DNA viruses (CMV, EBV, and the herpesviruses).
The human Herpesviridae family consists of eight members: cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1 and 2 (HSV-1, -2), varicella-zoster virus (VZV), and human herpesvirus 6, 7, and 8 (HHV-6, -7, -8). Lifelong latency may develop in the host with reactivation during periods of relative immunosuppression that occurs in transplant recipients. These are pleiotropic viruses: in addition to their direct effects of tissue injury and clinical illness, they exhibit several indirect effects, including immunomodulation and effects on angiogenesis and tumorigenesis, which may result in long-term adverse sequelae in the lung allograft. CMV and HHV-6 and -7 are increasingly recognized as major causes of morbidity and mortality in lung transplant recipients. EBV and HHV-8 have proven oncogenic potential. HSV-1 and -2 and VZV are neurotropic, causing perioral fever blisters, genital ulcerations, and, rarely, encephalitis. This article discusses the individual pathogens, preventive strategies in the era of potent treatment regimens for established viral infection or disease and their potential impact on the indirect effects of these viruses on long-term allograft function, and the incidence, risk factors for, and impact of antiviral resistance.


Recombination-deficient deletions in bacteriophage lambda and their interaction with chi mutations.
We have isolated a new class of deletion mutants of phage lambda that extend from the prophage attachment site, att, into the gam and cIII genes. In this respect they are similar to certain of the lambda pbio transducing phage, but they differ in having a low burst size and in forming minute plaques. Lytically grown stocks of the deletions contain a variable proportion of phage that produce large plaques. These have been shown to carry an additional point mutation. Similar mutations, called chi, have been described by Lam et al. (1974), who showed that they result in a hot-spot for recombination produced by the host recombination system (Rec). We show that chi mutations can occurat several sites in the lambda genome and produce a Rec-dependent increase in the burst size of the one deletion tested.---In addition to reducing burst size, the one deletion tested reduces synthesis of DNA and emdolysin but increases production of serum blocking protein. A chi mutation partially restores DNA synthesis and endolysin production and reduces serum blocking protein to normal levels. Our results are consistent with the hypothesis put forward by Lam et al., that chi enhances the frequency of Rec-promoted recombination, which provides the only pathway for production of maturable DNAin a red gam infection. The mechanism of the differential effect on protein production is, however, unclear.---Chi mutations are found to occur in DNA other than that of lambda. We show that, as has been suggested elsewhere (McMilin, Stahl and Stahy 1974), the lambda pbio transducing phages carry a chi mutation within the E. coli DNA substitution. A chi mutation also arose in a new substitution of unknown origin isolated in the course of this work.


Selenium and tellurium-based nanoparticles as interfering factors in quorum sensing-regulated processes: violacein production and bacterial biofilm formation.
A cell-to-cell communication system called quorum sensing (QS) promotes the transcription of certain target genes in bacterial cells leading to the activation of different cellular processes, some of them related to bacterial biofilm formation. The formation of bacterial biofilms favours antibiotic resistance, which is nowadays a significant public-health problem. In this study, the effect of selenium (SeNPs) and tellurium (TeNPs) nanoparticles was examined in two bacterial processes mediated by QS: violacein production by Chromobacterium violaceum and biofilm formation by Pseudomonas aeruginosa. For this purpose, quantification of the pigment production in the presence of these nanoparticles was monitored using the C. violaceum strain. Additionally, a combination of different microscopical imaging techniques was applied to examine the changes in the 3D biofilm structure of P. aeruginosa, which were quantified through performing architectural metric calculations (substratum area, cell area coverage and biovolume). SeNPs produce an 80% inhibition in the violacein production by C. violaceum and a significant effect on the P. aeruginosa biofilm architecture (a reduction of 80% in the biovolume of the bacterial biofilm was obtained). TeNPs similarly affect violacein production and the P. aeruginosa biofilm structure but at lower concentration levels. The results obtained suggest an important disruption of the QS signalling system by SeNPs and TeNPs, supporting nanotechnology as a promising tool to fight against the emerging problem of bacterial resistance related to bacterial biofilm formation.


Proximal vs distal slowing of nerve conduction in chronic renal failure treated by long-term hemodialysis.
An F-wave conduction study was performed to determine proximal vs distal slowing of motor nerve conduction in the lower extremities in nine patients with chronic renal failure who were undergoing-long-term hemodialysis and in 11 normal control subjects. The values of the F-wave ratio and the difference between the longest and shortest F-wave latencies were significantly longer than the control values in five patients, implying predominant affection of the proximal peroneal nerve segments. In the remaining patients, the proximal and distal peroneal nerve segments were equally affected. The distal motor nerve conduction velocities of the posterior tibial nerves were also reduced, while the values for the median and ulnar nerves were generally within the normal range. It is important to study multiple F-wave characteristics, in addition to the conventional nerve conduction, for complete assessment of peripheral nerve function in these patients.


A 2010 evidence-based algorithm for the pharmacotherapy of social anxiety disorder.
A growing evidence base on the management of social anxiety disorder has yielded many meta-analyses and guidelines on the pharmacotherapy of this clinically important condition. We aimed to update a pharmacotherapy algorithm for the treatment of social anxiety disorder that was developed to be concise and user friendly and that was addressed to the primary care practitioner in particular. The updated algorithm attempts to summarize succinctly the recent literature in this area, as well as to include the views of an international panel of experts with diverse experience. The algorithm comprises eight sequential steps, beginning with those focused on diagnosis and initiating treatment and ending with the management of the treatment-refractory patient.


A comparison of new rapid urease tests for detection of Helicobacter pylori: test characteristics and factors affecting positivity and time to positivity.
We assessed two new rapid urease tests, the Helicobacter Urease Test (HUT, Astra, Sweden) and the Polish test, for accuracy, reaction time, and the effect of biopsy site and bacterial density on test characteristics and time to positivity. A prospective study was conducted in two groups of patients: 64 consecutive patients undergoing upper endoscopy for dyspepsia and 61 consecutive patients with duodenal ulcer on upper endoscopy. In the first group, test accuracy, time to positivity, and possible associations with biopsy site and bacterial density were assessed between the tests. In the second group, the two new tests were compared with the CLOtest for time to positivity and effect of bacterial density on test outcome. The Polish and HUT test had similar specificities (97%), but the Polish test was more sensitive (90.3% vs. 80.7%). The Polish test was positive within 10 minutes in 55% of the positive patients compared with 10% for the HUT test. There was no association between bacterial density (by histologic count) and reaction time in either test or in the CLOtest in the second group. The Polish test was more accurate and had a quicker time interval to positivity than the HUT. There was no significant association between bacterial density and reaction time in any of the urease tests assessed, and the biopsy site did not affect test accuracy in the HUT test.


A phenomenological exploration of the feedback experience of medical students after summative exam failure.
Preventing medical students entering cycles of underperformance following assessment is a priority due to the consequences for the student, faculty, and wider society. The benefits from feedback may be inadequately accessed by students in difficulty due to the emotional response evoked by examination failure. This study aims to explore medical students' experiences of receiving feedback after summative assessment failure and investigate the role of emotions on motivation for learning after underperformance, to better support remediation and preparation for future assessments. This study used interpretative phenomenological analysis (IPA) to explore the experiences of four medical students who failed summative assessments. Additionally, a content analysis was conducted using Linguistic Inquiry and Word Count (LIWC) to investigate the characteristics and use of language to describe their emotional response. Anger, fear, anxiety, and sadness were emotions frequently experienced after examination failure. These emotions led to feelings of mistrust of the medical school and subsequent distrust in the university's assessment processes, impacting on the desire to engage with feedback. There was dissonance between the students' perceptions of what feedback should provide and what benefit feedback provided after summative assessments. The linguistic inquiry further confirmed an initial (and sometimes long lived) negative affective state after experiencing failure, and a barrier to engagement with remediation when not effectively managed. A range of emotions, directed at themselves and the medical school are experienced by students following exam failure. These emotions lead to a range of negative feelings and responses that affect how students make sense of and move on from the failure experience. There is a need for educators to better understand and support students to manage, reflect and contextualise their emotional responses, minimise external attribution and to enable focus on remediation and learning.


