Pharmacokinetics and pharmacodynamics of benazepril hydrochloride in patients with major proteinuria.
We have investigated whether the pharmacokinetics and pharmacodynamics of the ACE inhibitor benazepril hydrochloride are altered with proteinuria by studying 8 patients with major proteinuria of different causes who were given a single dose of 10 mg p.o. The maximum plasma concentration of benazepril was found between 0.5 and 2 h after dosing (median 1 h). Its elimination was almost complete within 6 h. Peak plasma levels of benazeprilat, the active metabolite of benazepril, were observed between 1 and 6 h (median 2.5 h). The elimination of benazeprilat from plasma was biphasic, with mean initial and terminal half-lives of 3.0 and 17.3 h, respectively. On average, the pharmacokinetic parameters of benazepril and benazeprilat in the patients did not differ from those in a historical control group of healthy volunteers, but intersubject variability in the AUC and half-lives of benazeprilat was greater in the patients. Plasma ACE was completely inhibited from 1.5 to 6 h after dosing, and at 48 h the mean inhibition was still 42%. Plasma renin showed substantial intersubject variation. Mean supine blood pressure (systolic/diastolic) was reduced from baseline by a maximum of 18/13 mm Hg at 6 h. Proteinuria was diminished after benazepril in 7 patients. In conclusion, the results of this study suggest that proteinuria in the nephrotic range does not require a change in benazepril dosage.


The Medical Imaging & Technology Alliance conference on research endpoints appropriate for Medicare coverage of new PET radiopharmaceuticals.
The outcomes of a 2011 Medical Imaging & Technology Alliance (MITA) conference helped shape considerations about what might be the most appropriate pathways for the regulatory and payment considerations of new PET radiopharmaceuticals. As follow-up to that conference, MITA convened a second conference of stakeholders to advise payers on what might be acceptable endpoints for clinical trials to support the coverage of novel PET agents. The conference involved experts on imaging and clinical research, providers of PET services, as well as representatives of interested medical societies, the PET industry, and the regulatory and payer communities. The principal outcome of their deliberations was that it was unrealistic to expect trials of new PET radiopharmaceuticals to directly demonstrate a health benefit. Rather, intermediate outcomes, such as a positive change in patient management, would be more efficient and appropriate.


Gemcitabine in combination with EGF-Receptor antibody (Cetuximab) as a treatment of cholangiocarcinoma: a case report.
Extensive disease of cholangiocarcinoma (CC) determines the overall outcome and limits curative resection. Despite chemotherapy, which has been introduced to improve the outcome of biliary tract malignancies, the benefit in survival is still marginal. We report a 69-year-old patient with non-resectable CC showing hepatic metastasis and peritoneal carcinomatosis. Diagnosis was based on computed tomography, mini-laparoscopy and bioptic specimens. Histology revealed an adenocarcinoma of the biliary tract with expression of epithelial growth factor receptor. After informed consent the patient received experimental gemcitabine (1000 mg/m2) every other week and cetuximab (250 mg/m2) weekly for palliative chemotherapy. During the reported follow up (since time of first presentation) 20 cycles of chemotherapy were administered. Relevant chemotherapy-related toxicity was limited on gemcitabine-associated side effects. Predominantly, haematological toxicity (CTC, grade 3) and neutropenic fever (CTC, grade 3) promoted by catheter-related sepsis were observed. Cetuximab caused only mild skin toxicity (CTC, grade 1). Chemotherapy led to a partial response (> 30% reduction, according to RECIST) of the target lesions and disappearance of the peritoneal carcinomatosis as shown by computed tomography. Partial response occurred after 17 weeks of treatment and remained stable during the entire course of chemotherapy for 9.7 months. In parallel, Ca 19-9 serum levels, which were elevated 5-fold at time of diagnosis, returned to normal after 16 weeks of treatment. The performance status stabilized and intravenous alimentation could be discontinued. Our experience from one patient with CC suggests, that a combination of cytotoxic chemotherapy together with cetuximab may show promising efficacy in respect to survival and quality of life. Therefore cetuximab, as a component of palliative chemotherapy in biliary tract cancer, needs further evaluation in prospective randomized trials.


Receptors of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in fetal and adult human kidney: localization and [125I]VEGF binding sites.
Vascular endothelial growth factor (VEGF) has an important function in renal vascular ontogenesis and is constitutively expressed in podocytes of the adult kidney. The ability of VEGF to be chemotactic for monocytes and to increase the activity of collagenase and plasminogen activator may have implications for renal development and renal disease. In humans, the cellular actions of VEGF depend on binding to two specific receptors: Flt-1 and KDR. The aims of this study were: (1) to localize VEGF receptor proteins in human renal ontogenesis; (2) to quantify VEGF binding in human fetal and adult kidney; and (3) to dissect the binding into its two known components: the KDR and Flt-1 receptors. The latter aim was achieved by competitive binding of VEGF and placenta growth factor-2, which only binds to Flt-1. Quantification of 125I-VEGF binding sites was performed by autoradiography and computerized densitometry. By double-label immunohistochemistry, VEGF receptor proteins were localized solely to endothelial cells of preglomerular vessels, glomeruli, and postglomerular vessels. In developing glomeruli, VEGF receptor protein appeared as soon as endothelial cells were positive for von Willebrand factor. Specific 125I-VEGF binding could be localized to renal arteries and veins, glomeruli, and the tubulointerstitial capillary network in different developmental stages. Affinity (Kd) of adult (aK) and fetal (fK) kidneys was: Kd: glomeruli 38.6 +/- 11.2 (aK, n = 5), 36.3 +/- 7.1 (fK, n = 5); cortical tubulointerstitium 19.4 +/- 2.6 (aK, n = 5), 11.6 +/- 7.0 (fK, n = 5) pmol. Placenta growth factor-2 displaced VEGF binding in all renal structures by approximately 60%. VEGF receptor proteins thus were found only in renal endothelial cells. A coexpression of both VEGF binding sites could be shown, with Flt-1 demonstrating the most abundant VEGF receptor binding sites in the kidney. These studies support the hypothesis of a function for VEGF in adult kidney that is independent of angiogenesis.


Effects of prolonged exposure to ethanol in vivo on functional parameters and sensitivity to nitrendipine in the isolated rat heart.
This study investigated the possibility that previously reported marked upregulation of binding sites for the dihydropyridine calcium channel antagonist nitrendipine in heart tissue during the development of ethanol dependence in the rat may represent functional L-type voltage-operated calcium channels (L-VOCCs). Isolated hearts obtained from adult Sprague-Dawley rats, which received intoxicating concentrations of ethanol for 6-10 days, by inhalation, were perfused with Krebs-Henseleit solution in the Langendorff mode. Basic measurements of cardiac function were compared with hearts from control rats not exposed to ethanol vapor. In another study, concentration-response curves were constructed for nitrendipine at concentrations in the range of 10(-10)-10(-6) M for hearts obtained from control and ethanol-exposed animals. Changes in measured cardiac parameters such as R-wave amplitude, heart rate, diastolic and systolic pressure, and (+)dP/dt(max) and coronary flow were recorded. All comparisons were made between preparations set to a similar left ventricular end-diastolic pressure. Under these conditions, there were no significant differences in R-wave amplitude, but isolated hearts from ethanol-dependent rats showed significantly greater indices of myocardial contraction than did controls. These included increased systolic and developed ventricular pressure and increased (+)dP/dt(max). Coronary flow also was significantly greater in hearts from ethanol-dependent rats compared with controls. Heart rate was higher in the alcohol-exposed group, but this difference did not achieve significance. When nitrendipine was added to the perfusate at concentrations between 10(-10) and 10(-6) M, hearts from ethanol-dependent animals showed a greater sensitivity to the effects of the drug on heart rate and systolic pressure. Effects on R-wave amplitude and (+)dP/dt(max) were less clear but also suggested a greater sensitivity to nitrendipine in hearts from ethanol-exposed rats. Effects on coronary flow were small and did not differ significantly between preparations from control and ethanol-dependent rats. The results suggest that the increase in Bmax of DHP binding previously observed in hearts from ethanol-dependent animals might represent an increase in L-VOCCs, which alters physiologic function, and pharmacologic responses in the isolated heart. These changes may represent the exposure of an adaptive mechanism designed to overcome the generally depressant effects of ethanol on cardiac function in vivo.


Simple training programme for ambulance personnel in the management of cardiac arrest in the community.
The extended training for ambulance personnel in Nottinghamshire includes a period of training in cardiac resuscitation by defibrillation, and defibrillators are now part of the standard equipment of vehicles used on the accident and emergency service. Comparison of recent results with previous attempts in the City of Nottingham to provide a service for out of hospital cardiac arrest has shown that an elementary training course and the provision of defibrillators on emergency vehicles enables the ambulance service to save the lives of a reasonable proportion of those who suffer sudden death in the community. The extended training programme as a whole has proved acceptable to ambulance personnel and we believe that this programme could be the basis for a more widespread introduction of post basic training.


Adaptive β-lactam resistance from an inducible efflux pump that is post-translationally regulated by the DjlA co-chaperone.
The acquisition of multidrug resistance (MDR) determinants jeopardizes treatment of bacterial infections with antibiotics. The tripartite efflux pump AcrAB-NodT confers adaptive MDR in the polarized α-proteobacterium Caulobacter crescentus via transcriptional induction by first-generation quinolone antibiotics. We discovered that overexpression of AcrAB-NodT by mutation or exogenous inducers confers resistance to cephalosporin and penicillin (β-lactam) antibiotics. Combining 2-step mutagenesis-sequencing (Mut-Seq) and cephalosporin-resistant point mutants, we dissected how TipR uses a common operator of the divergent tipR and acrAB-nodT promoter for adaptive and/or potentiated AcrAB-NodT-directed efflux. Chemical screening identified diverse compounds that interfere with DNA binding by TipR or induce its dependent proteolytic turnover. We found that long-term induction of AcrAB-NodT deforms the envelope and that homeostatic control by TipR includes co-induction of the DnaJ-like co-chaperone DjlA, boosting pump assembly and/or capacity in anticipation of envelope stress. Thus, the adaptive MDR regulatory circuitry reconciles drug efflux with co-chaperone function for trans-envelope assemblies and maintenance.


