Pharmacodynamic interaction of green tea extract with hydrochlorothiazide against ischemia-reperfusion injury-induced myocardial infarction.
Globally, the rate of development of myocardial diseases and hypertension is very common, which is responsible for incremental morbidity and mortality statistics. Treatment of ischemic hypertensive patients with diuretics such as hydrochlorothiazide (HCTZ) can precipitate myocardial infarction due to hypokalemia. This study was undertaken to evaluate the pharmacodynamic interaction of green tea extract (GTE) with HCTZ against ischemia-reperfusion induced myocardial toxicity. Wistar albino rats of either sex were taken and pretreated with high (500 mg/kg, p.o.) and low (100 mg/kg, p.o.) dose of GTE for 30 days. Standard, high and low dose of interactive groups received HCTZ (10 mg/kg, p.o.) for last 7 days. Ischemia-reperfusion injury was induced by modified Lagendorff apparatus, and the effect of different treatments was evaluated by percentage recovery in terms of heart rate and developed tension, serum biomarkers, and heart tissue antioxidant levels. Prophylactic treatment groups, such as high and low dose of GTE and their interactive groups with HCTZ, exhibited significant percentage recovery in terms of heart rate and developed tension. Apart from that, significant increase in superoxide dismutase and catalase, decrease in thiobarbituric acid reactive species in heart tissue, as well as significant decrease in serum lactate dehydrogenase, creatinine phosphokinase-MB and N-acetylcysteine levels have also been documented. The present findings clearly suggest that GTE dose-dependently reduces myocardial toxicity due to ischemia, and combination with HCTZ can reduce the associated side-effects and exhibits myocardial protection.


Stability and response of polygenic traits to stabilizing selection and mutation.
When polygenic traits are under stabilizing selection, many different combinations of alleles allow close adaptation to the optimum. If alleles have equal effects, all combinations that result in the same deviation from the optimum are equivalent. Furthermore, the genetic variance that is maintained by mutation-selection balance is [Formula: see text] per locus, where μ is the mutation rate and S the strength of stabilizing selection. In reality, alleles vary in their effects, making the fitness landscape asymmetric and complicating analysis of the equilibria. We show that that the resulting genetic variance depends on the fraction of alleles near fixation, which contribute by [Formula: see text], and on the total mutational effects of alleles that are at intermediate frequency. The interplay between stabilizing selection and mutation leads to a sharp transition: alleles with effects smaller than a threshold value of [Formula: see text] remain polymorphic, whereas those with larger effects are fixed. The genetic load in equilibrium is less than for traits of equal effects, and the fitness equilibria are more similar. We find that if the optimum is displaced, alleles with effects close to the threshold value sweep first, and their rate of increase is bounded by [Formula: see text] Long-term response leads in general to well-adapted traits, unlike the case of equal effects that often end up at a suboptimal fitness peak. However, the particular peaks to which the populations converge are extremely sensitive to the initial states and to the speed of the shift of the optimum trait value.


Localized VEGF signaling from ectoderm to mesenchyme cells controls morphogenesis of the sea urchin embryo skeleton.
During development, cell migration plays an important role in morphogenetic processes. The construction of the skeleton of the sea urchin embryo by a small number of cells, the primary mesenchyme cells (PMCs), offers a remarkable model to study cell migration and its involvement in morphogenesis. During gastrulation, PMCs migrate and become positioned along the ectodermal wall following a stereotypical pattern that determines skeleton morphology. Previous studies have shown that interactions between ectoderm and PMCs regulate several aspects of skeletal morphogenesis, but little is known at the molecular level. Here we show that VEGF signaling between ectoderm and PMCs is crucial in this process. The VEGF receptor (VEGFR) is expressed exclusively in PMCs, whereas VEGF expression is restricted to two small areas of the ectoderm, in front of the positions where the ventrolateral PMC clusters that initiate skeletogenesis will form. Overexpression of VEGF leads to skeletal abnormalities, whereas inhibition of VEGF/VEGFR signaling results in incorrect positioning of the PMCs, downregulation of PMC-specific genes and loss of skeleton. We present evidence that localized VEGF acts as both a guidance cue and a differentiation signal, providing a crucial link between the positioning and differentiation of the migrating PMCs and leading to morphogenesis of the embryonic skeleton.


Our 1-year experience in laparoscopic sleeve gastrectomy.
Sleeve gastrectomy was conceived in 1988 both as a first step to the duodenal switch procedure and as an extension of anti-reflux surgery where patients lost significant weight. It is now a stand-alone laparoscopic bariatric procedure worldwide with two international consensus summits identifying it as a safe and feasible restrictive and appetite-suppressing procedure. In our centre, it is a key component in the surgical armamentarium and used as a first-line and revisional procedure for morbid obesity. The procedure is performed using standard five port technique. One year results are reviewed for its feasibility in our Asian patients. Twenty of 48 laparoscopic sleeve gastrectomies have a 1-year follow-up with four of them a revisional procedure for bands with complications. There were 11 males and 9 females (average age 43.6) and a representation of all four major ethnic groups. Average weight and BMI improved from 116.3 to 90.2 kg and 42.5 to 33.1 kg m(-2) after 1 year, respectively. Average weight loss was 26.1 kg and excess weight loss (in percent) was 49.6%. There was an improvement in diabetes mellitus, hypertension, obstructive sleep apnoea and asthma and three complications including two leaks and a gastro-oesophageal spasm/stricture. Laparoscopic sleeve gastrectomy is safe and feasible as first-line surgery for morbid obesity and revisional procedures for band-related complications in the short term. Further studies are required to elucidate the exact mechanisms of weight loss in the sleeve gastrectomy to answer the appropriateness of the variations in the technique and long-term weight loss and morbidity.


Regulation of MHC class II expression, a unique regulatory system identified by the study of a primary immunodeficiency disease.
Major histocompatibility complex class II (MHC-II) molecules are of central importance for adaptive immunity. Defective MHC-II expression causes a severe immunodeficiency disease called bare lymphocyte syndrome (BLS). Studies of the molecular defects underlying BLS have been pivotal for characterization of the regulatory system controlling the transcription of MHC-II genes. The precisely controlled pattern of MHC-II gene expression is achieved by a very peculiar and highly specialized molecular machinery that involves the interplay between ubiquitous DNA-binding transcription factors and a highly unusual, tightly regulated, non-DNA-binding coactivator called the MHC class II transactivator (CIITA). CIITA single handedly coordinates practically all aspects of MHC-II gene regulation and has therefore been dubbed the master controller of MHC-II expression. Several of the unusual features of the MHC-II regulatory system may be a consequence of the fact that CIITA originated from an ancient family of cytoplasmic proteins involved in inflammation and innate immunity. The function of CIITA in transcriptional regulation of MHC-II genes could thus be a recent acquisition by an ancestral protein having a role in an unrelated system.


Current treatment of dysfunctional uterine bleeding.
We performed a review of the treatment modalities for dysfunctional uterine bleeding. Dysfunctional uterine bleeding can be treated medically or surgically. Medical treatment consists of anti-fibrinolytic tranexamic acid, non-steroidal anti-inflammatory drugs, the combined contraception pill, progestogen, danazol, or analogues of gonadotrophin releasing hormone. The levonorgestrel releasing intra uterine device is developed for contraception, but is also effective in the treatment of dysfunctional uterine bleeding. Surgical treatment includes endometrial ablation of the first and second-generation, and hysterectomy. This review contains current available evidence on the effectiveness of these therapies. Antifibrinolytic tranexamic acid is the most effective medical therapy to treat dysfunctional uterine bleeding. In general medical therapy is not as effective as endometrial resection in terms of patient satisfaction and health related quality of life. The levonorgestrel releasing intra uterine device is an effective treatment for dysfunctional uterine bleeding. No difference in quality of life was observed in patients treated with a levonorgestrel releasing intra uterine device as compared to hysterectomy. Ablation techniques of the first generation are effective and safe when used by trained surgeons, but have a learning curve. Ablation techniques of the second generation are effective, but long-term follow-up data are not available. Similarly, there are no large randomised controlled trials comparing the levonorgestrel releasing intra uterine device to first and second-generation ablation techniques. Hysterectomy, the traditional standard of care, has a relatively high complication rate, but it generates a high satisfaction rate and good health related quality of life scores. Since none of the treatments for dysfunctional bleeding is superior to one of the others, and since all treatments have their advantages and disadvantages, counselling of patients with dysfunctional bleeding should incorporate medical approach, levonorgestrel releasing IUD, endometrial ablation and hysterectomy.


Absence of recoverable infectious virus and unique immune responses in an asymptomatic HIV+ long-term survivor.
We have studied a woman with transfusion-acquired HIV who appears to have contained infectious virus to consistently undetectable levels over a 13-year period without antiviral treatment. She received the infected transfusion for intra- and postpartum blood loss immediately after delivery of her second child in 1981. She had no acute febrile syndrome and has never had HIV-associated clinical signs or symptoms in the 13 years since infection. She was first tested and found positive for HIV antibodies in 1985, and the infected blood donor was diagnosed with AIDS in 1986 and died of AIDS-related complications in 1989. Two other recipients of packed erythrocytes from this donor (in 1980 and 1982) also became infected and were subsequently diagnosed with AIDS. Between January 1986 and April 1994, in the setting of continuous and unambiguous Western blot HIV-specific antibodies and intermittently positive low-level HIV DNA signal after polymerase chain reaction (PCR) amplification, more than 30 separate cell cocultures performed in several independent laboratories failed to yield evidence of infectious virus, despite special efforts to induce and detect HIV replication. Immunologically, a strong in vitro proliferative response to HIV envelope proteins also distinguished this subject from other asymptomatic HIV+ individuals.


Minimally invasive osteotomy for symptomatic bunionette deformity is not advisable for severe deformities: a critical retrospective analysis of the results.
Bunionette, or tailor's bunion, is a painful protrusion on the plantar and/or lateral aspect of the fifth metatarsal head. Until recently, there have been very good results reported in literature when minimally invasive therapy is used to treat this deformity. In this study, the authors critically review the outcome of patients operated by the minimal invasive technique. A total of 31 feet were retrospectively reviewed with a mean follow-up of 52 months (range 14-106 months). The results were related to the preoperative severity of the bunionette deformity. The mean intermetatarsal angle IV/V was reduced from 12° to 7.5° postoperatively. The American Orthopaedic Foot and Ankle Society score showed good and excellent values (80-100 points) at follow-up in 16 (12 type I, 4 type III) feet. Fourteen (2 type I, 5 type II, 7 type III) feet were rated as satisfactory (60-80 points) and one (type III) foot with fair (56 points). Nine patients (5 type II and 4 type III) indicated that they would not undergo the operative procedure again. Our results show inclusive evidence that minimal invasive osteotomies have a good clinical outcome in the treatment of high-grade deformities. The best future option is to consider the classification of the deformity before a minimally invasive operation is to take place.


