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Does escitalopram regulate expression of TRH and TRH-like peptides in rat brain and peripheral tissues?

Escitalopram (eCIT) is a highly selective serotonin reuptake inhibitor (SSRI) that can be an effective treatment for a number of neuropsychiatric disorders including major depression. We, and others, have previously reported that thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH(2)) and TRH-like peptides with the general structure pGlu-X-Pro-NH(2), where 'X' can be any amino acid residue, have neuroprotective, antidepressant, analeptic, arousal, and anti-epileptic effects that could mediate the neuropsychiatric and therapeutic effects of a variety of neurotropic agents. The present work explores the possible mediation of the therapeutic effects of eCIT by TRH and TRH-like peptides. In order to extend our understanding of the range of neurotransmitter systems that are modulated by and, in turn, influence the expression of TRH and TRH-like peptides, 16 male Sprague-Dawley rats were injected i.p. with eCIT (24 mg/kg BW) and the brain levels of TRH and TRH-like peptides in various brain regions involved in mood regulation and peripheral tissues with serotonergic innervation were measured 0, 2, 4, and 6 h later by combined HPLC and RIA.

Remarkable 3- to 25-fold increases in TRH and TRH-like peptide levels were observed 2 h after i.p. eCIT in the epididymis. This reproductive tissue has the highest level of serotonin found in most mammals. The acute (2 h) effect of eCIT in brain regions involved in mood regulation, particularly the nucleus accumbens and medulla oblongata, cerebellum, and striatum was to increase the levels of TRH-like peptides, most consistently Phe-TRH. An important exception was a decrease in the level of TRH in the nucleus accumbens. These responses, in general, were the opposite of those we have previously observed after acute restraint stress in this same rat strain. We conclude that some of the therapeutic effects of inhibition of serotonin reuptake are mediated by altered release of TRH and TRH-like peptides.

Is normal intrauterine pregnancy unlikely in patients who have echogenic material identified within the endometrial cavity at transvaginal ultrasonography?

In first-trimester patients with abdominal pain or vaginal bleeding, pelvic ultrasonography (US) is often performed to assess the status of the pregnancy. Identification of echogenic material within the endometrial cavity in the absence of a gestational sac has been attributed to the presence of either retained products of conception or clotted blood. However, to the authors' knowledge, no study has directly addressed whether this finding reliably excludes the diagnosis of a normal intrauterine pregnancy (IUP). To determine whether the identification of echogenic material within the endometrial cavity at transvaginal US excludes the diagnosis of a normal IUP. Data were collected retrospectively from August 1991 to August 1997 on consecutive urban teaching hospital ED patients with abdominal pain or vaginal bleeding who had a transvaginal US performed during the ED visit that demonstrated echogenic material within the endometrial cavity. Patients were excluded if they had a dilatation and evacuation (D + E) procedure performed prior to the exclusion of a normal IUP by other means [open cervical os, falling quantitative beta--human chorionic gonadotropin (beta-hCG) values, a progesterone value < 5.0 ng/mL or beta-hCG > 3,000 mIU/mL] or if they were lost to follow-up. Patients were followed until a final diagnosis was ultimately determined. A total of 83 patients with echogenic material were identified. Of these, three patients were excluded because a D + E was performed prior to an IUP being excluded by other means, and two patients were lost to follow-up. Of the 78 enrolled patients, none had a final diagnosis of normal IUP. Ectopic pregnancy was confirmed in nine patients, five of whom had no adnexal or cul de sac findings to suggest this diagnosis.

In symptomatic patients who have echogenic material but no gestational sac visualized within the endometrial cavity at US, the likelihood of a normal IUP is low.

Is general immune dampening associated with disturbed metabolism at diagnosis of type 1 diabetes?

Type 1 diabetes (T1D) is a serious diagnosis with the prospect of grave short- and long-term complications and even death if poorly managed. An attempt has been made to describe how clinical and immunological deviations might influence each other close to the diagnosis of T1D. Sixty-nine newly diagnosed T1D children were studied together with a reference group of 30 healthy children. Cytokines (interleukin (IL)-6, IL-10, IL-13, IL-17, interferon-γ, and tumor necrosis factor-α) were detected in in vitro culture by multiplex fluorochrome technique. Information of clinical status of the patients such as BMI, weight loss, pubertal stage, duration of symptoms, previous and/or ongoing infections, insulin requirement, and ketoacidosis were gathered together with the analysis of C-peptide and glycosylated hemoglobin (HbA1c). In general, low cytokine secretion was found at diagnosis of T1D. However, high C-peptide, short duration of symptoms, or an infection prior to diagnosis was associated with increased immune activity including proinflammatory, Th2-associated, and Tr1-associated cytokines. In contrast, ketoacidosis and later pubertal stage at onset of disease were more related to a Th1-prone response.

There is a general immune dampening at diagnosis of T1D, which appears to be related to the metabolic state close to diagnosis.

Does heat shock protein 70 gene transfection protect mitochondrial and ventricular function against ischemia-reperfusion injury?

Upregulation of heat shock protein 70 (HSP70) is beneficial in cardioprotection against ischemia-reperfusion injury, but the mechanism of action is unclear. We studied the role of HSP70 overexpression through gene therapy on mitochondrial function and ventricular recovery in a protocol that mimics clinical donor heart preservation. Hemagglutinating virus of Japan (HVJ)-liposome technique was used to transfect isolated rat hearts via intracoronary infusion of either the HSP70 gene (HSP group, n=16) or no gene (CON group, n=16), which was heterotopically transplanted into recipient rats. Four days after surgery, hearts were either perfused on a Langendorff apparatus for 30 minutes at 37 degrees C (preischemia studies [n=8/group]) or perfused for 30 minutes at 37 degrees C, cardioplegically arrested for 4 hours at 4 degrees C, and reperfused for 30 minutes at 37 degrees C (postischemia studies [n=8/group]). Western blotting and immunohistochemistry confirmed HSP70 upregulation in the HSP group. Postischemic mitochondrial respiratory control indices (RCIs) were significantly better preserved in HSP than in CON hearts: NAD(+)-linked RCI values were 9.54+/-1.1 versus 10.62+/-0.46 before ischemia (NS) but 7.98+/-0.69 versus 1.28+/-0.15 after ischemia (P<0.05), and FAD-linked RCI values were 6.87+/-0.88 versus 6.73+/-0.93 before ischemia (NS) but 4.26+/-0.41 versus 1.34+/-0.13 after ischemia (P<0.05). Postischemic recovery of mechanical function was greater in HSP than in CON hearts: left ventricular developed pressure recovery was 72.4+/-6.4% versus 59.7+/-5.3% (P<0.05), maximum dP/dt recovery was 77.9+/-6.6% versus 52.3+/-5.2% (P<0.05), and minimum dP/dt recovery was 72.4+/-7.2% versus 54.8+/-6.9% (P<0.05). Creatine kinase release in coronary effluent after reperfusion was 0.20+/-0.04 versus 0.34+/-0.06 IU. min(-1). g wet wt(-1) (P<0.05) in HSP versus in CON hearts.

HSP70 upregulation protects mitochondrial function after ischemia-reperfusion injury; this was associated with improved preservation of ventricular function. Protection of mitochondrial function may be important in the development of future cardioprotective strategies.

Does serum procalcitonin have a role in evaluating the severity of acute pancreatitis?

This study was designed to evaluate the diagnostic accuracy of serum procalcitonin (PCT) for the diagnosis of severity in acute pancreatitis (AP), compared with routine clinical, biochemical, radiological, and combination severity scoring systems. Quantitative meta-analysis was performed on prospective studies, comparing serum PCT, against validated scoring systems for diagnosing severe AP. The sensitivity, specificity, and diagnostic odds ratio were calculated for each study. Summary receiver operating characteristic (SROC) curves and subgroup analysis were undertaken. Study quality and heterogeneity were evaluated. Meta-regression meta-analysis was used to evaluate the effect of using serum PCT in the diagnostic accuracy severity scoring in AP. Summary receiver operating characteristic analysis of nine studies showed an overall sensitivity and specificity of 74% (range: 66%-81%) and 83% (range: 79%-87%), respectively. Overall unweighted area under the curve (AUC) was 0.91 (DOR = 16.26 95% CI: 5.68-46.60), demonstrating significant heterogeneity (Q-value = 25.32; P = 0.001). When high-quality studies alone were evaluated, there was an increase in the overall sensitivity (89%); however, specificity was similar (82%), with an overall unweighted AUC of 0.94 (DOR 41.46, 95% CI: 17.95-95.80), with no significant heterogeneity. Meta-regression analysis confirmed the significant effect of study quality on the diagnostic accuracy of severity scoring using serum PCT (P = 0.025).

The use of PCT for severity scoring in AP has a moderate sensitivity but higher specificity. However, the overall accuracy for predicting severity in AP is high. The prognosis of severity, especially early on (<48 hours from onset of symptoms), and the evaluation of potential infectious complications of AP may be the most useful factors to assess in subsequent clinical trials to identify its exact application in clinical practice in the management of AP.

Is low-dose flecainide infusion followed by oral pilsicainide highly effective and safe for paroxysmal atrial fibrillation?

The aim of this study was to evaluate the efficacy and safety of intravenous infusion of low-dose flecainide (50 mg) followed by oral pilsicainide (50 mg t.i.d.)in patients with paroxysmal atrial fibrillation (AF). Thirty-one patients with symptomatic and hemodynamically stable AF lasting less than 48 h from its onset were enrolled. Firstly, intravenous flecainide was given, and if AF was maintained 1 h after the start of flecainide, oral pilsicainide was started. Sinus rhythm was restored in 14 patients by flecainide alone (45%), and 24 h later, AF was disappeared in additional 14 patients (45%), resulting in the overall conversion rate of 90%. No side effects were observed.

The combined therapy of i.v. low-dose flecainide followed by oral pilsicainide might be a promising strategy for the outpatient treatment of paroxysmal atrial fibrillation.

Does selective decontamination of the digestive tract help prevent bacterial infections in the early postoperative period after liver transplant?

In liver transplant (LTx) recipients, gut-associated bacterial and fungal organisms produce significant postoperative morbidity and mortality. We sought to assess the role of selective digestive decontamination (SDD) in preventing postoperative infections in a large single-center cohort of liver recipients transplanted under two non-simultaneous protocols. In 212 consecutive patients transplanted between 1/1/91 and 7/31/92, SDD (gentamicin 80 mg, polymyxin B 100 mg, nystatin suspension 10 mL) was employed, starting after induction of anesthesia and continued until POD 21 (SDD Group). In 157 consecutive patients transplanted between 1/1/93 and 12/31/93, SDD was not used (non-SDD Group). Both groups received IV vancomycin and cefotaxime prophylaxis. All culture-positive infections within the first 30 days post-LTx were recorded and classified as bacterial or fungal. Infection-related mortality (patients who died of infectious complications without any technical complication) was recorded. Groups did not differ in patient demographics, United Network for Organ Sharing (UNOS) status, use of veno-venous bypass, total/warm ischemia, or length of ICU stay. Infections developed in fewer SDD patients (56/212; 26%) than non-SDD patients (69/157; 44%) (p<0.001). The incidence of gram-negative infection was less in the SDD group (11% vs. 26%, p<0. 001) as was gram-positive infection (16% vs. 26%, p<0.001). Among patients who developed infection, there was no difference between groups in infections per patient. Primary graft non-function (PNF) developed in 20 SDD patients (7/20 had infections) and 8 non-SDD patients (6/8 had infections) (p=0.06). There were no differences in incidence of fungal infections or of infection-related mortality between groups. In the SDD group, there were fewer abdominal (p<0. 001), lung (p<0.001), wound (p<0.01), and urinary tract infections (p<0.05).

Use of SDD in liver recipients early after transplant was associated with significantly fewer infections in the early postoperative period.

Vaginal infections in diabetic women: is empiric antifungal therapy appropriate?

Diabetes mellitus is reported to predispose women to vaginal candidiasis and hence patients attending busy diabetic clinics are often treated empirically with antifungal agents for genital symptoms. To investigate the etiology of vaginal infections in diabetic women and to determine appropriateness of empiric antifungal therapy for symptomatic women. Prospective study performed on consecutive patients attending two diabetic clinics. Diabetic clinics serving developing communities belonging to two ethnic groups. Two hundred and one women (101 African and 100 Indian) comprising 90 women with symptoms of pruritus vulvae and/or vaginal discharge and 111 asymptomatic women. Candidiasis (50% vs. 24%; P = 0.012) and bacterial vaginosis (28% vs. 8%; P = 0.017) occurred significantly more frequently in symptomatic African women compared to asymptomatic African women. Among Indian women bacterial vaginosis (28% vs. 5%; P = 0.026) occurred more frequently in symptomatic women. The prevalence of trichomoniasis was similar in symptomatic and asymptomatic women of both ethnic groups. Mixed vaginal infections were detected significantly more often in African compared to Indian women (24% vs. 5%; P = 0.03).

In diabetic women with genital symptoms, an attempt at diagnosis should be made prior to commencement of therapy. However, in busy clinics with overstressed facilities where investigations cannot be performed, the use of empiric antifungal therapy alone is not appropriate and consideration should be given to the use of an antifungal plus a nitroimidazole agent which would be effective for both trichomoniasis and bacterial vaginosis.

Role of tissue Doppler imaging in assessing left ventricular diastolic dysfunction severity. Does it hold the same ability?

To validate the diagnostic capability of tissue Doppler imaging in assorting the extent of diastolic dysfunction. In this primary clinical research diagnostic study, we enrolled 70 patients with systemic hypertension presenting with shortness of breath between May 2010 to July 2010 to Salmaniya Medical Complex, Manama, Bahrain. Forty-eight patients satisfied the inclusion criteria. They underwent extensive echocardiographic assessment of their diastolic function with simultaneous NT pro-B-type natriuretic (BNP) assay. The latter being the reference marker of diastolic defragment. Patients were classified according to the severity of heart failure into 4 classes of New York Heart Association (NYHA) Classification. Twenty-eight (58%) were males and 20 (42%) were females. The tissue Doppler imaging (TDI) maintained a steady positive correlation with both NYHA functional class and the PRO-BNP titre. Correlation coefficient was 0.8 with a p<0.0001. N-terminal pro-B-type natriuretic peptide (NT-proBNP) can be calculated from simplified formula derived from the correlation-pro-B-NP = 93.8 x (E/E')-940.

The TDI can estimate the severity of diastolic dysfunction with striking certainty and tremendous clinical utility. Its limitation, however, has to be well addressed.

Are patients over 65 years assigned lower ECOG PS scores than younger patients , although objectively measured physical activity is no different?

The Eastern Cooperative Group Performance Status (ECOG PS) is a widely used standard functional classification in oncology practice, the verbal descriptors of which refer to physical activity (PA). Little is known about the cut-off points of this scale and measured PA levels. This research investigated the relationship between PS assigned, objectively measured PA, and patient age. One hundred ambulatory patients with treatment-naive cancer wore an accelerometer (RT3) for a mean (SD) of 5.6 (1.1) days before initial oncology evaluation and ECOG PS assignment. Seventy five participants (75%) were <65 years and 25 were ≥65 years. Eighty nine (89%) were assigned an ECOG PS of 0 or 1 and 11% a PS of 2 or 3. A weak but significant inverse association was found between objectively measured PA and PS (rho = -0.26, p = 0.01). Seventy one participants (80%) with a PS of 0 or 1 spent more than 50% of waking hours resting. Participants assigned a PS of 2-3 spent significantly more time resting than those assigned a PS of 0 (p = 0.01). Age ≥65 years was significantly related to PS assigned (p = 0.04), although the older cohort were no less sedentary than younger patients.

PA levels were low, but PS scoring reflected relative PA levels and differentiated between patients of PS 0 and 2-3. Chronological age was not predictive of activity levels, but older patients were assigned lower PS scores. Incorporation of objective PA measures may merit further investigation especially in the geriatric oncology setting.

Does rNA-seq analysis reveal extensive transcriptional plasticity to temperature stress in a freshwater fish species?

Identifying genes of adaptive significance in a changing environment is a major focus of ecological genomics. Such efforts were restricted, until recently, to researchers studying a small group of model organisms or closely related taxa. With the advent of next generation sequencing (NGS), genomes and transcriptomes of virtually any species are now available for studies of adaptive evolution. We experimentally manipulated temperature conditions for two groups of crimson spotted rainbowfish (Melanotaenia duboulayi) and measured differences in RNA transcription between them. This non-migratory species is found across a latitudinal thermal gradient in eastern Australia and is predicted to be negatively impacted by ongoing environmental and climatic change. Using next generation RNA-seq technologies on an Illumina HiSeq2000 platform, we assembled a de novo transcriptome and tested for differential expression across the treatment groups. Quality of the assembly was high with a N50 length of 1856 bases. Of the 107,749 assembled contigs, we identified 4251 that were differentially expressed according to a consensus of four different mapping and significance testing approaches. Once duplicate isoforms were removed, we were able to annotate 614 up-regulated transfrags and 349 that showed reduced expression in the higher temperature group.

Annotated blast matches reveal that differentially expressed genes correspond to critical metabolic pathways previously shown to be important for temperature tolerance in other fish species. Our results indicate that rainbowfish exhibit predictable plastic regulatory responses to temperature stress and the genes we identified provide excellent candidates for further investigations of population adaptation to increasing temperatures.

Does arcuate fasciculus laterality by diffusion tensor imaging correlate with language laterality by functional MRI in preadolescent children?

Language lateralization is unique to humans. Functional MRI (fMRI) and diffusion tensor imaging (DTI) enable the study of language areas and white matter fibers involved in language, respectively. The objective of this study was to correlate arcuate fasciculus (AF) laterality by diffusion tensor imaging with that by fMRI in preadolescent children which has not yet been reported. Ten children between 8 and 12 years were subjected to fMRI and DTI imaging using Siemens 1.5 T MRI. Two language fMRI paradigms--visual verb generation and word pair task--were used. Analysis was done using SPM8 software. In DTI, the fiber volume of the arcuate fasciculus (AFV) and fractional anisotropy (FA) was measured. The fMRI Laterality Index (fMRI-LI) and DTI Laterality Index (DTI-LI) were calculated and their correlation assessed using the Pearson Correlation Index. Of ten children, mean age 10.6 years, eight showed left lateralization while bilateral language lateralization was seen in two. AFV by DTI was more on the left side in seven of the eight children who had left lateralization by fMRI. DTI could not trace the AF in one child. Of the two with bilateral language lateralization on fMRI, one showed larger AFV on the right side while the other did not show any asymmetry. There was a significant correlation (p < 0.02) between fMRI-LI and DTI-LI. Group mean of AFV by DTI was higher on the left side (2659.89 ± 654.75 mm(3)) as compared to the right (1824.11 ± 582.81 mm(3)) (p < 0.01).

Like fMRI, DTI also reveals language laterality in children with a high degree of correlation between the two imaging modalities.

Does a molecular prognostic model predict esophageal squamous cell carcinoma prognosis?