Fibroblast growth factor receptor signaling dramatically accelerates tumorigenesis and enhances oncoprotein translation in the mouse mammary tumor virus-Wnt-1 mouse model of breast cancer.
Fibroblast growth factor (FGF) cooperates with the Wnt/beta-catenin pathway to promote mammary tumorigenesis. To investigate the mechanisms involved in FGF/Wnt cooperation, we genetically engineered a model of inducible FGF receptor (iFGFR) signaling in the context of the well-established mouse mammary tumor virus-Wnt-1 transgenic mouse. In the bigenic mice, iFGFR1 activation dramatically enhanced mammary tumorigenesis. Expression microarray analysis did not show transcriptional enhancement of Wnt/beta-catenin target genes but instead showed a translational gene signature that also correlated with elevated FGFR1 and FGFR2 in human breast cancer data sets. Additionally, iFGFR1 activation enhanced recruitment of RNA to polysomes, resulting in a marked increase in protein expression of several different Wnt/beta-catenin target genes. FGF pathway activation stimulated extracellular signal-regulated kinase and the phosphorylation of key translation regulators both in vivo in the mouse model and in vitro in a human breast cancer cell line. Our results suggest that cooperation of the FGF and Wnt pathways in mammary tumorigenesis is based on the activation of protein translational pathways that result in, but are not limited to, increased expression of Wnt/beta-catenin target genes (at the level of protein translation). Further, they reveal protein translation initiation factors as potential therapeutic targets for human breast cancers with alterations in FGF signaling.


Scintigraphy with 99mTc(V)-DMSA in monitoring patients with inflammatory bowel disease.
The clinical significance of pentavalent technetium-99m dimercaptosuccinic acid (99mTc(V)-DMSA) scintigraphy in diagnosing inflammatory bowel disease (IBD) has not yet been fully elucidated. The aim of this prospective paper was to study the above. This study included 54 patients, 22 females and 32 males (mean age: 36.68±11.49; range: 18-63 years) with IBD who came to our clinics for follow-up and were examined clinically by colonoscopy and 99mTc(V)-DMSA scintigraphy. On the follow-up studies, five patients (9.25%) relapsed, and 49 (90.74%) remained at a steady condition. There was a good correlation between the scintigraphic results and the clinical and colonoscopy data of the patients (P<0.05). In conclusion, our results indicated that 99mTc(V)DMSA scintigraphy can be complementary to colonoscopy for the diagnostic evaluation of IBD.


Vaccine-Induced Memory CD8+ T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study.
Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T-cell infiltration of tumors include vaccines targeting established oncogenic drivers such as the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2). In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and antitumor function were evaluated. We tested VRP-HER2 in a phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of 3 doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy. Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was 1 partial response and 2 patients with continued stable disease. Median OS was 50.2 months in cohort 1 (n = 4) and 32.7 months in cohort 2 (n = 18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS. VRP-HER2 increased HER2-specific memory CD8 T cells and had antitumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T-cell activity by combining with anti-PD-1.


Nano-droplet systems by surfactant self-assembly and applications in the pharmaceutical industry.
Liquid systems containing droplets with size in the nanoscale range are attractive from both scientific and technological points of view as they have many current and potential applications in several industries and products. The formation and stabilization of nano-droplet systems are mostly based on the self-assembly of surfactant (amphiphilic) molecules at interfaces, driven by the solvophobic effect. Surfactants are involved in both top-bottom (high energy) and bottom- up (low energy) methods. Several devices have also been developed to aid in liquid fragmentation down to the nanometer scale. Nano-droplet systems can be both thermodynamically stable (microemulsions) or metastable (nanoemulsions), and appropriate formulation is a key for optimum product design in terms of droplet size, maximum solubilization, colloidal stability, and optical and rheological properties, among others. Such characteristics are determined by molecular packing, interfacial curvature, droplet-droplet interactions, film elasticity and nature of the dispersed and continuous phase. These properties can be engineered by proper understanding of the molecular structure and phase behavior of the multicomponent systems involved and by a range of experimental characterization techniques. Nano-droplet systems can help to solve specific issues in pharmaceutical products such as processing, limitations in drug solubility or stability, control on drug release, drug targeting and absorption; there are many examples to prove that. However, several practical aspects should be considered for preclinical and clinical tests and product development.


The future in paediatric respirology.
The authors were given the charge of providing a vision of the future in paediatric respirology. Themes selected for being ripe for this visionary analysis include bronchopulmonary dysplasia (BPD), asthma, cystic fibrosis (CF), lung infections, obstructive sleep disordered breathing (OSDB) and pulmonary diagnostics and monitoring. A profound reduction or elimination of BPD is seen. Given the strong genetic component of this disease, genetic biomarkers will likely be identified that will permit much earlier recognition of BPD susceptibility and potentially the ability to modify disease course by altering gene expression. The ultimate prevention of BPD will be to prevent prematurity, but recognition of both the genetic basis of BPD and the inflammatory background should lead to improved prevention and therapy. A clear understanding and definition of asthma phenotypes will lead to more specific and targeted therapy, earlier detection and prevention, better monitoring of severity and adherence to therapy, lower mortality and decreased inappropriate diagnosis of asthma. The greatest opportunities in asthma care will likely come through tools to improve adherence to effective therapy. Also, areas are identified where better therapies are needed such as in patients with severe mucus hypersecretion (secretory hyperresponsiveness) especially in those with life-threatening asthma. The future of CF is easier to foresee with early successes seen in clinical trials. After the expected ability to correct the CF transmembrane regulator, care will need to change and additional research will be needed. Additionally, the face of CF is changing with more adults than children presently having the disease. This will necessitate changes to our approach to treating this disease in a fortunately aging population. If we are going to affect the worldwide lung health of children, we will need to address respiratory infections particularly pneumonia, tuberculosis and HIV-associated infections. Preventive, diagnostic and treatment strategies will shape the future face of these problems. The availability of inexpensive, readily available, and rapid molecular techniques to identify true infection (including HIV and tuberculosis) may permit earlier use of effective therapy while preventing the inappropriate use of antibiotics for common viral diseases. Sleep medicine will continue to be an important aspect of paediatric pulmonology. The evaluation of OSDB cannot rely on full-night attended polysomnography due to limited access. Identifying reliable markers of end organ dysfunction in children with OSDB may permit more rapid identification of patients in need of intervention like CPAP and assisted breathing. In addition, management options, as an alternative to adenotonsilectomy, are listed with a call for further research. Pulmonary diagnostics and monitoring will see the development and refinement of tools like the lung clearance index and the analysis of exhaled gases, volatiles and dissolved biomarkers of inflammation as techniques that might help clinicians identify both the initiation of inflammation while it is more amenable to therapy, and to identify more readily the early changes associated with chronic lung diseases in children. The authors hope that these visionary articles will generate comments, arguments, inspiration, and perhaps even motivate funding agencies.


What accounts for differences in the use of hospital emergency departments across U.S. communities?
Increases in the use of hospital emergency departments (EDs) might contribute to crowding at some EDs, higher health care costs, and lower-quality primary care. This study examines the extent to which differences in populations and health system factors account for variations in ED use across U.S. communities. Contrary to popular perceptions, communities with high ED use have fewer numbers of uninsured, Hispanic, and noncitizen residents. Outpatient capacity constraints also contribute to high ED use. However, high ED use in some communities also likely reflects generic preferences for EDs as a source of care for nonurgent problems.


Risk factors for early reoperation in patients after posterior lumbar interbody fusion surgery. A propensity-matched cohort analysis.
Reoperation is usually associated with poor results and increased morbidity and hospital costs. However, the rates, causes, and risk factors for reoperation in patients undergoing lumbar spinal fusion surgery remain controversial. This study aimed to identify the risk factors for early reoperation after posterior lumbar interbody fusion surgery and to compare the clinical outcomes between patients who underwent reoperation and those who did not. We investigated a multicenter medical record database of 1263 patients who underwent posterior lumbar interbody fusion surgery between 2012 and 2015. A total of 72 (5.7%) reoperations within two years after surgery were identified and were propensity-matched for age, sex, number of fusion segments, and surgeon's experience. We analyzed a total of 114 patients (57 who underwent reoperation (R group) and 57 who did not (C group)). The mean age was 62.6 ± 13.4 years, with 78 men and 36 women. The mean number of fused segments was 1.2 ± 0.5. Surgical site infection was the most common cause of reoperation. There were significant differences in the incidence of diabetes mellitus (p = 0.024), preoperative ambulation status (p = 0.046), and ASA grade (p < 0.001) between the C and R groups. The recovery rate of the Japanese Orthopaedic Association score was significantly lower in the R group compared to the C group (R: 50.5 ± 28.8%, C: 63.9 ± 33.7%, p = 0.024). There were significant differences in the bone fusion rate (R: 63.2%, C: 96.5%, p < 0.001) and incidence of screw loosening (R: 31.6%; C: 10.5%; p = 0.006). Diabetes mellitus, preoperative ambulation status, and ASA grade were significant risk factors for early reoperation following posterior lumbar interbody fusion surgery. The patients who underwent early reoperation had worse clinical outcomes than those who did not.


African trypanosomiasis: Synthesis & SAR enabling novel drug discovery of ubiquinol mimics for trypanosome alternative oxidase.
African trypanosomiasis is a parasitic disease affecting 5000 humans and millions of livestock animals in sub-Saharan Africa every year. Current treatments are limited, difficult to administer and often toxic causing long term injury or death in many patients. Trypanosome alternative oxidase is a parasite specific enzyme whose inhibition by the natural product ascofuranone (AF) has been shown to be curative in murine models. Until now synthetic methods to AF analogues have been limited, this has restricted both understanding of the key structural features required for binding and also how this chemotype could be developed to an effective therapeutic agent. The development of 3 amenable novel synthetic routes to ascofuranone-like compounds is described. The SAR generated around the AF chemotype is reported with correlation to the inhibition of T. b. brucei growth and corresponding selectivity in cytotoxic assessment in mammalian HepG2 cell lines. These methods allow access to greater synthetic diversification and have enabled the synthesis of compounds that have and will continue to facilitate further optimisation of the AF chemotype into a drug-like lead.