Tongue diagnosis: relationship between sublingual tongue morphology in three tongue protrusion angles and menstrual clinical symptoms.
The morphological and color characteristics of the tongue sublingual veins (SLVs) can manifest differently within the subjects, depending on the way their tongue is curled upward. This study was conducted in order to investigate the clinical relevancy of tongue SLV diagnosis in relation to menstrual clinical symptoms (pain, clots, heavy, and scanty), using three different inspection procedures (IP1, IP2, and IP3). Three-hundred and seventy-seven female patients were asked to stick out their tongues in three specific ways which were intended to create different tongue protrusion angles. The SLV parameters for thickness (TK), length (LE), color (CL), shape (SP), and nodules (ND) were then evaluated. According to the results of the Wald χ2 test, IP1 provides the best model for pain (R2=0.155), IP3 for clots (R2=0.437), IP2 for heavy (R2=0.268), and scanty (R2=0.192). Abnormal SLV diagnostic parameters were most strongly associated with the clinical symptom of clots (R2=0.492). While the study showed the relations between tongue SLV features and menstrual clinical symptoms, as well it showed that IP2 was the best overall predictor for the symptomatic indexes used in this study, and using one particular SLV inspection procedure may not be sufficient. The application of a particular inspection method alone may cause under- or over-estimation of SLV abnormalities.


Luminex(®) and its applications for solid organ transplantation, hematopoietic stem cell transplantation, and transfusion.
The detection of antibodies against the human leukocyte antigen (HLA) complex has become indispensable in every clinical practice. The development of solid-phase assays like the Luminex allows the standardized measurement of anti-HLA antibodies (HLAab) with high sensitivity, albeit the relevance for some clinical settings remains a matter of debate. In this review we aim to describe the principle of Luminex-based antibody detection, including two modifications that allow identifying solely complement-activating antibodies. We then describe three applications for Luminex: i) detection of HLAab preceding solid-organ transplantation and monitoring of donor-specific antibodies posttransplant as a risk factor for antibody-mediated rejection; ii) presence of HLAab in recipients as a risk for graft failure in hematopoietic stem cell transplantation, especially in haploidentical or mismatched transplantations; iii) role of HLAab in blood transfusion including refractory thrombocytopenia and selection of suitable platelet donors, transfusion-related lung injury after plasma transfusion, and immunization against HLA after red blood cell transfusion despite leukodepletion. Although the Luminex platform constitutes a potent technology for HLA antibody detection, some drawbacks require the well-educated analysis and interpretation of data in critical cases. In addition, Luminex has become an important tool to identify clinically relevant antibodies.


Stereotype threat in salary negotiations is mediated by reservation salary.
Women are stereotypically perceived as worse negotiators than men, which may make them ask for less salary than men when under stereotype threat (Kray et al., 2001). However, the mechanisms of stereotype threat are not yet properly understood. The current study investigated whether stereotype threat effects in salary negotiations can be explained by motivational factors. A total of 116 business students negotiated salary with a confederate and were either told that this was diagnostic of negotiating ability (threat manipulation) or not. Measures of minimum (reservation) and ideal (aspiration) salary goals and regulatory focus were collected. The finding (Kray et al., 2001) that women make lower salary requests than men when under stereotype threat was replicated. Women in the threat condition further reported lower aspiration salary, marginally significantly lower reservation salary and less eagerness/more vigilance than men. Reservation salary mediated the stereotype threat effect, and there was a trend for regulatory focus to mediate the effect. Thus, reservation salary partly explains why women ask for less salary than men under stereotype threat. Female negotiators may benefit from learning that stereotype threat causes sex-differences in motivation.


Effect of miconazole on warfarin disposition in rabbits.
To elucidate the mechanism underlying the reported potentiation of warfarin anticoagulant action after initiation of miconazole therapy, the effects of acute and chronic miconazole administration on warfarin disposition were examined in six adult New Zealand male rabbits. The rabbits received a 3.5 mg/kg iv dose of warfarin either alone, 1 hr after a single 100 mg/kg ip miconazole dose, or on day 5 of a 6-day 50 mg/kg/12 hr ip miconazole dosing regimen. Acute miconazole administration decreased the elimination rate constant of warfarin, but other warfarin disposition parameters were not altered. Chronic miconazole administration caused a 47% increase in warfarin plasma-free fraction (probably caused by competitive or noncompetitive protein binding displacement by miconazole metabolites) and a 42% decrease in warfarin intrinsic clearance (probably caused by a miconazole-induced inhibition in warfarin metabolism). As a consequence of these quantitatively similar but opposite changes, the total body clearance of warfarin (a low clearance drug) was marginally decreased. A significant decrease in the elimination rate constant and an increase in the tissue-free fraction of warfarin were also observed during chronic miconazole treatment. These results suggest that chronic miconazole administration should not significantly affect the steady-state plasma concentrations of total warfarin, but should increase the steady-state plasma concentrations of free warfarin. The expected increases in the steady-state plasma concentrations of free, pharmacologically active warfarin may account for the reported potentiation of the pharmacological action of warfarin when coadministered with chronic miconazole. Measurement of total plasma concentrations, and estimation of total body clearance might be misleading, and inadequate in identifying certain drug interactions involving low clearance drugs.


NKp46 identifies an NKT cell subset susceptible to leukemic transformation in mouse and human.
IL-15 may have a role in the development of T cell large granular lymphocyte (T-LGL) or NKT leukemias. However, the mechanisms of action and the identity of the cell subset that undergoes leukemic transformation remain elusive. Here we show that in both mice and humans, NKp46 expression marks a minute population of WT NKT cells with higher activity and potency to become leukemic. Virtually 100% of T-LGL leukemias in IL-15 transgenic mice expressed NKp46, as did a majority of human T-LGL leukemias. The minute NKp46+ NKT population, but not the NKp46⁻ NKT population, was selectively expanded by overexpression of endogenous IL-15. Importantly, IL-15 transgenic NKp46⁻ NKT cells did not become NKp46+ in vivo, suggesting that NKp46+ T-LGL leukemia cells were the malignant counterpart of the minute WT NKp46+ NKT population. Mechanistically, NKp46+ NKT cells possessed higher responsiveness to IL-15 in vitro and in vivo compared with that of their NKp46⁻ NKT counterparts. Furthermore, interruption of IL-15 signaling using a neutralizing antibody could prevent LGL leukemia in IL-15 transgenic mice. Collectively, our data demonstrate that NKp46 identifies a functionally distinct NKT subset in mice and humans that appears to be directly susceptible to leukemic transformation when IL-15 is overexpressed. Thus, IL-15 signaling and NKp46 may be useful targets in the treatment of patients with T-LGL or NKT leukemia.


Hospital transfer associated with increased mortality after endovascular revascularization for acute ischemic stroke.
Patients with an acute ischemic stroke (AIS) due to large vessel occlusion often require transfer to an endovascular center for treatment. To assess the effect of hospital transfer on outcomes after endovascular revascularization. Outcomes of endovascular revascularization were compared between directly admitted and transferred patients using data from a national database and our own institution. 118 institutions within the database reported outcomes of 8533 inpatient admissions for endovascular treatment of AIS. Mortality rate (14.9% vs 18.6%; p=0.049) and mortality index (1.1 vs 1.6; p=0.048) were significantly lower among directly admitted patients than among transferred patients. Within our institutional cohort of 140 patients who underwent endovascular therapy, directly admitted patients had a significantly faster time to revascularization than transferred patients (277.4 vs 420.4 min; p≤0.0001). Among transferred patients, an increasing distance of transferred hospital to our home institution was associated with an increasing risk of mortality (unit OR=1.26, 95% CI 1.07 to 1.54; p=0.0061). Outcomes of revascularization may improve with methods to identify patients with large vessel occlusion before hospital admission, thus increasing the likelihood of initial triage to a comprehensive stroke center for patients eligible for endovascular intervention.


Itraconazole therapy in a pancreatic adenocarcinoma patient: A case report.
To report the case of a patient receiving itraconazole for the treatment of histoplasmosis and his subsequent reduction in pancreatic tumor size. A 64-year-old male was diagnosed with Stage III locally advanced unresectable pancreatic adenocarcinoma. The patient was administered radiation plus chemotherapy, which included cisplatin and capecitabine. Upon restaging, the patient's tumor was again determined to be unresectable; therefore, palliative chemotherapy treatments were initiated, which included gemcitabine and erlotinib. After two gemcitabine cycles, he was admitted to the hospital because of loss of motor function due to spinal cord hemisection. After the surgery, the patient became neutropenic because of previous chemotherapy cycle and developed disseminated histoplasmosis. After he received his nine-month course of itraconazole, the pancreatic cancer was readdressed and he was then deemed to be resectable and had a Whipple procedure. Over the next several years, he showed no evidence of pancreatic metastases or relapse. Itraconazole has been shown to have many mechanisms by which it could potentially suppress tumor cell growth, which includes inhibition of the Hedgehog pathway, vascular endothelial growth factor receptor-2, and P-glycoprotein efflux pump. This azole antifungal has been studied in small patient populations with various types of cancers. Studies of basal cell carcinoma, nonsmall cell lung cancer, ovarian cancer, and malignant pleural mesothelioma have shown favorable results suggesting that more study of itraconazole is warranted to decide its clinical utility. There would need to be much more research performed to determine if this agent had a role as a chemotherapy agent; however, health care professionals should be aware of itraconazole's potential antineoplastic mechanisms.


All-printed thin-film transistors from networks of liquid-exfoliated nanosheets.
All-printed transistors consisting of interconnected networks of various types of two-dimensional nanosheets are an important goal in nanoscience. Using electrolytic gating, we demonstrate all-printed, vertically stacked transistors with graphene source, drain, and gate electrodes, a transition metal dichalcogenide channel, and a boron nitride (BN) separator, all formed from nanosheet networks. The BN network contains an ionic liquid within its porous interior that allows electrolytic gating in a solid-like structure. Nanosheet network channels display on:off ratios of up to 600, transconductances exceeding 5 millisiemens, and mobilities of >0.1 square centimeters per volt per second. Unusually, the on-currents scaled with network thickness and volumetric capacitance. In contrast to other devices with comparable mobility, large capacitances, while hindering switching speeds, allow these devices to carry higher currents at relatively low drive voltages.


