1-2 h) at various dose levels (70-115 mg/m2, the maximum tolerated dose) during 2 phase I studies. Two population analyses, one using NONMEM (nonlinear mixed-effect modeling) and the other using NPML (nonparametric maximum-likelihood), were performed sequentially to determine the structural model; estimate the mean population parameters, including clearance (Cl) and interindividual variability; and find influences of demographic covariates on them. Nine covariates were included in the analyses: age, height, weight, body surface area, sex, performance status, presence of liver metastasis, dose level, and type of formulation. A three-compartment model gave the best fit to the data, and the final NONMEM regression model for Cl was Cl = BSA(Theta1 + Theta02 x AGE), expressing Cl (in liters per hour) directly as a function of body surface area. Only these two covariates were considered in the NPML analysis to confirm the results found by NONMEM. Using NONMEM [for a patient with mean AGE (52.3 years) and mean BSA (1.68 m2)] and NPML, docetaxel Cl was estimated to be 35.6 l/h (21.2 lh-1 m-2) and 37.2 l/h with interpatient coefficients of variations (CVs) of 17.4% and 24.8%, respectively. The intraindividual CV was estimated at 23.8% by NONMEM; the corresponding variability was fixed in NPML in an additive Gaussian variance error model with a 20% CV. Discrepancies were found in the mean volume at steady state (Vss; 83.21 for NPML versus 1241 for NONMEM) and in terminal half-lives, notably the mean t1/2 gamma, which was shorter as determined by NPML (7.89 versus 12.2 h), although the interindividual CV was 89.1% and 62.7% for Vss and t1/2 gamma, respectively. However, the NPML-estimated probability density function (pdf) of t1/2 gamma was bimodal (5 and 11.4 h), probably due to the imbalance of the data. Both analyses suggest a similar magnitude of mean Cl decrease with small BSA and advanced age.

Electron paramagnetic resonance properties of liver fluke (Dicrocoelium dendriticum) nitrosyl hemoglobin. The electron paramagnetic resonance properties of the nitric oxide derivative of liver fluke (Dicrocoelium dendriticum) hemoglobin (DD-Hb) have been investigated in the pH range from 4.8 to 7.8. In the neutral and alkaline regions the spectra have a rhombic shape, with gx = 2.09, gy = 1.99 and gz = 2.009, and a triplet hyperfine structure of 2.2 mT, due to the nitrogen of the bound NO molecule, in the center resonance. No superhyperfine lines in the gz region, related to the interaction of the iron with the proximal histidine, are detected, suggesting a large distance between the metal and the N epsilon of the imidazole. By lowering the pH the EPR spectrum undergoes a reversible change showing a 3-line pattern in the high-field region. Such a spectrum is fully formed at pH 4.8 and is interpreted in terms of a dissociation of the proximal histidine from the heme iron.