Pharmacological aspects of Vipera xantina palestinae venom.
In Israel, Vipera xantina palestinae (V.x.p.) is the most common venomous snake, accounting for several hundred cases of envenomation in humans and domestic animals every year, with a mortality rate of 0.5 to 2%. In this review we will briefly address the research developments relevant to our present understanding of the structure and function of V.x.p. venom with emphasis on venom disintegrins. Venom proteomics indicated the presence of four families of pharmacologically active compounds: (i) neurotoxins; (ii) hemorrhagins; (iii) angioneurin growth factors; and (iv) different types of integrin inhibitors. Viperistatin, a α1β1selective KTS disintegrin and VP12, a α2β1 selective C-type lectin were discovered. These snake venom proteins represent promising tools for research and development of novel collagen receptor selective drugs. These discoveries are also relevant for future improvement of antivenom therapy towards V.x.p. envenomation.


Patient noncompliance with postvasectomy semen examination protocol.
This study determined the degree of patient compliance with postvasectomy semen examination protocol for verbal instructions as compared with verbal augmented by written instructions. The addition of written instructions did not improve patient compliance, and for a significant majority of patients (68 to 76 percent) there was no laboratory verification of the effectiveness of the vasectomy procedure. Results of the study raise serious concerns about physician reliance on patient compliance for postvasectomy semen examination protocol as assurance of successful vasectomy. When the potential for fertility among vasectomized men is uncertain, the complication of an unwanted pregnancy will fall on the woman. Educating physicians in the problems and strategies for gaining patient compliance is as essential as education in competent surgical technique.


Diversification, Introgression, and Rampant Cytonuclear Discordance in Rocky Mountains Chipmunks (Sciuridae: Tamias).
Evidence from natural systems suggests that hybridization between animal species is more common than traditionally thought, but the overall contribution of introgression to standing genetic variation within species remains unclear for most animal systems. Here, we use targeted exon capture to sequence thousands of nuclear loci and complete mitochondrial genomes from closely related chipmunk species in the Tamias quadrivittatus group that are distributed across the Great Basin and the central and southern Rocky Mountains of North America. This recent radiation includes six overlapping, ecologically distinct species (Tamias canipes, Tamias cinereicollis, Tamias dorsalis, T. quadrivittatus, Tamias rufus, and Tamias umbrinus) that show evidence for widespread introgression across species boundaries. Such evidence has historically been derived from a handful of markers, typically focused on mitochondrial loci, to describe patterns of introgression; consequently, the extent of introgression of nuclear genes is less well characterized. We conducted a series of phylogenomic and species-tree analyses to resolve the phylogeny of six species in this group. In addition, we performed several population-genomic analyses to characterize nuclear genomes and infer coancestry among individuals. Furthermore, we used emerging quartets-based approaches to simultaneously infer the species tree (SVDquartets) and identify introgression (HyDe). We found that, in spite of rampant introgression of mitochondrial genomes between some species pairs (and sometimes involving up to three species), there appears to be little to no evidence for nuclear introgression. These findings mirror other genomic results where complete mitochondrial capture has occurred between chipmunk species in the absence of appreciable nuclear gene flow. The underlying causes of recurrent massive cytonuclear discordance remain unresolved in this group but mitochondrial DNA appears highly misleading of population histories as a whole. Collectively, it appears that chipmunk species boundaries are largely impermeable to nuclear gene flow and that hybridization, while pervasive with respect to mtDNA, has likely played a relatively minor role in the evolutionary history of this group. [Cytonuclear discordance; hyridization; introgression, phylogenomics; SVDquartets; Tamias.].


Oil exposure disrupts early life-history stages of coral reef fishes via behavioural impairments.
Global demand for energy and oil-based products is progressively introducing petrogenic polycyclic aromatic hydrocarbons (PAHs) into sensitive marine environments, primarily from fossil-fuel exploration, transport, and urban and industrial runoff. These toxic pollutants are found worldwide, yet the long-term ecological effects on coral reef ecosystems are unknown. Here, we demonstrate that oil exposure spanning PAH concentrations that are environmentally relevant for many coastal marine ecosystems (≤5.7 μg l-1), including parts of the Great Barrier Reef, Red Sea, Asia and the Caribbean, causes elevated mortality and stunted growth rates in six species of pre-settlement coral reef fishes, spanning two evolutionarily distinct families (Pomacentridae and Lethrinidae). Furthermore, oil exposure alters habitat settlement and antipredator behaviours, causing reduced sheltering, shoaling and increased risk taking, all of which exacerbate predator-induced mortality during recruitment. These results suggest a previously unknown path, whereby oil and PAH exposure impair higher-order cognitive processing and behaviours necessary for the successful settlement and survival of larval fishes. This emphasizes the risks associated with industrial activities within at-risk ecosystems.


Variants on the promoter region of PTEN affect breast cancer progression and patient survival.
The PTEN gene, a regulator of the phosphatidylinositol-3-kinase (PI3K)/Akt oncogenic pathway, is mutated in various cancers and its expression has been associated with tumor progression in a dose-dependent fashion. We investigated the effect of germline variation in the promoter region of the PTEN gene on clinical characteristics and survival in breast cancer. We screened the promoter region of the PTEN gene for germline variation in 330 familial breast cancer cases and further determined the genotypes of three detected PTEN promoter polymorphisms -903GA, -975GC, and -1026CA in a total of 2,412 breast cancer patients to evaluate the effects of the variants on tumor characteristics and disease outcome. We compared the gene expression profiles in breast cancers of 10 variant carriers and 10 matched non-carriers and performed further survival analyses based on the differentially expressed genes. All three promoter variants associated with worse prognosis. The Cox's regression hazard ratio for 10-year breast cancer specific survival in multivariate analysis was 2.01 (95% CI 1.17 to 3.46) P = 0.0119, and for 5-year breast cancer death or distant metastasis free survival 1.79 (95% CI 1.03 to 3.11) P = 0.0381 for the variant carriers, indicating PTEN promoter variants as an independent prognostic factor. The breast tumors from the promoter variant carriers exhibited a similar gene expression signature of 160 differentially expressed genes compared to matched non-carrier tumors. The signature further stratified patients into two groups with different recurrence free survival in independent breast cancer gene expression data sets. Inherited variation in the PTEN promoter region affects the tumor progression and gene expression profile in breast cancer. Further studies are warranted to establish PTEN promoter variants as clinical markers for prognosis in breast cancer.


Acute kidney injury and hepatorenal syndrome in cirrhosis.
Cirrhosis is the eighth leading cause of "years of lost life" in the United States and accounts for approximately 1% to 2% of all deaths in Europe. Patients with cirrhosis have a high risk of developing acute kidney injury. The clinical characteristics of hepatorenal syndrome (HRS) are similar to prerenal uremia, but the condition does not respond to volume expansion. HRS type 1 is rapidly progressive whereas HRS type 2 has a slower course often associated with refractory ascites. A number of factors can precipitate HRS such as infections, alcoholic hepatitis, and bleeding. The monitoring, prevention, early detection, and treatment of HRS are essential. This paper reviews the value of early evaluation of renal function based on two new sets of diagnostic criteria. Interventions for HRS type 1 include terlipressin combined with albumin. In HRS type 2, transjugular intrahepatic portosystemic shunt (TIPS) should be considered. For both types of HRS patients should be evaluated for liver transplantation.


Increased expression of triggering receptor expressed on myeloid cells 1 and 2 in inflamed human gingiva.
Periodontitis is an infectious disease in which the host immune and inflammatory responses play essential roles in resistance to bacterial infection, as well as the induction of tissue destruction if the immune response is dysregulated. The triggering receptor expressed on myeloid cells (TREMs) modulates inflammatory and innate immune signaling. TREM-1 is considered as an amplifier of the immune response, while TREM-2 is a negative regulator that has yet to be explored in periodontal disease before. We hypothesized that TREMs participated in the innate immune responses during the pathogenesis of periodontitis. Therefore, the aim of this study was to evaluate TREM-1 and TREM-2 expression in the gingival tissues from patients with chronic periodontitis and healthy subjects as well as their correlation with clinical periodontal parameters. This study is the first to identify TREM-2 in periodontal tissue, as well as the protein expression changes of TREM-1 and TREM-2 in periodontal tissues. Gingival tissue sections were collected from 31 healthy subjects and 53 patients with chronic periodontitis. Immunohistochemistry and quantitative real-time polymerase chain reaction were employed to evaluate the protein and mRNA expression of these receptors in gingival tissues. The recorded clinical parameters were probing depth, clinical attachment loss, plaque index and bleeding on probing. In addition to myeloid cells in gingival connective tissues, TREM-1 and TREM-2 were also found expressed in gingival epithelial cells. In particular, TREM-1 was detected in almost all gingival epithelium from both healthy and inflamed biopsies. The expression levels of TREM-1 and TREM-2 were significantly increased in the periodontitis group compared to the healthy group. Increased levels of these receptors are to be positively correlated with site-specific periodontal parameters. The increased expression of TREM-1 and TREM-2 levels in periodontitis may confer diagnostic and potential therapeutic targets as well as indicating their association with the clinical severity of the disease.


Effect of Energy Drink Consumption on Power and Velocity of Selected Sport Performance Activities.
Jacobson, BH, Hester, GM, Palmer, TB, Williams, K, Pope, ZK, Sellers, JH, Conchola, EC, Woolsey, C, and Estrada, C. Effect of energy drink consumption on power and velocity of selected sport performance activities. J Strength Cond Res 32(6): 1613-1618, 2018-Energy drinks (ED) comprise a multibillion dollar market focused on younger, active, and competitive individuals. Marketing includes claims of improved alertness and performance. The purpose of this study was to assess power (W) and velocity (m·s) of a simulated, isolated forehand stroke (FHS), and a countermovement vertical jump (CVJ) before and after ingestion of a commercially available energy shot (ES) or a placebo (PL). Healthy college-aged men and women (N = 36) volunteers were randomly placed in the ES or PL. Before and 30 minutes after ingesting either the ES or PL, participants performed 3 FHSs and CVJs. Power and velocity of each performance was measured using a linear velocity transducer and the highest value for each measure was used for subsequent analysis. The ES group demonstrated a significant (p = 0.05) increase in velocity and W for the FHS, but not for the CVJ. All measures remained unchanged in the PL group for both, the FHS and CVJ. Females demonstrated a significant increase in velocity over males in FHS, but not in CVJ. It was concluded that while the dose of stimulants in the ES was adequate to improve performance of smaller muscle groups, it may not have been sufficient to affect the larger muscle groups of the lower legs which contribute to the CVJ. While the ES used in the present study contained a caffeine dosage within the NCAA limit and did improve performance for the upper body, it must be noted that there are health risks associated with ED consumption.