Fate of endocrine disrupters in waste stabilization pond systems.
The performance in the removal of estrogenicity from wastewater was studied in three wastewater treatment plants (WWTPs). Different treatment processes were evaluated: stabilization ponds and trickling filter. Sampling was performed from the input to the output of the treatment systems. The total estrogenic activity was determined with MCF-7-derived cell lines which express the endogenous estrogen receptor alpha. The two wastewater stabilization ponds with long retention time had high removal of estrogenicity (90% to 95%). Trickling filters despite being effective at removing organic load were less effective in removing estrogenicity (42%), and post tertiary ponds enhanced estrogenicity removal.


Increased risk of mortality after postoperative infection in hip fracture patients.
Postoperative infection is a common complication in hip fracture patients and the risk appears to have increased during the last decade. However, the impact of infection on mortality after hip fracture surgery remains unclear. We aimed to examine the association between infection (any, as well as specific infections), with all-cause mortality following hip fracture surgery. Using Danish nationwide registries, we conducted a population-based cohort study on 74,771 hip fracture patients ≥65 years old operated from 2005 to 2016. We included hospital-treated infection as a time-varying exposure, and calculated 30-days mortality rate per 1000 person-years (PY). We used time-varying Cox Proportional Hazard Regression to compute 30-days adjusted hazards ratios (aHRs) with 95% confidence interval (CI) comparing the mortality of hip fracture patients with and without infections. We adjusted for sex, age, comorbidities, medication use, and marital status. Within 30 days of surgery, 9592 (12.8%) patients developed a hospital-treated infection. Among these, 30-days mortality was 8.43 per 1000 PY compared with 3.34 among patients without infection (aHR = 2.72, 95% CI: 2.56-2.88). For patients who developed pneumonia, aHR was 4.18 (95% CI: 3.91-4.48), whereas the aHR was 8.86 (95% CI: 7.88-9.95) for patients who developed systemic sepsis. For patients who sustained reoperation due to infection, aHR was 2.95 (95%CI: 1.88-4.64). The mortality was higher in infected vs. non-infected patients irrespective of patients' age, sex and comorbidity. Infection within 30 days of hip fracture surgery is associated with substantially increased mortality risk. Further research should improve our knowledge about patients at increased risk and prevention measures for specific infections.


Real-time amyloid aggregation monitoring with a photonic crystal-based approach.
We propose the application of a new label-free optical technique based on photonic nanostructures to real-time monitor the amyloid-beta 1-42 (Aβ(1-42)) fibrillization, including the early stages of the aggregation process, which are related to the onset of the Alzheimer's Disease (AD). The aggregation of Aβ peptides into amyloid fibrils has commonly been associated with neuronal death, which culminates in the clinical features of the incurable degenerative AD. Recent studies revealed that cell toxicity is determined by the formation of soluble oligomeric forms of Aβ peptides in the early stages of aggregation. At this phase, classical amyloid detection techniques lack in sensitivity. Upon a chemical passivation of the sensing surface by means of polyethylene glycol, the proposed approach allows an accurate, real-time monitoring of the refractive index variation of the solution, wherein Aβ(1-42) peptides are aggregating. This measurement is directly related to the aggregation state of the peptide throughout oligomerization and subsequent fibrillization. Our findings open new perspectives in the understanding of the dynamics of amyloid formation, and validate this approach as a new and powerful method to screen aggregation at early stages.


Raising the Awareness of Undergraduate Nurses to the Psychosocial Impact of Living with Cancer: A Consumer Engagement in Teaching Initiative.
This article reflects on the development and implementation of a consumer engagement in teaching initiative by the authors. The authors highlight the challenges of engaging undergraduate nursing students on the psychosocial aspects of living with cancer and other chronic illnesses when students have very limited personal and professional experiences to draw on. The authors discuss how they have responded to these challenges by integrating the voices of consumers into their classrooms. Speakers from consumer advocacy organization, Cancer Voices SA, participated in a series of tutorials in a 1st year topic in the Undergraduate Nursing Program at the School of Nursing and Midwifery, Flinders University. Student feedback from the implementation of the initiative indicated that students found consumers' stories and experiences of living with cancer, "moving and powerful" and that they encouraged students to question their assumptions about the psychosocial impacts of cancer on individuals and families. The importance of good communication in reducing patient distress was identified by students as an important element of consumers' experiences of the health care system as was the need for transparency and information sharing between health care providers across the health care system. For many students, consumers' stories and experiences had reinforced students' commitment to studying nursing and pursuing a career in nursing. The article concludes that involving consumers in the education of health care professionals encourages a much deeper understanding of and empathy for how patients experience disease, which is integral to the provision of patient-centered and holistic care.


Strategies for the management of invasive fungal infections due to filamentous fungi in high-risk hemato-oncological patients.
In recent years, the introduction of new antifungals for the prevention of invasive fungal infections (IFIs) in hemato- oncological patients, particularly extended-spectrum azoles, has led to a change in the diagnostic and therapeutic strategies for established or suspected breakthrough IFI. The aim of the study was to identify the diagnostic and therapeutic strategies used in the management of IFIs in hemato-oncological patients in Spain, and to assess compliance with the recommendations of the consensus documents and clinical practice guidelines. An online, anonymous, cross-sectional survey was conducted between January and September 2016 involving 137 specialists from third-level hospitals in Spain with Departments of Hematology that regularly deal with IFIs. Galactomannan test was available to 95.6% of specialists, and was used in 61.7% of the cases for diagnostic confirmation and early treatment. The (1 → 3) β-D-glucan test was only available to 10.2%. A total of 75.3% of the participants estimated the incidence of breakthrough IFI due to filamentous fungus as being 1-10%. In turn, 83.3% of the participants decided a change in antifungal class after failure of prophylaxis, in concordance with the recommendations of the national and international consensus documents. The present study, the first of its kind conducted in Spain, shows that a high percentage of the medical professionals implicated in the management of hemato-oncological patients at high risk of suffering IFIs follow the recommendations of the national and international consensus documents and guidelines.


Folding of protein G B1 domain studied by the conformational characterization of fragments comprising its secondary structure elements.
The solution structure of the isolated fragments 1-20 (beta-hairpin), 21-40 (alpha-helix) and 41-56 (beta-hairpin), corresponding to all the secondary structure elements of the protein G B1 domain, have been studied by circular dichroism and nuclear magnetic resonance techniques. In the protein G B1-(1-20) fragment turn-like folded structures were detected in water though low populated. In the presence of 30% aqueous trifluoroethanol there is a complex conformational behaviour in which a helical structure at the N-terminal half is formed in equilibrium with random and native-like beta-hairpin structures. The peptide corresponding to the alpha-helix is predominantly unstructured in water, while in 30% trifluoroethanol it highly populates a native alpha-helical conformation, including a (i,i + 5) interaction between hydrophobic residues at its C-terminus. The third peptide was previously reported to form a monomeric native beta-hairpin structure in water [Blanco, F. J., Rivas, G. & Serrano, L. (1994a) Nature Struc. Biol. 1, 584-590]. We show in this work that the beta-hairpin structure is further stabilized in 30% trifluoroethanol and destabilised in the presence of 6 M urea, though some folded structure persists even in these highly denaturing conditions. The conformational properties of these peptides suggests that the second beta-hairpin could be an important folding initiation site on which the rest of the chain folds. Reconstitution experiments failed to show evidence of interaction between the peptides. Algorithms designed to predict the helical and extended conformations of peptides in aqueous solution successfully describe the complicated behaviour of these peptides. Comparison of the predicted and the experimental results with those for a structurally related protein, ubiquitin, shows very strong similarities, the main difference being the switch of the most stable beta-hairpin from the N-terminus in ubiquitin to the C-terminus in protein G.


Practice audits to reduce caesareans in a tertiary referral hospital in south-western China.
To assess the effectiveness of a three-stage intervention to reduce caesarean deliveries in a Chinese tertiary hospital. A retrospective study was conducted to assess whether educating staff, educating patients and auditing surgeon practices (introduced in 2005) had reduced caesarean delivery rates. Multiple logistic regression was used to check for a potential association between caesarean rates and rates of admission to the neonatal intensive care unit (NICU). The caesarean delivery rate ranged from 53.5% to 56.1% in 2001-2004 and from 43.9% to 36.1% in 2005-2011. When 2001-2004 and 2005-2011 were treated as "before" and "after" periods to evaluate the intervention's impact on the mean caesarean section rate, a significant reduction was noted: from 54.8% to 40.3% (odds ratio, OR: 0.56; 95% confidence interval, CI: 0.52-0.59; χ(2) test: P < 0.001). The overall drop in the caesarean section rate was significant (χ(2) test: P < 0.001) and inversely correlated with the years (Spearman's ρ: -0.096; P < 0.001). Although complicated pregnancies increased after 2004, the primary caesarean section rate decreased annually by 20% on average in 2005-2011, after practice audits were implemented. Multiple logistic regression showed a positive association between the caesarean delivery rate and the rate of admission to the NICU (adjusted OR: 1.26; 95% CI: 1.14-1.40). Patient and staff education and practice audits reduced the Caesarean section rate in a tertiary referral hospital without an increase in admissions to the NICU.


Over-diagnosis of laryngopharyngeal reflux as the cause of hoarseness.
The objectives of this study were: (1) to determine the percentage of patients seen in a private laryngology clinic with voice-related disorders previously diagnosed with and treated for laryngopharyngeal reflux (LPR); (2) to determine how many of those patients are found to have disorders other than LPR as a cause for their voice disorder. A retrospective, chart-review analysis of new patients was conducted from January 2005 through December 2007 in a private laryngology clinic setting. Patients with a previous diagnosis of LPR as the cause of hoarseness, with or without anti-reflux treatment were included. Incomplete charts and patients with additional diagnoses besides LPR where excluded. Patient charts were analyzed in search of different variables including chief complaint, previous medications and final diagnosis among others. 784 consecutive charts were reviewed. Inclusion criteria were met in 105 charts. 82 % had no improvement or felt worse after previous anti-reflux treatment while 18 % had significant or mild improvement. However, all patients remained with some degree of hoarseness. Final diagnosis by the author was diverse though none of the patients had laryngopharyngeal reflux as a final diagnosis and none of them noted worsening of their voice after respective treatment. Only 6 % felt the same after treatment and 9 % could not be found for follow-up. LPR has become an over-diagnosed entity. With a thorough history, vocal capability testing and physical exam, an accurate diagnosis for hoarseness can be made in the vast majority of cases. LPR may not be the cause of voice disorders and should not be assigned as a de facto diagnosis just because the cause of hoarseness is not readily identifiable.