Drug treatment of male fertility disorders.
Drug treatment remains an active domain in the therapy of male fertility disorders. Although there are only a few conditions that allow causal treatment, rational approaches are possible in many cases. Best results are obtained in cases requiring an anti-inflammatory treatment and in patients with an impaired sperm transport. High-dosage administration of FSH is a promising new development, aimed particularly at improving the disturbed sperm structures. A careful diagnostic work-up with elucidation of the underlying disease is essential to achieve a successful therapy.


Role of imaging in progressive-fibrosing interstitial lung diseases.
Imaging techniques are an essential component of the diagnostic process for interstitial lung diseases (ILDs). Chest radiography is frequently the initial indicator of an ILD, and comparison of radiographs taken at different time points can show the rate of disease progression. However, radiography provides only limited specificity and sensitivity and is primarily used to rule out other diseases, such as left heart failure. High-resolution computed tomography (HRCT) is a more sensitive method and is considered central in the diagnosis of ILDs. Abnormalities observed on HRCT can help identify specific ILDs. HRCT also can be used to evaluate the patient's prognosis, while disease progression can be assessed through serial imaging. Other imaging techniques such as positron emission tomography-computed tomography and magnetic resonance imaging have been investigated, but they are not commonly used to assess patients with ILDs. Disease severity may potentially be estimated using quantitative methods, as well as visual analysis of images. For example, comprehensive assessment of disease staging and progression in patients with ILDs requires visual analysis of pulmonary features that can be performed in parallel with quantitative analysis of the extent of fibrosis. New approaches to image analysis, including the application of machine learning, are being developed.


Control of helical chirality in supramolecular chromophore-DNA architectures.
Four different d- and l-configured chromophore-2'-deoxyuridine conjugates were applied to elucidate the helical chirality of their non-covalent assemblies along the d- and l-configured DNA templates by optical spectroscopy. There is no configuration-selective recognition between these nucleosides and the DNA templates. The helicity of the DNA assemblies is either controlled by the configuration of the DNA template or by the nucleoside configuration.


Venous thrombosis: the history of knowledge.
Venous thrombosis is a frequent disease. It is surprising, therefore, that no case truly compatible with a diagnosis of venous thrombosis was apparently reported in the antiquity. There is no case that could be reasonably attributed to a venous thrombus in the writings of Hippocrates, Galenus, Celius Aurelianus, Ibn an-Nafiz, Avicenna and others. Venous thrombosis is not among the many diseases mentioned in the Bible. The term "leucophlegmasia", first used by Hippocrates and then by Celius Aurelianus, refers to cases of bilateral leg edema, most likely due to conditions such as heart failure, liver cirrhosis and renal insufficiency. Nothing compatible with a diagnosis of venous thrombosis can be found in pieces of art from ancient Egypt, Greece, Rome, Persia and South America. While in these sources there are sometimes representations of varicose veins and ulcers, unilateral leg edema or other pictures compatible with venous thrombosis are not featured. The first well documented case of venous thrombosis is depicted in a beautifully illustrated manuscript written in the 13th century and currently preserved in Paris at the Bibliothèque Nationale (MS Fr 2829, Folio 87). The manuscript describes the case of a young man from Normandy named Raoul who at the age of twenty developed unilateral edema in the right ankle that subsequently extended up to the thigh, with no obvious symptoms in the contralateral leg. Raoul was advised to visit the tomb of Saint Louis who was buried in the church of Saint Denis, where the patient spent several days confessing his sins and praying the saint. Afterwards he chose to collect the dust accumulating below the stone that covered the tomb and to apply it on the fistulae and ulcers of his foot. The openings stopped running and were filled with flesh. He was first obliged to use crutches but subsequently he could walk with a cane, to be eventually able to dispose of all devices, even though his foot throbbed a little. Raoul was cured as described above in the year 1271 and was still alive and well in 1282. Not only this is the first case of venous thrombosis, the young age of the patients leads us to suspect that Raoul had a thrombophilic condition.


Experimental and numerical investigation of the equilibrium geometry of liquid lenses.
The equilibrium configuration of a nonwetted three fluid system takes the form of a floating liquid lens, where the lens resides between an upper and lower phase. The axisymmetric profiles of the three interfaces can be computed by solving the nonlinear Young-Laplace differential equation for each interface with coupled boundary conditions at the contact line. Here we describe a numerical method applicable to sessile or pendant lenses and provide a free, downloadable Mathematica Player file which uses a graphical interface for analyzing and plotting lens profiles. The results of the calculations were compared to optical photographs of various liquid lens systems which were analyzed using basic ray-tracing and Moiré imaging. The lens profile calculator, together with a measurement of the lens radius for a known volume, provides a simple and convenient method of determining the spreading coefficient (S) of a liquid lens system if all other fluid parameters are known. If surfactants are present, the subphase surface tension must also be self-consistently determined. A procedure is described for extracting characteristic features in the optical images to uniquely determine both parameters. The method gave good agreement with literature values for pure fluids such as alkanes on water and also for systems with a surfactant (hexadecane/DTAB), which show a transition from partial wetting to the pseudopartial wetting regime. Our technique is the analog of axisymmetric drop shape analysis, applied to a three fluid system.


MitoEM Dataset: Large-scale 3D Mitochondria Instance Segmentation from EM Images.
Electron microscopy (EM) allows the identification of intracellular organelles such as mitochondria, providing insights for clinical and scientific studies. However, public mitochondria segmentation datasets only contain hundreds of instances with simple shapes. It is unclear if existing methods achieving human-level accuracy on these small datasets are robust in practice. To this end, we introduce the MitoEM dataset, a 3D mitochondria instance segmentation dataset with two (30μm)3 volumes from human and rat cortices respectively, 3, 600× larger than previous benchmarks. With around 40K instances, we find a great diversity of mitochondria in terms of shape and density. For evaluation, we tailor the implementation of the average precision (AP) metric for 3D data with a 45× speedup. On MitoEM, we find existing instance segmentation methods often fail to correctly segment mitochondria with complex shapes or close contacts with other instances. Thus, our MitoEM dataset poses new challenges to the field. We release our code and data: https://donglaiw.github.io/page/mitoEM/index.html.


[Prevalence of fibromyalgia in diabetes mellitus and obesity].
To determine the prevalence of fibromyalgia in diabetes mellitus and obesity, 121 consecutive patients have been observed: 27 with obesity (6 males and 21 females; mean age 57 years, range 20-57; mean body mass index [BMI] 34); 88 with type 2 diabetes mellitus (T2DM; 40 males and 48 females; mean age 63 years, range 44-78; mean BMI 28.8; mean glycated haemoglobin [HbA1c] in the last year 8.3%); 6 with type 1 diabetes mellitus (T1DM; 2 males and 4 females; mean age 52 years, range 26-76; mean BMI 24.5; mean HbA1c < 7%). An original questionnaire has been proposed (answer yes/not) as follows: 1) chronic (more than 3 months) and diffuse musculoskeletal pain; 2) sleep disturbances; 3) generalized fatigue; 4) paresthesias at the extremities; 5) swollen impression at hands and feet; 6) symptoms referred to irritable bowel syndrome; 7) headache; 8) symptoms change related with environmental climatic variations and/or exercise. A chronic and diffuse musculoskeletal pain has been reported by 62% of patients as well as in 9% of patients 11/18 positive tender points have been documented. In the patients with a BMI less that 26 the diagnosis of fibromyalgia was negative. Our data seem to reveal the presence of a significant clinical association between obesity, diabetes mellitus and fibromyalgia.