Ankle osteoarthritis: an online survey of current treatment practices of UK-based podiatrists and physiotherapists.
Patients with painful ankle osteoarthritis (OA) have a mixed experience of non-surgical management which they may attribute to a lack of guidance for clinicians on usual care treatment. Therefore, the purpose of this study was to survey the current clinical practices of UK-based physiotherapists and podiatrists for the treatment of painful ankle osteoarthritis (OA). UK-based physiotherapists and podiatrists who treat patients with ankle OA completed a self-administered online questionnaire about their professional and clinical service characteristics, diagnostic criteria, treatment aims, preferred treatment options, and treatment outcome measures. Data were collected anonymously and stored on JISC online survey. 'Usual care' was defined as a combination of 'Always', and 'Frequently', and 'Not usual care' was defined as 'Sometimes' 'Rarely,' 'Never', and 'not applicable' combined. Statistically significant differences in responses between the physiotherapists and podiatrists were analysed using X2 tests for each treatment modality. Statistical significance was set at p < 0.05. Between 1st June 2021 and 31st August 2021, 100 responses were received; 2 were invalid. Of the 98 valid responses, 63 were from physiotherapists and 35 from podiatrists. The most common treatment aims in both professions were to reduce pain (n = 87, 89%) and improve quality of life (n = 82, 84%). 50 respondents (51%) offered 3 or 4 treatment sessions and 53 respondents (54%) saw patients for 30-40 min at the first treatment session. The five most common modalities used by physiotherapists were patient education (n = 63, 100%), teaching self-management (n = 58, 92%), lifestyle modification (n = 54, 86%), ankle strengthening (n = 55, 87%), and proprioception exercises (n = 54, 86%). For podiatrists, these were patient education (n = 35, 100%), ankle strengthening (n = 31, 89%), activity pacing (n = 28, 80%), lifestyle modification (n = 27, 77%), and gait training (n = 27, 77%). This first-ever survey revealed physiotherapists' and podiatrists' current practices to treat painful ankle OA. This study provides a better understanding of how ankle OA is treated in UK current clinical practice and can inform future clinical trials to compare current practice with new treatment modalities.


[Linsidomine, direct donor of EDRF/NO: a new treatment for unstable angina].
Linsidomine 10 mg, administered intravenously, has become available for the treatment of unstable angina since the beginning of 1996. It reinforces a range which consists of oral molsidomine, 2 and 4 mg, and the 1 mg intracoronary linsidomine dosage, thereby providing a more complete management of symptomatic coronary patients. Linsidomine is a direct donor of EDRF/NO which has an action on blood vessels (reduction of preload and dilatation of the large epicardial coronary vessels) and on platelets (inhibition of aggregation) without risk of tolerance. Linsidomine was compared with parenteral isosorbide dinitrate in a large scale French trial in patients with severe unstable angina (Braunwald's Class IIIb). The results showed linsidomine to be an effective treatment of unstable angina, controlling 75% of patients with a low incidence of severe clinical events (death, myocardial infarction, emergency myocardial revascularisation). In addition, intravenous linsidomine was well tolerated clinically, especially in terms of symptomatic hypotension.


Developing well-calibrated illness severity scores for decision support in the critically ill.
Illness severity scores are regularly employed for quality improvement and benchmarking in the intensive care unit, but poor generalization performance, particularly with respect to probability calibration, has limited their use for decision support. These models tend to perform worse in patients at a high risk for mortality. We hypothesized that a sequential modeling approach wherein an initial regression model assigns risk and all patients deemed high risk then have their risk quantified by a second, high-risk-specific, regression model would result in a model with superior calibration across the risk spectrum. We compared this approach to a logistic regression model and a sophisticated machine learning approach, the gradient boosting machine. The sequential approach did not have an effect on the receiver operating characteristic curve or the precision-recall curve but resulted in improved reliability curves. The gradient boosting machine achieved a small improvement in discrimination performance and was similarly calibrated to the sequential models.


Bone microenvironment and androgen status modulate subcellular localization of ErbB3 in prostate cancer cells.
ErbB-3, an ErbB receptor tyrosine kinase, has been implicated in the pathogenesis of several malignancies, including prostate cancer. We found that ErbB-3 expression was up-regulated in prostate cancer cells within lymph node and bone metastases. Despite being a plasma membrane protein, ErbB-3 was also detected in the nuclei of the prostate cancer cells in the metastatic specimens. Because most metastatic specimens were from men who had undergone androgen ablation, we examined the primary tumors from patients who have undergone hormone deprivation therapy and found that a significant fraction of these specimens showed nuclear localization of ErbB3. We thus assessed the effect of androgens and the bone microenvironment on the nuclear translocation of ErbB-3 by using xenograft tumor models generated from bone-derived prostate cancer cell lines, MDA PCa 2b, and PC-3. In subcutaneous tumors, ErbB-3 was predominantly in the membrane/cytoplasm; however, it was present in the nuclei of the tumor cells in the femur. Castration of mice bearing subcutaneous MDA PCa 2b tumors induced a transient nuclear translocation of ErbB-3, with relocalization to the membrane/cytoplasm upon tumor recurrence. These findings suggest that the bone microenvironment and androgen status influence the subcellular localization of ErbB-3 in prostate cancer cells. We speculate that nuclear localization of ErbB-3 may aid prostate cancer cell survival during androgen ablation and progression of prostate cancer in bone.


Fabrication of microlenses by laser chemical vapor deposition.
A new laser-based method was developed for fabrication of microlenses on flat quartz plates. In this method, a CO(2) laser is used to heat a quartz surface and induce thermal reactions for source gases of SiH(4) and NO. Even as-grown silicon oxide deposits have the spherical thickness distribution required for a lens at the center and this useful area can be further increased by wet etching. Microlenses were checked on a Fizeau interferometer for surface accuracy and aberrations. As a demonstration, a 14-microm thick microlens was used for collimating light from an optical fiber.


Incorporating quality and safety education for nurses competencies in simulation scenario design.
When planning a simulation scenario, even if adopting prepackaged simulation scenarios, faculty should first conduct a task analysis to guide development of learning objectives and cue critical events. The authors describe a strategy for systematic planning of simulation-based training that incorporates knowledge, skills, and attitudes as defined by the Quality and Safety Education for Nurses (QSEN) initiative. The strategy cues faculty to incorporate activities that target QSEN competencies (patient-centered care, teamwork and collaboration, evidence-based practice, quality improvement, informatics, and safety) before, during, and after simulation scenarios.


What is a migraine?
The migrainous patient appears to differ in reaction to stress or environmental changes from nonmigrainous subjects quantitatively rather than qualitatively. An inherited pattern of monoamine metabolism may render the patient more susceptible to such changes, which represent a threat, real or imagined, to the integrity of the brain. The migraine attack may thus be interpreted as a neurohumoral reaction aimed at protecting the brain from some noxious influence by shunting blood away from the cortex. The headache itself may be a by-product of such a reaction, serving, like any pain, to alert the organism to potential danger. The predominantly unilateral site of migraine remains unexplained. A more comprehensive clinical classification of migraine is proposed in the hope that certain entities may prove to correlate with variations in pathophysiology and thus permit more selective therapy.


Immunomodulatory therapy with tumour necrosis factor α inhibitors in children with antinuclear antibody-associated chronic anterior uveitis: long-term results.
The aim of the study was to assess the long-term efficacy and tolerability of tumour necrosis factor α (TNFα) inhibitors in the therapy of children with refractory antinuclear antibody (ANA)-associated chronic anterior uveitis. Retrospective analysis of 31 children with ANA-associated uveitis, treated with TNFα inhibitors with a follow-up period of at least 2 years. The outcome measures included: control of inflammation, corticosteroid-sparing potential and side effects. Twenty-three children (74%) were treated with adalimumab, five children (16%) with infliximab and three children (10%) with etanercept. Control of uveitis, defined as 0 anterior chamber cells while on ≤2 drops/day topical corticosteroids, was achieved in 22 of 31 patients (71%) after 1 year (95% CI 52% to 86%), and in 21 of 29 patients (72%) after 2 years of treatment (95% CI 53% to 87%). Control of uveitis was observed in 18 of 23 children (78%) treated with adalimumab, and in two of five children (40%) treated with infliximab. In all children treated with etanercept, no sufficient inflammatory control was found. Systemic corticosteroids could be discontinued in 71% (12/17 children) and topical corticosteroids in 55% (17/31) of the patients. Treatment-related side effects were found in nine children (29%, rate: 0.10/patient-year). Our data show that adalimumab and infliximab have beneficial effects in the therapy of severe ANA-associated anterior uveitis in children.


Maternal depression and intimate partner violence exposure: Longitudinal analyses of the development of aggressive behavior in an at-risk sample.
A substantial body of literature has documented the negative effects of intimate partner violence (IPV) on a wide range of children's developmental outcomes. However, whether a child's exposure to IPV leads to increased adjustment difficulties is likely to depend on a variety of factors, including the caregiver's mental health and the developmental time period when IPV exposure occurs. The present study seeks to improve our understanding of the long-term effects of IPV exposure and maternal depression on the development of children's overt aggressive behavior. Longitudinal analyses (i.e., latent growth curve modeling) examining three time points (toddler: age 2-3 years, preschool/kindergarten: age 4-5 years, and elementary school: age 6-8 years) were conducted using 1,399 at-risk children drawn from the National Survey of Child and Adolescent Well-Being (NSCAW-I). IPV exposure during age 2-3 years was significantly related to concurrent aggressive behavior and aggressive behavior during age 4-5 years. At all three time points, IPV was significantly associated with maternal depression, which in turn, was significantly related to higher levels of aggressive behavior. There was also a significant indirect lagged effect of IPV exposure at age 2-3 years through maternal depression on aggressive behavior at age 4-5 years. Results indicated that maternal depression was a strong predictor of increased reports of overt aggressive behavior, suggesting that interventions to buffer the effects of IPV exposure should focus on relieving maternal depression and fostering productive social behavior in children. Aggr. Behav. 43:375-385, 2017. © 2017 Wiley Periodicals, Inc.