Esophageal squamous cell carcinoma (ESCC) has the highest mortality rates in China. The 5-year survival rate of ESCC remains dismal despite improvements in treatments such as surgical resection and adjuvant chemoradiation, and current clinical staging approaches are limited in their ability to effectively stratify patients for treatment options. The aim of the present study, therefore, was to develop an immunohistochemistry-based prognostic model to improve clinical risk assessment for patients with ESCC. We developed a molecular prognostic model based on the combined expression of axis of epidermal growth factor receptor (EGFR), phosphorylated Specificity protein 1 (p-Sp1), and Fascin proteins. The presence of this prognostic model and associated clinical outcomes were analyzed for 130 formalin-fixed, paraffin-embedded esophageal curative resection specimens (generation dataset) and validated using an independent cohort of 185 specimens (validation dataset). The expression of these three genes at the protein level was used to build a molecular prognostic model that was highly predictive of ESCC survival in both generation and validation datasets (P = 0.001). Regression analysis showed that this molecular prognostic model was strongly and independently predictive of overall survival (hazard ratio = 2.358 [95% CI, 1.391-3.996], P = 0.001 in generation dataset; hazard ratio = 1.990 [95% CI, 1.256-3.154], P = 0.003 in validation dataset). Furthermore, the predictive ability of these 3 biomarkers in combination was more robust than that of each individual biomarker.

This technically simple immunohistochemistry-based molecular model accurately predicts ESCC patient survival and thus could serve as a complement to current clinical risk stratification approaches.

Does artificial formula induce precocious maturation of the small intestine of artificially reared suckling rats?

The artificially reared rat model was used successfully to study the effect of nutrition during the early postnatal period on growth and development of the neonate. Overgrowth and morphologic changes of the gastrointestinal tract are known consequences of artificial rearing. The major goal of our study was to elucidate whether artificial rearing-enhanced gut development is caused by artificial diet or by gastrostomy and the artificial rearing technique itself. Suckling rats at day 8 of age underwent intragastric cannulation and were machine fed either a cow's milk-based artificial rat's milk substitute or pooled rat's milk for 4 days. Dam-fed littermates served as a control. Body growth did not differ in the three experimental groups. In rats receiving rat's milk substitute, small intestinal wet weight was approximately 60% greater than in rats fed rat's milk or control rats. Additionally, the entire small intestine was approximately 20% longer in the rat's milk substitute group. Morphologically, rat's milk substitute-fed pups demonstrated significantly greater intestinal villus length and crypt depth compared with rat's milk-fed or control rats. Jejunum and midjejunum of the rat's milk and control groups did not differ in these parameters. Intestinal sucrase activity of rat's milk substitute-fed rats was significantly elevated compared with rat's milk-fed rats or control animals.

These results indicate that cow's milk-based formula, not gastrostomy or artificial feeding technique, is a principal cause of the small intestine overgrowth and precocious maturation of some intestinal functions observed in artificially reared sucklings.

Does stress-induced activation of the HPA axis predict connectivity between subgenual cingulate and salience network during rest in adolescents?

Responses to stress vary greatly in young adolescents, and little is known about neural correlates of the stress response in youth. The purpose of this study was to examine whether variability in cortisol responsivity following a social stress test in young adolescents is associated with altered neural functional connectivity (FC) of the salience network (SN) measured during resting-state functional magnetic resonance imaging (rs-fMRI). Forty-nine typically developing young adolescents participated in a social stress test during which they contributed salivary cortisol samples. Following this, they underwent rs-fMRI scanning. We examined the association of FC of the SN [composed of anterior cingulate cortex and bilateral anterior insula regions] with cortisol responsivity. Greater cortisol responsivity was significantly positively correlated with higher FC between subgenual anterior cingulate cortex (Cg25) and the SN, controlling for participant age. There were no regions of the brain that showed an inverse relation.

Brain systems that have been implicated in autonomic arousal and that influence subjective feeling states show altered FC associated with stress responsivity in early life.

Do chitosan/hyaluronic acid polyelectrolyte complex hydrogels in the management of burn wounds?

This paper is a short review on the state-of-the-art of the use of polyelectrolyte complexes containing polysaccharides for wound and burn healing and treatment using the chitosan/hyaluronic acid polyelectrolyte complex (PEC) hydrogel.

PEC is suitable for wound healing because a wet treatment can be realized and both components of PEC contribute by their properties to the enhanced antimicrobial activity, promote wound healing and prevent wound damage during treatment.

Does articulation time affect speeded cognitive performance in multiple sclerosis?

Cognitive test performance by individuals with multiple sclerosis (MS) may be biased because of MS-related speech problems. The purpose of this study was to compare articulation and pause durations between individuals with MS and controls on cognitive tests requiring an oral response. As part of a neuropsychological assessment, 41 patients with MS and 23 controls completed oral forms of 2 timed cognitive tests that are commonly used in MS. Acoustic analysis software segmented oral test responses into "articulation" and "pause" time durations. Overall cognitive test performance by the patients with MS was significantly associated with average pause duration, but not average articulation duration. Articulation time did not contribute to or confound the outcome of either test.

Articulation time did not contribute to differences in test performance between patients with MS and controls; rather, the time spent in silence between responses (pause time) largely accounted for group differences. Future research could use the methods described here to study speech characteristics during cognitive tests that require oral responses for patients with known speech impairments and more progressive forms of MS.

Preserves lower extremity arterial reconstruction in the very elderly : successful outcome only the limb but also residential status and ambulatory function?

The purpose of this study was to evaluate our results with lower extremity arterial reconstruction (LEAR) in patients 80 years of age or older and to assess its impact on ambulatory function and residential status. We performed a retrospective review of all patients 80 years of age or older undergoing LEAR at a single institution from January 1990 through December 1995. Preoperative information regarding residential status and ambulatory function was obtained from the hospital record and vascular registry. Telephone interviews with patients or next of kin were undertaken to provide information regarding postoperative residential status and ambulatory function. Residential status and level of ambulatory function were graded by a simple scoring system in which 1 indicates living independently, walking without assistance; 2 indicate living at home with family, walking with an ambulatory assistance device; 3 indicates an extended stay in a rehabilitation facility, using a wheelchair; and 4 indicates permanent nursing home, bedridden. Preoperative and postoperative scores for both residential status and ambulatory function were compared. Kaplan-Meier survival curves were generated for graft patency, limb salvage, and patient survival. Two hundred ninety-nine lower extremity bypass operations were performed in 262 patients 80 years of age or older (45% men, mean age 83.6 years, range 80 to 96 years). Sixty-seven percent of the patients had diabetes mellitus. Limb salvage was the indication for operation in 96%. The preoperative mean residential status and ambulatory function scores were 1.79+/-0.65 and 1.55+/-0.66, respectively. The perioperative mortality rate at 30 days was 2.3%. The median length of hospital stay decreased from 16 days in 1990 to 8 days in 1995 (range 4 to 145 days). Eighty-seven percent of grafts were performed with the autologous vein. The 5-year primary, assisted primary, and secondary graft patency rates for all grafts were 72%, 80%, and 87%, respectively. The limb salvage rate at 5 years was 92%. The patient survival rate at 5 years was 44%. The postoperative residential status and ambulatory function scores were 1.95+/-0.80 and 1.70+/-0.66, respectively. Overall scores remained the same or improved in 88% and 78% of patients, respectively.

LEAR in octogenarians is safe, with graft patency and limb salvage rates comparable to those reported for younger patients. LEAR preserves the ability to ambulate and reside at home for most patients.

Are movement-related EEG potentials force or end-effector dependent : evidence from a multi-finger experiment?

This study examined behavioral and electrocortical responses in producing 3 levels of force (25, 50 and 75% of MVC) at a constant rate of force development with each of 4 fingers both during the achievement of the desired force (ramp phase) and its maintenance (static phase). We were particularly interested in describing in more detail the interaction between nominal force and finger on various components of movement-related potential (MRP) associated with preparation and execution of isometric force production tasks. Our experimental design systematically controlled the rate of force development while nominal force level was experimentally manipulated during isometric force production tasks. We applied time-domain averaging of EEG single trials in order to extract 3 components of MRP (BP(-600 to -500); MP(-100 to 0); MMP) preceding and accompanying behavioral responses. Overall, as in our previous research the effect of force per se was not reflected in the EEG components. However, we did find an interaction between finger and force level in both the Bereitshaftspotential (BP) and motor potential (MP) components of the movement-related potentials. While the middle, ring and little finger produced no differences in EEG components at any of the 3 force levels, the index finger did. We further correlated the force trajectory and the EEG time series with the highest correlations found in the lowest force level with the index finger. As the force level was increased, the correlation was significantly reduced.

Overall, the whole complex of MRP components and evolution of EEG time series during multi-finger isometric force production tasks reflect a combination of factors including the primary end-effector performing the task and interaction of end-effector and the amount of nominal force.

Does prepubertal angiotensin blockade exert long-term therapeutic effect through sustained ATRAP activation in salt-sensitive hypertensive rats?

We previously showed that the molecule interacting with Ang II type 1 receptor (AT1R), ATRAP, promotes AT1R internalization and attenuates AT1R-mediated pathological responses. In this study we examined whether the regulation of renal ATRAP expression is related to the development of salt-induced hypertension and renal injury as well as to the beneficial effects of AT1R blockade. Dahl Iwai salt-sensitive hypertensive and Dahl Iwai salt-resistant rats were divided into six groups for the administration of vehicle or olmesartan either continuously from 3 to 16 weeks, or transiently from weaning to puberty (3-10 weeks), and fed high salt diet from 6 to 16 weeks. In Dahl Iwai salt-sensitive rats, not only continuous, but also prepubertal olmesartan treatment improved hypertension at 15 weeks. Renal ATRAP expression was suppressed in vehicle-treated Dahl Iwai salt-sensitive rats, concomitant with up-regulation of renal oxidative stress, inflammation and fibrosis-related markers such as p22phox, TGF-β, fibronectin, monocyte chemotactic protein-1 and type 1 collagen. However, prepubertal as well as continuous olmesartan treatment recovered the suppressed renal ATRAP expression and inhibited the renal activation of p22phox, TGF-β, fibronectin, MCP-1 and type 1 collagen. In Dahl Iwai salt-resistant rats, such suppression of renal ATRAP expression or induction of renal pathological responses by salt loading was not observed.

These results indicate that prepubertal transient blockade of AT1R signaling exerts a long-term therapeutic effect on salt-induced hypertension and renal injury in Dahl Iwai salt-sensitive rats, partly through a sustained enhancement of renal ATRAP expression, thereby suggesting ATRAP a novel molecular target in salt-induced hypertension and renal injury.

Is cYP2C93 variant associated with antidiabetes efficacy of gliclazide in Chinese type 2 diabetes patients?

The objective of the present study was to investigate the effects of CYP2C9*3 polymorphisms on the therapeutic response to gliclazide in type 2 diabetes patients. A total of 746 incident type 2 diabetes patients were included in this study. After enrolment, patients went on 4-week gliclazide monotherapy. Fasting plasma glucose was measured before and after treatment. Hypoglycemia episodes and lifestyle information were collected by weekly follow up. Genotyping of rs1057910 was carried out using the single base primer extension method. The t-test, analysis of variance and chisquare-test were used to evaluate the effects of rs1057910 alleles on the therapeutic response to gliclazide. After the therapy, fasting plasma glucose decreased significantly from 11.2 ± 2.7 mmol/L to 8.0 ± 2.2 mmol/L (P < 0.001). Patients with AC/CC genotypes of rs1057910 had a greater reduction of fasting plasma glucose (3.6 vs 3.0 mmol/L, P < 0.001; 31.4 vs 24.5%, P < 0.001) and a higher rate of treatment success (54.7 vs 37.5%, P < 0.001; 51.4 vs 32.3%, P < 0.001; 71.6 vs 48.3%, P < 0.001 for criterion 1, 2 and 3, respectively).

The present study showed that the polymorphism at rs1057910 significantly affected the therapeutic response of gliclazide in type 2 diabetes mellitus patients. The risk allele is associated with a greater decrease of fasting blood glucose and a higher rate of treatment success with gliclazide monotherapy.

Anti-corpus luteum antibody: a novel serological marker for ovarian dysfunction in systemic lupus erythematosus?

To investigate the presence of autoantibodies directed to corpus luteum (CoL) in systemic lupus erythematosus (SLE) sera and its correlation with menstrual disturbances. We evaluated 87 female patients with SLE,<40 years old, and 23 women with normal menses as controls. Anti-corpus luteum antibody was detected by immunoblot technique. Reactivity to a bovine CoL antigen was found in 22% of SLE sera. Characterization of the target antigen revealed a 67 kDa glycoprotein highly enriched in corpus luteum, but nearly absent in total ovary extract. Similarly, target antigen was also weakly detectable in tissues that produce or metabolize steroids, such as testis, adrenal cortex, and liver, and it was absent in adrenal medulla or HEp-2 cells. Anti-CoL antibody was easily distinguished from other frequent reactivities of SLE sera, including anti-RNP, anti-Sm, anti-Ro/La, anti-dsDNA, or anticardiolipin. The observation of anti-67 kDa reactivity to human CoL suggests a possible pathogenic role in gonadal dysfunction. Indeed, we observed an inverse association of anti-CoL antibody with the duration of hypergonadotropic amenorrhea. Supporting this hypothesis, in patients with normal or irregular menses, the presence of this antibody was associated with elevated serum level of follicle stimulating hormone, an early and specific sign of ovarian lesion.

Anti-CoL antibody seems to be associated with early stages of ovarian dysfunction in SLE. Moreover, since similar association of antiovarian antibodies has been observed in an experimental model of autoimmune oophoritis, our findings raise the possibility of autoimmune ovarian lesion in patients with SLE.

Is prognostic role of carcinoembryonic antigen influenced by microsatellite instability genotype and stage in locally advanced colorectal cancers?

Carcinoembryonic antigen (CEA) is the most frequently used marker for colorectal cancer (CRC). Influence of genetic instability on tumor marker expression is not known. The aim of this study was to investigate microsatellite instability (MSI) of CEA serum levels in locally advanced CRC. The observational cohort consisted of stage II-III CRC patients (n = 131) 75 years old or youngerwho underwent surgery with curative intent. CEA serum levels were measured before (preCEA) and immediately after surgery (postCEA). DNA from the extracted tumors was investigated for MSI. Survival was analyzed in univariate and multivariate analyses. The median preCEA was 3 U/ml (IQR = 1-3, range = 1-136 U/ml). Stage III cancers with MSI had an elevated preCEA more often than those without MSI (25% vs. 0%; p = 0.026). A preCEA >10 U/ml was significantly associated with elevated postCEA (CEA >1 U/ml; odds ratio [OR] = 5.4, 95% CI = 2.1-14.2; p < 0.001). Survival wasnot significantly different between those with postCEA <10 U/ml vs. postCEA ≥ 10 U/ml or when stratified by MSI status. A cutoff of postCEA ≤ 1 U/ml conferred significantly improved survival compared to higher CEA levels. Stratified for MSI status, this difference was significant for microsatellite stable (MSS) cancers only (p = 0.021). In multivariate analysis, postCEA >1 U/ml (hazard ratio [HR] = 3.5, 95% CI = 1.7-7.3, p = 0.001) and stage III (HR = 6.7, 95% CI = 3.0-14.9; p < 0.001) were predictors of decreased survival.

Preoperative CEA levels were significantly higher in stage III cancers with the MSI genotype, and high preoperative CEA was associated with increased postoperative CEA. Absent postoperative CEA in serum conferred improved long-term survival.

Does simvastatin increase osteoblasts and osteogenic proteins in ovariectomized rats?

Previous reports have indicated that statins could prevent bone loss in ovariectomized (OVX) rats and increase the expressions of osteogenic genes in cultured osteoblasts. In this study, we hypothesized that simvastatin might increase osteoblast number and protein expressions of osteogenic markers localized in bones in concomitance with the prevention of bone loss in OVX rats. Fifty-four 3-month-old OVX and sham-operated (SHAM) female Sprague-Dawley rats were used. Simvastatin (10-20 mg kg(-1) day(-1)) was administrated orally for 6 weeks. Trabecular volume, osteoblast number and osteogenic proteins including BMP2, collagen type I and osteocalcin on bone sections obtained from lumbar vertebral body, distal femur and proximal tibia were measured. The results showed that SHAM rats had significantly less trabecular bone volume and osteoblast number than that of OVX rats 6 weeks after operation. Oral simvastatin treatment (10-20 mg kg(-1) day(-1)) increased bone volume and osteoblast number in the distal femurs, proximal tibiae and vertebrae of OVX rats. Furthermore, the osteoblastic cells with immuno-stained BMP2, collagen type I and osteocalcin in vertebral bones were significantly increased by simvastatin treatment (20 mg kg(-1) day(-1)) in OVX rats.

This study demonstrates that simvastatin enhances the production of osteogenic proteins in bone and this effect may contribute to the prevention of bone loss in OVX rats.

Does twenty-four hour prophylaxis with increased dosage of octreotide reduce the incidence of post-ERCP pancreatitis?

Acute pancreatitis is a common complication of ERCP, occurring in up to 10% of cases. Chemoprevention of post-ERCP pancreatitis remains a debated issue. This study evaluated whether increased dosage of octreotide, a potent inhibitor of pancreatic secretion, could reduce the incidence of post-ERCP pancreatitis. In a randomized, double-blind, placebo controlled trial, the effect of 500 microg octreotide, given 3 times daily subcutaneously starting 24 hours before the ERCP procedure, was compared with that of placebo in patients who underwent diagnostic and/or therapeutic ERCP. A total of 202 patients were included in the trial. The 2 groups were similar in regards to age, sex, indications for treatment, underlying diseases, and types of therapeutic procedures. Patients were clinically evaluated, and serum amylase levels were determined before ERCP and at 6 to 8 hours thereafter. Standardized criteria were used to diagnose and to grade the severity of post-ERCP pancreatitis. The medication was discontinued because of an allergic reaction in 1 patient in the octreotide group. The incidence of post-ERCP pancreatitis was significantly lower in the octreotide group compared with the placebo group (2/10 [2%] vs 9/101 [8.9%], P = .03). All cases of acute pancreatitis were mild, except 2 (1 moderate and 1 severe) in the placebo group.

The results of this trial support the use of 24-hour prophylaxis with high dose of octreotide in the prevention of post-ERCP pancreatitis.

Does the heme oxygenase 1 product biliverdin interfere with hepatitis C virus replication by increasing antiviral interferon response?