How To Make Nitroaromatic Compounds Glow: Next-Generation Large X-Shaped, Centrosymmetric Diketopyrrolopyrroles.
Red-emissive π-expanded diketopyrrolopyrroles (DPPs) with fluorescence reaching λ=750 nm can be easily synthesized by a three-step strategy involving the preparation of diketopyrrolopyrrole followed by N-arylation and subsequent intramolecular palladium-catalyzed direct arylation. Comprehensive spectroscopic assays combined with first-principles calculations corroborated that both N-arylated and fused DPPs reach a locally excited (S1 ) state after excitation, followed by internal conversion to states with solvent and structural relaxation, before eventually undergoing intersystem crossing. Only the structurally relaxed state is fluorescent, with lifetimes in the range of several nanoseconds and tens of picoseconds in nonpolar and polar solvents, respectively. The lifetimes correlate with the fluorescence quantum yields, which range from 6 % to 88 % in nonpolar solvents and from 0.4 % and 3.2 % in polar solvents. A very inefficient (T1 ) population is responsible for fluorescence quantum yields as high as 88 % for the fully fused DPP in polar solvents.


Physical and Mental Fatigue Reduce Psychomotor Vigilance in Professional Football Players.
Professional football players experience both physical and mental fatigue (MF). The main aims of this randomized crossover study were to investigate the effect of MF on repeated-sprint ability (RSA) and the effects of both physical fatigue and MF on psychomotor vigilance. Seventeen male professional football players performed 10 maximal 20-m shuttle sprints interspaced by incomplete recovery (RSA test). Running speed, heart rate, brain oxygenation, and rating of perceived exertion were monitored during each sprint. The RSA test was preceded by either a 30-minute Stroop task to induce MF or by watching a documentary for 30 minutes (control [CON]) in a randomized counterbalanced order. Participants performed a psychomotor vigilance test at baseline, after the cognitive task (MF or CON), and after the RSA test. Heart rate and rating of perceived exertion significantly increased, while running speed and brain oxygenation significantly decreased over the repeated sprints (P < .001) with no significant differences between conditions. Response speed during the psychomotor vigilance test significantly declined after the Stroop task but not after CON (P = .001). Response speed during the psychomotor vigilance test declined after the RSA test in both conditions (P < .001) and remained lower in the MF condition compared to CON (P = .012). MF does not reduce RSA. However, the results of this study suggest that physical fatigue and MF have negative and cumulative effects on psychomotor vigilance. Therefore, strategies to reduce both physical fatigue and MF should be implemented in professional football players.


Total glucosides of paeony improves the immunomodulatory capacity of MSCs partially via the miR-124/STAT3 pathway in oral lichen planus.
Mesenchymal stem cells (MSCs) have been used clinically and experimentally to relieve severe immune-related diseases due to their immunomodulatory properties, but these are impaired by inflammation. Oral lichen planus (OLP) is a T cell-mediated chronic inflammatory mucosal disease. In the present study, we found MSCs from OLP with higher expression of interleukin (IL)-6, tumour necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β) and IL-10 compared with control. Total glucosides of paeony (TGP) significantly improves the immunomodulatory function of MSCs by inhibiting IL-6 and TNF-α expression and increasing TGF-β and IL-10 expression. Moreover, TGP can downregulate p-STAT3 expression through upregulation of miR-124. The changes of IL-6, TGF-β and p-STAT3 were further confirmed by overexpression and knockdown of miR-124 in MSCs. Taken together, the immune-regulating function of MSCs can be improved by TGP via the miR-124/STAT3 pathway.


Extended replacement of a calcified ascending aorta in adulthood sporadic, diffuse type, supravalvular aortic stenosis.
The diffuse variant of supravalvular aortic stenosis (SVAS) is one of the most rare congenital vascular pathological conditions of adulthood. Due to its rarity, surgical treatment of this clinical entity is still a matter of debate because of the variable degree of aortic narrowing, presence of multilevel obstruction, and age at presentation, all factors that strongly influence the disease prognosis. We report a case of an adult patient with an extremely calcified diffuse SVAS who underwent successful replacement of the ascending aorta through the interposition of a tubular prosthesis. Six months' follow-up showed complete relief of the aortic gradient and an improvement in clinical performance.


Prevalence and distribution of (micro)albuminuria in toddlers.
Microalbuminuria is common in the general adult population, with a prevalence of ∼7%, and is an independent indicator of renal and cardiovascular risks. Whether albuminuria is acquired during life (as a result of hypertension/diabetes) or is congenital and already present at birth is unknown. We studied the prevalence of microalbuminuria in toddlers and compared the distribution of albuminuria with that of the general adult population. In addition, we looked for possible associations between microalbuminuria and antenatal, postnatal and maternal factors. The urinary albumin concentration (UAC) was measured in 1352 children and the urinary albumin:creatinine ratio (UACR) in 1288 children from the Groningen Expert Center for Kids with Obesity (GECKO) Drenthe cohort (age range 20-40 months). Albuminuria distribution was compared with the albuminuria distribution in 40 854 participants of the general adult cohort of the Prevention of Renal and Vascular End stage Disease (PREVEND) study. Associations between albuminuria (expressed as UAC and UACR) and antenatal, postnatal and maternal factors were tested with linear regression analysis. The median UAC in the GECKO study was 2.3 mg/L (5th-95th percentiles: 2.1-25.5) and in the PREVEND study it was 6.0 mg/L (2.3-28.6) (P distribution comparison 0.053). The prevalence of UAC ≥ 20 mg/L was 6.9% in the GECKO study and 7.8% in the PREVEND study (P = 0.195). The prevalence of UACR ≥ 30 mg/g in the GECKO study was 23.4%. UAC and UACR were lower in boys. UAC was not associated with other determinants, but UACR was associated with age and gestational diabetes. The distribution of UAC and the prevalence of UAC > 20 mg/L in toddlers and in the young general adult population are comparable. These findings suggest that microalbuminuria is a congenital condition that may predispose to a higher cardiovascular risk later in life.


Identity construction and British Muslims' political activity: beyond rational actor theory.
Political activity is often addressed in terms of rational actor theory (RAT). We review RAT's psychological assumptions and highlight the neglect of collective identity. In turn, we view the perception of 'interest' as contingent upon constructions of identity and explore how different characterizations of collective identity are organized strategically so as to shape people's understandings of their interests and how they should act to realize them. Using examples taken from a study of British Muslims' political activity we emphasize the contested and strategic dimension to identity construction and analyse how activists addressing the same constituency construe Muslim identity in different ways so as to promote different conceptions of collective interest. Specifically, we explore the contested invocations of Prophetic example in the definition of Muslim identity. The broader thrust behind this work is a critique of the sharp dichotomization of Muslim and non-Muslim political activity. We maintain that essentially similar processes of identity construction underlie all attempts to organize collective sentiment and political action (including that comprising so-called 'conventional' electoralist politics in the West), and that conceiving of identity as a site of political struggle underscores the inadequacy of Orientalist characterizations of Muslim identity in terms of a singular, transhistorical essence.


[Changes in weight, length and head circumference in premature newborn babies weighing less than 1,500 grams at birth].
The objective of this study was to analyze the weight, length and head circumference development in prematurely born babies who weighed less than 1,500 grams and who were included in the follow-up program of our neonatal unit. Review of data of the cohort included in the follow-up program between May 1990 and September 1995 was carried out. The weight and length were measured from 3 months of corrected age to 4 years of age. The head circumference was measured until 2 years of age. We recruited 259 premature newborns (136 boys and 123 girls). The median gestational age was 30 weeks (23 to 36) and the median weight was 1,150 g (500 to 1,499 g). Twenty-seven percent were underweight for their gestational age (LWGA). The proportion of cases with weight below the 3rd percentile in the follow-up was stable around 25% in the group of adequate weight for gestational age. (AWGA). At 3 months of corrected age this proportion was 70% in the LWGA group, but there was a trend towards catch-up at 2 years of age. The worst results were obtained in the group that weighed less than 750 g at birth. The head circumference was better preserved than longitudinal growth and thus better than weight. All cases of head circumference below the 3rd percentile in the follow-up occurs in the LWGA group. Weight was the parameter with the worst evolution during follow-up, especially in the group that weighed less than 750 g at birth. The group of LWGA tended to catch-up at 2 years of age.