Comparison of Photon-counting Detector and Energy-integrating Detector CT for Visual Estimation of Coronary Percent Luminal Stenosis.
Background Compared with energy-integrating detector (EID) CT, the improved resolution of photon-counting detector (PCD) CT coupled with high-energy virtual monoenergetic images (VMIs) has been shown to decrease calcium blooming on images in phantoms and cadaveric specimens. Purpose To determine the impact of dual-source PCD CT on visual and quantitative estimation of percent diameter luminal stenosis compared with dual-source EID CT in patients. Materials and Methods This prospective study recruited consecutive adult patients from an outpatient facility between January and March 2022. Study participants underwent clinical dual-source EID coronary CT angiography followed by a research dual-source PCD CT examination. For PCD CT, multienergy data were used to create VMIs at 50 and 100 keV. Two readers independently reviewed EID CT images followed by PCD CT images after a washout period. Readers visually graded the most severe stenosis in terms of percent diameter luminal stenosis for the left main, left anterior descending, right, and circumflex coronary arteries, unblinded to scanner type. Quantitative measures of percent stenosis were made using commercial software. Visual and quantitative estimates of percent stenosis were compared between EID CT and PCD CT using the Wilcoxon signed-rank test. Results A total of 25 participants (median age, 59 years [range, 18-78 years]; 16 male participants) were enrolled. On EID CT images, readers 1 and 2 identified 39 and 32 luminal stenoses, respectively, with a percent diameter luminal stenosis greater than 0%. Visual estimates of percent stenosis were lower on PCD CT images than EID CT images (reader 1: median 20.6% [IQR, 8.8%-61.2%] vs 31.8% [IQR, 12.9%-69.7%], P < .001; reader 2: 6.5% [IQR, 0.4%-54.1%] vs 22.9% [IQR, 1.8%-67.4%], P = .002). No difference was observed between EID CT and PCD CT for quantitative measures of percent stenosis (median difference, -1.5% [95% CI: -3.0%, 2.5%]; P = .51). Conclusion Relative to using EID CT, using PCD CT led to decreases in visual estimates of percent stenosis. © RSNA, 2023 See also the editorial by Murphy and Donnelly in this issue.


Roll Back Malaria in the aftermath of complex emergencies: the example of Afghanistan.
The Roll Back Malaria (RBM) partnership was established in 1998 to address the worldwide malaria burden through a new approach. It was founded by four multilateral agencies that were already committed to supporting malaria control: the United Nations Development Programme, the United Nations Children's Fund, the World Bank and the World Health Organization. In contrast to previous campaigns, RBM focuses on strengthening existing health services to ensure that malaria can be controlled through an integrated approach, rather than through creation and maintenance of a separate structure. Field experience of RBM is rarely documented in the open scientific literature, making it difficult to judge its success and apply lessons learned to other settings. This paper aims at improving on this by documenting experience of RBM support in Afghanistan during initial post-conflict reconstruction. From the analysis some recommendations emerged: (i) technical in-country support needs to be provided for a number of years, as short postings are likely to provide only temporary solutions and may fail to contribute towards medium or long-term development; (ii) the role and responsibilities of support staff need to be clear to all RBM partners; (iii) part of this role should be to act as focal point, in an attempt to improve on coordination and (iv) if possible, support staff should be seconded to the MoH, to avoid association of the RBM initiative with a specific international organization and to further the multi-sectorial partnership approach.


Do special occasions trigger psychological distress among older bereaved spouses? An empirical assessment of clinical wisdom.
Mental health professionals have suggested that widowed persons experience heightened psychological distress on dates that had special meaning for them and their late spouse, such as a wedding anniversary or the late spouse's birthday. This study examined the effects of such occasions on grief, anxiety, and depressive symptoms in a community sample of older widowed persons. OLS regression models were estimated using data from the Changing Lives of Older Couples (CLOC) study, a large prospective probability study of late-life widowhood. Participants were interviewed prior to and both 6 and 18 months after spousal loss; married matched controls were interviewed at comparable times. Widowed persons reported heightened psychological distress when interviewed during the month of their late spouse's birthday, a post-holiday period (January), and in June, a month associated with wedding anniversaries and graduations in the United States. The distressing effects of special occasions on psychological symptoms were evidenced only within the first 6 months postloss, and were not apparent at the 18-month follow-up. Our results support the clinical observation that persons in the early stages of spousal bereavement are at increased risk of psychological distress at times with special significance to the couple. We highlight methodological and clinical implications.


TPIA2: an updated tea plant information archive for Camellia genomics.
The genus Camellia consists of about 200 species, which include many economically important species widely used for making tea, ornamental flowers and edible oil. Here, we present an updated tea plant information archive for Camellia genomics (TPIA2; http://tpia.teaplants.cn) by integrating more novel large-scale genomic, transcriptomic, metabolic and genetic variation datasets as well as a variety of useful tools. Specifically, TPIA2 hosts all currently available and well assembled 10 Camellia genomes and their comprehensive annotations from three major sections of Camellia. A collection of 15 million SNPs and 950 950 small indels from large-scale genome resequencing of 350 diverse tea accessions were newly incorporated, followed by the implementation of a novel 'Variation' module to facilitate data retrieval and analysis of the functionally annotated variome. Moreover, 116 Camellia transcriptomes were newly assembled and added, leading to a significant extension of expression profiles of Camellia genes to 13 developmental stages and eight abiotic/biotic treatments. An updated 'Expression' function has also been implemented to provide a comprehensive gene expression atlas for Camellia. Two novel analytic tools (e.g. Gene ID Convert and Population Genetic Analysis) were specifically designed to facilitate the data exchange and population genomics in Camellia. Collectively, TPIA2 provides diverse updated valuable genomic resources and powerful functions, and will continue to be an important gateway for functional genomics and population genetic studies in Camellia.


Parallel confocal detection of single molecules in real time.
The confocal detection principle is extended to a highly parallel optical system that continuously analyzes thousands of concurrent sample locations. This is achieved through the use of a holographic laser illumination multiplexer combined with a confocal pinhole array before a prism dispersive element used to provide spectroscopic information from each confocal volume. The system is demonstrated to detect and identify single fluorescent molecules from each of several thousand independent confocal volumes in real time.


Human fallopian tube epithelium co-culture with murine ovarian follicles reveals crosstalk in the reproductive cycle.
Do interactions between human fallopian tube epithelium and murine follicles occur during an artificial reproductive cycle in a co-culture system in vitro? In a co-culture system, human fallopian tissues responded to the menstrual cycle mimetic by changes in morphology and levels of secreted factors, and increasing murine corpus luteum progesterone secretion. The entire fallopian tube epithelium, including ciliated and secretory cells, can be regulated in the reproductive cycle. Currently, there are no in vitro culture models that can monitor fallopian tissues in real time in response to factors produced by the ovary. In addition, there are no reports on the impact of fallopian tissue on ovarian function during the menstrual cycle. Human fallopian tissue (n = 24) was obtained by routine hysterectomies from women (aged 26-50 years, mean age = 43.6) who had not undergone exogenous hormonal treatment for at least 3 months prior to surgery. CD1 female mice were used for ovarian follicle isolation. The human fallopian epithelium layers were either co-cultured with five murine multilayer secondary follicles (150-180 μm follicles, encapsulated in one alginate gel bead) for 15 days or received stepwise steroid hormone additions for 13 days. The fallopian tissue morphology and cilia beating rate, as measured by an Andor Spinning Disk Confocal, were investigated. Oviduct-specific glycoprotein 1 (OVGP1), human insulin-like growth factor 1 (hIGF1), vascular endothelial growth factor A (VEGF-A) and interleukin 8 (IL8) as biological functional markers were measured either by ELISA or western blot to indicate dynamic changes in the fallopian epithelium during the reproductive cycle generated by mouse follicles or by stepwise steroid hormone induction. Three or four patients in each experiment were recruited for replicates. Data were presented as mean ± SD and further analyzed using one-way ANOVA followed by Tukey's multiple comparisons test. The cultured fallopian tube epithelium responded to exogenous steroid hormone stimulation, as demonstrated by enhanced cilia beating rate (~25% increase, P = 0.04) and an increase in OVGP1 secretion (P = 0.02) in response to 1 nM estradiol (E2) treatment when compared with 0.1 nM E2. Conversely, 10 nM progesterone plus 1 nM E2 suppressed cilia beating rate by ~30% (P = 0.008), while OVGP1 secretion was suppressed by 0.1 nM E2 plus 50 nM progesterone (P = 0.002 versus 1 nM E2 alone). Human fallopian tube epithelium was co-cultured with murine secondary follicles to mimic the human menstrual cycle. OVGP1 and VEGF-A secretion from fallopian tissue was similar with stepwise hormone treatment and when cultured with murine follicles. However, the secretion patterns of hIGF1 and IL8 differed in the luteal phase when comparing steroid treatment with follicle co-culture. In co-culture, hIGF1 secretion was suppressed in the luteal versus follicular phase (P = 0.005) but stepwise hormone treatment had no effect on hIGF1. In co-culture, IL8 secretion was also suppressed on luteal phase day 15 (P = 0.013) versus follicular phase day 7, but IL8 secretion increased continuously under high E2/progesterone treatment (P = 0.003 for D13 versus D3). In the co-culture system, the corpus luteum continuously produced progesterone in the presence of fallopian tube tissue until Day 18 while, without fallopian tissue, progesterone started to drop from Day 13. One limitation of this study is that murine follicles were used to mimic the human menstrual cycle. However, although secretion patterns of peptide hormones such as inhibins and activins differ in mice and humans, the co-culture system used here did reveal interactions between the tissues that govern reproductive function. In vitro co-culture models of fallopian reproductive tissues with ovarian follicles can provide an important tool for understanding fertility and for uncovering the mechanisms responsible for reduced fertility. In addition, the role of oviductal secretions and how they influence ovarian function, such as the production of progesterone during the menstrual cycle, can be uncovered using this model. None. This work was funded by grants from the NIH (UH3TR001207), the American Cancer Society (RSG-12-230-01-TBG) and NIH (R01EB014806). The authors declare no competing financial interest.