The anti-inflammatory and antiapoptotic heme degrading enzyme heme oxygenase-1 (HO-1) has been shown recently to interfere with replication of hepatitis C virus (HCV). We investigated the effect of HO-1 products carbon monoxide (CO), iron and biliverdin on HCV replication using the replicon cell lines Huh-5-15 and LucUbiNeo-ET, stably expressing HCV proteins NS3 through NS5B. Incubation of these cell lines in the presence of the CO donor methylene chloride transiently reduced HCV replication, whereas an increase of iron in cell culture by administration of FeCl(3) or iron-saturated lactoferrin did not interfere with HCV replication. Likewise, depletion of iron by deferoxamine during induction of HO-1 by cobalt-protoporphyrin IX did not restore HCV replication. The most prominent effect was observed after incubation of replicon cell lines in the presence of biliverdin. Biliverdin seems to interfere with HCV replication-mediated oxidative stress by inducing expression of antiviral interferons, such as interferon alpha2 and alpha17.

The antioxidant biliverdin reduces HCV replication in vitro by triggering the antiviral interferon response and might improve HCV therapy in the future.

Can juvenile justice detention facilities meet the call of the American Academy of Pediatrics and National Commission on Correctional Health Care?

Despite the recommendation of the American Academy of Pediatrics, just 53 of the approximately 3500 juvenile justice residential facilities in the United States have received voluntary accreditation for facility health care from the National Commission on Correctional Health Care. This suggests either that facilities do not meet the standards of care or do not seek accreditation. This study describes whether and under what conditions juvenile detention facilities (a narrowly defined subset of all facility types) adhere to some of the standards outlined by the National Commission on Correctional Health Care and promoted by the American Academy of Pediatrics. Data from 2 national censuses of juvenile justice residential facilities (n = 726) were used to describe detention facility performance in terms of 10 types of service provision, ranging from health screening to communicable-disease testing. Multivariate models predicting high levels of service provision were estimated. Juvenile detention centers partially meet some of the minimum standards. Most services can be garnered at some level; however, they tend to be provided on an ad hoc basis for portions of the population rather than systematically for the whole population. Detention centers most likely to provide a higher tier of services tend to be those that have longer average lengths of stay, are larger, and are government owned. There are also geographic and racial differences in quality and scope of health services.

Juvenile facilities have been provided a single set of standards for a diverse system with tremendous variation across and within facility types. Detention centers are just one specialized type. Very few detention centers meet a minimum standard of care, which suggests that standards are simply not being met (hence the low levels of accreditation). The findings of this study call into question whether detention facilities with little in the way of health care infrastructure can benefit from National Commission on Correctional Health Care standards as they are currently packaged, regardless of whether accreditation is the ultimate goal.

Do reoxygenation-derived toxic reactive oxygen/nitrogen species modulate the contribution of bone marrow progenitor cells to remodeling after myocardial infarction?

The core region of a myocardial infarction is notoriously unsupportive of cardiomyocyte survival. However, there has been less investigation of the potentially beneficial spontaneous recruitment of endogenous bone marrow progenitor cells (BMPCs) within infarcted areas. In the current study we examined the role of tissue oxygenation and derived toxic species in the control of BMPC engraftment during postinfarction heart remodeling. For assessment of cellular origin, local oxygenation, redox status, and fate of cells in the infarcted region, myocardial infarction in mice with or without LacZ(+) bone marrow transplantation was induced by coronary ligation. Sham-operated mice served as controls. After 1 week, LacZ(+) BMPC-derived cells were found inhomogeneously distributed into the infarct zone, with a lower density at its core. Electron paramagnetic resonance (EPR) oximetry showed that pO2 in the infarct recovered starting on day 2 post-myocardial infarction, concomitant with wall thinning and erythrocytes percolating through muscle microruptures. Paralleling this reoxygenation, increased generation of reactive oxygen/nitrogen species was detected at the infarct core. This process delineated a zone of diminished BMPC engraftment, and at 1 week infiltrating cells displayed immunoreactive 3-nitrotyrosine and apoptosis. In vivo treatment with a superoxide dismutase mimetic significantly reduced reactive oxygen species formation and amplified BMPC accumulation. This treatment also salvaged wall thickness by 43% and left ventricular ejection fraction by 27%, with significantly increased animal survival.

BMPC engraftment in the infarct inversely mirrored the distribution of reactive oxygen/nitrogen species. Antioxidant treatment resulted in increased numbers of engrafted BMPCs, provided functional protection to the heart, and decreased the incidence of myocardial rupture and death.

Does desflurane but not sevoflurane impair airway and respiratory tissue mechanics in children with susceptible airways?

Although sevoflurane and desflurane exert bronchoactive effects, their impact on the airway and respiratory tissue mechanics have not been systematically compared in children, especially in those with airway susceptibility (AS). The aim of this study was to assess airway and respiratory tissue mechanics in children with and without AS during sevoflurane and desflurane anesthesia. Respiratory system impedance was measured in healthy control children (group C, n = 20) and in those with AS (group AS, n = 20). Respiratory system impedance was determined during propofol anesthesia and during inhalation of sevoflurane and desflurane 1 minimum alveolar concentration in random order. Airway resistance, tissue damping, and elastance were determined from the respiratory system impedance spectra by model fitting. Children in group AS exhibited significantly higher respiratory impedance parameters compared with those in group C. Sevoflurane slightly decreased airway resistance (-7.0 +/- 1.5% vs. -4.8 +/- 2.4% in groups C and AS, respectively) in both groups. In contrast, desflurane caused elevations in airway resistance and tissue mechanical parameters, with markedly enhanced airway narrowing in children with AS (18.2 +/- 2.8% vs. 53.9 +/- 5%; P < 0.001 for airway resistance in groups C and AS, respectively). Neither the order of drug administration nor the time after the establishment of their steady state concentrations affected these findings.

These results emphasized the deleterious effects of desflurane on the airways, particularly in children with susceptible airways in contrast with the consistent beneficial effects of sevoflurane, questioning the use of desflurane in children with AS.

Is cytoglobin upregulated by tumour hypoxia and silenced by promoter hypermethylation in head and neck cancer?

Cytoglobin (Cygb) was first described in 2002 as an intracellular globin of unknown function. We have previously shown the downregulation of cytoglobin as a key event in a familial cancer syndrome of the upper aerodigestive tract. Cytoglobin expression and promoter methylation were investigated in sporadic head and neck squamous cell carcinoma (HNSCC) using a cross-section of clinical samples. Additionally, the putative mechanisms of Cygb expression in cancer were explored by subjecting HNSCC cell lines to hypoxic culture conditions and 5-aza-2-deoxycitidine treatment. In clinically derived HNSCC samples, CYGB mRNA expression showed a striking correlation with tumour hypoxia (measured by HIF1A mRNA expression P=0.013) and consistent associations with histopathological measures of tumour aggression. CYGB expression also showed a marked negative correlation with promoter methylation (P=0.018). In the HNSCC cell lines cultured under hypoxic conditions, a trend of increasing expression of both CYGB and HIF1A with progressive hypoxia was observed. Treatment with 5-aza-2-deoxycitidine dramatically increased CYGB expression in those cell lines with greater baseline promoter methylation.

We conclude that the CYGB gene is regulated by both promoter methylation and tumour hypoxia in HNSCC and that increased expression of this gene correlates with clincopathological measures of a tumour's biological aggression.

Does deoxyribonucleic acid analysis facilitate the pretreatment identification of high-risk endometrial cancer patients?

Our purpose was to assess the proficiency with which cytometrically determined deoxyribonucleic acid variables from pretreatment curettage specimens identify patients at high risk for extrauterine disease or posttreatment relapse. Flow cytometrically determined deoxyribonucleic acid ploidy, S-phase fraction, deoxyribonucleic acid index, and proliferative index were assessed in 140 paraffin-embedded curettage specimens containing endometrial carcinoma. Although clinical staging identified only 19% of patients with advanced disease, 46% of surgical stages III and IV were aneuploid, 69% had an S-phase fraction > or = 9%, and 69% had a proliferative index > or = 14%. Documented recurrences and cancer-related deaths correlated with nondiploid patterns (29% of 140, 50% of recurrences, 54% of deaths), S-phase fraction > or = 9% (41% of 140, 67% of recurrences, 75% of deaths), and proliferative index > or = 14% (45% of 140, 73% of recurrences, 79% of deaths). Deoxyribonucleic acid index (< 1.5 vs > 1.5) provided additional stratification of aneuploid tumors (p < 0.01). Multivariate analysis identified the proliferative index as the most cogent independent prognostic factor (p < 0.01).

Deoxyribonucleic acid ploidy and proliferative activity in pretreatment curettage specimens identified the majority of patients at high risk for extrauterine metastasis and relapses.

Do ureteral stents cause bacterial infections in children after ureteral reimplantation?

To determine, in a prospective study, the incidence of bacterial colonization and the risk of bacterial infection of indwelling double-J stents in children undergoing ureteral reimplantation. In a balance between the safety and comfort of the child, the need for postoperative stenting of the reimplanted ureters has been discussed. It is unknown whether an indwelling double-J stent after ureteral reimplantation would be a risk factor for postoperative urinary tract infection. From 2005 to 2010, 209 children (138 girls and 71 boys; median age 3.8 years) with vesicoureteral reflux underwent unilateral or bilateral cross-trigonal ureteral reimplantation (352 ureters). All children received a single dose of gentamicin (2 mg/kg body weight) and a preoperative bladder rinse with 10% polividone-saline solution. A transurethral catheter was also left postoperatively for 2 (unilateral) or 3 (bilateral) days. The ureter was stented with a 8-22 cm multilength catheter. At 3 weeks postoperatively, the ureteral catheters were removed and investigated for bacterial colonization. Of the 209 children, 10 (4.8%) developed a urinary tract infection within the first 6 weeks after ureteral reimplantation. Of the remaining 199 children without any symptoms, 13 (6.5%) had a positive urine culture at removal of the catheters. Of the 199 children without any symptoms, 90 (45.2%) had a positive culture of one or more segments of the double-J catheter.

Although the colonization rate of ureteral stents in our study was 42.9%, the rate of urinary tract infection during the first 6 weeks after ureteral reimplantation using indwelling ureteral stents was only 4.6%. We have concluded that the clinical significance of bacterial colonization of an indwelling ureteral stent is low, and therefore, ureteral stents can be used safely.

Does bombesin preserve Goblet Cell Resistin-Like Molecule β During Parenteral Nutrition but Not Other Goblet Cell Products?

Parenteral nutrition (PN) increases the risk of infection in critically ill patients and is associated with defects in gastrointestinal innate immunity. Goblet cells produce mucosal defense compounds, including mucin (principally MUC2), trefoil factor 3 (TFF3), and resistin-like molecule β (RELMβ). Bombesin (BBS), a gastrin-releasing peptide analogue, experimentally reverses PN-induced defects in Paneth cell innate immunity. We hypothesized that PN reduces goblet cell product expression and PN+BBS would reverse these PN-induced defects. Two days after intravenous cannulation, male Institute of Cancer Research mice were randomized to chow (n = 15), PN (n = 13), or PN+BBS (15 µg tid) (n = 12) diets for 5 days. Defined segments of ileum and luminal fluid were analyzed for MUC2, TFF3, and RELMβ by quantitative reverse transcriptase polymerase chain reaction and Western blot. Th2 cytokines interleukin (IL)-4 and IL-13 were measured by enzyme-linked immunosorbent assay. Compared with chow, PN significantly reduced MUC2 in ileum (P < .01) and luminal fluid (P = .01). BBS supplementation did not improve ileal or luminal MUC2 compared with PN (P > .3). Compared with chow, PN significantly reduced TFF3 in ileum (P < .02) and luminal fluid (P < .01). BBS addition did not improve ileal or luminal TFF3 compared with PN (P > .3). Compared with chow, PN significantly reduced ileal RELMβ (P < .01). BBS supplementation significantly increased ileal RELMβ to levels similar to chow (P < .03 vs PN; P > .6 vs chow). Th2 cytokines were decreased with PN and returned to chow levels with BBS.

PN significantly impairs the goblet cell component of innate mucosal immunity. BBS only preserves goblet cell RELMβ during PN but not other goblet cell products measured.

Does laryngopharyngeal Reflux have Negative Effects on Taste and Smell Functions?

We evaluated the halimetric, olfactory, and taste functions of patients with laryngopharyngeal reflux (LPR). Prospective clinical study. Multicenter tertiary care hospital. Patients who were diagnosed with LPR for the first time on the basis of a Reflux Finding Score (RFS) >11 and a Reflux Symptom Index (RSI) >13 were enrolled in this study. A control group was selected from patients without a complaint of LPR. OralChroma was used for the halimetric measurement; Sniffin' Sticks were used for the smelling test; Taste Strips were used for the taste test; and monosodium L-glutamate was used for the umami test. A total of 110 subjects were included, with a mean age of 36.8 ± 10 years (range, 19-57 years). The differences in odor threshold scores were significant between the groups (P < .001), but no change was detected for the odor identification or discrimination scores between the groups. Bitter taste scores were significantly diminished in the reflux group compared with those in the control group (P = .001), whereas no impairments were found in the other taste scores (sweet, salty, and sour). The reflux group had significantly higher umami taste scores than those of the control group for the posterior tongue and soft palate anatomic sites (P < .001 and P < .001, respectively). Dimethyl sulfite levels were significantly higher in the reflux group than in the control (P = .001).

Questioning patients who present with halitosis, taste, or smelling disorders is important to diagnose LPR.

Is configuration of the circle of Willis associated with less symptomatic intracerebral hemorrhage in ischemic stroke patients treated with intravenous thrombolysis?

The circle of Willis (CoW) is a primary collateral pathway that compensates quickly for a drop in cerebral blood flow. Using the complete CoW as a surrogate marker for good collateral circulation, its prognostic value after intravenous thrombolysis was examined. We prospectively studied 64 consecutive patients with acute ischemic stroke treated with tissue plasminogen activator within 3 hours of stroke onset between October 2005 and June 2012 in our hospital. The study protocol was based on standard guidelines for intravenous thrombolysis. On computed tomographic angiography 24 hours after thrombolysis, the CoW was complete in 21 (32.8%) cases and incomplete in 43 (67.2%). Patients with complete CoW were more likely to have early improvement in National Institute of Health Stroke Scale (NIHSS) score (median improvement 2 vs 0 at 2 hours; 4 vs 1 at 24 hours), be independent at 3 months (42% vs 19%). In the incomplete CoW group, the rate of symptomatic intracerebral haemorrhage (SICH) according to the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) definition was almost 3 times higher. Complete CoW was one of the strongest predictors of good functional outcome at 3 months (odds ratio 2.32; P = .01).

Complete CoW independently predicted functional independence and survival.

Does mutation in the AChR ion channel gate underlie a fast channel congenital myasthenic syndrome?

Most congenital myasthenic syndromes (CMS) have postsynaptic defects from mutations within the muscle acetylcholine receptor (AChR). Mutations underlying the slow channel syndrome cause a "gain of function" and usually show dominant inheritance, whereas mutations underlying AChR deficiency or the fast channel syndrome cause a "loss of function" and show recessive inheritance. To characterize the disease mechanism underlying an apparently dominantly inherited CMS that responds to IV edrophonium. DNA from CMS patients was analyzed for mutations by single-strand conformation polymorphism analysis, DNA sequence analysis, and restriction endonuclease digestion. Functional analysis of mutations was by alpha-bungarotoxin binding studies and by patch clamp analysis of mutant AChR expressed in human embryonic kidney cells. Analysis of muscle biopsies from father and son in an affected kinship showed normal endplate morphology and AChR number but severely reduced miniature endplate potentials. DNA analysis revealed that each harbors a single missense mutation in the AChR alpha-subunit gene, alphaF256L. Expression studies demonstrate this mutation underlies a fast channel phenotype with fewer and shorter ion channel activations. The major effect of alphaF256L, located within the M2 transmembrane domain, is on channel gating, both reducing the opening and increasing the closure rate.

Mutation alphaF256L results in fast channel kinetics. Expression studies suggest a dominant-negative effect within the AChR pentamer, severely compromising receptor function.

Is pediatric chronic pancreatitis associated with genetic risk factors and substantial disease burden?

To determine the clinical presentation, diagnostic variables, risk factors, and disease burden in children with chronic pancreatitis. We performed a cross-sectional study of data from the International Study Group of Pediatric Pancreatitis: In Search for a Cure, a registry of children with acute recurrent pancreatitis and chronic pancreatitis. Between-group differences were compared using Wilcoxon rank-sum test. Among 170 subjects in the registry, 76 (45%) had chronic pancreatitis; 57% were female, 80% were white; median age at diagnosis was 9.9 years. Pancreatitis-predisposing genetic mutations were identified in 51 (67%) and obstructive risk factors in 25 (33%). Toxic/metabolic and autoimmune factors were uncommon. Imaging demonstrated ductal abnormalities and pancreatic atrophy more commonly than calcifications. Fifty-nine (77%) reported abdominal pain within the past year; pain was reported as constant and receiving narcotics in 28%. Children with chronic pancreatitis reported a median of 3 emergency department visits and 2 hospitalizations in the last year. Forty-seven subjects (70%) missed 1 day of school in the past month as the result of chronic pancreatitis; 26 (34%) missed 3 or more days. Children reporting constant pain were more likely to miss school (P = .002), visit the emergency department (P = .01), and experience hospitalizations (P = .03) compared with children with episodic pain. Thirty-three children (43%) underwent therapeutic endoscopic retrograde pancreatography; one or more pancreatic surgeries were performed in 30 (39%).

Chronic pancreatitis occurs at a young age with distinct clinical features. Genetic and obstructive risk factors are common, and disease burden is substantial.

Do bile acids directly augment caudal related homeobox gene Cdx2 expression in oesophageal keratinocytes in Barrett 's epithelium?

The mechanism of transformation to intestinal metaplasia in Barrett's oesophagus has not been clarified. We investigated the effects of various bile acids on expression of the caudal related homeobox gene Cdx2 in cultured oesophageal squamous epithelial cells. In addition, morphological and histochemical changes in squamous cells to intestinal epithelial cells were studied in response to bile acid induced expression of Cdx2. A rat model of Barrett's oesophagus was created by anastomosing the oesophagus and jejunum, and Cdx2 expression was investigated by immunohistochemistry. Also, the response of various bile acids on Cdx2 gene expression was studied in the human colon epithelial cell lines Caco-2 and HT-29, as well as in cultured rat oesophageal squamous epithelial cells using a Cdx2 promoter luciferase assay. In addition, primary cultured oesophageal squamous epithelial cells were transfected with Cdx2 expression vectors and their possible transformation to intestinal-type epithelial cells was investigated. Oesophagojejunal anastomoses formed intestinal goblet cell metaplasia in rat oesophagus specimens and metaplastic epithelia strongly expressed Cdx2. When the effects of 11 types of bile acids on Cdx2 gene expression were examined, only cholic acid (CA) and dehydrocholic acid dose dependently increased Cdx2 promoter activity and Cdx2 protein production in Caco-2 and HT-29 cells, and cultured rat oesophageal keratinocytes. Results from mutation analysis of Cdx2 promoter suggested that two nuclear factor kappaB (NFkappaB) binding sites were responsible for the bile acid induced activation of the Cdx2 promoter. When bile acids were measured in oesophageal refluxate of rats with experimental Barrett's oesophagus, the concentration of CA was found to be consistent with the experimental dose that augmented Cdx2 expression in vitro. Furthermore, transfection of the Cdx2 expression vector in cultured rat oesophageal keratinocytes induced production of intestinal-type mucin, MUC2, in cells that expressed Cdx2.