Inhibition of Listeria monocytogenes and Escherichia coli O157:H7 on Beef by Application of Organic Acids †.
Lean beef surfaces were inoculated with Escherichia coli O157:H7 and Listeria monocytogenes and then sanitized with fumaric, acetic, or lactic acid alone and in combined solutions of those acids at 55°C for 5 s. The initial inoculum level was 8.62 log CFU/cm2 and 5.13 log CFU/cm2 for L. monocytogenes and E. coli O157:H7, respectively. Fumaric acid at a concentration of 1% was the most effective acid in reducing the populations of L. monocytogenes by up to 1 log unit and E. coli O157:H7 by up to 1.3 log units when compared with acetic or lactic acids. The rank order of acids tested against the growth of L. monocytogenes and E. coli O157:H7 was fumaric acid followed by lactic and acetic acids. Fumaric acid at concentrations of 1.0% and 1.5% was more effective than any of the combined solutions of acids.


Tolerance and immunological changes of chemically modified allergen vaccine of Parietaria judaica in accelerated schedules.
The physicochemical modification of allergen vaccines provides a chance for administering higher doses in a shorter period of time. We sought to assess the safety and immunological changes of using a biologically standardized and modified Parietaria judaica pollen extract in accelerated schedules. Two accelerated schedules were tested in 45 P. judaica-allergic patients: 20 patients reached the maximum dose after two visits using two different concentrations and 25 patients reached the maximum dose after only one visit with two injections of the maximum concentration vial. The tolerance was assessed by recording all side effects related with immunotherapy. Specific antibody levels against native extract and rPar j 2 allergen were evaluated at the beginning and the end of the study. Allergenic potency determined by enzyme allergosorbent test (EAST) inhibition and skin prick test showed that modified P. judaica pollen had a 99.9% less allergenicity than native extract. After 650 doses administered, two clinically irrelevant local reactions (diameter<0 x 5 cm) and no systemic reactions were registered. Significant increases in allergen-specific IgG4 and IgG against P. judaica extract and rPar j 2 and significant decrease of specific IgE against Par j 2 were observed. The modified extract of P. judaica is safe to treat sensitive patients, even at accelerated regimens, and induces significant immunological changes.


CXCR4 expression accounts for clinical phenotype and outcome in acute myeloid leukemia.
Background. In acute myeloid leukemia (AML), CXCR4 expression has been correlated with leukocytosis and prognosis. Methods. We quantified CXCR4 expression by flow cytometry on leukemic cells in 142 AML patients. Results. We confirm a correlation between high CXCR4 expression and leukemic burden. Furthermore, we documented a correlation with platelet count, dysplastic megakaryopoiesis, hepato-splenomegaly and extra-hematological disease. NPM1-mutated AML displayed a significantly higher intensity of CXCR4 compared to NPM1-wt cases: it is conceivable its clinical phenotype to be driven by high CXCR4 expression. Conclusions. CXCR4 expression resulted an independent prognostic factor. Our data support CXCR4 targeting as a potential therapeutic strategy. © 2014 Clinical Cytometry Society.


High-resolution, >1 GHz NMR in unstable magnetic fields.
Resistive or hybrid magnets can achieve substantially higher fields than those available in superconducting magnets, but their spatial homogeneity and temporal stability are unacceptable for high-resolution NMR. We show that modern stabilization and shimming technology, combined with detection of intermolecular zero-quantum coherences (iZQCs), can remove almost all of the effects of inhomogeneity and drifts, while retaining chemical shift differences and J couplings. In a 25-T electromagnet (1 kHz/s drift, 3 kHz linewidth over 1 cm(3)), iZQC detection removes >99% of the remaining inhomogeneity, to generate the first high-resolution liquid-state NMR spectra acquired at >1 GHz.


Cholesteryl ester transfer-protein modulator and inhibitors and their potential for the treatment of cardiovascular diseases.
Elevated low-density lipoprotein (LDL) cholesterol and lowered high-density lipoprotein (HDL) cholesterol are important risk factors for cardiovascular disease. Accordingly, raising HDL cholesterol induced by cholesteryl ester transfer protein (CETP) inhibition is an attractive approach for reducing the residual risk of cardiovascular events that persist in many patients receiving low-density LDL cholesterol-lowering therapy with statins. The development of torcetrapib, a CETP inhibitor, was terminated due to its adverse cardiovascular effects. These adverse effects did not influence the mechanism of CETP inhibition, but affected the molecule itself. Therefore a CETP modulator, dalcetrapib, and a CETP inhibitor, anacetrapib, are in Phase III of clinical trials to evaluate their effects on cardiovascular outcomes. In the dal-VESSEL (dalcetrapib Phase IIb endothelial function study) and the dal-PLAQUE (safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging) clinical studies, dalcetrapib reduced CETP activity by 50% and increased HDL cholesterol levels by 31% without changing LDL cholesterol levels. Moreover, dalcetrapib was associated with a reduction in carotid vessel-wall inflammation at 6 months, as well as a reduced vessel-wall area at 24 months compared with the placebo. In the DEFINE (determining the efficacy and tolerability of CETP inhibition with anacetrapib) clinical study, anacetrapib increased HDL cholesterol levels by 138% and decreased LDL cholesterol levels by 36%. In contrast with torcetrapib, anacetrapib had no adverse cardiovascular effects. The potential of dalcetrapib and anacetrapib in the treatment of cardiovascular diseases will be revealed by two large-scale clinical trials, the dal-OUTCOMES (efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome) study and the REVEAL (randomized evaluation of the effects of anacetrapib through lipid modification, a large-scale, randomized placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular disease) study. The dal-OUTCOMES study is testing whether dalcetrapib can reduce cardiovascular events and the REVEAL study is testing whether anacetrapib can reduce cardiovascular events. These reports are expected to be released by 2013 and 2017, respectively.


Patterns of protein synthesis and metabolism during sea urchin embryogenesis.
We have analyzed the patterns of protein synthesis in developing embryos of the sea urchin Strongylocentrotus purpuratus by two-dimensional gel electrophoresis. There was an increase in the number of proteins detectably synthesized during development, as well as significant changes in relative rates of synthesis involving approximately 20% of the nearly 900 newly synthesized polypeptides. The majority of these changes were increases rather than decreases in synthesis; about half were of at least 10-fold, while a few were of more than 100-fold. Very few changes were detected upon fertilization and during the first several hours of development, while about 60% of the changes detected occurred between the hatching and the beginning of invagination. An analysis of proteins detected by silver staining indicated that most remained nearly constant in mass during embryonic development, but several increased or declined substantially. Many proteins present in eggs were not detectably synthesized in either eggs or embryos.


A counterclockwise bias in running.
A bias in spontaneous turning has been observed in several animal species, at the individual or group level. There has been no consensus so far on the existence of such a bias in humans, probably due to lack of control of the factors likely to modulate this bias. We tested the spontaneous behavior of thirteen human adults required to run around a circle in an empty, symmetrical space, as a function of starting position (from the left, the center, or the right), and gaze direction (to one of five targets going from left to right). A clear significant overall tendency to turn counterclockwise across all conditions was observed. This was particularly striking when the participants were required to start from the center position and look straight ahead before starting, with more than 80% of the participants turning counterclockwise in this perfectly symmetrical condition. Starting position, gaze and head direction modulated the bias, without masking the counterclockwise tendency. We discuss some of the factors likely to be partly responsible for this clear turning bias, including cognitive space representation, and preference for keeping the peripheral vision to one's left visual field during running due to hemispheric asymmetry.