A comparison of the tympanic and axillary temperatures of the preterm and term infant.
A correlational research design was used to examine the accuracy between the axillary and tympanic temperature measurements of the preterm and term infant. Also examined was the effect of weight and environment on the temperature measurements. A convenience sample of 40 neonates (preterm, n = 20; term, n = 20) was selected. A correlation of 0.815 (p = 0.001) was found between the axillary and tympanic temperatures of all subjects, and correlations of 0.861 (p = 0.001) and 0.582 (p = 0.01) were revealed for the preterm and term infants, respectively. When weight was used as a covariate, there was no significant difference in the two temperature measurements by group (preterm, term), but there was a trend for tympanic temperatures, and the difference between axillary and tympanic temperatures, to differ by environment (radiant warmer, incubator, or open crib).


Printed Flexible Microelectrode for Application of Nanosecond Pulsed Electric Fields on Cells.
Medical treatment is increasingly benefiting from biomedical microsystems, especially the trending telemedical application. A promising modality for tumor therapy showed the application of nanosecond pulsed electric fields (nsPEF) on cells to achieve nanoporation, cell death, and other cell reactions. A key technology for this method is the generation of pulsed fields in the nanosecond range with high-field strengths in the range of several kilovolts per centimeter. For further biomedical applications, state-of-the-art setups need to decrease in size and improve their capability of integration into microsystems. Due to demanding electronic requirements, i.e., using high voltages and fast pulses, miniaturization and low-cost fabrication of the electrode is first considered. This paper proposes a proof-of-concept for a miniaturized printed flexible electrode that can apply nsPEF on adherent fibroblast cells. The interdigital gold electrode was printed on polyimide with line-width of about 10 µm using an electrohydrodynamic inkjet printer. Furthermore, an electrical circuit was developed to generate both electrical pulses in the nano-second range and voltages up to 180 V. The electrode was integrated into an experimental setup for in-vitro application to human fibroblasts. Field strengths up to 100 kV/cm with 45 ns pulse duration were applied, depending on the degree of cell confluence. The cells show contraction, detachment from the electrode, and lethal reactions after the nsPEF treatment. Furthermore, this printed miniaturized electrode was found to be suitable for subsequent microsystem integration and further cell experiments to optimize pulse parameters for control of cell reaction and behavior.


Recto-colonic reflex is impaired in patients with irritable bowel syndrome.
Motor and sensory dysfunction of the gut are present in a subset of patients with irritable bowel syndrome (IBS). Recent studies have demonstrated the presence of a recto-colonic inhibitory reflex in healthy humans. It is not known whether this reflex exists in IBS. We studied rectal compliance, perception and the recto-colonic reflex by measuring volume responses of the descending colon to rectal distentions by barostat in 26 IBS patients and 13 healthy controls under both fasting and postprandial conditions. In the fasting state, rectal distention inhibited colonic tone and phasic motility to a similar extent in health and IBS. After a meal, rectal distention inhibited colonic tone and phasic motility to a lesser degree (P < 0.05) in IBS than health. Under postprandial but not fasting conditions, rectal distentions of increasing intensity were associated with higher pain scores in IBS than in health. Rectal distention inhibits tonic and phasic motility of the descending colon in healthy controls and in IBS patients. Postprandially this recto-colonic inhibitory reflex is impaired and attenuated in IBS patients compared with controls. These findings point to an altered reflex function in IBS and have implications for pathophysiology and therapy.


The prevalence, etiologic agents and risk factors for urinary tract infection among spinal cord injury patients.
Urinary tract infections (UTIs) are important causes of morbidity and mortality in patients with spinal cord injury and 22% of patients with acute spinal cord injury develop UTI during the first 50 days. The aim of this study was to determine the prevalence, etiologic agents and risk factors for asymptomatic bacteriuria and symptomatic urinary tract infections in patients with spinal cord injury. This was a prospective investigation of spinal cord injury patients with asymptomatic bacteriuria and symptomatic urinary tract infections in Baskent University Medical Faculty Ayas Rehabilitation Center and Ankara Physical Therapy and Rehabilitation Center between January 2008 and December 2010. The demographic status, clinical and laboratory findings of 93 patients with spinal cord injury were analyzed in order to determine the risk factors for asymptomatic or symptomatic bacteriuria. Sixty three (67.7%) of 93 patients had asymptomatic bacteriuria and 21 (22.6%) had symptomatic urinary tract infection. Assessment of the frequency of urinary bladder emptying methods revealed that 57 (61.3%) of 93 patients employed permanent catheters and 24 (25.8%) employed clean intermittent catheterization. One hundred and thirty-five (48.0%) of 281 strains isolated form asymptomatic bacteriuria attacks and 16 (66.6%) of 24 strains isolated from symptomatic urinary tract infection attacks, totaling 151 strains, had multidrug resistance (P > 0.05). One hundred (70.4%) of 142 Escherichia coli strains and 19 (34.5%) of 55 Klebsiella spp strains proliferated in patients with asymptomatic bacteriuria; 8 (80%) of 10 E. coli strains and 4 (80%) of 5 Klebsiella spp. strains were multidrug resistant. The most common infectious episode among spinal cord injury patients was found to be urinary tract ınfection. E. coli was the most common microorganism isolated from urine samples. Antibiotic use in the previous 2 weeks or 3 months, hospitalization during the last one-year and previous diagnosis of urinary tract ınfection were the risk factors identified for the development of infections with multi-drug resistant isolates. Urinary catheterization was found to be the only independent risk factor contributing to symptomatic urinary tract infection.


Paecilomyces Keratitis in Western India: A Case Report.
Cases of ocular trauma with vegetative matter are commonly encountered in ophthalmic practice in India. Many of these present with keratitis/corneal ulceration, of which fungi have a predominant share. We report a case of fungal keratitis and graft infection with Paecilomyces lilacinus, which was successfully treated with topical and systemic Voriconazole. A farmer presented with corneal ulcer and hypopyon in left eye following vegetative trauma during farming. A provisional diagnosis of fungal corneal ulcer was made based on clinical features and topical anti-fungal therapy with Natamycin was initiated. After deterioration, Therapeutic Penetrating Keratoplasty (TPK) was performed to prevent corneal perforation. Postoperatively, the graft responded well to treatment initially. Signs of graft infection appeared on the second postoperative day with perforation within 72 hours. Culture report of recipient corneal button obtained after first TPK revealed growth of P.lilacinus. A second TPK was performed and patient was started on local and oral Voriconazole. After one month follow up, the graft was clear of infection. To our knowledge, this is a rare case reported from western India, at least in recent years. With no definite consensus existing regarding management in such a scenario, extensive research is needed in this direction.


Expression of the infectious salmon anemia virus receptor on atlantic salmon endothelial cells correlates with the cell tropism of the virus.
Infectious salmon anemia (ISA) is a World Organization for Animal Health (OIE)-listed disease of farmed Atlantic salmon, characterized by slowly developing anemia and circulatory disturbances. The disease is caused by ISA virus (ISAV) in the Orthomyxoviridae family; hence, it is related to influenza. Here we explore the pathogenesis of ISA by focusing on virus tropism, receptor tissue distribution, and pathological changes in experimentally and naturally infected Atlantic salmon. Using immunohistochemistry on ISAV-infected Atlantic salmon tissues with antibody to viral nucleoprotein, endotheliotropism was demonstrated. Endothelial cells lining the circulatory system were found to be infected, seemingly noncytolytic, and without vasculitis. No virus could be found in necrotic parenchymal cells. From endothelium, the virus budded apically and adsorbed to red blood cells (RBCs). No infection or replication within RBCs was detected, but hemophagocytosis was observed, possibly contributing to the severe anemia in fish with this disease. Similarly to what has been done in studies of influenza, we examined the pattern of virus attachment by using ISAV as a probe. Here we detected the preferred receptor of ISAV, 4-O-acetylated sialic acid (Neu4,5Ac(2)). To our knowledge, this is the first report demonstrating the in situ distribution of this sialic acid derivate. The pattern of virus attachment mirrored closely the distribution of infection, showing that the virus receptor is important for cell tropism, as well as for adsorption to RBCs.


Estimating the impact of prevention action: a simulation model of cervical cancer progression.
Cervical cancer is one of the highest occurring cancers for women in East Africa. Many studies have shown that disease occurrences and particularly the number of deaths due to the disease can be reduced significantly by screening and vaccination. East Africa and Kenya in particular are undergoing change and taking actions to reduce disease levels. However, up until today disease level in the different districts in Kenya is not known nor what be the prevalence of disease when prevention actions take place. In this paper we propose a novel Bayesian model for estimating disease levels based on available partial reports and demographic information. The result is a simulation engine that provides estimations of the impact of various potential prevention actions.


[Perineal gangrene: report of 30 cases observed at Abidjan].
Perineal gangrene may be classified as primary, e.g. Fournier's gangrene of the external genitals, or secondary due to locoregional injury. Perineal gangrene is still a topic of interest in tropical zones where mortality remains high despite current therapeutic modalities. The purpose of this retrospective study was to analyze etiologic, bacteriologic, and therapeutic data in 30 cases observed over a one-year period in a surgical setting in the Ivory Coast. There were 26 men and 4 women with a mean age of 43 years. All were treated by extensive removal of necrotic tissue in association with antimicrobial therapy for the likeliest agent and appropriate supportive measures. Colostomy was performed in 6 cases and drainage of the urinary tract was required in 11 cases. Anti-tetanus treatment was administered in all cases. Thirteen patients were HIV-positive, five were diabetic, and two presented chronic renal insufficiency. Perineal gangrene was classified as secondary in 17 cases and primary (Fournier's gangrene) in 13 cases. Bacteriologic study of puss and tissue specimens collected from necrotic areas demonstrated a mixed population of microbial organisms predominated by streptococcus A (n = 19) and Escherichia coli (n = 13). Positive diagnostic results were obtained in 5 of 20 hemocultures and in 8 of 11 cystobacteriologic tests. Eight patients died and nine presented complications including necrosis of the testicles, atrophy of the testicles, shock, and coma. Healing was obtained without skin grafting in 22 survival cases but 5 of them required secondary suturing. The mean duration of hospitalization was 45 days. In our experience, perineal gangrene led to severe consequences despite adequate management especially in HIV-infected patients. The treatment of choice is still extensive emergency surgical removal (repeated, if necessary) of necrotic tissue in association with adequate supportive measures and wide spectrum antimicrobial therapy.