We found that CA activates Cdx2 promoter via NFkappaB and stimulates production of Cdx2 protein in oesophageal keratinocytes with production of intestinal-type mucin. This may be one of the mechanisms of metaplasia in Barrett's oesophagus.

Is non-receptor tyrosine kinase Src required for ischemia-stimulated neuronal cell proliferation via Raf/ERK/CREB activation in the dentate gyrus?

Neurogenesis in the adult mammalian hippocampus may contribute to repairing the brain after injury. However, Molecular mechanisms that regulate neuronal cell proliferation in the dentate gyrus (DG) following ischemic stroke insult are poorly understood. This study was designed to investigate the potential regulatory capacity of non-receptor tyrosine kinase Src on ischemia-stimulated cell proliferation in the adult DG and its underlying mechanism. Src kinase activated continuously in the DG 24 h and 72 h after transient global ischemia, while SU6656, the Src kinase inhibitor significantly decreased the number of bromodeoxyuridine (BrdU) labeling-positive cells of rats 7 days after cerebral ischemia in the DG, as well as down-regulated Raf phosphorylation at Tyr(340/341) site, and its down-stream signaling molecules ERK and CREB expression followed by 24 h and 72 h of reperfusion, suggesting a role of Src kinase as an enhancer on neuronal cell proliferation in the DG via modifying the Raf/ERK/CREB cascade. This hypothesis is supported by further findings that U0126, the ERK inhibitor, induced a reduction of adult hippocampal progenitor cells in DG after cerebral ischemia and down-regulated phospho-ERK and phospho-CREB expression, but no effect was detected on the activities of Src and Raf.

Src kinase increase numbers of newborn neuronal cells in the DG via the activation of Raf/ERK/CREB signaling cascade after cerebral ischemia.

Does expression of TIP-1 confer radioresistance of malignant glioma cells?

Malignant gliomas represent one group of tumors that poorly respond to ionizing radiation (IR) alone or combined with chemotherapeutic agents because of the intrinsic or acquired resistance. In this study, TIP-1 was identified as one novel protein that confers resistance of glioma cells to IR. Meta-analysis indicated that high TIP-1 expression levels correlate with the poor prognosis of human malignant gliomas after radiotherapy. Studies with established human glioma cell lines demonstrated that TIP-1 depletion with specific shRNAs sensitized the cells to IR, whereas an ectopic expression of TIP-1 protected the glioma cells from the IR-induced DNA damage and cell death. Biochemical studies indicated that TIP-1 protein promoted p53 ubiquitination and resulted in a reduced p53 protein level. Furthermore, p53 and its ubiquitination are required for the TIP-1 regulated cellular response to IR. A yeast two-hybrid screening identified that TIP-1, through its single PDZ domain, binds to the carboxyl terminus of LZAP that has been studied as one tumor suppressor functioning through ARF binding and p53 activation. It was revealed that the presence of TIP-1 enhances the protein association between LZAP and ARF and modulates the functionality of ARF/HDM2 toward multi-ubiquitination of p53, while depleting TIP-1 rescued p53 from polyubiquitination and degradation in the irradiated glioma cells. Studies with a mouse xenograft model indicated that depleting TIP-1 within D54 cells improved the tumor growth control with IR.

This study provided the first evidence showing that TIP-1 modulates p53 protein stability and is involved in the radioresistance of malignant gliomas, suggesting that antagonizing TIP-1 might be one novel approach to sensitize malignant gliomas to radiotherapy.

Is relief learning dependent on NMDA receptor activation in the nucleus accumbens?

Recently, we demonstrated that the nucleus accumbens (NAC) is required for the acquisition and expression of relief memory. The purpose of this study was to investigate the role of NMDA receptors within the NAC in relief learning. The NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) was injected into the NAC. The effects of these injections on the acquisition and expression of relief memory, as well as on the reactivity to aversive electric stimuli, were tested. Intra-accumbal AP-5 injections blocked the acquisition but not the expression of relief memory. Furthermore, reactivity to aversive electric stimuli was not affected by the AP-5 injections.

The present data indicate that NMDA-dependent plasticity within the NAC is crucial for the acquisition of relief memory.

Hydatidosis in the province of Salamanca (Spain): should we let down our guard?

Hydatid disease is a major health problem in endemic countries. In Spain, this disease was notifiable from 1981 to 1996, although its incidence kept increasing until the end of this period. From 1997 on, hydatid disease is only surveyed by endemic autonomous regions. Thus, true incidences for human hydatid disease in Spain are currently unknown. In this study the cases recorded from 1996 to 2003 at the Hospital Universitario (Salamanca) which receives patients from all Salamanca province, were analyzed. Method. We obtained epidemiological and clinical data from patients at the University Hospital (reference hospital in Salamanca province) with registered CIE-10 codification 122.0 to 122.9 (hydatid disease), from January 1996 to December 2003, excluding those patients not arriving from Salamanca. We estimated the incidence of hydatid disesase in Salamanca province regarding the total population of the province. Our data show that the mean incidence (1996-2003) was 10,8/100.000 inhabitants, twice as many as previously reported by the notifiable diseases scheme. 30% of infected patients were younger than 45. In addition, during the last three years of study, several cases of paediatric hydatid disease were observed. The analysis of the origin of the cases showed a broad distribution throughout the whole province of Salamanca.

The real incidence of this disease seems to be higher than previously estimated. Importantly, the several cases of paediatric hydatid disease detected within the last two years of our study, suggest a possible re-emergence of hydatid disease.

Do comparative proteomics and global genome-wide expression data implicate role of ARMC8 in lung cancer?

Cancer loci comprise heterogeneous cell populations with diverse cellular secretions. Therefore, disseminating cancer-specific or cancer-associated protein antigens from tissue lysates could only be marginally correct, if otherwise not validated against precise standards. In this study, 2DE proteomic profiles were examined from lysates of 13 lung-adenocarcinoma tissue samples and matched against the A549 cell line proteome. A549 matched-cancer-specific hits were analyzed and characterized by MALDI-TOF/MS. Comparative analysis identified a total of 13 protein spots with differential expression. These proteins were found to be involved in critical cellular functions regulating pyrimidine metabolism, pentose phosphate pathway and integrin signaling. Gene ontology based analysis classified majority of protein hits responsible for metabolic processes. Among these, only a single non-predictive protein spot was found to be a cancer cell specific hit, identified as Armadillo repeat-containing protein 8 (ARMC8). Pathway reconstruction studies showed that ARMC8 lies at the centre of cancer metabolic pathways.

The findings in this report are suggestive of a regulatory role of ARMC8 in control of proliferation and differentiation in lung adenocarcinomas.

Thrombocytopenia: an important indicator for the application of partial exchange transfusion in polycythemic newborn infants?

The conventional therapeutic approach in polycythemic newborn infants is to apply partial exchange transfusion (PET) when hematocrit value exceeds 70% or when the infant develops symptoms with the exception of plethora. In order to investigate the possibility of using platelet count as a simple criterion implying the PET requirement, we retrospectively reviewed polycythemic newborn infants with respect to the relationship between thrombocytopenia and severity of symptoms, and the association of platelet count and the PET performance. Thrombocytopenia has been defined as a platelet count<150,000/microL. We studied 18 polycythemic infants with thrombocytopenia (group 1, 35%) and 34 without it (group 2, 65%). Perinatal asphyxia, gestational toxemia and intrauterine growth retardation, which are the three common causative factors leading to polycythemia, were not significantly different in the two groups. No correlation existed between platelet counts and hematocrit values within each group, but there was a very significant difference between the two groups in terms of severity of clinical findings (P<0001); no difference in terms of moderate findings and moderately significant difference with respect to mild symptoms and asymptomatic situation (P<0.05). Partial exchange transfusion was performed in all patients in group 1, while only 12 infants in group 2 (32%) received transfusion and the difference was statistically significant (P<0.05). A significant rise in platelet counts has been achieved only in group 1, while hematocrit values decreased significantly in both groups following PET.

This study emphasizes the relationship between thrombocytopenia and the severity of clinical findings and PET performance rate in polycythaemic newborn infants, implying that thrombocytopenia is a possible marker of hyperviscosity, the results of which warrant further investigation.

Is bmi1 required for regeneration of the exocrine pancreas in mice?

Bmi1 is a member of the Polycomb protein family and represses transcription by modifying chromatin organization at specific promoters. Bmi1 is implicated in the control of stem cell self-renewal and has been shown to regulate cell proliferation, tissue homeostasis, and differentiation. Bmi1 is present in a subpopulation of self-renewing pancreatic acinar cells and is expressed in response to pancreatic damage. We investigated the role of Bmi1 in regeneration of exocrine pancreas. Acute pancreatitis was induced in Bmi1(-/-) mice with cerulein; pancreatic cell regeneration, differentiation, and apoptosis were assessed. Cultured Bmi1(-/-) and wild-type primary acini were analyzed in vitro to determine acinar-specific consequences of Bmi1 deletion. To investigate cell autonomous versus non-cell autonomous roles for Bmi1 in vivo, pancreatitis was induced in Bmi1(-/-) mice reconstituted with a wild-type hematopoietic system. Bmi1 expression was up-regulated in the exocrine pancreas during regeneration after cerulein-induced pancreatitis. Exocrine regeneration was impaired following administration of cerulein to Bmi1(-/-) mice. Pancreata of Bmi1(-/-) mice were hypoplastic, and the exocrine pancreas was replaced with ductal metaplasia that had increased apoptosis and decreased cell proliferation compared with that of wild-type mice. Expression of Cdkn2a and p53-dependent apoptotic genes was markedly up-regulated in Bmi1(-/-) pancreas compared with wild-type mice after injury. Furthermore, after transplantation of bone marrow from wild-type to Bmi1(-/-) mice, the chimeric mice had intermediate levels of pancreatic hypoplasia and significant but incomplete rescue of impaired exocrine regeneration after cerulein injury.

Bmi1 contributes to regeneration of the exocrine pancreas after cerulein-induced injury through cell autonomous mechanisms, in part by regulating Cdkn2a expression, and non-cell autonomous mechanisms.

Is angiotensinogen polymorphism associated with risk for malignancy but not for oral cancer?

In light of the recently found contribution of angiogenic and inflammation-related factors to malignancies, this study investigated the possible association of the angiotensinogen gene (AGT) with increased risk of oral cancer. The M235T polymorphism, which influences AGT gene expression, was evaluated by restriction fragment length polymorphism analysis in the DNA samples of 163 German and Greek patients with oral squamous cell carcinoma (OSCC) and 124 healthy controls of equivalent gender, ethnicity and age. No significant difference of the mutant (235T) allele, which results in higher AGT gene expression, was observed in the whole patient group in comparison with the normal controls. Similarly, compared to the controls no significant difference of either allele or carrier frequency was detected in almost every subgroup of patients. Only in the subgroup of patients with a positive family history of cancer was a significant increase of mutant T allele and carrier frequencies observed, compared to the controls (50% vs. 36.7% and 79.3% vs. 61.3%, respectively, p < 0.05 in both cases). In this particular subgroup of patients the odds ratio for OSCC of TT homozygotes was 3.57 (CI 95% 1.2-10.62), while for the MT heterozygotes it was 2.41 (CI 95% 1.06-5.49).

This study did not reveal an association of the AGT M235T polymorphism with oral oncogenesis, but certainly suggested a possible association of this specific polymorphism with other types of cancer. The present findings support a previous suggestion that the pathway of oral oncogenesis is probably based on angiotensin-converting enzyme and bradykinin interaction and not on AGT and angiotensin peptides.

Does morphometric evaluation of tumor matrix metalloproteinase 9 predict survival after surgical resection of adenocarcinoma of the lung?

Recently, several matrix metalloproteinases (MMPs) have shown promise as prognosticators in non-small cell lung cancer. In this study, we sought to validate the importance of MMP-9 and to study the relationships between MMP-9 and several other tumor or stromal markers. We examined MMP-9 and several other markers in tumor tissues from 152 patients with surgically excised adenocarcinomas of the lung. Their preoperative clinical stages were T(1-4)N(0)M(0); however, pathological exam of their resected tissues demonstrated that 33 were stage II, and 64 were stage III. We used immunohistochemistry and morphometry to evaluate the amount of tumor staining for MMP-9, and the outcome for our study was survival time until death from recurrent lung cancer. Multivariate Cox model analysis demonstrated that pathological stage was significantly related to survival time (P < 0.01), but quantitative staining of the tumor for MMP-9 added prognostic information (P < 3.0 x10(-16)) and was more strongly prognostic than pathological stage. In the subset of pathological stage I patients, staining for MMP-9 was also significantly associated with survival (P < 1.0 x10(-6)), and a cutpoint at the median staining of 11.2% for MMP-9 divided them into two groups with distinctive survival times. Those with MMP-9 > 11.2% had a median survival time of just 11 months. Those with MMP-9 < 11.2% had not reached a median survival and had a mean survival time of >62 months.

Tumor staining for MMP-9 in resected adenocarcinoma of the lung is strongly related to survival. Patients with >11.2% staining in their tumors comprise a subset with a high hazard for dying of lung cancer and may be an appropriate target for prospective studies of adjuvant chemotherapy after surgical resection.

Does health insurance coverage of office visits influence colorectal cancer testing?

To assess the effect of differing health insurance coverage of physician office visits on the use of colorectal cancer (CRC) tests among an employed and insured population. Cohort study of persons ages 50 to 64 years enrolled in fee-for-service (FFS) or preferred provider organization (PPO) health plans, where FFS plan enrollees bear disproportionate share of office visit coverage, for the period 1995 through 1999. Compared with FFS plans, enrollees in PPO plans were significantly more likely to obtain CRC tests [adjusted relative risk (RR(a)), 1.27; 95% confidence intervals (CI), 1.21-1.24]. The association was more pronounced among hourly individuals (RR(a), 1.43; 95% CI, 1.41-1.45) than among salaried individuals (RR(a), 1.09; 95% CI, 1.05-1.10), consistent with a greater differential in office visit coverage among the hourly group.

Disproportionate cost-sharing seems to have a negative effect on the use of CRC tests most likely by discouraging nonacute care physician office visits.

Are long-term care residents referred appropriately to hospital emergency departments?

To explore the rate of referrals of long-term care (LTC) residents to emergency departments (EDs) and to determine the appropriateness of the referrals. Retrospective analysis of 2 administrative data sets, paramedic records and hospital records, for the year 2000. Catchment area of Hamilton, Ont. Nineteen LTC facilities and 3 EDs of Hamilton Health Sciences. Number and appropriateness of referrals were the main outcomes measured; we also examined the timing of and reasons for referrals, arrival status of patients, admissions to hospital, referrals to specialists, and treatments. Unit of analysis was the referral. As no evidence-based guidelines exist for appropriateness of referral, we defined appropriateness as a balance of issues with blinded physician judgment calls on anonymous random subsamples of patients admitted to hospital and those not admitted to determine appropriateness of referrals. Descriptive statistics were used, as well as chi and t tests. Out of 2473 licensed LTC beds, 606 residents were referred to 1 of 3 EDs of the Hamilton Health Sciences hospitals, giving a referral rate of 24.5%. The average age of these LTC residents was 81.6 years, and 63.2% were women. Peak referral months were late winter; peak days were Tuesday and Friday. Time of arrival to the EDs was reported in 6-hour segments, with just over half (51.2%) of residents arriving during the day and one-third in the evening. Respiratory and cardiovascular problems comprised 48.6% of referrals. At arrival 67.3% of cases were deemed urgent or emergent. Wait times ranged from 0 to 60 hours, with 25% of residents seen within 1 hour, 44% within 2 hours, and 50% within 4 hours. Two-thirds (66.7%) of residents were admitted to hospital and of these 62% stayed 1 week.

Our results agree with previous studies that cast doubt on the idea that LTC residents are "dumped" on EDs. Most referrals appeared appropriate as defined by criteria established by the physician team and given the number of hospital admissions, diagnostic tests, and treatments provided. Potentially, more acute care could be provided in LTC facilities with enhancement of services. Prospective studies could tell us more.

Do differences in hospital and surgeon quality explain racial disparities in lower-extremity vascular amputations?

To understand whether racial disparities in surgery for lower-extremity arterial disease are minimized by high-quality providers, or instead, differential treatment of otherwise similar patients pervades all settings. Black patients are substantially more likely than whites to undergo amputation rather than revascularization for lower-extremity arterial disease. Because their care is disproportionately concentrated among a small share of providers, some have attributed such disparities to the quality and capacity of these sites. We evaluated all 86,865 white or black fee-for-service Medicare beneficiaries 65 and older who underwent major lower-extremity vascular procedures. Using generalized linear mixed models with random effects, we computed risk-adjusted odds of amputation by race overall, and after serial substratification by salient patient and provider characteristics. Blacks were far more likely to undergo amputation (45% vs. 20%). Their procedures were performed more often by nonspecialists (41% vs. 27%; P<0.001), in low-volume hospitals (40% vs. 32%; P<0.001), with high amputation rates (53% vs. 29%; P<0.001). Controlling for differences in comorbidity, disease severity, and surgeon and hospital performance, blacks' odds of amputation remained 1.7 times greater (95% confidence interval: 1.6-1.9). Even among highest-performing providers-vascular specialists in high-volume, urban teaching hospitals with angioplasty facilities-racial gaps persisted (risk-adjusted amputation rates: 7% for blacks vs. 4% for whites, P<0.001; odds ratio: 1.8, 95% confidence interval: 1.5-2.1).

Black patients with critical limb ischemia face significantly higher risk of major amputation, even when treated by providers with highest likelihoods of revascularization. Increased referral to high-performing providers might increase limb-preservation, but cannot eliminate disparities until equitable treatment can be ensured in all settings.

Is effective treatment of psoriasis with etanercept linked to suppression of IL-17 signaling , not immediate response TNF genes?

TNF inhibitors have revolutionized the treatment of psoriasis vulgaris as well as psoriatic and rheumatoid arthritis and Crohn disease. Despite our understanding that these agents block TNF, their complex mechanism of action in disease resolution is still unclear. To analyze globally the genomic effects of TNF inhibition in patients with psoriasis, and to compare genomic profiles of patients who responded or did not respond to treatment. In a clinical trial using etanercept TNF inhibitor to treat psoriasis vulgaris (n = 15), Affymetrix gene arrays were used to analyze gene profiles in lesional skin at multiple time points during drug treatment (baseline and weeks 1, 2, 4, and 12) compared with nonlesional skin. Patients were stratified as responders (n = 11) or nonresponders (n = 4) on the basis of histologic disease resolution. Cluster analysis was used to define gene sets that were modulated with similar magnitude and velocity over time. In responders, 4 clusters of downregulated genes and 3 clusters of upregulated genes were identified. Genes downmodulated most rapidly reflected direct inhibition of myeloid lineage immune genes. Upregulated genes included the stable dendritic cell population genes CD1c and CD207 (langerin). Comparison of responders and nonresponders revealed rapid downmodulation of innate IL-1beta and IL-8 sepsis cascade cytokines in both groups, but only responders downregulated IL-17 pathway genes to baseline levels.