Transcranial Doppler monitoring during language tasks in stroke patients with aphasia.
To investigate the pattern of hemispheric activation, according to cerebral blood flow changes, as measured by Transcranial Doppler Ultrasonography (TCD) during language tasks in stroke patients with aphasia. Prospective study investigating results of TCD monitoring during language naming and recognition tasks in ischemic stroke patients (n = 32) with and without aphasia and 5 control subjects. Delta mean flow velocity (MFV) in the left Middle Cerebral Artery (MCA) was found to be much lower in aphasia patients as compared to healthy subjects. Negative statistical correlation was found between the improvement of language ability and the blood flow velocity parameters in the left hemisphere. Aphasia patients with good language ability showed much higher MFV in the right MCA during the first test. Left hemispheric blood flow velocity shift was found to be higher during speech tasks in the patients with poor language ability. Our study suggests that the performance of language tasks in aphasia patients during early recovery after stroke is associated with relatively high right hemisphere activation. High blood flow velocity in the right MCA of aphasia patients was found to be a good prognostic sign for better language ability. Arterial blood flow that shifted towards the left hemisphere during speech tasks was associated with poor language ability.


Mapping susceptibility loci in inflammatory bowel disease: why and how?
The cause of the inflammatory bowel diseases Crohn's disease and ulcerative colitis is unknown, but epidemiological evidence suggests that it is multifactorial with a strong genetic component. Several genetic loci probably contribute to disease susceptibility, accounting for the complex pattern of inheritance and heterogeneous clinical manifestations. The combination of candidate gene studies and, more recently, genome-wide searches has resulted in the identification of a number of putative susceptibility loci. With large-scale, fine-mapping studies under way, and accelerating progress in the physical mapping of the human genome, rapid progress is now being made towards the identification of the genes responsible for inflammatory bowel disease.


Photodynamic endometrial ablation in the nonhuman primate.
To test the effectiveness of 5-aminolevulinic acid (ALA)-induced photodynamic endometrial ablation in the rhesus monkey under varying conditions of light delivery (fractionated versus continuous) and steroid priming. Photodynamic endometrial ablation was carried out in 17 rhesus monkeys that were either postmenopausal or in the early proliferative phase. Four hours after intralumenal injection of ALA (250 mg in 1 mL hyskon), a quartz fiber with a diffusing tip was inserted. A KTP tunable dye laser delivered 300 mW of light (635 nm) for 60 minutes in either continuous or fractionated fashion (20 minutes on, 5 minutes off, and 40 minutes on). In some experiments, thermistors were used to monitor temperature in the lumen and myometrium during light treatment. Hysterectomy was performed 3 or 4 days after treatment, and endometrial damage was assessed histologically. Two additional monkeys (one rhesus and one cynomolgus monkey) were exposed to the same protocol, except hyskon was substituted for ALA to control for potential ablative effects due to light treatment alone. Endometrial ablation was evident in all ALA-photosensitized specimens. The degree of ablation around the light fiber ranged from moderate to complete. The depth of ablation ranged from 1.14 +/- 0.54 to 2.15 +/- 1.62 mm (mean +/- standard deviation). Ablation was most complete in uteri of menopausal monkeys. Light treatment after ALA increased lumenal temperature from 36 C to 50 C, whereas temperature was not significantly increased by light treatment in the controls. This is the first report of endometrial destruction in the primate using a photodynamic approach. Whereas clinical application of photodynamic therapy (PDT) requires complete endometrial ablation to produce long-lasting amenorrhea, our results suggest that PDT may offer a simple office-based approach to endometrial ablation.


Mechanisms underlying synapse-specific clustering of GABA(A) receptors.
A principle that arises from a body of previous work is that each presynaptic terminal recognises its postsynaptic partner and that each postsynaptic site recognises the origin of the synaptic bouton innervating it. In response, the presynaptic terminal sequesters the proteins whose interactions result in the dynamic transmitter release pattern and chemical modulation appropriate for that connection. In parallel, the postsynaptic site sequesters, inserts or captures the receptors and postsynaptic density proteins appropriate for that type of synapse. The focus of this review is the selective clustering of GABA(A) receptors (GABA(A)R) at synapses made by each class of inhibitory interneurone. This provides a system in which the mechanisms underlying transynaptic recognition can be explored. There are many synaptic proteins, often with several isoforms created by post-translational modifications. Complex cascades of interactions between these proteins, on either side of the synaptic cleft, are essential for normal function, normal transmitter release and postsynaptic responsiveness. Interactions between presynaptic and postsynaptic proteins that have binding domains in the synaptic cleft are proposed here to result in a local cleft structure that captures and stabilises only the appropriate subtype of GABA(A)Rs, allowing others to drift away from that synapse, either to be captured by another synapse, or internalised.


Compatibility of omega-functionality in the electrochemically directed self-assembly of monolayers on gold from alkyl thiosulfates.
Self-assembled monolayers were formed on gold electrochemically from omega-functionalized alkyl thiosulfates (Bunte salts). The resulting SAMs were characterized using X-ray photoelectron spectroscopy (XPS), contact-angle goniometry, and ellipsometry. A range of terminal functionality was examined, including CH(3), perfluoroalkyl, CO(2)H, CO(2)CH(3), CONH(2), CH(2)OH, and vinyl groups. Side-reactions involving some of these functional groups were consistent with intermediates proposed in our earlier publications and begin to define the scope of this method for building chemical structures at interfaces.


Structure-based studies on species-specific inhibition of thymidylate synthase.
Thymidylate synthase (TS) is a well-recognized target for anticancer chemotherapy. Due to its key role in the sole de novo pathway for thymidylate synthesis and, hence, DNA synthesis, it is an essential enzyme in all life forms. As such, it has been recently recognized as a valuable new target against infectious diseases. There is also a pressing need for new antimicrobial agents that are able to target strains that are drug resistant toward currently used drugs. In this context, species specificity is of crucial importance to distinguish between the invading microorganism and the human host, yet thymidylate synthase is among the most highly conserved enzymes. We combine structure-based drug design with rapid synthetic techniques and mutagenesis, in an iterative fashion, to develop novel antifolates that are not derived from the substrate and cofactor, and to understand the molecular basis for the observed species specificity. The role of structural and computational studies in the discovery of nonanalog antifolate inhibitors of bacterial TS, naphthalein and dansyl derivatives, and in the understanding of their biological activity profile, are discussed.


Defactinib, Pembrolizumab, and Gemcitabine in Patients with Advanced Treatment Refractory Pancreatic Cancer: A Phase I Dose Escalation and Expansion Study.
Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse model. Defactinib is a highly potent oral FAK inhibitor that has a tolerable safety profile. We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a recommended phase II dose (RP2D). In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had stable disease (SD) after at least 4 months of standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and posttreatment tumor biopsies were performed to evaluate tumor immunity. The triple drug combination was well-tolerated, with no dose-limiting toxicities. Among 20 treated patients with refractory PDAC, the disease control rate (DCR) was 80%, with one partial response (PR) and 15 SDs, and the median progression-free survival (PFS) and overall survival (OS) were 3.6 and 7.8 months, respectively. Among 10 evaluable patients in the maintenance cohort, DCR was 70% with one PR and six SDs. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS on study treatment were 5.0 and 8.3 months, respectively. The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated and safe, had promising preliminary efficacy, and showed biomarker activity in infiltrative T lymphocytes. Efficacy of this strategy may require incorporation of more potent chemotherapy in future studies.