Fumarate hydratase deficiency and cancer: activation of hypoxia signaling?
Molecular genetic analysis of hereditary leiomyomatosis and renal cell cancer (HLRCC) unexpectedly revealed germline defects in the gene encoding the Krebs cycle enzyme fumarate hydratase (FH), stimulating great interest in the underlying mechanism of oncogenesis. It has been proposed that the associated accumulation of fumarate competitively inhibits the 2-oxoglutarate-dependent dioxygenases that regulate hypoxia-inducible factor (HIF), thus activating oncogenic hypoxia pathways. In this issue of Cancer Cell, Pollard and colleagues describe a genetic mouse model of FH deficiency that recapitulates aspects of the human disease, including HIF activation and renal cysts, enabling further insights into this unusual cancer syndrome.


Vibrational solvatochromism and electrochromism. II. Multipole analysis.
Small infrared probe molecules have been widely used to study local electrostatic environment in solutions and proteins. Using a variety of time- and frequency-resolved vibrational spectroscopic methods, one can accurately measure the solvation-induced vibrational frequency shifts and the timescales and amplitudes of frequency fluctuations of such IR probes. Since the corresponding frequency shifts are directly related to the local electric field and its spatial derivatives of the surrounding solvent molecules or amino acids in proteins, one can extract information on local electric field around an IR probe directly from the vibrational spectroscopic results. Here, we show that, carrying out a multipole analysis of the solvatochromic frequency shift, the solvatochromic dipole contribution to the frequency shift is not always the dominant factor. In the cases of the nitrile-, thiocyanato-, and azido-derivatized molecules, the solvatochromic quadrupole contributions to the corresponding stretch mode frequency shifts are particularly large and often comparable to the solvatochromic dipole contributions. Noting that the higher multipole moment-solvent electric field interactions are short range effects in comparison to the dipole interaction, the H-bonding interaction-induced vibrational frequency shift can be caused by such short-range multipole-field interaction effects. We anticipate that the present multipole analysis method specifically developed to describe the solvatochromic vibrational frequency shifts will be useful to understand the intermolecular interaction-induced vibrational property changes and to find out a relationship between vibrational solvatochromism and electrochromism of IR probes in condensed phases.


TNF-alpha and serum induce SKALP/elafin gene expression in human keratinocytes by a p38 MAP kinase-dependent pathway.
Keratinocytes of inflamed epidermis (psoriasis, wound healing) are hyperproliferative and display an abnormal differentiation programme. This regenerative differentiation pathway is characterized by the induction of genes that are not expressed by keratinocytes in normal skin, such as the cytokeratins CK6, CK16, CK17, and the proteinase inhibitor SKALP/elafin. In the study reported here we investigated the induction and regulation of SKALP expression as a marker for regenerative differentiation in epidermal keratinocytes. Various cytokines and growth factors known to be present in psoriatic epidermis were examined for their ability to induce SKALP gene expression in cultured human keratinocytes. Tumour necrosis factor-alpha (TNF-alpha) and serum were found to be potent inducers of SKALP expression at both the mRNA and the protein levels. SB202190 or SB203580, two specific p38 MAP kinase inhibitors almost completely blocked the induction of SKALP expression by TNF-alpha and serum. These results suggest that in keratinocytes, p38 activity is crucial for the induction of SKALP gene expression. These findings could be relevant for the elucidation of the mechanisms involved in normal and disturbed epidermal differentiation.


Cytotoxicity and Oxidative Stress Responses of Imidacloprid and Glyphosate in Human Prostate Epithelial WPM-Y.1 Cell Line.
Insecticide imidacloprid and herbicide glyphosate have a broad spectrum of applicable use in the agricultural sector of Egypt. Their ability to induce in vitro cytotoxic and oxidative stress on normal human cells (prostate epithelial WPM-Y.1 cell line) was evaluated with the methyl tetrazolium test (MTT) and histopathological investigation. Cell viability was evaluated with an MTT test for 24 h. The median inhibition concentration (IC50) values were 0.023 and 0.025 mM for imidacloprid and glyphosate, respectively. Sublethal concentrations: 1/10 and 1/50 of IC50 and IC50 levels significantly induced an increase in the lactate dehydrogenase (LDH) activity and malondialdehyde (MDA) level compared with the untreated cells. Rapid decrease in the glutathione (GSH) content and glutathione-S-transferase (GST) activity was induced. Significant increases were recorded in activities of catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR), respectively, compared with the control group. Transmission electron microscopic (TEM) investigation showed significant defects in the cells following pesticide treatments for 24 h. Therefore, it is concluded that imidacloprid and glyphosate are very toxic in vitro assays and able to induce apoptotic effects as well as oxidative stress. So, these findings provide a scenario of multibiomarkers to achieve the imposed risks of pesticides at low doses.


Vascular stem/progenitor cells: current status of the problem.
Stem/progenitor cells residing in the vascular wall of post-natal vessels play a crucial role in angiogenesis and vascular regeneration after damage. There are four major populations of vascular-resident stem/progenitor cells with differentiated clonogenic and proliferative potential, namely mesenchymal stem cells, pericytes, endothelial progenitor cells, and smooth muscle progenitor cells. These progenitors reside in vascular stem cell niches, which are more likely to be in the adventitia, a vascular wall layer in which increased concentration of stem cell surface markers has been shown. Indeed, vascular resident progenitors are not uniformly distributed across the vessel wall and the circulatory system. The heterogeneity of such a distribution could contribute to the differentiated susceptibility of various vessel regions to chronic vascular diseases such as atherosclerosis. In cardiovascular pathology, adult vascular resident progenitors could play either a negative or a positive role.


Illicit cigarettes and hand-rolled tobacco in 18 European countries: a cross-sectional survey.
Little evidence, other than that commissioned by the tobacco industry, exists on the size of the illicit tobacco trade. This study addresses this gap by examining the level and nature of illicit cigarettes and hand-rolled tobacco in 18 European countries. Face-to-face cross-sectional survey on smoking. 18 European countries. For each country, around 1000 subjects representative of the population aged 15 and over were enrolled. Current cigarette smokers were asked to show their latest purchased pack of cigarettes or hand-rolled tobacco. A comprehensive measure called an Identification of an Illicit Pack (IIP) was used to study the extent of illicit trade, defining a pack as illicit if it had at least one of the following tax evasion indicators: (1) it was bought from illicit sources, as reported by smokers, (2) it had an inappropriate tax stamp, (3) it had an inappropriate health warning or (4) its price was substantially below the known price in their market. Overall, the proportion of illicit packs was 6.5%. The highest prevalence of IIP was observed in Latvia (37.8%). Illicit packs were more frequent among less educated smokers and among those living in a country which shared a land or sea border with Ukraine, Russia, Moldova or Belarus. No significant association was found with price of cigarettes. This study indicates that IIP is less than 7% in Europe and suggests that the supply of illicit tobacco, rather than its price, is a key factor contributing to tax evasion.


Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism.
In patients with acute pulmonary embolism, systemic thrombolysis improves right ventricular (RV) dilatation, is associated with major bleeding, and is withheld in many patients at risk. This multicenter randomized, controlled trial investigated whether ultrasound-assisted catheter-directed thrombolysis (USAT) is superior to anticoagulation alone in the reversal of RV dilatation in intermediate-risk patients. Fifty-nine patients (63±14 years) with acute main or lower lobe pulmonary embolism and echocardiographic RV to left ventricular dimension (RV/LV) ratio ≥1.0 were randomized to receive unfractionated heparin and an USAT regimen of 10 to 20 mg recombinant tissue plasminogen activator over 15 hours (n=30; USAT group) or unfractionated heparin alone (n=29; heparin group). Primary outcome was the difference in the RV/LV ratio from baseline to 24 hours. Safety outcomes included death, major and minor bleeding, and recurrent venous thromboembolism at 90 days. In the USAT group, the mean RV/LV ratio was reduced from 1.28±0.19 at baseline to 0.99±0.17 at 24 hours (P<0.001); in the heparin group, mean RV/LV ratios were 1.20±0.14 and 1.17±0.20, respectively (P=0.31). The mean decrease in RV/LV ratio from baseline to 24 hours was 0.30±0.20 versus 0.03±0.16 (P<0.001), respectively. At 90 days, there was 1 death (in the heparin group), no major bleeding, 4 minor bleeding episodes (3 in the USAT group and 1 in the heparin group; P=0.61), and no recurrent venous thromboembolism. In patients with pulmonary embolism at intermediate risk, a standardized USAT regimen was superior to anticoagulation with heparin alone in reversing RV dilatation at 24 hours, without an increase in bleeding complications. http://www.clinicaltrials.gov. Unique identifier: NCT01166997.


Esophageal tissue engineering: an in-depth review on scaffold design.
Treatment of esophageal cancer often requires surgical procedures that involve removal. The current approaches to restore esophageal continuity however, are known to have limitations which may not result in full functional recovery. In theory, using a tissue engineered esophagus developed from the patient's own cells to replace the removed esophageal segment can be the ideal method of reconstruction. One of the key elements involved in the tissue engineering process is the scaffold which acts as a template for organization of cells and tissue development. While a number of scaffolds range from traditional non-biodegradable tubing to bioactive decellularized matrix have been proposed to engineer the esophagus in the past decade, results are still not yet favorable with many challenges relating to tissue quality need to be met improvements. The success of new esophageal tissue formation will ultimately depend on the success of the scaffold being able to meet the essential requirements specific to the esophageal tissue. Here, the design of the scaffold and its fabrication approaches are reviewed. In this paper, we review the current state of development in bioengineering the esophagus with particular emphasis on scaffold design.