Although both responders and nonresponders to etanercept inactivated sepsis cascade cytokines, response to etanercept is dependent on inactivation of myeloid dendritic cell genes and inactivation of the T(H)17 immune response.

Does lidocaine protect from myocardial damage due to ischemia and reperfusion in mice by its antiapoptotic effects?

Perioperative myocardial ischemia poses a vital threat to surgical patients. Means to protect postischemic myocardium are clinically not available. Lidocaine has been demonstrated to exert antiinflammatory pleiotropic effects. The authors set out to test if lidocaine protects ischemic myocardium from reperfusion injury. A mouse model of transient coronary artery ligation (30 min) and reperfusion (24 h) was used with animal care committee approval. Infarct size and area-at-risk were determined. Leukocyte recruitment was quantified on immunohistochemical stainings. Apoptosis was assessed using enzyme-linked immunosorbent assay to detect histone modifications and terminal deoxynucleotidyl transferase dUTP nick end labeling assays. Lidocaine effects on leukocyte-endothelial interactions were assessed in vitro by using a parallel-plate flow chamber or static adhesion assays. Infarct size per area-at-risk was reduced by 27% in mice treated with a lidocaine bolus (1 mg/kg) before a continuous infusion (0.6 mg . kg(-1) . h(-1)) during ischemia (P < 0.005). Neutrophil density in the infarct and periinfarct zone was not reduced by lidocaine, although the size of the infiltrated area was. Terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cardiomyocytes and endothelial cells were significantly reduced in the periinfarct zone by lidocaine. In vitro, no effect on leukocyte rolling or firm adhesion to resting or activated endothelium was demonstrable. In vitro, lidocaine reduced cardiomyocyte apoptosis induced by hypoxia and reoxygenation (3h/1h) significantly. Infarct size and in vitro cardiomyocyte apoptosis were likewise reduced when lidocaine bolus and infusion were administered after the ischemic insult.

Lidocaine exerts cardioprotective effects when administered before or after the ischemic insult. This effect is mediated through an antiapoptotic and not through an antiinflammatory pathway and may be therapeutically exploitable.

Is paradoxical sphincter contraction rarely indicative of anismus?

Anismus is thought to be a cause of chronic constipation by producing outlet obstruction. The underlying mechanism is paradoxical contraction of the anal sphincter or puborectalis muscle. However, paradoxical sphincter contraction (PSC) also occurs in healthy controls, so anismus may be diagnosed too often because it may be based on a non-specific finding related to untoward conditions during the anorectal examination. To investigate the pathophysiological importance of PSC found at anorectal manometry in constipated patients and in patients with stool incontinence. Digital rectal examination and anorectal manometry were performed in 102 chronically constipated patients, 102 patients with stool incontinence, and in 18 controls without anorectal disease. In 120 of the 222 subjects defaecography was also performed. Paradoxical sphincter contraction was defined as a sustained increase in sphincter pressure during straining. Anismus was assumed when PSC was present on anorectal manometry and digital rectal examination and the anorectal angle did not widen on defaecography. Manometric PSC occurred about twice as often in constipated patients as in incontinent patients (41.2% versus 25.5%, p < 0.017) and its prevalence was similar in incontinent patients and controls (25.5% versus 22.2%). Oroanal or rectosigmoid transit times in constipated patients with and without PSC did not differ significantly (total 64.6 (8.9) hours versus 54.2 (8.1) hours; rectosigmoid 14.9 (2.4) hours versus 13.8 (2.5) hours).

Paradoxical sphincter contraction is a common finding in healthy controls as well as in patients with chronic constipation and stool incontinence. Hence, PSC is primarily a laboratory artefact and true anismus is rare.

Does cardiology consultation reduce provocative testing rates in an ED observation unit?

In evaluating patients with chest pain, emergency department observation units (EDOUs) may use a staffing model in which emergency physicians determine patient testing (EP model) or a model similar to a chest pain unit (CPU) in which cardiologists determine provocative testing (CPU model). We performed a prospective study with 30-day telephone follow-up for all chest pain patients placed in our EDOU. Halfway through the study period, our EDOU transitioned from an EP model to a CPU model. We compared provocative testing rates and outcomes between the 2 models. Over the 34-month study period, our EDOU evaluated 1190 patients for chest pain. Patients placed in the EDOU during the 17-month CPU model were more likely to be moderate risk (Thrombolysis in Myocardial Infarction score 3-5) than those during the 17-month EP model: 24.9% vs 18.8%, P = .011. Despite this difference, rates of provocative testing (stress testing or coronary computed tomography) were lower during the CPU model: 47.1% vs 56.5%, P = .001. This reduction was particularly evident among low-risk patients (Thrombolysis in Myocardial Infarction score 0-2): 49.8% vs 58.1%, P = .011. Rates of myocardial infarction, percutaneous coronary intervention, or coronary artery bypass graft were similar between the 2 groups (2.8% vs 3.2%, P = .140). We noted no significant events or missed diagnoses in either group during the 30-day follow-up.

An EDOU model that used mandatory cardiology consultation resulted in decreased provocative testing, particularly among low-risk chest pain patients. Future research should explore the cost-effectiveness of this model.

Is breast artery calcium noted on screening mammography predictive of high risk coronary calcium in asymptomatic women : a case control study?

The relationship between breast artery calcification (BAC) noted on mammography and both coronary artery disease and cardiovascular risk remains controversial. Few studies have examined the clinical significance of BAC in asymptomatic women. In the present study we evaluated the relationship between BAC and coronary artery calcium (CAC) as identified by multi-slice CT scanning (MSCT). Consecutive women (n = 98) with BAC noted on routine mammography but without known coronary artery disease (CAD) were assessed for CAD risk factors and had assessment of coronary calcium by MSCT. A control cohort of consecutive women who were BAC(-) (n = 104) underwent an identical assessment. Women who were BAC(+) were older than those who were BAC(-); otherwise, there were no differences between the 2 groups with regard to traditional cardiac risk factors. Significantly more BAC(+) vs. BAC(-) women were found to have “high risk” CAC scores, defined as CAC > 400 (11.2 % vs. 1.0 %, p = 0.006). However, the rates of CAC scores of 0 were not different between the two groups (50.0 % vs. 54.8 % for BAC(+) and BAC(-) , respectively, p = 0.586). When examined in a multivariate model including the traditional risk factors of diabetes, increasing age, smoking, hyperlipidemia, and family history of CAD, the presence of BAC remained significantly associated with CAC > 400 (OR = 22.6, 95 % CI = 2.1 - 237.1).

The presence of breast artery calcium on screening mammography was a strong independent predictor (odds ratio > 22) of high risk coronary artery calcium scores (defined as CAC > 400). The presence of BAC in those with significant CAD risk factors may warrant further evaluation.

Is low estradiol-to-testosterone ratio associated with oligo-anovulatory cycles and atherogenic lipidic pattern in women with polycystic ovary syndrome?

The estradiol-to-testosterone (E2/T) ratio has been investigated in different diseases but few in vivo data are available with regard to its role in women with ovary syndrome (PCOS). The aim of this study was to evaluate the role of the E2/T ratio in the ovulatory function and metabolic pattern in such women. We retrospectively evaluated hyperandrogenemia, clinical hyperandrogenism, ovarian morphology, hypothalamo-hypophyseal axis and metabolic syndrome parameters in a cohort of 202 consecutive women affected by PCOS. An oral glucose tolerance test measured areas under the curve for insulin (AUC(2hIRI)), for glucose (AUC(2hglucose)), and the HOMA-IR and Matsuda index of insulin resistance were evaluated. Serum progesterone (Pg) was determined from day 20 to day 24 of the menstrual cycle and chronic oligo-anovulation was established if two consecutive cycles were anovulatory. Women with PCOS with normal ovulation [66/202 (32.7%)] showed a significantly higher E2/T ratio than women with PCOS with chronic oligo/anovulation [136/202 (67.3%)] (p < 0.05). Using a series of multiple linear regression models, we also investigated which variables correlated with the E2/T ratio. The analysis showed a strongly positive correlation of the E2/T ratio with Pg (β =  0.473, p < 0.001) and a negative correlation with total cholesterol (β =  -0.433, p < 0.001).

Our data suggest that in women with PCOS a low E2/T ratio is not only associated with chronic oligo-anovulation, but is also a determinant factor of the atherogenic lipid profile.

Does pathogenic Network Analysis predict Candidate Genes for Cervical Cancer?

The objective of our study was to predicate candidate genes in cervical cancer (CC) using a network-based strategy and to understand the pathogenic process of CC. A pathogenic network of CC was extracted based on known pathogenic genes (seed genes) and differentially expressed genes (DEGs) between CC and normal controls. Subsequently, cluster analysis was performed to identify the subnetworks in the pathogenic network using ClusterONE. Each gene in the pathogenic network was assigned a weight value, and then candidate genes were obtained based on the weight distribution. Eventually, pathway enrichment analysis for candidate genes was performed. In this work, a total of 330 DEGs were identified between CC and normal controls. From the pathogenic network, 2 intensely connected clusters were extracted, and a total of 52 candidate genes were detected under the weight values greater than 0.10. Among these candidate genes, VIM had the highest weight value. Moreover, candidate genes MMP1, CDC45, and CAT were, respectively, enriched in pathway in cancer, cell cycle, and methane metabolism.

Candidate pathogenic genes including MMP1, CDC45, CAT, and VIM might be involved in the pathogenesis of CC. We believe that our results can provide theoretical guidelines for future clinical application.

Does curcumin induce Pancreatic Adenocarcinoma Cell Death Via Reduction of the Inhibitors of Apoptosis?

The inhibitor of apoptosis (IAP) proteins are critical modulators of chemotherapeutic resistance in various cancers. To address the alarming emergence of chemotherapeutic resistance in pancreatic cancer, we investigated the efficacy of the turmeric derivative curcumin in reducing IAP protein and mRNA expression resulting in pancreatic cancer cell death. The pancreatic adenocarcinoma cell line PANC-1 was used to assess curcumin's effects in pancreatic cancer. Curcumin uptake was measured by spectral analysis and fluorescence microscopy. AlamarBlue and Trypan blue exclusion assays were used to determine PANC-1 cell viability after curcumin treatment. Visualization of PANC-1 cell death was performed using Hoffman Modulation Contrast microscopy. Western blot, and polymerase chain reaction analyses were used to evaluate curcumin's effects on IAP protein and mRNA expression. Curcumin enters PANC-1 cells and is ubiquitously present within the cell after treatment. Furthermore, curcumin reduces cell viability and induces morphological changes characteristic of cell death. Additionally, curcumin decreases IAP protein and mRNA expression in PANC-1 cells.

These data demonstrate that PANC-1 cells are sensitive to curcumin treatment. Futthermore, curcumin is a potential therapeutic tool for overcoming chemotherapeutic resistance mediated by IAPs. Together, this data supports a role for curcumin as part of the therapeutic approach for the treatment of pancreatic cancer.

Does tapered-cuff Endotracheal Tube Prevent Early Postoperative Pneumonia Compared with Spherical-cuff Endotracheal Tube after Major Vascular Surgery : A Randomized Controlled Trial?

Patients undergoing major vascular surgery often develop postoperative pneumonia that impacts their outcomes. Conflicting data exist concerning the potential benefit of tapered-shaped cuffs on tracheal sealing. The primary objective of this study was to assess the efficiency of a polyvinyl chloride tapered-cuff endotracheal tube at reducing the postoperative pneumonia rate after major vascular surgery. Secondary objectives were to determine its impact on microaspiration, ventilator-associated pneumonia rate, and inner cuff pressure. This prospective randomized controlled study included 109 patients who were randomly assigned to receive either spherical- (standard cuff) or taper-shaped (tapered cuff) endotracheal tubes inserted after anesthesia induction and then admitted to the intensive care unit after major vascular surgery. Cuff pressure was continuously recorded over 5 h. Pepsin and α-amylase concentrations in tracheal aspirates were quantified on postoperative days 1 and 2. The primary outcome was the early postoperative pneumonia frequency. Comparing the tapered-cuff with standard-cuff group, respectively, postoperative pneumonia rates were comparable (42 vs. 44%, P = 0.87) and the percentage (interquartile range) of cuff-pressure time with overinflation was significantly higher (16.1% [1.5 to 50] vs. 0.6% [0 to 8.3], P = 0.01), with a 2.5-fold higher coefficient of variation (20.2 [10.6 to 29.4] vs. 7.6 [6.2 to 10.2], P < 0.001). Although microaspiration frequencies were high, they did not differ between groups.

For major vascular surgery patients, polyvinyl chloride tapered-cuff endotracheal tubes with intermittent cuff-pressure control did not lower the early postoperative pneumonia frequency and did not prevent microaspiration.

Experiences of supernumerary status and the hidden curriculum in nursing: a new twist in the theory-practice gap?

This paper aims to increase our understanding about how student nurses' experiences of supernumerary status are embedded in the hidden curriculum in clinical practice and contribute to the theory-practice gap in nursing. Current literature suggests that the hidden curriculum exists in many professional curricula and that it functions to socialise students into professional behaviours and practice. However, in nursing, there is a gap in our understanding of how these socialisation processes have been influenced by supernumerary status and what forms the hidden curriculum might take currently in clinical practice. An ethnographic case study design. Data were collected in four sites using fieldwork in clinical practice as well as interviews with students, mentors and key stakeholders, an online survey of student bodies and curriculum analysis in four universities. The findings in this paper are drawn from the qualitative fieldwork and interviews and were analysed thematically. The findings suggest that supernumerary status is an important aspect of the hidden curriculum in clinical learning for nursing students; that students are expected by trained staff to work while they learn and that on registration, they are expected to be competent to work immediately as registered nurses. These expectations are at odds with those of academic nurses and contribute to a theory-practice gap for student nurses. These expectations form part of the hidden curriculum that shapes the clinical context, and students have to learn to negotiate their status as supernumerary students in practice to meet these expectations.

Consequently, students have to learn in a disintegrated learning context where opposing values of learning exist.

Does self-Reported Sleep Disturbance mediate the Relationship Between PTSD and Cognitive Outcome in Blast-Exposed OEF/OIF Veterans?

To examine the contribution of sleep disturbance to cognitive performance following blast exposure. Correlational research evaluating self-reported sleep disturbance as a mediator of the association between the primary blast-related comorbidities of mild traumatic brain injury (mTBI) and posttraumatic stress disorder and cognitive outcome. One hundred sixty Operation Enduring Freedom/Operation Iraqi Freedom Veterans with a history of blast exposure assigned to 1 of 3 groups (no TBI, mTBI without loss of consciousness, and mTBI with loss of consciousness). Neuropsychological measures and self-report of sleep disturbance. Increased posttraumatic stress disorder symptomatology was associated with worse performance in multiple cognitive domains. This association was mediated in part by self-reported sleep disturbance. Traumatic brain injury with loss of consciousness was associated with lower manual dexterity, but this association was not mediated by sleep disturbance.

Our results highlight the importance of sleep disturbance as a factor contributing to cognitive outcome in individuals with posttraumatic stress disorder symptoms. They point to the importance of considering sleep problems in the diagnosis and treatment of cognitive deficits in veterans with blast exposure.

Do [ Effects of fluid resuscitation programs on the levels of inflammatory mediators during burn shock stage ]?

To explore the effects of different methods of fluid resuscitation on the levels of inflammatory mediators during burn shock stage. Twenty-four miniature swine were numbered from 1 to 24 and randomly divided by EXCEL 2007 into 4 groups of succinylated gelatin, hydroxyethyl starch, Parkland and allogeneic plasma (n = 6 each). Severe burn shock model was established. Succinylated gelatin, hydroxyethyl starch (130/0.4), Ringer's lactate and swine allogenic plasma were used as resuscitation fluid (alternative colloid) according to the burn shock recovery principles (beginning at 2 h post-injury). The parameters of heart rate (HR), blood pressure (BP), urine volume and central venous pressure (CVP) before and within 48 h post-burn were recorded. And the levels of tumor necrosis factor alpha (TNF-α), interleukin (IL) -1β and IL-8 were measured at the time of pre-injury as well as 4 h, 8 h, 24 h and 48 h post-injury. Statistical analyses were performed. All swine survived the shock stage. TNF-α in succinylated gelatin group was significantly higher at 48 h post-injury than that in allogeneic plasma group ((351 ± 74) vs (215 ± 44) ng/L, P < 0.05). TNF-α in hydroxyethyl starch group was significantly higher at 8 h post-injury than that in allogeneic plasma group ((327 ± 38) vs (249 ± 29) ng/L, P < 0.05). And they were both higher than the pre-burn levels (both P < 0.05). Compared with pre-injury ((508 ± 64) ng/L), the level of IL-1β in succinylated gelatin group increased substantially at 4 h ((563 ± 76) ng/L), 8 h ((589 ± 76) ng/L) and 48 h ((736 ± 42) ng/L) post-injury (all P < 0.05). The hydroxyethyl starch group was higher at 48 h post-injury than that at pre-injury ((574 ± 72) vs (492 ± 41) ng/L, P < 0.05). Also in Parkland group, the levels were higher at 24 h and 48 h hours post-injury than that at pre-injury ((575 ± 31), (584 ± 65) vs (498 ± 33) ng/L, both P < 0.05). Only succinylated gelatin group was significantly higher (P < 0.01) at 48 h post-injury than allogeneic plasma group ((561 ± 48) ng/L). Compared with pre-injury ((561 ± 48) ng/L), the level of IL-8 in succinylated gelatin group increased significantly at 8 h ((1012 ± 100) ng/L), 24 h post-burn ((993 ± 87) ng/L), significantly higher than allogeneic plasma group ((866 ± 99) ng/L) at 24 h (all P < 0.05). Although hydroxyethyl starch and Parkland groups increased significantly at 4 h post-injury and 8 h, 48 h post-injury versus those at pre-injury (all P < 0.05). There was no significant difference at each time point compared with pre-burn (P > 0.05).

The recovery regimens of hydroxyethyl starch and Parkland groups may restrain the levels of inflammatory mediators. And the effects are similar to those of allogeneic plasma group.

Is ketone body production differentially altered in steatosis and non-alcoholic steatohepatitis in obese humans?