Role of Nasal Ventilation Function in Obstructive Sleep Apnea Syndrome in Children.
Background: The association between increased nasal resistance (NR) and obstructive sleep apnea syndrome (OSAS) is controversial. The purpose of this study was to examine nasal ventilation function (NVF) in children with OSAS, with a focus on its pathogenetic role. Methods: Children were recruited and divided into the OSAS group (n = 109) and control group (n = 116). The participants underwent polysomnography (PSG), measurement of NR, and acoustic rhinometry (AR). A combination of intranasal corticosteroids (ICS) and oral montelukast (OM) was administered to 90 children with mild to moderate OSAS for 12 weeks. After excluding participants who dropped out or were lost to follow-up, there were 58 children who responded to the treatment, who were divided into 2 groups-A and B. We compared the size of the tonsil adenoids, the PSG, NR, and AR before and after treatment in the 2 groups. Results: Children aged 6 to 12 years with OSAS had significantly higher NR than the control group (P < .05). The OSAS group had a smaller nasal minimal cross-sectional area (NMCA), nasal cavity volume (NCV) from 0 to 5 cm, and nasopharyngeal volume (NPV) from 6 to 8 cm than the control group, and the difference was statistically significant (P < .05 or P < .01). A total of 58 (84.1%) children responded to the 12-week ICS+OM treatment and 11 (15.9%) children did not respond to the treatment. Effective treatment was achieved in 32 children, as evidenced by a significant reduction in tonsil adenoid size and variations in NR and AR values. There were significant improvements in NR, NMCA, and NCV in the remaining 26 children who were successfully treated, but there was no change in tonsil adenoids and NPV value. Conclusion: NVF may play an important pathogenetic role in children with OSAS.


Neglected tropical diseases in the People's Republic of China: progress towards elimination.
Since the founding of the People's Republic of China in 1949, considerable progress has been made in the control and elimination of the country's initial set of 11 neglected tropical diseases. Indeed, elimination as a public health problem has been declared for lymphatic filariasis in 2007 and for trachoma in 2015. The remaining numbers of people affected by soil-transmitted helminth infection, clonorchiasis, taeniasis, and echinococcosis in 2015 were 29.1 million, 6.0 million, 366 200, and 166 100, respectively. In 2017, after more than 60 years of uninterrupted, multifaceted schistosomiasis control, has seen the number of cases dwindling from more than 10 million to 37 600. Meanwhile, about 6000 dengue cases are reported, while the incidence of leishmaniasis, leprosy, and rabies are down at 600 or fewer per year. Sustained social and economic development, going hand-in-hand with improvement of water, sanitation, and hygiene provide the foundation for continued progress, while rigorous surveillance and specific public health responses will consolidate achievements and shape the elimination agenda. Targets for poverty elimination and strategic plans and intervention packages post-2020 are important opportunities for further control and elimination, when remaining challenges call for sustainable efforts.


Composition and significance of detergent resistant membranes in mouse spermatozoa.
Mammalian spermatozoa acquire the ability to fertilize an oocyte as they ascend the female reproductive tract. This process is characterized by a complex cascade of biophysical and biochemical changes collectively know as "capacitation." The attainment of a capacitated state is accompanied by a dramatic reorganization of the surface architecture to render spermatozoa competent to recognize the oocyte and initiate fertilization. Emerging evidence indicates that this process is facilitated by molecular chaperone-mediated assembly of a multimeric receptor complex on the sperm surface. However, the mechanisms responsible for gathering key recognition molecules within this putative complex have yet to be defined. In this study, we provide the first evidence that chaperones partition into detergent resistant membrane fractions (DRMs) within capacitated mouse spermatozoa and co-localize in membrane microdomains enriched with the lipid raft marker, G(M1) ganglioside. During capacitation, these microdomains coalesce within the apical region of the sperm head, a location compatible with a role in sperm-zona pellucida interaction. Significantly, DRMs isolated from spermatozoa possessed the ability to selectively bind to the zona pellucida of unfertilized, but not fertilized, mouse oocytes. A comprehensive proteomic analysis of the DRM fractions identified a total of 100 proteins, a number of which have previously been implicated in sperm-oocyte interaction. Collectively, these data provide compelling evidence that mouse spermatozoa possess membrane microdomains that provide a platform for the assembly of key recognition molecules on the sperm surface and thus present an important mechanistic insight into the fundamental cell biological process of sperm-oocyte interaction.


Post-exercise recovery of contractile function and endurance in humans and mice is accelerated by heating and slowed by cooling skeletal muscle.
We investigated whether intramuscular temperature affects the acute recovery of exercise performance following fatigue-induced by endurance exercise. Mean power output was better preserved during an all-out arm-cycling exercise following a 2 h recovery period in which the upper arms were warmed to an intramuscular temperature of ̴ 38°C than when they were cooled to as low as 15°C, which suggested that recovery of exercise performance in humans is dependent on muscle temperature. Mechanisms underlying the temperature-dependent effect on recovery were studied in intact single mouse muscle fibres where we found that recovery of submaximal force and restoration of fatigue resistance was worsened by cooling (16-26°C) and improved by heating (36°C). Isolated whole mouse muscle experiments confirmed that cooling impaired muscle glycogen resynthesis. We conclude that skeletal muscle recovery from fatigue-induced by endurance exercise is impaired by cooling and improved by heating, due to changes in glycogen resynthesis rate. Manipulation of muscle temperature is believed to improve post-exercise recovery, with cooling being especially popular among athletes. However, it is unclear whether such temperature manipulations actually have positive effects. Accordingly, we studied the effect of muscle temperature on the acute recovery of force and fatigue resistance after endurance exercise. One hour of moderate-intensity arm cycling exercise in humans was followed by 2 h recovery in which the upper arms were either heated to 38°C, not treated (33°C), or cooled to ∼15°C. Fatigue resistance after the recovery period was assessed by performing 3 × 5 min sessions of all-out arm cycling at physiological temperature for all conditions (i.e. not heated or cooled). Power output during the all-out exercise was better maintained when muscles were heated during recovery, whereas cooling had the opposite effect. Mechanisms underlying the temperature-dependent effect on recovery were tested in mouse intact single muscle fibres, which were exposed to ∼12 min of glycogen-depleting fatiguing stimulation (350 ms tetani given at 10 s interval until force decreased to 30% of the starting force). Fibres were subsequently exposed to the same fatiguing stimulation protocol after 1-2 h of recovery at 16-36°C. Recovery of submaximal force (30 Hz), the tetanic myoplasmic free [Ca2+ ] (measured with the fluorescent indicator indo-1), and fatigue resistance were all impaired by cooling (16-26°C) and improved by heating (36°C). In addition, glycogen resynthesis was faster at 36°C than 26°C in whole flexor digitorum brevis muscles. We conclude that recovery from exhaustive endurance exercise is accelerated by raising and slowed by lowering muscle temperature.


Structure of a rabbit muscle fructose-1,6-bisphosphate aldolase A dimer variant.
Fructose-1,6-bisphosphate aldolase (aldolase) is an essential enzyme in glycolysis and gluconeogenesis. In addition to this primary function, aldolase is also known to bind to a variety of other proteins, a property that may allow it to perform 'moonlighting' roles in the cell. Although monomeric and dimeric aldolases possess full catalytic activity, the enzyme occurs as an unusually stable tetramer, suggesting a possible link between the oligomeric state and these noncatalytic cellular roles. Here, the first high-resolution X-ray crystal structure of rabbit muscle D128V aldolase, a dimeric form of aldolase mimicking the clinically important D128G mutation in humans associated with hemolytic anemia, is presented. The structure of the dimer was determined to 1.7 angstroms resolution with the product DHAP bound in the active site. The turnover of substrate to produce the product ligand demonstrates the retention of catalytic activity by the dimeric aldolase. The D128V mutation causes aldolase to lose intermolecular contacts with the neighboring subunit at one of the two interfaces of the tetramer. The tertiary structure of the dimer does not significantly differ from the structure of half of the tetramer. Analytical ultracentrifugation confirms the occurrence of the enzyme as a dimer in solution. The highly stable structure of aldolase with an independent active site is consistent with a model in which aldolase has evolved as a multimeric scaffold to perform other noncatalytic functions.