Intratumoral microhemorrhages on T2*-weighted gradient-echo imaging helps differentiate vestibular schwannoma from meningioma.
Vestibular schwannomas (VS) may be difficult to differentiate from cerebellopontine angle (CPA) meningiomas. Demonstration of microhemorrhages in VS on T2*-weighted gradient-echo (GRE) sequences may have potential value to differentiate VS from CPA meningiomas. In this prospective study of 20 patients, MR imaging was performed with T2*-weighted GRE in addition to all basic sequences. Histopathologic examination was performed after surgery. Intratumoral hemosiderin was confirmed by pigment staining. There were 15 patients in the VS group with 16 VS and 5 in the meningioma group with 5 posterior fossa meningiomas. Fourteen of the 16 VS and all 5 meningiomas were treated surgically and were confirmed on histopathologic examination. T2*-weighted GRE identified microhemorrhages on T2*-weighted sequence in 15 (93.75%) of the 16 VS. CT excluded calcification in all VS. T2-weighted turbo spin-echo (TSE) and fluid-attenuated inversion recovery (FLAIR) images recognized microhemorrhages in 2 cases. Pigment staining confirmed hemosiderin in all 14 surgically treated VS, and none of the meningiomas showed microhemorrhages on MR imaging. For the detection of microhemorrhages, T2*-weighted GRE showed a sensitivity of 93.8%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 83.3%. The sensitivity of T2 TSE and FLAIR for microhemorrhage was 12.5%. The Fisher exact test showed a statistically significant difference in the differentiation of VS from meningioma on the basis of detection of microhemorrhages (P < .01). Most VS demonstrate microhemorrhages on T2*-weighted GRE. This finding is useful to differentiate VS from CPA meningiomas. T2*-weighted GRE should be used as a basic sequence to evaluate CPA tumors. Identification of microhemorrhages may have the potential to assess the aggressive biologic behavior of VS.


Peace and war: trajectories of posttraumatic stress disorder symptoms before, during, and after military deployment in Afghanistan.
In the study reported here, we examined posttraumatic stress disorder (PTSD) symptoms in 746 Danish soldiers measured on five occasions before, during, and after deployment to Afghanistan. Using latent class growth analysis, we identified six trajectories of change in PTSD symptoms. Two resilient trajectories had low levels across all five times, and a new-onset trajectory started low and showed a marked increase of PTSD symptoms. Three temporary-benefit trajectories, not previously described in the literature, showed decreases in PTSD symptoms during (or immediately after) deployment, followed by increases after return from deployment. Predeployment emotional problems and predeployment traumas, especially childhood adversities, were predictors for inclusion in the nonresilient trajectories, whereas deployment-related stress was not. These findings challenge standard views of PTSD in two ways. First, they show that factors other than immediately preceding stressors are critical for PTSD development, with childhood adversities being central. Second, they demonstrate that the development of PTSD symptoms shows heterogeneity, which indicates the need for multiple measurements to understand PTSD and identify people in need of treatment.


Noise equalization in Stokes parameter images obtained by use of variable-retardance polarimeters.
An imaging variable retardance polarimeter was developed and tested by Tyo and Turner [Proc. SPIE 3753, 214 (1999)]. The signal-to-noise ratio (SNR) in the reconstructed polarization images obtained with this system varied for the four Stokes parameters. The difference in SNR is determined to be due to differences in the Euclidean lengths of the rows of the synthesis matrix used to reconstruct the Stokes parameters from the measured intensity data. I equalize (and minimize) the lengths of the rows of this matrix by minimizing the condition number of the synthesis matrix, thereby maximizing the relative importance of each of the polarimeter measurements. The performance of the optimized system is demonstrated with simulated data, and the SNR is shown to increase from a worst case of -3.1 dB for the original settings to a worst case of +5.0 dB for the optimized system.


Conspiracy theories as quasi-religious mentality: an integrated account from cognitive science, social representations theory, and frame theory.
Conspiracy theories (CTs) can take many forms and vary widely in popularity, the intensity with which they are believed and their effects on individual and collective behavior. An integrated account of CTs thus needs to explain how they come to appeal to potential believers, how they spread from one person to the next via communication, and how they motivate collective action. We summarize these aspects under the labels of stick, spread, and action. We propose the quasi-religious hypothesis for CTs: drawing on cognitive science of religion, social representations theory, and frame theory. We use cognitive science of religion to describe the main features of the content of CTs that explain how they come to stick: CTs are quasi-religious representations in that their contents, forms and functions parallel those found in beliefs of institutionalized religions. However, CTs are quasi-religious in that CTs and the communities that support them, lack many of the institutional features of organized religions. We use social representations theory to explain how CTs spread as devices for making sense of sudden events that threaten existing worldviews. CTs allow laypersons to interpret such events by relating them to common sense, thereby defusing some of the anxiety that those events generate. We use frame theory to explain how some, but not all CTs mobilize collective counter-conspiratorial action by identifying a target and by proposing credible and concrete rationales for action. We specify our integrated account in 13 propositions.


Increased serum uric acid level predicts poor prognosis in mildly severe chronic heart failure with reduced ejection fraction. An analysis from the MECKI score research group.
Hyperuricemia prognostic impact on clinical outcomes in chronic heart failure (HF) patients has been investigated with inconclusive results. Aim of the study was to evaluate the prognostic impact of serum uric acid (SUA) on long-term clinical outcomes in HF. An analysis of MECKI (Metabolic Exercise Cardiac Kidney Index) database, with median follow-up of 3.4 years. Relation between SUA and all-cause/ cardiovascular (CV) deaths have been analysed in 4,577 patients (3,688 males, age 62.7 ± 12.9 years), with reduced ejection fraction HF (35 ± 11%), peakVO2 1151 ± 440 ml/min; NYHA class I-II (72.6%), III-IV (27.4%). SUA was associated with increased total and CV mortality (HR 1.120 and HR 1.128, respectively p < 0.0001), also after adjustment for peakVO2, VE/VCO2 slope, diuretic use and MECKI score. SUA was significantly associated with CV mortality only in NYHA class I-II (HR 1.17, p < 0.0001) while there was no association in class III-IV (HR 1.03, p = NS). No prognostic added values of SUA with respect to the MECKI score was observed at the ROC analysis. SUA is confirmed to be associated with increased mortality, but in less severe HF only. However SUA did not show additional prognostic power to the MECKI score.


Suppressive activities of OGG1 and MYH proteins against G:C to T:A mutations caused by 8-hydroxyguanine but not by benzo[a]pyrene diol epoxide in human cells in vivo.
8-Hydroxyguanine (8OHG), an oxidatively damaged base, and benzo[a]pyrene-diol-epoxide (BPDE), a metabolite of benzo[a]pyrene found in cigarette smoke, are thought to be major causes for G:C to T:A transversions in DNA of human cells. In this study, we assessed the abilities of OGG1, MYH and APE1 proteins, which are components of a base excision repair pathway, to suppress G:C to T:A transversions caused by 8OHG or BPDE by a bacterial suppressor tRNA (supF) forward mutation assay using a shuttle plasmid, pMY189. The introduction of a single 8OHG residue at position 159 of the supF gene and treatment with BPDE led to a 65- and 34-fold increase in mutation frequencies of the pMY189 plasmid, respectively, after replication in the NCI-H1299 human lung cancer cell line. G:C to T:A transversions were predominantly induced in these plasmids. Both the mutation frequency of the 8OHG-containing plasmid in NCI-H1299 cells and the occurrence of G:C to T:A transversions at position 159 in the supF gene were significantly reduced by overexpression of OGG1 and MYH proteins, but not by that of APE1 protein. In contrast, neither mutation frequency nor the occurrence of G:C to T:A transversion of the BPDE-treated plasmid was reduced by overexpression of OGG1, MYH and APE1 proteins. These results indicate that OGG1 and MYH function as suppressors for G:C to T:A transversions by 8OHG but not by BPDE in human cells.


Impact of physician assistants on the outcomes of patients with acute myelogenous leukemia receiving chemotherapy in an academic medical center.
Inpatient academic medical center care historically has been delivered by faculty physicians in conjunction with physicians in training (house officers [HOs]). Alternative staffing models have emerged secondary to American Counsel for Graduate Medical Education work-hour restrictions. The purpose of this study was to assess the quality of acute myelogenous leukemia (AML) care provided by a physician assistant (PA) service compared with a traditional model. Data were retrospectively collected on patients admitted with AML for reinduction chemotherapy from 2008 to 2012. Primary outcome measures were inpatient mortality and length of stay (LOS). Secondary measures included readmissions, intensive care unit (ICU) transfers, consults requested, and radiologic studies ordered. Ninety-five patients with AML were reviewed. Forty-seven patients (49.5%) were admitted to the HO service, and 48 patients (50.5%) were admitted to the PA service. Demographic data were similar between services. LOS was significantly different between the services, with a mean of 36.8 days with the HO model compared with 30.9 days with the PA service (P=.03). The 14-day readmission rate also differed significantly; it was 10.6% (five of 47 patients) and zero for the HO and PA models, respectively (P=.03). The mean number of consults with the HO model was 2.11 (range, zero to five) versus 1.47 (range, zero to four) with the PA service (P=.03). Mortality and ICU transfers were not significantly different. The data demonstrate equivalent mortality and ICU transfers, with a decrease in LOS, readmission rates, and consults for patients cared for in the PA service. This suggests that the PA service is associated with increased operational efficiency and decreased health service use without compromising health care outcomes.


Determinants of (sustained) overweight and complaints in children and adolescents in primary care: the DOERAK cohort study design.
Almost half of the adult Dutch population is currently overweight and the prevalence of overweight children is rising at alarming rates as well. Obese children consult their general practitioner (GP) more often than normal weight children. The Dutch government has assigned a key role to the GP in the prevention of overweight.The DOERAK cohort study aims to clarify differences between overweight and non-overweight children that consult the GP; are there differences in number of consultations and type and course of complaints? Is overweight associated with lower quality of life or might this be influenced by the type of complaint? What is the activity level of overweight children compared to non-overweight children? And is (sustained) overweight of children associated with parameters related to the energy balance equation? A total of 2000 overweight (n = 500) and non-overweight children (n = 1500) aged 2 to 18 years who consult their GP, for any type of complaint in the South-West of the Netherlands are included.At baseline, height, weight and waist circumference are measured during consultation. The number of GP consultations over the last twelve months and accompanying diagnoses are acquired from the medical file. Complaints, quality of life and parameters related to the energy balance equation are assessed with an online questionnaire children or parents fill out at home. Additionally, children or parents keep a physical activity diary during the baseline week, which is validated in a subsample (n = 100) with an activity monitor. Parents fill out a questionnaire about demographics, their own activity behaviour and perceptions on dietary habits and activity behaviour, health and weight status of their child. The physical and lifestyle behaviour questions are repeated at 6, 12 and 24 months follow-up. The present study is a prospective observational cohort in a primary care setting. The DOERAK cohort study is the first prospective study that investigates a large cohort of overweight and non-overweight children in primary care. The total study population is expected to be recruited by 2013, results will be available in 2015.