Levels of ketone bodies have been reported to be both increased and decreased in individuals with non-alcoholic fatty liver disease. We investigated whether the metabolism of ketone bodies is different in simple steatosis and in non-alcoholic steatohepatitis (NASH). Serum low molecular weight molecules including ketone bodies were measured using high-throughput proton (1H) nuclear magnetic resonance in 116 (76 categorized unequivocally to those with normal liver, simple steatosis or NASH) morbidly obese individuals [age 47.3 ± 8.7 (mean ± SD) years, body mass index 45.1 ± 6.1 kg/m(2) , 39 men and 77 women] with histological assessment of NASH and analysis of gene expression in the liver. Finally, we correlated β-hydroxybutyrate (β-OHB) levels with NASH predicting score in Metabolic Syndrome in Men Study (METSIM) population study (n = 8749 non-diabetic men). Levels of ketone bodies were lower in individuals with NASH compared to individuals with simple steatosis (P = 0.004 and P = 0.018 for β-OHB and acetoacetate respectively). Lower levels of β-OHB were associated with the NASH predicting score in the METSIM study (P = 0.001). Liver inflammation correlated with mRNA expression of genes regulating ketolysis in the liver (Spearman correlation 0.379-0.388, P < 0.0006 for ACAT1, ACSS2 and BDH1).

Lower levels of ketone bodies in individuals with NASH compared to individuals with simple steatosis suggest a decrease in ketone body metabolism in NASH.

Transferring patients for primary angioplasty in eastern Melbourne (the SHIPEM registry): are we meeting the guidelines?

To compare clinical outcomes between patients with ST-elevation myocardial infarction (STEMI) presenting to a hospital with facilities for primary percutaneous coronary intervention (PCI) and patients transferred from a non-PCI-capable unit, and to determine the success rate of meeting clinical guidelines for management of STEMI. Prospective study of patients with STEMI who underwent PCI at Box Hill Hospital (BHH), Melbourne, between 1 July 2002 and 30 June 2008. We compared two patient groups: "BHH patients", who were admitted directly to BHH (a hospital with PCI capability), and "SHIPEM (Shipping Infarcts for Primary Angioplasty in Eastern Melbourne Registry) patients", who were transferred from other hospitals without PCI capability. Clinical outcomes; symptom-to-first-door time (time between symptom onset and arrival at first hospital); first-door-to-balloon time (time between arrival at the first hospital and inflation of the angioplasty balloon); compliance with Cardiac Society of Australia and New Zealand/National Heart Foundation of Australia (CSANZ/NHFA) guidelines for management of patients with STEMI. There were 598 patients in the BHH group and 189 in the SHIPEM group. The median first-door-to-balloon time was 89 minutes (interquartile range [IQR], 69-107 minutes) for BHH patients and 128 minutes (IQR, 104-157 minutes) for SHIPEM patients. These figures did not vary significantly over the 6 years of the registry. In the BHH group, 180 patients (30.1%) had a symptom-to-first-door time of<or = 60 minutes, with 32 (17.8%) receiving PCI in<or = 60 minutes. The corresponding figure for the SHIPEM group was 48 patients (25.4%), with 1 (2.1%) receiving PCI within 60 minutes. In the BHH group, 304 patients (50.8%) had a symptom-to-first-door time of 61-180 minutes, with 166 (54.6%) receiving PCI in<or = 90 minutes. In the SHIPEM group, 50 patients (26.5%) had a symptom-to-first-door time of>180 minutes, with 21 (42.0%) receiving PCI in<or = 120 minutes.

Our study demonstrates that transfer for PCI is feasible and safe in selected patients, with outcomes comparable to those of patients presenting to a PCI-capable unit. However, the CSANZ/NHFA targets, predicated by symptom-to-first-door time, are not being met and have not improved over time, which suggests that strategies to improve symptom-to-first-door, first-door-to-balloon and transfer times need to be addressed.

Does severe cranial neuropathies caused by fall from heights in children?

Falls from heights are the most common traumatic event associated with emergency department visits in children. This study investigated the incidence and clinical course of cranial neuropathies caused by falls from heights in children. The computerized records of a tertiary pediatric medical center were searched for all patients admitted to the emergency department in 2004-2014 with a head injury caused by falling from a height. Those with cranial neuropathies involving optic and eye-motility disturbances were identified, and their clinical, imaging, and outcome data were evaluated. Of the estimated 61,968 patients who presented to the emergency department during the study period because of a fall, 18,758 (30.3 %) had head trauma. Only 12 (seven boys, five girls, average age 6.7 years) had a visual disturbance. Eight were diagnosed with traumatic optic neuropathy, one after a 6-month delay, including two with accompanying cranial nerve (CN) III injuries. Five patients had anisocoria or an abnormal pupillary response to light at presentation, one patient had CN VI paralysis and temporary vision loss, and one patient had an isolated CN III injury diagnosed on follow-up. Visual improvement varied among the patients.

Cranial neuropathies due to falls from heights are rare in children and are associated with high visual morbidity. Vision or ocular motility impairment, especially monocular vision loss, may be missed during acute intake to the emergency department, and a high index of suspicion is needed. Assessment of the pupillary response to light is essential.

Do few Danish pregnant women follow guidelines on periconceptional use of folic acid?

Approximately 60-70 pregnancies are affected by neural tube defects (NTD) in Denmark annually. Folic acid (FA) deficiency can cause NTD. Periconceptional FA supplementation reduces the risk of NTD by up to 70-80%. Danish women planning pregnancy are recommended 0.4 mg of FA daily from at least one month before planned conception and continuing throughout the first 12 weeks of pregnancy. The aim of the present study was to examine the knowledge about and use of FA supplementation among Danish pregnant women. From 11 October 2012 to 15 November 2012, all women attending for a routine nuchal translucency scan were given a questionnaire regarding their knowledge and use of FA supplementation during their current pregnancy. A total of 462 women answered the questionnaire. 95% had taken FA supplements at some point during their pregnancy, but only 10.4% as recommended. More than 80% stated knowledge about recommendations before the current pregnancy. Positive predictors of knowledge were: age > 30 years, multiparity, Danish origin and education > 3 years.

Despite national recommendations on periconceptional FA supplementation, our study showed that women do not follow these recommendations. Especially women with a low socio-economic status were likely to lack knowledge about FA supplementation in relation to pregnancy. There is a need for revision of the existing national recommendations and for other initiatives aiming to improve women's intake of FA, including FA fortification of flour and/or other food products.

Is pre-hospital electrocardiogram triage with tele-cardiology support associated with shorter time-to-balloon and higher rates of timely reperfusion even in rural areas : data from the Bari- Barletta/Andria/Trani public emergency medical service 118 registry on primary angioplasty in ST-elevation myocardial infarction?

We report the preliminary data from a regional registry on ST-elevation myocardial infarction (STEMI) patients treated with primary angioplasty in Apulia, Italy; the region is covered by a single public health-care service, a single public emergency medical service (EMS), and a single tele-medicine service provider. Two hundred and ninety-seven consecutive patients with STEMI transferred by regional free public EMS 1-1-8 for primary-PCI were enrolled in the study; 123 underwent pre-hospital electrocardiograms (ECGs) triage by tele-cardiology support and directly referred for primary-PCI, those remaining were just transferred by 1-1-8 ambulances for primary percutaneous coronary intervention (PCI) (diagnosis not based on tele-medicine ECG; already hospitalised patients, emergency-room without tele-medicine support). Time from first ECG diagnostic for STEMI to balloon was recorded; a time-to-balloon <1 h was considered as optimal and patients as timely treated. Mean time-to-balloon with pre-hospital triage and tele-cardiology ECG was significantly shorter (0:41 ± 0:17 vs 1:34 ± 1:11 h, p<0.001, -0:53 h, -56%) and rates of patients timely treated higher (85% vs 35%, p<0.001, +141%), both in patients from the 'inner' zone closer to PCI catheterisation laboratories (0:34 ± 0:13 vs 0:54 ± 0:30 h, p<0.001; 96% vs 77%, p<0.01, +30%) and in the 'outer' zone (0:52 ± 0:17 vs 1:41 ± 1:14 h, p<0.001; 69% vs 29%, p<0.001, +138%). Results remained significant even after multivariable analysis (odds ratio for time-to-balloon 0.71, 95% confidence interval (CI) 0.63-0.80, p<0.001; 1.39, 95% CI 1.25-1.55, p<0.001, for timely primary-PCI).

Pre-hospital triage with tele-cardiology ECG in an EMS registry from an area with more than one and a half million inhabitants was associated with shorter time-to-balloon and higher rates of timely treated patients, even in 'rural' areas.

Does hormonal control obviate positive airway pressure therapy in acromegaly with sleep-disordered breathing?

Acromegaly is a disease in which uncontrolled release of growth hormone occurs after closure of epiphyseal plates, causing changes in the body that can lead to sleep disordered breathing (SDB). No definite guidelines regarding the treatment of SDB in acromegaly are available. In this study, we aimed to investigate the prevalence of SDB in acromegaly and whether hormonal control alters the necessity of positive airway pressure (PAP) therapy in acromegaly patients with SDB. Forty-two acromegaly patients were included in the study and divided into two groups according to disease status, i.e., active or well controlled. All patients underwent polysomnography. Fourteen patients with active acromegaly were diagnosed with SDB and were evaluated for PAP therapy with polysomnography both before and 6 months after disease control was achieved. Sleep-disorder breathing was diagnosed in 22 of 42 patients, 7 of 20 patients with controlled-disease and 15 of 20 patients with active diseases. There were significant reductions in respiratory disturbance index (RDI), apnea index, desaturation index, central apnea number, and rapid eye movement-phase RDI at the control polysomnography. Initially, PAP therapy was indicated in 12 of 14 patients and PAP therapy indication held in 11 patients after acromegaly control was achieved.

Our study revealed that over half of patients with acromegaly had SDB. Furthermore, SDB severity decreases with acromegaly treatment; however, this decrease does not change the indication for PAP therapy; therefore, PAP therapy should not be delayed in acromegalic SDB patients.

Is asymptomatic cryptococcal antigenemia associated with mortality among HIV-positive patients in Indonesia?

Previous studies, mostly from Africa, have shown that serum cryptococcal antigenemia may precede the development of cryptococcal meningitis and early death among patients with advanced HIV infection. We examined cryptococcal antigenemia as a risk factor for HIV-associated mortality in Indonesia, which is experiencing a rapidly growing HIV epidemic. We included ART-naïve HIV patients with a CD4 cell count below 100 cells/μL and no signs of meningitis in an outpatient HIV clinic in Bandung, West Java, Indonesia. Baseline clinical data and follow-up were retrieved from a prospective database, and cryptococcal antigen was measured in stored serum samples using a semiquantitative lateral flow assay. Cox regression analysis was used to identify factors related to mortality. Among 810 patients (median CD4 cell count 22), 58 (7.1%) had a positive cryptococcal antigen test with a median titre of 1:80 (range: 1:1 to 1:2560). Cryptococcal antigenemia at baseline was strongly associated with the development of cryptococcal meningitis and early death and loss to follow-up. After one year, both death (22.4% vs. 11.6%; p=0.016; adjusted HR 2.19; 95% CI 1.78-4.06) and the combined endpoint of death or loss to follow-up (67.2% vs. 40.4%; p<0.001; adjusted HR 1.57; 95% CI 1.12-2.20) were significantly higher among patients with a positive cryptococcal antigen test.

Cryptococcal antigenemia is common and clinically relevant among patients with advanced HIV in this setting. Routine screening for cryptococcal antigen followed by lumbar puncture and pre-emptive antifungal treatment for those who are positive may help in reducing early mortality.

Do glucocorticoids and phenobarbital induce murine CYP2B genes by independent mechanisms?

Genes for CYP of the 2B subfamily (CYP2B genes) have long been known to be inducible in murine liver by phenobarbital and phenobarbital-like inducers. More recently, it has become clear that glucocorticoids can also induce these genes by a mechanism independent of that of phenobarbital-like inducers. To summarize the evidence for the existence of two distinct molecular mechanisms for induction of murine CYP2B genes and to analyze the wider implications of this situation for inducible xenobiotic metabolism. The mechanism of action of phenobarbital-like inducers of murine CYP2B genes is first briefly summarized. The role of glucocorticoids in the induction of various proteins, particularly rat phosphoenolpyruvate carboxykinase, where transcriptional activation is achieved via a glucocorticoid response unit, is also discussed. Finally, recent results are presented on glucocorticoid induction of murine CYP2B genes, including evidence for the presence of a functional glucocorticoid response unit in the rat CYP2B2 gene and for the role of constitutive androstane receptor as an accessory factor in this response.

Murine CYP2B genes are seen to respond to two distinct regulatory mechanisms, but much remains to be learned concerning the interactions between these two regulatory loops, as well as the details of glucocorticoid induction.

Does foxo3 circular RNA promote cardiac senescence by modulating multiple factors associated with stress and senescence responses?

Circular RNAs are a subclass of non-coding RNAs detected within mammalian cells. This study was designed to test the roles of a circular RNA circ-Foxo3 in senescence using in vitro and in vivo approaches. Using the approaches of molecular and cellular biology, we show that a circular RNA generated from a member of the forkhead family of transcription factors, Foxo3, namely circ-Foxo3, was highly expressed in heart samples of aged patients and mice, which was correlated with markers of cellular senescence. Doxorubicin-induced cardiomyopathy was aggravated by ectopic expression of circ-Foxo3 but was relieved by silencing endogenous circ-Foxo3. We also found that silencing circ-Foxo3 inhibited senescence of mouse embryonic fibroblasts and that ectopic expression of circ-Foxo3 induced senescence. We found that circ-Foxo3 was mainly distributed in the cytoplasm, where it interacted with the anti-senescent protein ID-1 and the transcription factor E2F1, as well as the anti-stress proteins FAK and HIF1α.

We conclude that ID-1, E2F1, FAK, and HIF1α interact with circ-Foxo3 and are retained in the cytoplasm and could no longer exert their anti-senescent and anti-stress roles, resulting in increased cellular senescence.

Do oxidative species increase arginase activity in endothelial cells through the RhoA/Rho kinase pathway?

NO produced by endothelial NOS is needed for normal vascular function. During diabetes, aging and hypertension, elevated levels of arginase can compete with NOS for available l-arginine, reducing NO and increasing superoxide (O(2) (.-)) production via NOS uncoupling. Elevated O(2) (.-) combines with NO to form peroxynitrite (ONOO(-)), further reducing NO. Oxidative species increase arginase activity, but the mechanism(s) involved are not known. Our study determined the mechanism involved in peroxynitrite and hydrogen peroxide-induced enhancement in endothelial arginase activity. We hypothesized that oxidative species increase arginase activity through PKC-activated RhoA/Rho kinase (ROCK) pathway. Arginase activity/expression was analysed in bovine aortic endothelial cells (BAEC) treated with an ONOO(-) generator (SIN-1) or H(2) O(2). Pretreatment with inhibitors of Rho kinase (Y-27632) or PKC (Gö6976) was used to investigate the mechanism involved in arginase activation. Exposure to SIN-1 (25 µM, 24 h) or H(2) O(2) (25 µM, 8 h) increased arginase I expression and arginase activity (35% and 50%, respectively), which was prevented by ROCK inhibitor, Y-27632, PKC inhibitor, Gö6976 or siRNA to p115-Rho GEF. There was an early activation of p115-Rho GEF (SIN-1, 2 h; H(2) O(2), 1 h) and Rho A (SIN-1, 4 h; H(2) O(2), 1 h) that was prevented by using the PKC inhibitor. Exposure to SIN-1 and H(2) O(2 ) also reduced NOS activity, which was blocked by pretreatment with p115-RhoGEF siRNA.

Our data indicate that the oxidative species ONOO(-) and H(2) O(2) increase arginase activity/expression through PKC-mediated activation of RhoA/Rho kinase pathway.

Is the ultrasound-estimated bladder weight a reliable method for evaluating bladder outlet obstruction?

• To evaluate the correlation between ultrasound-estimated bladder weight (UEBW) in patients with different degrees of bladder outlet obstruction (BOO). • We evaluated 50 consecutive non-neurogenic male patients with lower urinary tract symptoms (LUTS) referred to urodynamic study (UDS). All patients self-answered the International Prostate Score Symptoms (IPSS) questionnaire. After the UDS, the bladder was filled with 150 mL to determine UEBW. • Patients with a bladder capacity under 150 mL, a previous history of prostate surgery or pelvic irradiation, an IPSS score<8, a bladder stone or urinary tract infection were excluded. • After a pressure-flow study, the Schafer linear passive urethral resistance relation nomogram was plotted to determine the grade of obstruction: Grades I-II/VI were defined as mild obstruction, Grades III-IV/VI as moderate obstruction, and Grades V-VI/VI as severe obstruction. • The UEBW was 51.7 ± 26.9, 54.1 ± 30.0 and 54.8 ± 28.2 in patients with mild, moderate and severe BOO, respectively (P= 0.130). The UEBW allowed us to define four groups: (i) UEBW<35 g; (ii) 35 g ≤ UEBW<50 g; (iii) 50 g ≤ UEBW<70 g; and (4) UEBW ≥ 70 g. • We did not find any differences in age, prostate weight, IPSS, PVR, cystometric bladder capacity, presence of detrusor overactive and degree of obstruction in the aforementioned groups.

• Despite the fact that some studies have emphasized the value of UEBW as an efficient non-invasive method for evaluating lower urinary tract obstruction, our study suggests that UEBW does not present any individual correlation with LUTS or objective measurements of BOO.

Does activation of a novel c-Myc-miR27-prohibitin 1 circuitry in cholestatic liver injury inhibit glutathione synthesis in mice?

We showed that chronic cholestatic liver injury induced the expression of c-Myc but suppressed that of glutamate-cysteine ligase (GCL, composed of catalytic and modifier subunits GCLC and GCLM, respectively). This was associated with reduced nuclear antioxidant response element (ARE) binding by nuclear factor-erythroid 2 related factor 2 (Nrf2). Here, we examined whether c-Myc is involved in this process. Similar to bile duct ligation (BDL), lithocholic acid (LCA) treatment in vivo induced c-Myc but suppressed GCL subunits expression at day 14. Nrf2 expression and Nrf2 ARE binding fell markedly. However, Nrf2 heterodimerization with MafG was enhanced by LCA, which prompted us to examine whether LCA treatment in vivo altered proteins that bind to ARE using biotinylated ARE in pull-down assay followed by proteomics. LCA treatment enhanced c-Myc but lowered prohibitin 1 (PHB1) binding to ARE. This was a result of c-Myc-mediated induction of microRNA 27a/b (miR27a/b), which target both PHB1 and Nrf2 to reduce their expression. Knockdown of c-Myc or miR27a/b attenuated LCA-mediated suppression of Nrf2, PHB1, and GCL subunit expression, whereas overexpression of PHB1 protected against the fall in Nrf2 and GCL subunits. Both c-Myc and PHB1 directly interact with Nrf2 but c-Myc lowers Nrf2 binding to ARE while PHB1 enhances it. This is the first work that shows how activation of this circuit in cholestatic liver injury inhibits GCL expression.

LCA feeding and BDL activate c-Myc-miR27a/b-PHB1 circuit, with the consequence of inhibiting Nrf2 expression and ARE binding, resulting in decreased reduced glutathione synthesis and antioxidant capacity.

Do sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease?