Epidemiological correlations between diet and cancer frequency.
The literature concerning international correlations between dietary items and cancer frequency is reviewed. An updated correlation of the most recent data on cancer mortality and food consumption is made. Strong and consistent correlations are reported between death rates of cancers of the colon and breast and the per capita consumption of total fat and of nutrients derived from animal sources, especially beef, pork, eggs, and milk. Similar but less consistent correlations have been reported with cancers of the prostate, ovary, and endometrium. In addition, correlations between precursor lesions of coronary heart disease and colon cancer in New Orleans autopsy populations are reported. Some studies suggest that milk intake correlates better with atherosclerotic disease while beef intake correlates better with colon cancer. Negative correlations of colon cancer rates and vegetable consumption are reported. Colon cancer rates also show negative correlations with stool weight, irrespective of the type of vegetable responsible for the increased bulk. Epidemiological data are consistent with the hypothesis that excessive beef and low vegetable consumption are causally related to colon cancer. These food items probably do not have a direct carcinogenic role but rather provide a microenvironment favorable to the actions of carcinogens.


Childhood non-Hodgkin's lymphoma: an immunophenotypic analysis.
To observe the frequency of histological subtypes of childhood non-Hodgkin's lymphoma and its immunohistochemical profile. All cases of non-Hodgkin's lymphoma diagnosed in children (< 15 years) in the section of histopathology at the Aga Khan University Hospital Karachi during the period of three years. These consecutive cases were evaluated on H&E stained sections and then immunohistochemistry analysis of these tumors was performed by employing Peroxidase Anti-Peroxidase (PAP) technique. The present series included 61 cases of non-Hodgkin's lymphoma. NHL was more common in males as compared to females with male to female ratio of 5.8:1. High grade NHL comprised 87% of childhood lymphoma. The mode of presentation in majority of NHL (57%) was extranodal. Burkitt's lymphoma (33%) was the most prevalent histological subtypes, followed by lymphoblastic (28%), diffuse large cell (15%), diffuse mix small and large cell (13%), small non cleaved Non-Burkitt's (7%) and immunoblastic (4%). Immunophenotypic analysis of the childhood Non-Hodgkin's lymphoma revealed that 67% of the Non-Hodgkin's lymphoma are B-cell type while 33%, are those of T-cell lineage. NHL was more common in males. Majority of NHL in children were high grade tumors. Burkitt's lymphoma was the most frequent histological subtype. T-cell NHL comprised a significant portion of childhood lymphomas.


Technology Courage: Implications for Faculty Development.
This article was migrated. The article was marked as recommended. Purpose: From a decade of technology-focused faculty development, the authors recognized that academic physicians adopt educational technology at varying rates and with variable confidence. This work is an exploration of the phenomenon of technology courage and how the concept can inform faculty development. Method: Qualitative methods of interpretative phenomenological analysis (IPA) were used. Faculty interviews were transcribed using Google Docs voice typing. Data were analyzed, themes developed, and supportive narratives were identified using IPA methodology. Results: Two themes emerged. The theme of Willingness includes willingness to try, explore, or risk learning a new technology; and willingness to persist in the face of fear or anxiety. The theme of Benefit Evaluation relates to motivators for technology courage, i.e., assessing benefit to self and learners before learning and using a new technology. Conclusions: From a theme analysis, a definition of technology courage has emerged: willingness to try and to persist when using a new technology because of perceived benefit to self and/or others. The authors discuss how further research of the construct might be guided by theoretical frameworks of grit, self-efficacy, teacher identity, and generational learning differences. Recommendations are offered on how the construct of technology courage can be valuable for technology-focused faculty development.


Place of Death of Geriatric Population in Turkey: A 7-Year Observational Study.
End-of-life care has become an important public health issue in recent years. Place of death is a major component of end-of-life care. Despite attempts to improve end-of-life care, there has not been published any data about place of deaths in Turkey. Aim: This retrospective, cross-sectional study investigates the place of death and trends over the years in geriatric age groups in Turkey. Methods: Patients who were admitted to geriatric outpatient clinic of a university hospital during a 7-year period were included. Place and date of death information were received from the death notification system and recorded as hospital or out-of-hospital death. Demographic and clinical data were collected from the hospital information system. Deaths occurring after March 1, 2020 were not included to eliminate the effect of coronavirus disease-2019 pandemic. Results: A total of 4025 (20.7%) patients were determined to be dead. Approximately three-quarters of deaths (73.0%) occurred in hospital. The number of deaths reported from nursing homes was only 13 (3.0%). Patients with dementia less frequently died in hospital, however, it was not statistically significant (12.4% vs 14.7%, P = .05). The prevalence of death in hospital was significantly higher in patients with chronic renal failure (3.1% vs 1.7%, P = .02). The presence of comorbid conditions such as heart failure, cerebrovascular disease, Parkinson's disease, chronic obstructive pulmonary disease/asthma, and cancer did not affect the place of death (P = .24, .21, .24, .51, and .18). Out-of-hospital mortality increased with advanced age (P < .001). No significant difference was found in the place of death over the years (P = .41). Conclusion: To the best of our knowledge, this is the first study examining the place of death in Turkey, an aging country. Our results may help to establish policies about end-of-life care in elderly people to improve quality of life by using resources effectively.


Lymphocyte subsets in patients with idiopathic dilated cardiomyopathy.
Although chronic myocardial inflammatory process mediated by viral and autoimmune factors has been postulated in the pathogenesis of idiopathic dilated cardiomyopathy (IDC), the role of autoimmune mechanisms still remains unclear. The aim of the present study was to investigate the rates of various T cell subsets and natural killer (NK) cells in peripheral blood in order to see whether they had a role in the immunoregulation of IDC. The surface markers of peripheral T and B lymphocytes were detected and percentages of pan T and B cells as well as helper (CD4+) and suppressor (CD8+) T lymphocytes subsets in the peripheral blood and their ratio (CD4+/CD8+) were determined in 27 patients with IDC and in 20 healthy controls. NK cell percentage was also studied. There were no significant differences between IDC and control groups with respect to T and B cell percentages. The percentages of CD4+ T cell subsets were similar in both groups (48.7 +/- 8.7% vs. 43.5 +/- 9.7% respectively; p = 0.107). CD8+ T cell percentage was significantly decreased in patients with IDC than in controls (22.6 +/- 7.7% vs. 28.2 +/- 8.2%, respectively; p = 0.044). CD4+/CD8+ ratio was markedly higher in patients with IDC than controls (2.6 +/- 1.8 vs. 1.6 +/- 0.6, respectively; p = 0.006). There was no significant difference in the NK cell percentage between groups. Decreased CD8+ T cell subset is the cause of increased CD4+/CD8+ ratio, which may imply decreased self-tolerance and an immunoregulatory defect in the pathogenesis of IDC.


Operative results of non-small cell lung cancer clinically presenting mediastinal lymph adenopathy.
Selection of treatment for operable N2 non-small cell lung cancer (NSCLC) is still controversial. If considered resectable, we have actively performed surgery even for clinical stage IIIA-N2 disease. In this retrospective study, surgical results in NSCLC with clinically presenting mediastinal lymph adenopathy examined to investigate its indication. Consecutive 202 patients who were preoperatively diagnosed or suspected of mediastinal lymph adenopathy and underwent operation were investigated for such as pathological judgement of nodal metastasis, completeness of operation and prognosis. Perioperative chemotherapy and/or radiotherapy was performed in 56 patients. Pathological diagnosis of nodal status was N0 in 64 patients, N1 in 27, N2 in 104 and N3 in 7. Complete resection was performed in 109 patients (54%). In 111 patients with pathologically proven N2 (pN2), only 40 (36%) were completely resected. The reason of incomplete resection included extranodal extension of mediastinal nodal metastasis in 31 patients, pleural dissemination in 18, extension of primary tumor to mediastinum in 11. Median post-operative survival time was 553 days, and survival rates at 2- and 5-years were 43% and 22%, respectively. In all pN2, survival rates at 2- and 5-years were 33% and 11%, respectively. In 40 patients of completely resected pN2, survival rates at 2- and 5-years were 42% and 22%, respectively, whereas those were 17% and 5% in 64 patients with incompletely resected pN2. The positive effect of perioperative treatment on survival was not apparent. If resectable, surgical approach to N2 might be approved, however, extensive examination is required prior to therapy to avoid incomplete resection.