Improved prediction of breast cancer outcome by identifying heterogeneous biomarkers.
Identification of genes that can be used to predict prognosis in patients with cancer is important in that it can lead to improved therapy, and can also promote our understanding of tumor progression on the molecular level. One of the common but fundamental problems that render identification of prognostic genes and prediction of cancer outcomes difficult is the heterogeneity of patient samples. To reduce the effect of sample heterogeneity, we clustered data samples using K-means algorithm and applied modified PageRank to functional interaction (FI) networks weighted using gene expression values of samples in each cluster. Hub genes among resulting prioritized genes were selected as biomarkers to predict the prognosis of samples. This process outperformed traditional feature selection methods as well as several network-based prognostic gene selection methods when applied to Random Forest. We were able to find many cluster-specific prognostic genes for each dataset. Functional study showed that distinct biological processes were enriched in each cluster, which seems to reflect different aspect of tumor progression or oncogenesis among distinct patient groups. Taken together, these results provide support for the hypothesis that our approach can effectively identify heterogeneous prognostic genes, and these are complementary to each other, improving prediction accuracy. https://github.com/mathcom/CPR. firstname.lastname@example.com. Supplementary data are available at Bioinformatics online.


Nursing services as perceived by inmates in correctional facilities in Jakarta, Indonesia: A qualitative study.
Nursing services play a crucial role in addressing the healthcare needs of inmates in correctional facilities while upholding their human rights. However, delivering nursing services in this context is challenging. Unfortunately, there is a dearth of research on this topic in Indonesia. This study aimed to explore the experiences of inmates in receiving nursing services in order to provide insights into professional nursing services in the correctional context in Indonesia. A qualitative phenomenological approach was used in this study. Twenty inmates were selected purposively from four prisons, three jails, and one child penitentiary in Jakarta, Indonesia. Semi-structured in-depth interviews were conducted from August to October 2021, and thematic analysis was used to analyze the data. Five themes were generated: (1) conditions requiring nursing services, (2) types of nursing services received, (3) nurse competence, (4) barriers to receiving nursing services, and (5) expectations for nursing services in the future. This study highlights the importance of nursing services in correctional facilities and the unique challenges that correctional nurses face in providing services professionally and ethically. Strategies to enhance nursing services, advance nurse competence, and reduce barriers to accessing care are needed to improve inmates' health outcomes.


The Oxidation of Phytocannabinoids to Cannabinoquinoids.
Spurred by a growing interest in cannabidiolquinone (CBDQ, HU-313, 2) as a degradation marker and alledged hepatotoxic metabolite of cannabidiol (CBD, 1), we performed a systematic study on the oxidation of CBD (1) to CBDQ (2) under a variety of experimental conditions (base-catalyzed aerobic oxidation, oxidation with metals, oxidation with hypervalent iodine reagents). The best results in terms of reproducibility and scalability were obtained with λ5-periodinanes (Dess-Martin periodinane, 1-hydroxy-1λ5,2-benziodoxole-1,3-dione (IBX), and SIBX, a stabilized, nonexplosive version of IBX). With these reagents, the oxidative dimerization that plagues the reaction under basic aerobic conditions was completely suppressed. A different reaction course was observed with the copper(II) chloride-hydroxylamine complex (Takehira reagent), which afforded a mixture of the hydroxyiminodienone 11 and the halogenated resorcinol 12. The λ5-periodinane oxidation was general for phytocannabinoids, turning cannabigerol (CBG, 18), cannabichromene (CBC, 10), and cannabinol (CBN, 19) into their corresponding hydroxyquinones (20, 21, and 22, respectively). All cannabinoquinoids modulated to a various extent peroxisome proliferator-activated receptor gamma (PPAR-γ) activity, outperforming their parent resorcinols in terms of potency, but the iminoquinone 11, the quinone dimers 3 and 23, and the haloresorcinol 12 were inactive, suggesting a specific role for the monomeric hydroxyquinone moiety in the interaction with PPAR-γ.


Biosynthesis of gamma-linolenic acid in cotyledons and microsomal preparations of the developing seeds of common borage (Borago officinalis).
The developing seeds of Borago officinalis (common borage) accumulate a triacylglycerol oil that is relatively rich in the uncommon fatty acid gamma-linolenate (octadec-6,9,12-trienoic acid). Incubation of developing, whole, cotyledons with [14C]oleate and [14C]linoleate showed that the gamma-linolenate was synthesized by the sequential desaturation of oleate----linoleate----gamma-linolenate. Microsomal membrane preparations from the developing cotyledons contained an active delta 6-desaturase enzyme that catalysed the conversion of linoleate into gamma-linolenate. Experiments were designed to manipulate the [14C]linoleate content of the microsomal phosphatidylcholine. The [14C]linoleoyl phosphatidylcholine labelled in situ was converted into gamma-linolenoyl phosphatidylcholine in the presence of NADH. The substrate for the delta 6-desaturase in borage was, therefore, the linoleate in the complex microsomal lipid phosphatidylcholine, rather than, as in animals, the acyl-CoA. This was further confirmed in experiments that compared the specific radioactivity of the gamma-linolenate, in acyl-CoA and phosphatidylcholine, that was synthesized when [14C]linoleoyl-CoA was incubated with microsomal membranes, NADH and non-radioactive gamma-linolenoyl-CoA. The delta 6-desaturase was positionally specific and only utilized the linoleate in position 2 of sn-phosphatidylcholine. Analysis of the positional distribution of fatty acids in the endogenous microsomal sn-phosphatidylcholine showed that, whereas position 1 contained substantial linoleate, only small amounts of gamma-linolenate were present. The results shed further light on the synthesis of C18 polyunsaturated fatty acids in plants and in particular its relationship to the regulation of the acyl quality of the triacylglycerols in oilseeds.


Primer effect in the detection of mitochondrial DNA point heteroplasmy by automated sequencing.
The correct detection of mitochondrial DNA (mtDNA) heteroplasmy by automated sequencing presents methodological constraints. The main goals of this study are to investigate the effect of sense and distance of primers in heteroplasmy detection and to test if there are differences in the accurate determination of heteroplasmy involving transitions or transversions. A gradient of the heteroplasmy levels was generated for mtDNA positions 9477 (transition G/A) and 15,452 (transversion C/A). Amplification and subsequent sequencing with forward and reverse primers, situated at 550 and 150 bp from the heteroplasmic positions, were performed. Our data provide evidence that there is a significant difference between the use of forward and reverse primers. The forward primer is the primer that seems to give a better approximation to the real proportion of the variants. No significant differences were found concerning the distance at which the sequencing primers were placed neither between the analysis of transitions and transversions. The data collected in this study are a starting point that allows to glimpse the importance of the sequencing primers in the accurate detection of point heteroplasmy, providing additional insight into the overall automated sequencing strategy.


CEST and nuclear Overhauser enhancement imaging with deep learning-extrapolated semisolid magnetization transfer reference: Scan-rescan reproducibility and reliability studies.
To develop a novel MR physics-driven, deep-learning, extrapolated semisolid magnetization transfer reference (DeepEMR) framework to provide fast, reliable magnetization transfer contrast (MTC) and CEST signal estimations, and to determine the reproducibility and reliability of the estimates from the DeepEMR. A neural network was designed to predict a direct water saturation and MTC-dominated signal at a certain CEST frequency offset using a few high-frequency offset features in the Z-spectrum. The accuracy, scan-rescan reproducibility, and reliability of MTC, CEST, and relayed nuclear Overhauser enhancement (rNOE) signals estimated from the DeepEMR were evaluated on numerical phantoms and in heathy volunteers at 3 T. In addition, we applied the DeepEMR method to brain tumor patients and compared tissue contrast with other CEST calculation metrics. The DeepEMR method demonstrated a high degree of accuracy in the estimation of reference MTC signals at ±3.5 ppm for APT and rNOE imaging, and computational efficiency (˜190-fold) compared with a conventional fitting approach. In addition, the DeepEMR method achieved high reproducibility and reliability (intraclass correlation coefficient = 0.97, intersubject coefficient of variation = 3.5%, and intrasubject coefficient of variation = 1.3%) of the estimation of MTC signals at ±3.5 ppm. In tumor patients, DeepEMR-based amide proton transfer images provided higher tumor contrast than a conventional MT ratio asymmetry image, particularly at higher B1 strengths (>1.5 μT), with a distinct delineation of the tumor core from normal tissue or peritumoral edema. The DeepEMR approach is feasible for measuring clean APT and rNOE effects in longitudinal and cross-sectional studies with low scan-rescan variability.


Image Processing for Public Health Surveillance of Tobacco Point-of-Sale Advertising: Machine Learning-Based Methodology.
With a rapidly evolving tobacco retail environment, it is increasingly necessary to understand the point-of-sale (POS) advertising environment as part of tobacco surveillance and control. Advances in machine learning and image processing suggest the ability for more efficient and nuanced data capture than previously available. The study aims to use machine learning algorithms to discover the presence of tobacco advertising in photographs of tobacco POS advertising and their location in the photograph. We first collected images of the interiors of tobacco retailers in West Virginia and the District of Columbia during 2016 and 2018. The clearest photographs were selected and used to create a training and test data set. We then used a pretrained image classification network model, Inception V3, to discover the presence of tobacco logos and a unified object detection system, You Only Look Once V3, to identify logo locations. Our model was successful in identifying the presence of advertising within images, with a classification accuracy of over 75% for 8 of the 42 brands. Discovering the location of logos within a given photograph was more challenging because of the relatively small training data set, resulting in a mean average precision score of 0.72 and an intersection over union score of 0.62. Our research provides preliminary evidence for a novel methodological approach that tobacco researchers and other public health practitioners can apply in the collection and processing of data for tobacco or other POS surveillance efforts. The resulting surveillance information can inform policy adoption, implementation, and enforcement. Limitations notwithstanding, our analysis shows the promise of using machine learning as part of a suite of tools to understand the tobacco retail environment, make policy recommendations, and design public health interventions at the municipal or other jurisdictional scale.