Frontotemporal lobar degeneration (FTLD) is the most common cause of early-onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) comprise trans-activating response element (TAR) DNA binding protein (TDP-43) and/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD-MND pedigree with no mutations in known dementia genes. A mutation screen of candidate genes, luciferase assays, and quantitative polymerase chain reaction (PCR) was performed to identify the biological role of the putative mutation. Neuropathological characterization of affected individuals and western blot studies of cell lines were performed to identify the pathological mechanism of the mutation. We identified a nonpolymorphic mutation (c.672*51G>T) in the 3'-untranslated region (UTR) of the Sigma nonopioid intracellular receptor 1 (SIGMAR1) gene in affected individuals from the FTLD-MND pedigree. The c.672*51G>T mutation increased gene expression by 1.4-fold, corresponding with a significant 1.5-fold to 2-fold change in the SIGMAR1 transcript or Sigma-1 protein in lymphocyte or brain tissue. Brains of SIGMAR1 mutation carriers displayed a unique pathology with cytoplasmic inclusions immunopositive for either TDP-43 or FUS but not Sigma-1. Overexpression of SIGMAR1 shunted TDP-43 and FUS from the nucleus to the cytoplasm by 2.3-fold and 5.2-fold, respectively. Treatment of cells with Sigma-1 ligands significantly altered translocation of TDP-43 by up to 2-fold.

SIGMAR1 is a causative gene for familial FTLD-MND with a unique neuropathology that differs from other FTLD and MND cases. Our findings also suggest Sigma-1 drugs as potential treatments for the TDP-43/FUS proteinopathies.

Is there an increased risk of TB relapse in patients treated with fixed-dose combination drugs in Indonesia?

South Sulawesi Province, Republic of Indonesia. To compare relapse rates among tuberculosis (TB) patients treated with fixed-dose combination drugs (FDCs) and patients treated with the same regimen using loose drugs. Between 1999 and 2001, new smear-positive TB patients were randomly allocated to treatment with four-drug FDCs or loose drugs to study differences in treatment outcomes. Although it was not in the original study design, in 2004-2005 we performed a follow-up study by home visit of cured patients. We conducted an interview and tried to collect a sputum sample from each patient. If the patient was absent or had died, a proxy interview was conducted. The sputum samples were examined by microscopy and culture. The overall relapse rate was 7.0% in patients who were able to produce a sputum sample. Relapse appeared to be more frequent in the FDC group compared to the loose drug group (10.1% vs. 2.7%, P = 0.074).

This is the first documented long-term follow-up study of patients treated with four-drug FDCs. There is an indication that treatment of new sputum smear-positive TB patients with FDCs provides an increased risk of relapse compared to treatment with loose drugs. The long-term results of treatment with FDCs should be carefully evaluated in other settings.

Do we get it right?

A patient-centred approach to discussing life expectancy with cancer patients is recommended in Western countries. However, this approach to eliciting and meeting patient preferences can be challenging for clinicians. The aims of this study were the following: (i) to examine cancer patients' preferences for life expectancy disclosure; and (ii) to explore agreement between cancer patients' preferences for, and perceived experiences of, life expectancy disclosure. Cancer patients undergoing radiotherapy treatment in metropolitan Australia completed a cross-sectional touchscreen computer survey including optional questions about their life expectancy disclosure preferences and experiences. Of the 208 respondents, 178 (86%) indicated that they would prefer their clinician to ask them before discussing life expectancy, and 30 (14%) indicated that they would prefer others (i.e. clinicians, family) to decide whether they were given life expectancy information. Of the 175 respondents who were classified as having a self- determined or other-determined disclosure experience, 105 (60%) reported an experience of life expectancy disclosure that was in accordance with their preferences. Cohen's κ was -0.04 (95% CI, -0.17, 0.08), indicating very poor agreement between patients' preferences for and perceived experiences of life expectancy disclosure (p = 0.74).

In light of patient-centred prognosis disclosure guidelines, our findings of a majority preference for, and experience of, a self-determined approach to life expectancy disclosure amongst radiation oncology patients are encouraging. However, poor agreement between preferences and experiences highlights that additional effort from clinicians is required in order to achieve a truly patient-centred approach to life expectancy disclosure.

Does screening for physical and psychosocial symptoms vary between medical oncology treatment centres?

Our aim is to examine whether provider screening for physical and emotional symptoms, as reported by medical oncology outpatients, varies across medical oncology treatment centres. A cross-sectional sample of 716 patients attending the outpatient medical oncology department of six public cancer treatment centres across five Australian states participated. Four patient-report survey items explored how often patients were specifically asked by clinical staff at the treatment centre about their (i) emotional distress (anxiety, distress and depression), (ii) pain, (iii) fatigue and (iv) other physical symptoms (e.g. nausea and constipation). Asking at less than half of all appointments was classified as infrequent screening. No significant associations were found between treatment centre and symptom screening for emotional distress (p = 0.65), pain (p = 0.21), fatigue (p = 0.95) and other physical symptoms (p = 0.40). The proportion of patients who were regularly screened versus infrequently screened was significantly higher for physical symptoms than emotional symptoms (p < 0.001): 36% infrequently screened for emotional distress (range: 33-45%), 15% infrequently screened for pain (range: 9-21%), 16% infrequently screened for fatigue (range: 15-19%) and 11% infrequently screened for other physical symptoms (range: 5-17%).

No significant variation in symptom screening was found across treatment centres. While the majority of patients received recommended care, treatment centres must continue to improve symptom screening rates, particularly for emotional distress. However, screening is only the first step and must be accompanied by the offer of help and provision of help to relieve patient suffering.

Does therapeutic mammoplasty allow for clear surgical margins in large and multifocal tumours without delaying adjuvant therapy?

Therapeutic mammoplasty (TM) is suggested to have a number of advantages by comparison to standard breast conservation surgery in selected patients, however, data to support such assertions are sparse and outcomes remain uncertain. We assess the ability of TM to achieve some of its suggested benefits, specifically obtaining clear surgical margins (CSM) around large or multifocal tumours, and examine whether TM is associated with delay in administering adjuvant therapies. Data were extracted from a prospectively maintained database on all patients undergoing TM over 8 years. Key oncological outcomes and time to initiation of adjuvant therapies were recorded. Sixty eight patients underwent TM, sixty two for invasive disease and six for in-situ disease only. Tumour size ranged from 3 mm to 85 mm. Twenty-one (30.8%) patients received neo-adjuvant therapy, with 15 (22.0%) receiving chemotherapy and six (8.8%) receiving endocrine therapy prior to surgery. CSM were obtained in 65 patients (95.6%). Where margins were involved, two were due to Ductal Carcinoma in situ and one from undiagnosed invasive lobular cancer, resulting in one wider excision and two completion mastectomies. Radiotherapy was delayed in one patient with delayed wound healing. No local recurrence has been recorded.

These data support the ability of TM to consistently achieve CSM around large and multifocal tumours in selected patients, with acceptable local control and minimal morbidity and delay in adjuvant therapies.

Are serum hs-CRP levels increased in de Novo Parkinson 's disease independently from age of onset?

Microglia in the brain are the counterpart of macrophages and it functions as a first defense in the brain. The double-edged feature of microglia has explained that the inflammatory state of microglia in aged brains induces them to over-respond to small stimuli that are otherwise well controlled in young brains. The clinical effect of microglia in patients with Parkinson's disease (PD) is poorly defined. This prospective study assessed the peripheral concentrations of hs-CRP, a protein able to reflect neuroinflammation in the CNS, in de novo PD patients with varying ages of onset. We examined 435 patients with de novo PD and 221 healthy subjects and the differences in hs-CRP between these groups were investigated. The PD group was classified into 4 subgroups according to the age of de novo PD to investigate the relationship between hs-CRP and the aging process in de novo PD. There were significantly higher serum hs-CRP levels in patients with PD compared with healthy subjects. A post-hoc analysis of the 4 PD subgroups showed no significant differences in serum hs-CRP level.

We assumed that neuroinflammatory reactions play a role in the pathogenesis of PD, but found no clinical evidence of a neuroprotective effect against PD in young brains. To clarify the role of microglia and aging in the pathogenesis of PD, future longitudinal studies involving a large cohort are required.

Does binge ethanol administration enhance the MDMA-induced long-term 5-HT neurotoxicity in rat brain?

Ecstasy abuse commonly occurs in hot, overcrowded environments in combination with alcohol. Around 90% of ecstasy users take ethanol; over 70% of these users also often drink alcohol at hazardous levels. We wished to examine whether binge ethanol administration enhanced the long-lasting 5-HT neurotoxicity induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats maintained at high ambient temperature and the role of acetaldehyde. Rats were treated with a 4-day ethanol regimen leading to plasma ethanol levels of around 450 mg/dl. On day 5, rats were placed at 30 degrees C and administered MDMA (5 mg/kg). Rectal temperature and hydroxyl radical formation were measured immediately before and up to 6 h after MDMA. 5-HT concentration and 5-HT transporter density were determined 7 days later. A group of rats received cyanamide (50 mg/kg) on days 1 and 3 of the 4-day-ethanol inhalation. In ethanol treated rats, MDMA produced a hyperthermic response similar to that observed in controls but enhanced the loss of 5-HT concentration and 5-HT transporter density in the hippocampus. Cyanamide elevated the plasma acetaldehyde concentration fivefold to sevenfold, reduced the MDMA-induced hyperthermia and increased the neuronal damage with neurotoxicity also appearing in the cortex. MDMA increased hydroxyl radical production in the hippocampus, the effect being more marked in rats pre-exposed to ethanol.

Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity by a mechanism not related to changes in acute hyperthermia but probably involving hydroxyl radical formation. The magnitude of this effect is more pronounced after increasing plasma acetaldehyde levels by aldehyde dehydrogenase inhibition.

Central retroperitoneal recurrences from colorectal cancer: are lymph node and locoregional recurrences the same disease?

Central retroperitoneal recurrences (CRRs) from colorectal carcinoma carry a poor prognosis. A CRR is sometimes defined as a locoregional recurrence (LR) and sometimes as a lymph node recurrence (NR). This study was conducted to determine the nature of CRR and evaluate prognostic factors after complete CRR resection. Between January 1988 and December 2008, 31 patients underwent a complete resection of CRR. CRRs were divided into NR (n = 23) and LR (n = 8), whether pathological examination disclosed lymph node involvement or not. No differences were found between LR and NR regarding TNM stage, primary tumour location, time interval from primary tumour resection to CRR, number of metastatic sites, number of metastatic lesions and therapeutic management. The median preoperative CEA level was higher in the NR group (p = 0.003). After a median follow-up of 47 months NRs were associated with better overall survival (OS) (p = 0.03). Three-year OS and disease-free survival (DFS) in the LR and NR groups were 27% and 0% versus 81% and 26%, respectively. Twenty-seven (87%) patients developed a re-recurrence within a median interval of 15 months. The number of metastatic sites or lesions, the size of the CRR, the type of chemotherapy, radiotherapy, the interval between the primary resection and CRR and the TNM stage had no impact on OS.

LR in patients with CRR had a poorer prognosis than NR. A multimodality approach with complete resection may yield long-term survival for NR.

Does transcript length bias in RNA-seq data confound systems biology?

Several recent studies have demonstrated the effectiveness of deep sequencing for transcriptome analysis (RNA-seq) in mammals. As RNA-seq becomes more affordable, whole genome transcriptional profiling is likely to become the platform of choice for species with good genomic sequences. As yet, a rigorous analysis methodology has not been developed and we are still in the stages of exploring the features of the data. We investigated the effect of transcript length bias in RNA-seq data using three different published data sets. For standard analyses using aggregated tag counts for each gene, the ability to call differentially expressed genes between samples is strongly associated with the length of the transcript.

Transcript length bias for calling differentially expressed genes is a general feature of current protocols for RNA-seq technology. This has implications for the ranking of differentially expressed genes, and in particular may introduce bias in gene set testing for pathway analysis and other multi-gene systems biology analyses.

Does fetal fibronectin improve the accuracy of diagnosis of preterm labor?

Our purpose was to assess the utility of cervicovaginal expression of fetal fibronectin in the diagnosis of preterm labor. Women seen between 24 and 34 weeks' gestation with symptoms of preterm labor, intact membranes, and cervical dilatation < 3 cm were enrolled at five university medical centers. Cervicovaginal swabs were obtained and assayed for the presence of fetal fibronectin by means of a monoclonal antibody assay. Results were compared with cervical dilatation and uterine contraction frequency as indicators of interval to delivery and delivery before 37 weeks. A total of 192 eligible women at a mean gestational age of 30.8 +/- 2.9 weeks were enrolled from a population of 418 subjects screened. The rate of preterm birth was 32.3% (62/192). The mean interval from presentation to delivery was 25.3 +/- 24.1 days in the 45 subjects with a positive fibronectin assay and 52.4 +/- 24.8 days in the 147 subjects with a negative assay (p = 0.0001). The sensitivity, specificity, and positive and negative predictive values of fetal fibronectin expression for delivery < 37 weeks were 44% (27/62), 86% (112/130), 60% (27/45), and 76% (112/147). The fetal fibronectin assay was especially useful in predicting risk of delivery within 7 days (sensitivity 93% [13/14], specificity 82% [146/178], positive predictive value 29% [13/45], and negative predictive value 99% [146/147]) and was notably superior to both cervical dilatation > 1 cm and contraction frequency greater than or equal to eight per hour (sensitivities 29% and 42%, specificities 82% and 67%, positive predictive values 11% and 9%, and negative predictive values 94% and 94%, respectively.

Cervicovaginal fetal fibronectin predicts delivery within 7 days more accurately than do cervical dilatation and contraction frequency in a population of women evaluated for early preterm labor.

Do the level of nodal disease according to the TNM classification and the number of involved cervical nodes reflect prognosis in patients with differentiated carcinoma of the thyroid gland?

The importance of nodal involvement as a prognostic factor in differentiated carcinoma of the thyroid gland remains controversial. We therefore attempted to confirm the prognostic factors in differentiated thyroid carcinoma, with special reference to nodal status. A total of 139 patients with differentiated thyroid cancer followed for 2-27 years, with a median follow-up of 7 years were studied. All patients underwent surgical resection, either subtotal, total, or lobectomy, with modified radical neck dissection. Survival was calculated using the Kaplan-Meier method. Ten (7%) patients have died from thyroid cancer. Adverse prognostic factors included age>45 years (P=0.0120), the presence of distant metastases (P=0.0006), and TNM stage (P=0.0002). The number of lymph nodes dissected ranged from 6 to 92, with an average of 26. Lymph node metastases were found in 102 (73%) patients. There was no difference in survival according to the level of nodal disease by the TNM classification. Furthermore, the number of cervical lymph nodes involved had no effect on the survival.

Our results suggest that the presence of histologically confirmed lymph node metastases is not an important prognostic factor in patients with differentiated thyroid carcinoma.

Do general practitioners' attitudes towards depression predict their clinical behaviour?

GPs' attitudes towards depression vary, as do their abilities to detect and manage it effectively. Associations between attitudes and clinical behaviour have not yet been demonstrated directly. We tested two hypotheses: (1) that questionnaire measures of GPs' confidence in identifying depression predict their ability to identify depression in their patients; and (2) that GPs who prefer antidepressants prescribe more than those who prefer psychotherapy. Forty GPs in Liverpool and Manchester completed the Depression Attitude Questionnaire (DAQ) and were asked for prescribing (PACT) information. Attender surveys using the General Health Questionnaire (GHQ-12), in combination with GP ratings of patients' psychological status, generated indices for GPs' case identification, bias and accuracy. We tested associations between these indices and the four DAQ components, in particular GPs' confidence in diagnosis, across a total of 1436 patients. We also compared the DAQ component on attitudes to treatment with relevant PACT data. The DAQ assessment of GPs' ability to identify cases of depression bore no relationship to their observed ability, as measured by accuracy, bias, or identification indices. However, there were significant associations between observed diagnostic ability and: preference for psychotherapy; ease in managing depression; and, belief in successful treatment. PACT data were available for 26 (65%) GPs. There was an association between preference for antidepressants and prescription of SSRIs (rs 0.3981, P<0.044), but not for overall antidepressant or tricyclic prescribing, or for dose of dothiepin.

The DAQ measure of ease of identification is not valid when compared to actual clinical practice. The ability of GPs to identify depression may not be an independent variable, but may rather reflect other beliefs, attitudes and skills. This has considerable implications for educational interventions in primary care.

Are common variants in genes related to lipid and energy metabolism associated with weight loss after an intervention in overweight/obese adolescents?

Some SNPs related to lipid and energy metabolism may be implicated not only in the development of obesity and associated comorbidities, but also in the weight loss response after a nutritional intervention. In this context, the present study analyzed four SNPs located within four genes known to be associated with obesity and other obesity-related complications, and their putative role in a weight-loss intervention in overweight/obese adolescents. The study population consisted of 199 overweight/obese adolescents (13-16 yr old) undergoing 10 weeks of a weight loss multidisciplinary intervention: the EVASYON programme (www.estudioevasyon.org). Adolescents were genotyped for 4 SNPs, and anthropometric measurements and biochemical markers were analyzed at the beginning and after the intervention. Interestingly, APOA5(rs662799) was associated with the baseline anthropometric and biochemical outcomes, whereas FTO (rs9939609) seemed to be related with the change of these values after the 10-week intervention. The other two SNPs, located in the CETP (rs1800777) and the APOA1 (rs670) genes, showed important relationships with adiposity markers. Specifically, a combined model including both SNPs turned up to explain up to 24% of BMI-SDS change after 10 weeks of the multidisciplinary intervention, which may contribute to under - stand the weight loss response.

Common variants in genes related to lipid and energy metabolism may influence not only biochemical outcomes but also weight loss response after a multidisciplinary intervention carried out in obese/overweight adolescents..

Is generalization of exhaled CO assessment in primary care helpful for early diagnosis of COPD?

COPD is largely under-diagnosed and once diagnosed usually at a late stage. Early diagnosis is thoroughly recommended but most attempts failed as the disease is marginally known and screening marginally accepted. It is a rare cause of concern in primary care and spirometry is not very common. Exhaled carbon monoxide (eCO) is a 5-seconds easy-to-use device dedicated to monitor cigarette smoke consumption. We aimed to assess whether systematic eCO measurement in primary care is a useful tool to improve acceptance for early COPD diagnosis. This was a two-center randomized controlled trial enrolling 410 patients between March and May, 2013. Whatever was the reason of attendance to the clinic, all adults were proposed to measure eCO during randomly chosen days and outcomes were compared between the two different groups of patients (performing and not performing eCO). Primary outcome was the rates of acceptance for COPD screening. Rate of acceptance for COPD screening was 28% in the eCO group and 26% in the other (P = 0.575). These rates increased to 48 and 51% in smokers (current and former). eCO significantly increased the rate of clinics during which a debate on smoking was initiated (42 vs. 24%, P = 0.001). eCO at 2.5 ppm was the discriminative concentration for identifying active smokers (ROC curve AUC: 0.935). Smoking was the only independent risk factor associated with acceptance for early COPD screening (OR = 364.6 (82.5-901.5) and OR = 78.5 (18.7-330.0) in current and former smokers, respectively) while eCO measurement was not.