Activation and regulation of purinergic P2X receptor channels.
Mammalian ATP-gated nonselective cation channels (P2XRs) can be composed of seven possible subunits, denoted P2X1 to P2X7. Each subunit contains a large ectodomain, two transmembrane domains, and intracellular N and C termini. Functional P2XRs are organized as homomeric and heteromeric trimers. This review focuses on the binding sites involved in the activation (orthosteric) and regulation (allosteric) of P2XRs. The ectodomains contain three ATP binding sites, presumably located between neighboring subunits and formed by highly conserved residues. The detection and coordination of three ATP phosphate residues by positively charged amino acids are likely to play a dominant role in determining agonist potency, whereas an AsnPheArg motif may contribute to binding by coordinating the adenine ring. Nonconserved ectodomain histidines provide the binding sites for trace metals, divalent cations, and protons. The transmembrane domains account not only for the formation of the channel pore but also for the binding of ivermectin (a specific P2X4R allosteric regulator) and alcohols. The N- and C- domains provide the structures that determine the kinetics of receptor desensitization and/or pore dilation and are critical for the regulation of receptor functions by intracellular messengers, kinases, reactive oxygen species and mercury. The recent publication of the crystal structure of the zebrafish P2X4.1R in a closed state provides a major advance in the understanding of this family of receptor channels. We will discuss data obtained from numerous site-directed mutagenesis experiments accumulated during the last 15 years with reference to the crystal structure, allowing a structural interpretation of the molecular basis of orthosteric and allosteric ligand actions.


Food responsiveness regulates episodic behavioral states in Caenorhabditis elegans.
Animals optimize survival and reproduction in part through control of behavioral states, which depend on an organism's internal and external environments. In the nematode Caenorhabditis elegans a variety of behavioral states have been described, including roaming, dwelling, quiescence, and episodic swimming. These states have been considered in isolation under varied experimental conditions, making it difficult to establish a unified picture of how they are regulated. Using long-term imaging, we examined C. elegans episodic behavioral states under varied mechanical and nutritional environments. We found that animals alternate between high-activity (active) and low-activity (sedentary) episodes in any mechanical environment, while the incidence of episodes and their behavioral composition depend on food levels. During active episodes, worms primarily roam, as characterized by continuous whole body movement. During sedentary episodes, animals exhibit dwelling (slower movements confined to the anterior half of the body) and quiescence (a complete lack of movement). Roaming, dwelling, and quiescent states are manifest not only through locomotory characteristics but also in pharyngeal pumping (feeding) and in egg-laying behaviors. Next, we analyzed the genetic basis of behavioral states. We found that modulation of behavioral states depends on neuropeptides and insulin-like signaling in the nervous system. Sensory neurons and the Foraging homolog EGL-4 regulate behavior through control of active/sedentary episodes. Optogenetic stimulation of dopaminergic and serotonergic neurons induced dwelling, implicating dopamine as a dwell-promoting neurotransmitter. Our findings provide a more unified description of behavioral states and suggest that perception of nutrition is a conserved mechanism for regulating animal behavior.NEW & NOTEWORTHY One strategy by which animals adapt to their internal states and external environments is by adopting behavioral states. The roundworm Caenorhabditis elegans is an attractive model for investigating how behavioral states are genetically and neuronally controlled. Here we describe the hierarchical organization of behavioral states characterized by locomotory activity, feeding, and egg-laying. We show that decisions to engage in these behaviors are controlled by the nervous system through insulin-like signaling and the perception of food.


Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation.
Stable inheritance of DNA methylation is critical for maintaining differentiated phenotypes in multicellular organisms. We have recently identified dual mono-ubiquitylation of histone H3 (H3Ub2) by UHRF1 as an essential mechanism to recruit DNMT1 to chromatin. Here, we show that PCNA-associated factor 15 (PAF15) undergoes UHRF1-dependent dual mono-ubiquitylation (PAF15Ub2) on chromatin in a DNA replication-coupled manner. This event will, in turn, recruit DNMT1. During early S-phase, UHRF1 preferentially ubiquitylates PAF15, whereas H3Ub2 predominates during late S-phase. H3Ub2 is enhanced under PAF15 compromised conditions, suggesting that H3Ub2 serves as a backup for PAF15Ub2. In mouse ES cells, loss of PAF15Ub2 results in DNA hypomethylation at early replicating domains. Together, our results suggest that there are two distinct mechanisms underlying replication timing-dependent recruitment of DNMT1 through PAF15Ub2 and H3Ub2, both of which are prerequisite for high fidelity DNA methylation inheritance.


The psychometric properties of the Composite International Diagnostic Interview.
The Composite International Diagnostic Interview, or CIDI, is a fully structured interview that maps the symptoms elicited during the interview onto DSM-IV and ICD-10 diagnostic criteria and reports whether the diagnostic criteria are satisfied--nothing more, nothing less. The inter-rater reliability has been demonstrated to be excellent, the test-retest reliability good, and the validity has been demonstrated to be good, given the methodological constraints. The CIDI is available in lifetime and 12-month versions, and in both paper-and-pencil and computer-administered forms. The latter version is suitable for self-administration in cooperative subjects. The CIDI is available in many languages. It is supported by ten centres around the world, which conduct regular training programmes for interviewers. The training programmes are standardised and the training materials are comprehensive. The data from the CIDI is entered into standard data entry and scoring programmes that give as output the diagnostic criteria satisfied. The interviews, the training materials, and the scoring programmes are copyright by the World Health Organization (WHO) and are supervised by an advisory committee on behalf of WHO. That committee and the training centres welcome enquiries from researchers and clinicians who are interested in using the CIDI.


Study of patients with indwelling catheters.
Indwelling urethral catheters are used for the long-term management of intractable urinary incontinence or bladder outlet obstruction with resultant retention of urine. There are well-described problems associated with their use including urinary tract infections and mechanical problems. Urinary tract infections have been well researched, however mechanical problems associated with blockage of the catheter lumen due to encrustation, leakage of urine and general discomfort, have been the least investigated. To date, there has been no research of patients' views, understanding or feelings in relation to their catheters. This paper comprises a preliminary investigation of patients' understanding and knowledge of their catheter's location and function, its acceptance, problems associated with its use, social implications and its subsequent management. Thirty-six patients from the community of one health district were surveyed. It was concluded that an indwelling catheter is a prosthesis which, to be successful, requires adequate patient education and management. Education of the patient and carers is particularly important since an understanding of the catheter and its function will lead to better acceptance of the device and will enable better management of the urine drainage system.


Electronic stability of magnetic Fe/Co superlattices with monatomic layer alternation.
We report a surprising observation that the growth of the [Fe(1 ML)/Co(1 ML)](n) superlattice of L1(0) structure on Cu(100) is stable only up to six atomic layers (n=3), which cannot be rationalized by stress arguments. Instead, first-principles calculations reveal a transition from the L1(0) to the B2 structure due to the effect of dimensionality on the stability of the electronic structure of the superlattice. Whereas the majority-spin electrons are energetically insensitive to the layer thickness, the minority-spin electrons induce the transition at n=3.


The spectrum of statin myopathy.
This review discusses the spectrum of myopathies associated with statin use, with special attention given to a recently identified statin-associated autoimmune-necrotizing myopathy. The clinical characteristics of these patients, pathologic findings, associated autoantibody and immunogenetic risk factors are discussed. In the past several years, a novel form of autoimmunemyopathy associated with statin use has been described. Patients with this form of myositis have unique clinical, pathologic and pathophysiologic features when compared with those with self-limited statin toxic myopathy. An autoantibody directed against HMG-CoA reductase (HMGCR), the pharmacologic target of statins, characterizes the disease and can be used in clinical practice to identify these patients and direct therapy. Still, many questions remain to be answered regarding the pathogenic mechanisms at play, risk factors for developing the disease, long-term prognosis and effects of rechallenge with statins or other cholesterol-lowering drugs. Statins can cause a spectrum of muscle diseases, most of which are self-limited and improve with discontinuation of the offending agent. In a subgroup, an autoimmune necrotizing myopathy develops that persists after discontinuation of statins. Specific autoantibody testing can help identify these patients in clinical practice and determine the need for immunosuppressive therapy.


Involvement of TRPV1 Channels in Energy Homeostasis.
The ion channel TRPV1 is involved in a wide range of processes including nociception, thermosensation and, more recently discovered, energy homeostasis. Tightly controlling energy homeostasis is important to maintain a healthy body weight, or to aid in weight loss by expending more energy than energy intake. TRPV1 may be involved in energy homeostasis, both in the control of food intake and energy expenditure. In the periphery, it is possible that TRPV1 can impact on appetite through control of appetite hormone levels or via modulation of gastrointestinal vagal afferent signaling. Further, TRPV1 may increase energy expenditure via heat production. Dietary supplementation with TRPV1 agonists, such as capsaicin, has yielded conflicting results with some studies indicating a reduction in food intake and increase in energy expenditure, and other studies indicating the converse. Nonetheless, it is increasingly apparent that TRPV1 may be dysregulated in obesity and contributing to the development of this disease. The mechanisms behind this dysregulation are currently unknown but interactions with other systems, such as the endocannabinoid systems, could be altered and therefore play a role in this dysregulation. Further, TRPV1 channels appear to be involved in pancreatic insulin secretion. Therefore, given its plausible involvement in regulation of energy and glucose homeostasis and its dysregulation in obesity, TRPV1 may be a target for weight loss therapy and diabetes. However, further research is required too fully elucidate TRPV1s role in these processes. The review provides an overview of current knowledge in this field and potential areas for development.