A multi-responsive intrinsically disordered protein (IDP)-directed green synthesis of fluorescent gold nanoclusters.
Herein we demonstrate the green synthesis of fluorescent gold nanoclusters (AuNCs) using a multi-responsive intrinsically disordered protein (IDP) polymer, Rec1-resilin, as a multi-functional template. In a controlled environment, Rec1-resilin acts simultaneously as the directing agent and the reducer, and performs the role of a highly efficient stabilizer once AuNCs are formed. The evolution of the photophysical properties and the chemical states of AuNCs formed are measured using UV-Vis, fluorescence and X-ray photoelectron spectroscopy. Circular dichroism (CD) spectroscopy measures the intrinsically disordered nature of Rec1-resilin stabilizing AuNCs. High resolution transmission electron microscopy (HR-TEM) reveals the detailed structure and morphology of the generated AuNCs of <1.5 nm size. A local ordering resembling that of a face-centered cubic (FCC) structure with evidence of twinning was observed for the generated AuNCs. The AuNCs so formed exclude the use of toxic reducing agents and display excellent water dispersibility, photostability and environmental stability towards aggregation.


Atrial-selective K+ channel blockers: potential antiarrhythmic drugs in atrial fibrillation?
In the wake of demographic change in Western countries, atrial fibrillation has reached an epidemiological scale, yet current strategies for drug treatment of the arrhythmia lack sufficient efficacy and safety. In search of novel medications, atrial-selective drugs that specifically target atrial over other cardiac functions have been developed. Here, I will address drugs acting on potassium (K+) channels that are either predominantly expressed in atria or possess electrophysiological properties distinct in atria from ventricles. These channels include the ultra-rapidly activating, delayed outward-rectifying Kv1.5 channel conducting IKur, the acetylcholine-activated inward-rectifying Kir3.1/Kir3.4 channel conducting IK,ACh, the Ca2+-activated K+ channels of small conductance (SK) conducting ISK, and the two-pore domain K+ (K2P) channels (tandem of P domains, weak inward-rectifying K+ channels (TWIK-1), TWIK-related acid-sensitive K+ channels (TASK-1 and TASK-3)) that are responsible for voltage-independent background currents ITWIK-1, ITASK-1, and ITASK-3. Direct drug effects on these channels are described and their putative value in treatment of atrial fibrillation is discussed. Although many potential drug targets have emerged in the process of unravelling details of the pathophysiological mechanisms responsible for atrial fibrillation, we do not know whether novel antiarrhythmic drugs will be more successful when modulating many targets or a single specific one. The answer to this riddle can only be solved in a clinical context.


Connecting parts with processes: SubtiWiki and SubtiPathways integrate gene and pathway annotation for Bacillus subtilis.
Bacillus subtilis is the model organism for a large group of Gram-positive bacteria, the Firmicutes. Several online databases have been established over time to manage its genetic and metabolic information, but they differ greatly in their rate of update and their focus on B. subtilis. Therefore, a European systems biology consortium called for an integrated solution that empowers its users to enrich online content. To meet this goal we created SubtiWiki and SubtiPathways, two complementary online tools for gene and pathway information on B. subtilis 168. SubtiWiki (http://subtiwiki.uni-goettingen.de/ ) is a scientific wiki for all genes of B. subtilis and their protein or RNA products. Each gene page contains a summary of the most important information; sections on the gene, its product and expression; sections concerning biological materials and laboratories; and a list of references. SubtiWiki has been seeded with key content and can be extended by any researcher after a simple registration, thus keeping it always up to date. As a complement, SubtiPathways (http://subtipathways.uni-goettingen.de/) is an online tool for navigation of the metabolism of B. subtilis and its regulation. Each SubtiPathways diagram presents a metabolic pathway with its participating enzymes, together with the regulatory mechanisms that act on their expression and activity, in an intuitive interface that is based on Google Maps. Together, SubtiWiki and SubtiPathways provide an integrated view of the processes that make up B. subtilis and its components, making it the most comprehensive web resource for B. subtilis researchers.


Claudication secondary to Perclose use after percutaneous procedures.
The use of suture-mediated arterial closure devices has dramatically increased with the increased number of percutaneous procedures being performed. Complications from suture-mediated closure devices have been underreported. Specifically, arterial stenosis resulting in claudication has not been previously described in detail. We present nine patients who presented with various leg symptoms after Perclose was used to achieve arterial hemostasis following percutaneous procedures. All cases were found to have significant arterial stenoses from the Perclose sutures. Once diagnosis was correctly made, the patients either underwent surgical repair or percutaneous balloon angioplasty and in all cases the symptoms abated.


Epidemiology of ambulatory anesthesia for children in the United States: 2006 and 1996.
There are few data that describe the frequency, anesthetic type, provider, or disposition of children requiring outpatient anesthesia in the United States (US). Since the early 1980s, the frequency of ambulatory surgery has increased dramatically because of advances in medical technology and changes in payment arrangements. Our primary aim in this study was to quantify the number of ambulatory anesthetics for children that occur annually and to study the change in utilization of pediatric anesthetic care over a decade. The US National Center for Health Statistics performed the National Survey of Ambulatory Surgery in 1994 through 1996 and again in 2006. The survey is based on data abstracted from a national sample of ambulatory surgery centers and provides data on visits for surgical and nonsurgical procedures for patients of all ages. We abstracted data for children who had general anesthesia, regional anesthesia, or monitored anesthesia care during the ambulatory visit. We obtained the information from the 2006 and 1996 databases and used population census data to estimate the annual utilization of ambulatory anesthesia per 1000 children in the US. In 2006, an estimated 2.3 million ambulatory anesthesia episodes of care were provided in the US to children younger than 15 years (38 of 1000 children). This amount compares with 26 per 1000 children of the same age group in 1996. In most cases, an anesthesiologist was involved in both time periods (74% in 2006 and 85% in 1996). Of the children, 14,200 were admitted to the hospital postoperatively, a rate of 6 per 1000 ambulatory anesthesia episodes. The number and rate of ambulatory anesthesia episodes for US children increased dramatically over a decade. This study provides an example of how databases can provide useful information to health care policy makers and educators on the utilization of ambulatory surgical centers by children.


Drug Induced Lupus Erythematosus Due to Capecitabine and Bevacizumab Treatment Presenting with Prolonged Thrombocytopenia.
Drug induced lupus erythematosus (DLE) is a syndrome that is formed by lupus-like symptoms and laboratory characteristics. Capecitabine is an orally administered tumor-selective fluoropyrimidine that acts as a prodrug of 5-Fluorouracil and bevacizumab is an antivascular endothelial growth factor (anti-VEGF) antibody, both are used for the treatment of patients with colorectal cancer. Herein we report the first case of DILE in a 68-year-old woman who presented with arthralgia, myalgia and prolonged thrombocytopenia after receiving capecitabine and bevacizumab combination treatment as palliative treatment for metastatic colon cancer. Platelet-levels were increased and joint complaints disappeared in the first week of hydroxychloroquine and methylprednisolone treatment after chemotherapy had been discontinued. In conclusion, physicians should be alert to the possibility of DILE in patients presenting with thrombocytopenia under a capecitabine and bevacizumab chemotherapy regimen.


Micronodular basal cell carcinoma. A deceptive histologic subtype with frequent clinically undetected tumor extension.
Micronodular basal cell carcinoma (BCC) is thought to have a greater potential for clinically surreptitious tumor spread compared with the majority of BCCs that are nodular. However, most supporting data are anecdotal. This study gives objective evidence that micronodular BCCs have wider and deeper tumor extensions than nodular BCCs of similar clinical size. In this retrospective study, 69 cases of micronodular BCC excised by Mohs' micrographic surgery (MMS) were matched to a control group of 69 cases of nodular BCC that were similarly excised. They were paired by site, size, number of recurrences, age, gender, and previous treatment type. The cases were selected and paired by computer from 1070 consecutive BCCs (primary and recurrent) referred for MMS over a 4-year period. The MMS technique allowed us to quantitate and compare the extent of tumor spread using three measurements: the number of surgical stages required for complete removal of the tumor, the width of tissue required to remove subclinical extension of tumor, and the depth of defect at completion of MMS. Analysis showed the micronodular BCC to have significantly more covert tumor extension, making it more difficult to detect and to eradicate than the nodular BCC. The number of surgical stages required for complete removal of tumor, the width of tissue required to remove subclinical extension of tumor, and the depth of defect at completion of MMS were all greater with micronodular BCCs when compared with nodular BCCs regardless of whether cases were primary or recurrent. These differences were all statistically significant. Micronodular BCCs can be significantly more destructive than nodular BCCs because tumor extension is difficult to detect clinically. When treating micronodular BCC, clinicians should keep in mind its potential for clandestine invasion.


Three-dimensional chemical concentration maps in a microfluidic device using two-photon absorption fluorescence imaging.
Two-photon absorption fluorescence is employed within a microfluidic device to create a three-dimensional chemical concentration map for mixing uniformity characterization. This multiphoton technique images fluorescence intensity directly and provides a simple, rapid, and readily employed route to composition characterization within microfluidic systems.


Diazepam-binding inhibitor. A brain neuropeptide present in human spinal fluid: studies in depression, schizophrenia, and Alzheimer's disease.
Diazepam-binding inhibitor is a novel peptide purified to homogeneity from rat and human brain. Diazepam-binding inhibitor is present, though not exclusively, in gamma-aminobutyric acid (GABA)-containing neurons where it is believed to inhibit GABAergic neurotransmission mediated by GABA by binding to the benzodiazepine-GABA receptor complex. Since an impairment of central GABAergic tone has been postulated to be associated with a number of neuropsychiatric disorders, we measured human diazepam-binding inhibitor immunoreactivity in the cerebrospinal fluid (CSF) of patients suffering from endogenous depression, schizophrenia, and dementia of the Alzheimer's type. Patients with major depression had significantly higher concentrations of human diazepam-binding inhibitor immunoreactivity in CSF when compared with age- and sex-matched normal volunteers, while no difference in CSF diazepam-binding inhibitor immunoreactivity was found in schizophrenics or patients with dementia of the Alzheimer's type when compared with controls. The possibility is discussed that the increased CSF human diazepam-binding inhibitor immunoreactivity observed in depressed patients may represent a functional disinhibition of GABAergic neurotransmission associated with depression.