Early COPD diagnosis is a minor cause of concern in primary care. Systematic eCO assessment failed to improve acceptance for early COPD screening.

Does the neurotrophic factor artemin influence the extent of neural damage and growth in chronic pancreatitis?

Chronic pancreatitis is characterised by severe abdominal neuropathic pain, perineural inflammatory cell infiltrations and intrapancreatic neural growth. Artemin was recently shown to eliminate neuropathic pain and reverse neurochemical damage after nerve injury. The role of artemin and its receptor GFRalpha3 was investigated in patients with chronic pancreatitis. Expression of artemin and its receptor GFRalpha3 was studied in chronic pancreatitis (n = 66) and normal (n = 22) pancreatic tissues by quantitative reverse transcription-polymerase chain reaction (QRT-PCR) and western blot analysis. Artemin expression was correlated with pain and pathomorphological changes (inflammation, perineural inflammatory cell infiltration, neural alterations and fibrosis). Immunohistochemistry was used to localise artemin and GFRalpha3 in the tissues. To detect sources of artemin, primary human pancreatic stellate cells (hPSCs) were isolated and analysed by QRT-PCR and immunocytology analysis. In chronic pancreatitis, artemin and GFRalpha3 were significantly overexpressed and located in smooth muscle cells of arteries, Schwann cells and neural ganglia. Increased levels of artemin mRNA correlated with pain severity, inflammation, perineural inflammatory cell infiltration, neural density and hypertrophy. Furthermore, the severity of fibrosis was positively related with artemin expression and neural alterations. Activated hPSCs expressed low basal levels of artemin mRNA which were upregulated by exposure to transforming growth factor (TGF)beta1.

Overexpression of artemin in chronic pancreatitis might function as a compensatory upregulation in order to repair neural damage incurred by ongoing pancreatic inflammation. Upregulation of TGFbeta1 seems not only to increase pancreatic fibrosis but also to contribute to neural alteration by stimulating artemin expression in hPSCs. However, overexpression of endogenous artemin does not seem to be sufficient to prevent pain in chronic pancreatitis.

Do trends in serum total cholesterol and dietary fat intakes in New Zealand between 1989 and 2009?

To describe trends in serum cholesterol and dietary fat intakes for New Zealand adults between 1989 and 2008/09. Serum total cholesterol concentrations and dietary fat intakes were analysed for 9,346 New Zealanders aged 15-98 years (52% women) who participated in three national surveys in 1989, 1997 and 2008/09. Population mean serum cholesterol decreased from 6.15 mmol/L in 1989 to 5.39 mmol/L in 2008/09. Mean saturated fat intake decreased from 15.9% of energy intake in 1989 to 13.1% in 2008/09. Between 1997 and 2008/09, unsaturated fat intake increased and fat from butter and milk decreased. Older adults had the largest decrease in serum cholesterol (1.35 mmol/L).

The decrease in serum cholesterol is substantially larger than reported for many other high-income countries, and occurred in parallel with changes in dietary fat intakes and, for older adults, increased use of cholesterol-lowering medications.

Are high peripheral levels of h-FABP associated with poor prognosis in end-stage heart failure patients with mechanical circulatory support?

To associate the time-course of h-FABP and N-terminal pro B-type natriuretic peptide (NT-proBNP)after left ventricular assist device (LVAD) implantation to outcome in end-stage heart failure patients. Patients (n = 14, NYHA class III/IV; left ventricular ejection fraction <25% were enrolled; ten survived up to 1 month after LVAD (survivors) and four died of multiorgan failure within 2 weeks (nonsurvivors). Blood samples were obtained at admission; at 4, 24 and 72 h; and at 1 and 4 weeks after LVAD. h-FABP significantly increases after surgery, decreasing since 72 h in all patients. At 72 h all survivor patients present h-FABP lower than the median value. N-terminal pro B-type natriuretic peptide is not associated with patient outcome at any time.

High h-FABP levels, indicating the presence of more severe myocardial damage, are associated with a poor prognosis in patients with LVAD, suggesting that an early cardiac injury marker could improve the prediction of clinical outcome.

Do cCR9-positive lymphocytes and thymus-expressed chemokine distinguish small bowel from colonic Crohn 's disease?

Thymus-expressed chemokine (TECK) or CCL25) is selectively expressed in the small bowel (SB), where lamina propria lymphocytes (LPL) and intraepithelial leukocyte expressing the cognate chemokine receptor CCR9 predominate. We characterize the role of TECK and CCR9-expresing lymphocytes in small intestinal Crohn's disease. CCR9 expression on lymphocytes from lamina propria, mesenteric lymph node, and peripheral blood was analyzed by flow cytometry and by Northern blotting for LPL. TECK expression was analyzed in inflamed SB and colon by reverse-transcription polymerase chain reaction and immunohistochemistry. The fraction of CCR9(+) T cells in inflamed SB was significantly lower than in uninvolved SB mucosa. In contrast, in peripheral blood lymphocytes, CCR9(+) lymphocytes were markedly elevated in patients with small bowel Crohn's or celiac disease, but not in patients with purely colonic Crohn's. Also, TECK expression is altered in inflamed small bowel, being intensely expressed in a patchy distribution in crypt epithelial cells in proximity to lymphocytic infiltrates. TECK is not expressed in either normal or inflamed colon.

In SB immune-mediated diseases, there is repartitioning of CCR9(+) lymphocytes between SB and blood and an altered pattern of TECK expression in SB Crohn's. The TECK/CCR9 ligand/receptor pair may play an important role in the pathogenesis of SB Crohn's disease.

Complex sleep apnea syndrome: is it a unique clinical syndrome?

Some patients with apparent obstructive sleep apnea hypopnea syndrome (OSAHS) have elimination of obstructive events but emergence of problematic central apneas or Cheyne-Stokes breathing pattern. Patients with this sleep-disordered breathing problem, which for the sake of study we call the "complex sleep apnea syndrome," are not well characterized. We sought to determine the prevalence of complex sleep apnea syndrome and hypothesized that the clinical characteristics of patients with complex sleep apnea syndrome would more nearly resemble those of patients with central sleep apnea syndrome (CSA) than with those of patients with OSAHS. Retrospective review Sleep disorders center. Two hundred twenty-three adults consecutively referred over 1 month plus 20 consecutive patients diagnosed with CSA. NA. Prevalence of complex sleep apnea syndrome, OSAHS, and CSA in the 1-month sample was 15%, 84%, and 0.4%, respectively. Patients with complex sleep apnea syndrome differed in gender from patients with OSAHS (81% vs 60% men, p<.05) but were otherwise similar in sleep and cardiovascular history. Patients with complex sleep apnea syndrome had fewer maintenance-insomnia complaints (32% vs 79%; p<.05) than patients with CSA but were otherwise not significantly different clinically. Diagnostic apnea-hypopnea index for patients with complex sleep apnea syndrome, OSAHS, and CSA was 32.3 +/- 26.8, 20.6 +/- 23.7, and 38.3 +/- 36.2, respectively (p = .005). Continuous positive airway pressure suppressed obstructive breathing, but residual apnea-hypopnea index, mostly from central apneas, remained high in patients with complex sleep apnea syndrome and CSA (21.7 +/- 18.6 in complex sleep apnea syndrome, 32.9 +/- 30.8 in CSA vs 2.14 +/- 3.14 in OSAHS; p<.001).

Patients with complex sleep apnea syndrome are mostly similar to those with OSAHS until one applies continuous positive airway pressure. They are left with very disrupted breathing and sleep on continuous positive airway pressure. Clinical risk factors don't predict the emergence of complex sleep apnea syndrome, and best treatment is not known.

Is hepatitis E virus infection highly prevalent among pregnant women in Accra , Ghana?

Hepatitis E virus (HEV) is highly endemic in several African countries with high mortality rate among pregnant women. The prevalence of antibodies to HEV in Ghana is not known. Therefore we evaluated the prevalence of anti-HEV IgG and anti-HEV IgM among pregnant women seen between the months of January and May, 2008 at the Obstetrics and Gynaecology Department, Korle-Bu Teaching Hospital, Accra, Ghana. One hundred and fifty-seven women provided blood samples for unlinked anonymous testing for the presence of antibodies to HEV. The median age of participants was 28.89 +/- 5.76 years (range 13-42 years). Of the 157 women tested, HEV seroprevelance was 28.66% (45/157). Among the seropositive women, 64.40% (29/45) tested positive for anti-HEV IgM while 35.60% (16/45) tested positive to HEV IgG antibodies. HEV seroprevalence was highest (46.15%) among women 21-25 years of age, followed by 42.82% in = 20 year group, then 36.84% in = 36 year group. Of the 157 women, 75.79% and 22.92% were in their third and second trimesters of pregnancy, respectively. Anti-HEV antibodies detected in women in their third trimester of pregnancy (30.25%) was significantly higher, P < 0.05, than in women in their second trimester of pregnancy (25.0%).

Consistent with similar studies worldwide, the results of our studies revealed a high prevalence of HEV infection in pregnant women.

Are [ Both myeloma cells and bone marrow stromal cells involved in the overproduction of interleukin 6 in multiple myeloma ]?

To investigate the mechanism of interleukin 6 (IL-6) overexpression in multiple myeloma(MM). Human myeloma cells(KM3) and bone marrow stromal cells(BMSCs) were fixed by paraformaldehyde. KM3 cells and BMSCs (fixed and non-fixed) were co-cultured in 10%FCS-RPMI1640. IL-6 activity in the supernatant was determined by B9 cell proliferation test. Both non-fixed myeloma cells and BMSCs could automatically secret IL-6, while the fixed cells did not. Co-cultures of fixed one with non-fixed the other of either kind of the cells could significantly increase the IL-6 activity in the supernatants. The promoting effect on IL-6 production was greater in BMSCs from MM patients than that in BMSCs from normal controls.

There exists dual mechanism of IL-6 overproduction in MM, i.e. both autocrine and paracrine of IL-6 are involved in the pathogenesis of MM.

Does aspirin-triggered lipoxin prevent antiphospholipid antibody effects on human trophoblast migration and endothelial cell interactions?

Antiphospholipid antibodies (aPL) interfere with several physiologic functions of human trophoblasts, including reducing their ability to migrate, decreasing their production of angiogenic factors, and inducing an inflammatory response. This may provide the underlying mechanism by which aPL responses lead to recurrent pregnancy loss or preeclampsia in women with obstetric antiphospholipid syndrome (APS). Although treatment with heparin may reduce the rate of recurrent pregnancy loss, the risk of preeclampsia remains high. Therefore, alternative treatments are needed for the management of pregnant patients with APS. Since aspirin-triggered lipoxins (ATLs) have immune and angiogenic modulatory properties, the objective of this study was to determine the effects of the ATL 15-epi-lipoxin A4 on the function of aPL-altered human trophoblasts in the first trimester of pregnancy. A first-trimester human trophoblast cell line (HTR8) was treated with mouse anti-human β2 -glycoprotein I monoclonal antibodies (aPL) in the presence or absence of the ATL 15-epi-lipoxin A4 . Trophoblast migration and interactions with endometrial endothelial cells were measured using Transwell and coculture assays. Trophoblast secretion of cytokines and angiogenic factors was measured by enzyme-linked immunosorbent assay. Treatment of HTR8 cells with ATL reversed the aPL-induced decrease in trophoblast migration, an effect that appeared to be regulated through restoration of interleukin-6 production. Using a model of spiral artery transformation, aPL and sera from APS patients with pregnancy morbidity disrupted trophoblast-endothelial cell interactions, and treatment with ATL restored the stability of the cocultures. In contrast, ATL treatment did not resolve the proinflammatory and antiangiogenic responses of trophoblasts induced by aPL.

These findings indicate that ATLs may have some benefits in terms of preventing the effects of aPL on trophoblast function, which raises the possibility of the use of ATLs as an adjuvant therapy in women with aPL.

Does increased Notch Signaling enhance Radioresistance of Malignant Stromal Cells Induced by Glioma Stem/ Progenitor Cells?

Host malignant stromal cells induced by glioma stem/progenitor cells were revealed to be more radiation-resistant than the glioma stem/progenitor cells themselves after malignant transformation in nude mice. However, the mechanism underlying this phenomenon remains unclear. Malignant stromal cells induced by glioma stem/progenitor cell 2 (GSC-induced host brain tumor cells, ihBTC2) were isolated and identified from the double color-coded orthotopic glioma nude mouse model. The survival fraction at 2 Gy (SF2) was used to evaluate the radiation resistance of ihBTC2, the human glioma stem/progenitor cell line SU3 and its radiation-resistant sub-strain SU3-5R and the rat C6 glioma cell line. The mRNA of Notch 1 and Hes1 from ihBTC2 cells were detected using qPCR before and after 4 Gy radiation. The expression of the Notch 1, pAkt and Bcl-2 proteins were investigated by Western blot. To confirm the role of the Notch pathway in the radiation resistance of ihBTC2, Notch signaling blocker gamma secretase inhibitors (GSIs) were used. The ihBTC2 cells had malignant phenotypes, such as infinite proliferation, hyperpentaploid karyotype, tumorigenesis in nude mice and expression of protein markers of oligodendroglia cells. The SF2 of ihBTC2 cells was significantly higher than that of any other cell line (P<0.05, n = 3). The expression of Notch 1 and Hes1 mRNAs from ihBTC2 cells was significantly increased after radiation. Moreover, the Notch 1, pAkt and Bcl-2 proteins were significantly increased after radiation (P<0.05, n = 3). Inhibition of Notch signaling markedly enhanced the radiosensitivity of ihBTC2 cells.

In an orthotopic glioma model, the malignant transformation of host stromal cells was induced by glioma stem/progenitor cells. IhBTC2 cells are more radiation-resistant than the glioma stem/progenitor cells, which may be mediated by activation of the Notch signaling pathway.

Are high Amounts of Total and Extracellular Vesicle-Derived Soluble HLA-G Associated with HLA-G 14-bp Deletion Variant in Women with Embryo Implantation Failure?

Human leukocyte antigen-G (HLA-G) expression is related to 14-bp insertion/deletion polymorphism at the 3'UTR of the HLA-G gene. Soluble forms of HLA-G are released as free molecules or via extracellular vesicles (EVs). Due to the crucial role of HLA-G during pregnancy, we analyzed the 14-bp polymorphism and the two secreted forms in implantation failure women (IF) and in fertile women (FW). For the genetic analysis, 49 IF and 34 FW were genotyped. For sHLA-G quantification, serum samples from 35 IF and 23 FW were available. ExoQuick(™) kit was used for EVs precipitation. The total soluble HLA-G (sHLA-Gtot ) and vesicular sHLA-GEV were quantified by ELISA. The EVs size and concentration were determined by nanoparticle tracking analysis (NTA). An increased proportion of IF presented high levels of sHLA-Gtot (P = 0.02) and vesicular sHLA-GEV (P = 0.0003) compared to FW. The 14-bp deletion allele is more frequent in IF (P = 0.0002) and associated with high levels of sHLA-Gtot and vesicular sHLA-GEV .

The high expression of sHLA-Gtot and sHLA-GEV , together with the presence of the 14-bp deletion allele, might be involved in implantation failure.

Is pdlim7 required for maintenance of the mesenchymal/epidermal Fgf signaling feedback loop during zebrafish pectoral fin development?

Vertebrate limb development involves a reciprocal feedback loop between limb mesenchyme and the overlying apical ectodermal ridge (AER). Several gene pathways participate in this feedback loop, including Fgf signaling. In the forelimb lateral plate mesenchyme, Tbx5 activates Fgf10 expression, which in turn initiates and maintains the mesenchyme/AER Fgf signaling loop. Recent findings have revealed that Tbx5 transcriptional activity is regulated by dynamic nucleocytoplasmic shuttling and interaction with Pdlim7, a PDZ-LIM protein family member, along actin filaments. This Tbx5 regulation is critical in heart formation, but the coexpression of both proteins in other developing tissues suggests a broader functional role. Knock-down of Pdlim7 function leads to decreased pectoral fin cell proliferation resulting in a severely stunted fin phenotype. While early gene induction and patterning in the presumptive fin field appear normal, the pectoral fin precursor cells display compaction and migration defects between 18 and 24 hours post-fertilization (hpf). During fin growth fgf24 is sequentially expressed in the mesenchyme and then in the apical ectodermal ridge (AER). However, in pdlim7 antisense morpholino-treated embryos this switch of expression is prevented and fgf24 remains ectopically active in the mesenchymal cells. Along with the lack of fgf24 in the AER, other critical factors including fgf8 are reduced, suggesting signaling problems to the underlying mesenchyme. As a consequence of perturbed AER function in the absence of Pdlim7, pathway components in the fin mesenchyme are misregulated or absent, indicating a breakdown of the Fgf signaling feedback loop, which is ultimately responsible for the loss of fin outgrowth.

This work provides the first evidence for the involvement of Pdlim7 in pectoral fin development. Proper fin outgrowth requires fgf24 downregulation in the fin mesenchyme with subsequent activation in the AER, and Pdlim7 appears to regulate this transition, potentially through Tbx5 regulation. By controlling Tbx5 subcellular localization and transcriptional activity and possibly additional yet unknown means, Pdlim7 is required for proper development of the heart and the fins. These new regulatory mechanisms may have important implications how we interpret Tbx5 function in congenital hand/heart syndromes in humans.

Does antioxidant vitamin C improve endothelial dysfunction in chronic smokers?

Chronic smoking is associated with endothelial dysfunction, an early stage of atherosclerosis. It has been suggested that endothelial dysfunction may be a consequence of enhanced degradation of nitric oxide secondary to formation of oxygen-derived free radicals. To test this hypothesis, we investigated the effects of the antioxidant vitamin C on endothelium-dependent responses in chronic smokers. Forearm blood flow responses to the endothelium-dependent vasodilator acetylcholine (7.5, 15, 30, and 60 micrograms/min) and the endothelium-independent vasodilator sodium nitroprusside (1, 3, and 10 micrograms/min) were measured by venous occlusion plethysmography in 10 control subjects and 10 chronic smokers. Drugs were infused into the brachial artery, and forearm blood flow was measured for each drug before and during concomitant intra-arterial infusion of the antioxidant vitamin C (18 mg/min). In control subjects, vitamin C had no effect on forearm blood flow in response to acetylcholine and sodium nitroprusside. In contrast, in chronic smokers the attenuated forearm blood flow responses to acetylcholine were markedly improved by concomitant administration of vitamin C, whereas the vasodilator responses to sodium nitroprusside were not affected.

The present studies demonstrate that the antioxidant vitamin C markedly improves endothelium-dependent responses in chronic smokers. This observation supports the concept that endothelial dysfunction in chronic smokers is at least in part mediated by enhanced formation of oxygen-derived free radicals.