Glycolipid acquisition by human glycolipid transfer protein dramatically alters intrinsic tryptophan fluorescence: insights into glycolipid binding affinity.
Glycolipid transfer proteins (GLTPs) are small, soluble proteins that selectively accelerate the intermembrane transfer of glycolipids. The GLTP fold is conformationally unique among lipid binding/transfer proteins and serves as the prototype and founding member of the new GLTP superfamily. In the present study, changes in human GLTP tryptophan fluorescence, induced by membrane vesicles containing glycolipid, are shown to reflect glycolipid binding when vesicle concentrations are low. Characterization of the glycolipid-induced "signature response," i.e. approximately 40% decrease in Trp intensity and approximately 12-nm blue shift in emission wavelength maximum, involved various modes of glycolipid presentation, i.e. microinjection/dilution of lipid-ethanol solutions or phosphatidylcholine vesicles, prepared by sonication or extrusion and containing embedded glycolipids. High resolution x-ray structures of apo- and holo-GLTP indicate that major conformational alterations are not responsible for the glycolipid-induced GLTP signature response. Instead, glycolipid binding alters the local environment of Trp-96, which accounts for approximately 70% of total emission intensity of three Trp residues in GLTP and provides a stacking platform that aids formation of a hydrogen bond network with the ceramide-linked sugar of the glycolipid headgroup. The changes in Trp signal were used to quantitatively assess human GLTP binding affinity for various lipids including glycolipids containing different sugar headgroups and homogenous acyl chains. The presence of the glycolipid acyl chain and at least one sugar were essential for achieving a low-to-submicromolar dissociation constant that was only slightly altered by increased sugar headgroup complexity.


Regional cerebral blood flow and cognitive deficits in chronic lyme disease.
This study examined brain functioning in patients with Lyme encephalopathy. Eleven patients underwent neuropsychological tests and Xenon(133)-regional cerebral blood flow (rCBF) studies, using an external detector system. Each rCBF scan was age- and sex-matched to two archival, normal controls. While few differences were noted on gray-matter flow indices (ISI, fg), Lyme patients demonstrated significant flow reductions in white matter index (k(2)) (p=.004), particularly in the posterior temporal and parietal lobes bilaterally (p=.003). Flow reductions in white matter areas were significantly associated with deficits in memory (r=.66, p=.027) and visuospatial organization (r=.62, p=.041). Results suggest that Lyme encephalopathy may be a disease primarily affecting the cerebral white matter.


Xanthorrhizol inhibits 12-O-tetradecanoylphorbol-13-acetate-induced acute inflammation and two-stage mouse skin carcinogenesis by blocking the expression of ornithine decarboxylase, cyclooxygenase-2 and inducible nitric oxide synthase through mitogen-activated protein kinases and/or the nuclear factor-kappa B.
Xanthorrhizol is an active component isolated from Curcuma xanthorrhiza Roxb. (Zingiberaceae) that is traditionally used in Indonesia for medicinal purposes. In the present study, we found that the topical application of xanthorrhizol before 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment significantly inhibits TPA-induced mouse ear edema and TPA-induced tumor promotion in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated ICR mouse skin. The topical application of xanthorrhizol following the induction of papillomas with TPA-induced hyperplasia and dysplasia also reduced tumor multiplicity and incidence in DMBA-initiated mouse skin. To further elucidate the molecular mechanisms underlying the antitumor-promoting activity of xanthorrhizol, its effect on the TPA-induced expression of ornithine decarboxylase (ODC), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) and the upstream signaling molecules controlling these proteins were explored in mouse skin. The pre-treatment with xanthorrhizol inhibited the expression of ODC, iNOS and COX-2 proteins and nuclear factor-kappaB (NF-kappaB) activation in both mouse skin with TPA-induced acute inflammation and DMBA-initiated mouse skin promoted by TPA for 19 weeks. When mouse skin was treated after TPA-induced production of papillomas, xanthorrhizol remarkably suppressed the expression of ODC, iNOS and COX-2 and inhibited the activation of NF-kappaB. Furthermore, western blot analysis showed that xanthorrhizol suppressed the activation of extracellular signal-regulated protein kinase, p38, c-Jun-N-terminal kinase and Akt in mice after topical application for 6 weeks following the induction of papillomas. Taken together, the present study demonstrates that xanthorrhizol not only delays or inhibits tumor formation, but also reverses the carcinogenic process at pre-malignant stages by reducing the protein levels of ODC, iNOS and COX-2 regulated by the NF-kappaB, mitogen-activated protein kinases and/or Akt.


Mild traumatic brain injury screening, diagnosis, and treatment.
The majority of combat-related traumatic brain injury (TBI) within the U.S. Armed Forces is mild TBI (mTBI). This article focuses specifically on the screening, diagnosis, and treatment aspects of mTBI within the military community. Aggressive screening measures were instituted in 2006 to ensure that the mTBI population is identified and treated. Screenings occur in-theater, outside the contiguous United States, and in-garrison. We discuss specific screening procedures at each screening setting. Current diagnosis of mTBI is based upon self-report or through witnesses to the event. TBI severity is determined by specific Department of Defense criteria. Abundant clinician resources are available for mTBI in the military health care setting. Education resources for both the patient and the clinician are discussed in detail. An evidence-based clinical practice guideline for the care of mTBI was created through collaborative efforts of the DoD and the U.S. Department of Veterans Affairs. Although symptoms following mTBI generally resolve with time, active treatment is centered on symptom management, supervised rest, recovery, and patient education. Medical specialty care, ancillary services, and other therapeutic services may be required.


Ion mobility mass spectrometry provides novel insights into the expression and structure of gangliosides in the normal adult human hippocampus.
Clustered into the so-called "glycosynaptic" microdomains in the central nervous system (CNS), gangliosides (GGs) are involved in the formation of functional synapses and neural circuits. Therefore, GGs are important biomarkers in the early diagnosis of CNS pathologies, which are the focus of our research as potential therapeutic targets. A series of neuropsychiatric disorders, including Alzheimer's disease and schizophrenia, are characterized by amnesia and disorientation caused by hippocampal atrophy and diminished cholinergic activity. Based on ion mobility mass spectrometry (IM-MS) capability for the reliable determination of glycopatterns, the changes in the diversity and number of GGs with age and the occurrence of neurological disorders, we report here the development of a high performance IM-MS strategy for assessing the GG profile in a complex mixture extracted from a 20 year old hippocampus. IM separation of GGs based on the charge state, carbohydrate chain length and degree of sialylation led to the detection and identification of 140 species, the largest number of GGs ever reported in an adult hippocampus. Moreover, the obtained data support the concept of GG cholinergic activity. IM tandem MS experiments using collision induced dissociation (CID) confirmed the incidence of GD1b(d18:1/24:1) in the investigated hippocampus specimen.


Anti-inflammatory activity of silymarin in patients with knee osteoarthritis. A comparative study with piroxicam and meloxicam.
To evaluate the anti-inflammatory effect of Silymarin in patients with knee osteoarthritis (OA) in comparison with piroxicam and meloxicam. A double-blind clinical trial was performed at the Department of Rheumatology, Baghdad Teaching Hospital, Baghdad, Iraq during the period from October 2004 to September 2005, in which 220 patients (79 males and 141 females) with painful knee osteoarthritis were randomized into 5 groups, treated with either silymarin (300 mg/day), piroxicam (20 mg/day), meloxicam (15 mg), or a combination of silymarin with piroxicam or meloxicam. Serum levels of interleukin-1 alpha, interleukin-8, and the complement proteins C3 and C4 were assessed at zero time, and after 8 weeks. Silymarin reduces significantly serum levels of IL-1 alpha and IL-8, C3 and C4 after 8 weeks compared to the pre-treatment levels. Piroxicam showed no significant reduction in IL-1 alpha levels, while IL-8 decreased significantly, compared to pre-treatment value. Meloxicam elevates serum levels of IL-1 alpha significantly, while IL-8 did not significantly change compared to the pre-treatment value. Piroxicam or meloxicam produced slight, non-significant increase in serum levels of complement proteins after the 8-week treatment period. Adjunct use of silymarin with piroxicam results in significant reduction in both cytokines (IL-1 alpha and IL-8), and serum levels of C3 and C4. However, its adjunct use with, meloxicam did not reveal any significant changes in this respect. Silymarin reduces the elevated levels of interleukins and complement proteins, when used alone, or in combination with NSAIDs for the treatment of knee OA.


Alterations of tear neuromediators in dry eye disease.
To evaluate tear levels of neuromediators in patients with dry eye disease and to identify statistical correlations with the clinical findings. Nineteen patients with dry eye disease (Sjögren syndrome, n = 5 patients; non-Sjögren syndrome, n = 10; and ocular cicatricial pemphigoid, n = 4) and 12 healthy volunteers were enrolled. The eyes of all participants were evaluated by slitlamp examination, Schirmer testing, fluorescein staining, and tear film break-up time. Grading of dry eye severity was recorded. Tear samples were collected, and substance P, calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), vasoactive intestinal peptide, and nerve growth factor (NGF) concentrations were evaluated by enzyme-linked immunoassay and correlated with the clinical findings. Nerve growth factor tear levels were significantly increased in participants with dry eye disease; CGRP and NPY concentrations were significantly decreased when compared with those in healthy participants. Dry eye severity showed a direct correlation with NGF and an inverse correlation with CGRP and NPY tear levels. Nerve growth factor tear levels showed a direct correlation with conjunctival hyperemia and fluorescein staining results, CGRP directly correlated with Schirmer test values, and NPY inversely correlated with tear film break-up time. Subgroup analysis showed that CGRP and NPY but not NGF were changed in autoimmune (ie, Sjögren syndrome and ocular cicatricial pemphigoid) dry eye disease. The decreased tear levels of NPY and CGRP in dry eye disease are related to impaired lacrimal function, and tear levels of NGF are more closely related to corneal epithelial damage. Our findings suggest that NPY, CGRP, and NGF could become useful markers of dry eye severity.


Prognostic implications of stage of disease and sites of metastases in patients with small cell carcinoma of the lung treated with intensive combination chemotherapy.
The influence of various sites of distant metastases on response and survival was analyzed in 106 consecutive previously untreated patients with small cell carcinoma whose disease was systematically staged. All patients received 6 wk of intensive induction chemotherapy with cyclophosphamide, methotrexate, and lomustine; therapy thereafter varied without differential effects on survival. Staging procedures included physical examination, chest roentgenogram, fiberoptic bronchoscopy, bone marrow and liver biopsies, and radionuclide bone, brain, and liver scans. On the basis of pretreatment staging, 33 patients (31%) had limited disease. In the remaining 73 patients, sites of extensive disease included bone in 40; with bone as the sole site of metastatic disease in 13; liver in 30, with liver as the only site in 5; soft tissues in 25 (only site in 7); bone marrow in 22 (only 2); central nervous system in 9 (only site in 4); opposite lung in 7 (only site in 4). Although patients with limited disease live longer than those with extensive disease (median length of survival, 12 versus 10 months), this difference was not significant. This lack of major impact of traditional stage on survival was explained by the similar survival of patients with limited disease and a single site of extensive disease. Prognosis worsened with increasing number of sites of extensive disease (median survival, 11.5, 10, and 8 months for one, two, and three or more sites, respectively). Metastases to the liver or central nervous system significantly shortened survival, whereas involvement of bone, soft tissues, or bone marrow had little adverse effect. In patients with small cell carcinoma whose disease is thoroughly staged and who are given aggressive chemotherapy, certain sites or a small number of sites of extensive disease may be treated as successfully as limited disease.


The effect of hydration status on plasma FGF21 concentrations in humans: A subanalysis of a randomised crossover trial.
Fibroblast growth factor 21 (FGF21) has recently been implicated in thirst in rodent models. The mechanisms for this are currently uncertain, and it is unclear whether hydration status can alter FGF21 concentrations, potentially providing an additional mechanism by which hypohydration induces thirst. The aim of this study is therefore to understand whether hydration status can alter circulating FGF21 in humans. Using a heat tent and fluid restriction, we induced hypohydration (1.9% body mass loss) in 16 healthy participants (n = 8 men), and compared their glycaemic regulation to a rehydration protocol (heat tent and fluid replacement) in a randomised crossover design. After the hypohydration procedure, urine specific gravity, urine and serum osmolality, and plasma copeptin (as a marker for arginine vasopressin) increased as expected, with no change after the rehydration protocol. In the fasted state, the median paired difference in plasma FGF21 concentrations from the rehydrated to hypohydrated trial arm was -37 (interquartile range -125, 10) pg∙mL-1(P = 0.278), with average concentrations being 458 ± 462 pg∙mL-1 after hypohydration and 467 ± 438 pg∙mL-1 after rehydration; mean difference -9 ± 173 pg∙mL-1. To our knowledge, these are the first causal data in humans investigating hydration and FGF21, demonstrating that an acute bout of hypohydration does not impact fasted plasma FGF21 concentrations. These data may suggest that whilst previous research has found FGF21 administration can induce thirst and drinking behaviours, a physiological state implicated in increased thirst (hypohydration) does not appear to impact plasma FGF21 concentrations in humans.


Recovery of poliovirus from turbid estuarine water on microporous filters by the use of celite.
The application of a new step for recovering poliovirus from moderately to highly turbid estuarine water by the filter virus-adsorption technique was investigated. The experiments were conducted under both (i) laboratory-based conditions (200-ml volumes) where the turbidity was controlled and (ii) simulated field conditions (15- to 100-gal volumes) where the turbidity varied depending upon the hydrology of the raw estuarine water. The new step consisted of adding Celite to the turbid water prior to sampling for virus. In the experiments, the pH of the water was first adjusted to 3.5 and then AlCl(3) was added to 0.0005 M. Celite was added to a concentration of 0.01% and mixed thoroughly. Either an HE Cox M-780 microfilter (Cox Instrument, Div. of Lynch Corp., Detroit, Mich.) or an MF-membrane filter (Millipore Corp., Bedford, Mass.) was used as the virus adsorbent. Virus was eluted from the Celite-filter complex in situ at pH 9 with 5x nutrient broth. In the laboratory-based experiments, when turbidity ranged from 5.0 to 30.0 Jackson turbidity units (JTU), virus recovery ranged from 66 to 89%. In the simulated field experiments, when the turbidity ranged from 8.5 to 80.0 JTU, virus recovery ranged from <1 to 74%, depending upon the multiplicity of virus input and the level of turbidity. The new step greatly improved the filtration-flux of turbid water and significantly reduced the premature clogging problem usually observed with microporous filters.


Validity and item response theory properties of the Patient Health Questionnaire-9 for primary care depression screening in Mozambique (PHQ-9-MZ).
Depression is one of the leading causes of disability in Mozambique; however, few patients with depression are identified in primary care. To our knowledge, there are no validated tools for depression screening in Mozambique. The aim of this study was to validate the Patient Health Questionnaire-9 (PHQ-9) for use in primary care settings in Mozambique. The PHQ-9 was adapted using a structured multi-phase process led by a team of bilingual experts followed by a review by lay individuals and pilot-testing including cognitive interviews. The final Mozambican PHQ-9 (PHQ-9-MZ) was applied among 502 individuals randomly selected from antenatal, postpartum, and general outpatient consultations in three Ministry of Health primary healthcare clinics in Sofala Province, Mozambique. The PHQ-9-MZ was evaluated against the MINI 5.0-MZ as a gold standard diagnostic tool. The majority of participants were female (74%), with a mean age of 28. Using the MINI 5.0-MZ, 43 (9%) of the sample tested positive for major depressive disorder. Items of the PHQ-9-MZ showed good discrimination and factor loadings. One latent factor of depression explained 54% of the variance in scores. Questions 3 (sleep) and 5 (appetite) had the lowest item discrimination and factor loadings. The PHQ-9-MZ showed good internal consistency, with a Cronbach's alpha of 0.84, and an area under the receiver operating characteristic curve (AUROC) of 0.81 (95% CI: 0.73, 0.89). The PHQ-2-MZ had an AUROC of 0.78 (95% CI: 0.70, 0.85). Using a cut-point of ≥9, the PHQ-9-MZ had a sensitivity of 46.5% and a specificity of 93.5%. Using a cut-point of ≥2, the PHQ-2-MZ had a sensitivity of 74.4% and a specificity of 71.7%. Increasing the cut-point to ≥3, the PHQ-2-MZ has a sensitivity of 32.6% and a specificity of 94.6%. The PHQ-9-MZ and PHQ-2-MZ emerge as two valid alternatives for screening for depression in primary health care settings in Mozambique. Depending on program needs and weighing the value of minimizing false positives and false negatives, the PHQ-9-MZ can be employed with cut-points ranging from ≥8 to ≥11, and the PHQ-2-MZ with cut-points ranging from ≥2 to ≥3.


In-home telerehabilitation for post-knee arthroplasty: a pilot study.
The purpose of this study was to investigate the efficacy of in-home telerehabilitation as an alternative to conventional rehabilitation services following knee arthroplasty. Five community-living elders who had knee arthroplasty were recruited prior to discharge from an acute care hospital. A pre/post-test design without a control group was used for this pilot study. Telerehabilitation sessions (16) were conducted by two trained physiotherapists from a service center to the patient's home using H264 videoconference CODECs (Tandberg 550 MXP) connected at 512 Kb\s. Disability (range of motion, balance and lower body strength) and function (locomotor performance in walking and functional autonomy) were measured in face-to-face evaluations prior to and at the end of the treatments by a neutral evaluator. The satisfaction of the health care professional and patient was measured by questionnaire. Results are as follows. One participant was lost during follow-up. Clinical outcomes improved for all subjects and improvements were sustained two months post-discharge from in-home telerehabilitation. The satisfaction of the participants with in-home telerehabilitation services was very high. The satisfaction of the health care professionals with the technology and the communication experience during the therapy sessions was similar or slightly lower. In conclusion, telerehabilitation for post-knee arthroplasty is a realistic alternative for dispensing rehabilitation services for patients discharged from an acute care hospital.


Developmental aspects of the basal ganglia and therapeutic perspectives.
Development and sex hormones play an important role in the expression of seizures. Sex-specific differences in the development of seizure suppressing neuronal networks may account, at least in part, for age- and sex related susceptibility to seizures. The substantia nigra pars reticulata is a site involved in the control of seizures. In adult male rats, there are two distinct GABAA sensitive regions within the substantia nigra pars reticulata, which mediate opposite effects in flurothyl seizures. Muscimol infused into the anterior region is anticonvulsant while similar infusions into the posterior region are proconvulsant. These two regions differ morphologically, and utilize different efferent networks. In contrast, in postnatal day 15 male rats, there is no such differentiation and muscimol infusions have only proconvulsant effects. The hallmark of the female substantia nigra pars reticulata is the fact that muscimol- mediated proconvulsant effects cannot be demonstrated in any region at any age. The sex-related difference in nigral seizure control may be related to the lack of testosterone in females. Accordingly, neonatal castration of males results in the loss of the proconvulsant region. The male type of the substantia nigra pars reticulata effects can be induced by exogenous testosterone administration in neonatally castrated male or in female rats. The phenotype of nigral GABAergic neurons, as characterized by GABAA receptor subunit composition, muscimol-induced electrophysiological responses, and connectivity of output networks may each be altered by the presence of testosterone. Better understanding of the influence of the endocrine system on brain development and neuronal activity may provide new insight into the treatment of age- and sex-dependent seizure disorders.


Detection, quantification, metabolism, and behavioral effects of selegiline in horses.
Selegiline ([R]-[-]N,alpha-dimethyl-N-2- propynylphenethylamine or l-deprenyl), an irreversible inhibitor of monoamine oxidase, is a classic antidyskinetic and antiparkinsonian agent widely used in human medicine both as monotherapy and as an adjunct to levodopa therapy. Selegiline is classified by the Association of Racing Commissioners International (ARCI) as a class 2 agent, and is considered to have high abuse potential in racing horses. A highly sensitive LC/MS/MS quantitative analytical method has been developed for selegiline and its potential metabolites amphetamine and methamphetamine using commercially available deuterated analogs of these compounds as internal standards. After administering 40 mg of selegiline orally to two horses, relatively low (<60 ng/ml) concentrations of parent selegiline, amphetamine, and methamphetamine were recovered in urine samples. However, relatively high urinary concentrations of another selegiline metabolite were found, tentatively identified as N- desmethylselegiline. This metabolite was synthesized and found to be indistinguishable from the new metabolite recovered from horse urine, thereby confirming the chemical identity of the equine metabolite. Additionally, analysis of urine samples from four horses dosed with 50 mg of selegiline confirmed that N-desmethylselegiline is the major urinary metabolite of selegiline in horses. In related behavior studies, p.o. and i.v. administration of 30 mg of selegiline produced no significant changes in either locomotor activities or heart rates.