Loss of Long-Term Potentiation at Hippocampal Output Synapses in Experimental Temporal Lobe Epilepsy.
Patients suffering from temporal lobe epilepsy (TLE) show severe problems in hippocampus dependent memory consolidation. Memory consolidation strongly depends on an intact dialog between the hippocampus and neocortical structures. Deficits in hippocampal signal transmission are known to provoke disturbances in memory formation. In the present study, we investigate changes of synaptic plasticity at hippocampal output structures in an experimental animal model of TLE. In pilocarpine-treated rats, we found suppressed long-term potentiation (LTP) in hippocampal and parahippocampal regions such as the subiculum and the entorhinal cortex (EC). Subsequently we focused on the subiculum, serving as the major relay station between the hippocampus proper and downstream structures. In control animals, subicular pyramidal cells express different forms of LTP depending on their intrinsic firing pattern. In line with our extracellular recordings, we could show that LTP could only be induced in a minority of subicular pyramidal neurons. We demonstrate that a well-characterized cAMP-dependent signaling pathway involved in presynaptic forms of LTP is perturbed in pilocarpine-treated animals. Our findings suggest that in TLE, disturbances of synaptic plasticity may influence the information flow between the hippocampus and the neocortex.


Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity.
Anti-apoptotic protein BCL-XL plays a key role in tumorigenesis and cancer chemotherapy resistance, rendering it an attractive target for cancer treatment. However, BCL-XL inhibitors such as ABT-263 cannot be safely used in the clinic because platelets solely depend on BCL-XL to maintain their viability. To reduce the on-target platelet toxicity associated with the inhibition of BCL-XL, we designed and synthesized PROTAC BCL-XL degraders that recruit CRBN or VHL E3 ligase because both of these enzymes are poorly expressed in human platelets compared to various cancer cell lines. We confirmed that platelet-toxic BCL-XL/2 dual inhibitor ABT-263 can be converted into platelet-sparing CRBN/VHL-based BCL-XL specific degraders. A number of BCL-XL degraders are more potent in killing cancer cells than their parent compound ABT-263. Specifically, XZ739, a CRBN-dependent BCL-XL degrader, is 20-fold more potent than ABT-263 against MOLT-4 T-ALL cells and has >100-fold selectivity for MOLT-4 cells over human platelets. Our findings further demonstrated the utility of PROTAC technology to achieve tissue selectivity through recruiting differentially expressed E3 ligases.


The complete blood count to diagnose septic shock.
The complete blood count has a longstanding role in the diagnosis of septic shock. Despite its limitations, this is a pragmatic tool because patients will generally have a blood count measured upon presentation to the hospital. Therefore, it is sensible to extract as much information from these values as possible. Although the white blood cell count continues to attract the most attention, it is the least useful. Emerging evidence suggests that emphasis should be shifted to the neutrophil to lymphocyte ratio (NLR) and perhaps the fraction of immune granulocytes.


The Groningen Meander Walking Test: a dynamic walking test for older adults with dementia.
Current dynamic walking tests, used in studies with older adults with dementia, rely strongly on healthy cognitive and physical function. Therefore, the Groningen Meander Walking Test (GMWT) was developed specifically for people with dementia. The aim of the GMWT is to measure dynamic walking ability by walking over a meandering curved line, with an emphasis on walking speed and stepping accuracy, while changing direction. The purpose of this study was to investigate the feasibility, test-retest reliability, and minimal detectable change (MDC) of the GMWT. A repeated-measures design was used. Forty-two people with dementia participated in the study. Adherence rate, adverse events, repetition of instructions during test performance, test duration, and number of oversteps were assessed. The adherence rate was excellent, with no adverse events. No repetitive instructions were given during test performance, and test duration was short (mean=17.16 seconds) with few oversteps (mean=1.94 oversteps). Test-retest reliability for participants without a walking device was excellent for the GMWT time score (intraclass correlation coefficient [ICC]=.942), with an MDC of 2.96 seconds. Test-retest reliability for participants with a 4-wheeled walker (4WW) was moderate (ICC=.837), with an MDC of 10.35 seconds. For the overstep score, a marginal ICC of .630 was found, with an MDC of 4.38 oversteps. No fall data were available, and there was a volunteer bias. The GMWT is a feasible test for people with dementia. With the GMWT time score, a reliable and sensitive field test to measure walking abilities in older adults with dementia is available. The GMWT overstep score can be used to give information about the execution according to protocol and should be emphasized during the instructions. Future studies need to investigate the validity of the GMWT.


Investigating the paradox of hypothyroidism and increased serum thyrotropin (TSH) levels in Sheehan's syndrome: characterization of TSH carbohydrate content and bioactivity.
Serum TSH levels are often paradoxically elevated in patients with hypothyroidism due to Sheehan's syndrome. To investigate this apparent discrepancy, the biological activity and glycosylation of serum TSH were studied in 9 untreated patients with Sheehan's syndrome and 11 normal controls. TSH bioassay was based on cAMP generation, measured by RIA, in a culture system of CHO cells transfected with recombinant human TSH receptor. The oligosaccharide branching of TSH was studied by Con A lectin affinity chromatography, which discriminates TSH isoforms according to their mannose content, and the sialic acid content of TSH was studied by Ricinus communis affinity chromatography in combination with enzymatic removal of sialic acid with neuraminidase treatment. TSH bioactivity was expressed as the ratio between biological and immunofluorometric assays (B/I). Bioactive TSH concentrations were calculated by multiplying serum TSH intrinsic bioactivity by serum immunoreactive TSH concentration (B/I x I). Serum free T(4) (FT(4)) levels were lower in patients than in controls (3.7 +/- 0.4 vs. 14.0 +/- 0.9 pmol/L, respectively; P < 0.0001). Circulating immunoreactive TSH was higher in patients with Sheehan's syndrome than in controls (3.8 +/- 0.8 vs. 1.8 +/- 0.2 mU/L, respectively; P = 0.01). In contrast, TSH B/I was significantly decreased in Sheehan's patients compared with controls (0.6 +/- 0.4 vs. 1.7 +/- 0.8, respectively; P = 0.003). However, the resultant bioactive TSH concentrations in serum of Sheehan's patients were not significantly different from control values (2.1 +/- 0.6 vs. 3.0 +/- 0.4; P = 0.25). A significant correlation was found between the bioactive TSH concentrations and serum FT(4) levels in patients with Sheehan's syndrome (r = 0.66; P = 0.05), but not between serum immunoreactive TSH and FT(4) levels (r = 0.21; P = 0.59) or between intrinsic TSH bioactivity and FT(4) levels (r = 0.56; P = 0.12). The Con A chromatography of serum TSH showed a similar distribution (0.3 < P < 0.5) of unbound, weakly bound, and firmly bound TSH in Sheehan's patients (16%, 38%, and 47%, respectively) and controls (15%, 34%, and 52%, respectively). The ricin chromatography of serum TSH showed a higher proportion of sialylated TSH molecules in Sheehan's patients than in controls (55% vs. 29%; P = 0.02). These results show that circulating TSH in Sheehan's syndrome, albeit increased, has decreased biological activity. The relevance of this finding is supported by the direct correlation between bioactive serum TSH concentrations and circulating FT(4). The reduced intrinsic TSH bioactivity in pituitary hypothyroidism of Sheehan's syndrome results from increased sialylation of TSH.


Different dietary carbohydrate component intakes and long-term outcomes in patients with NAFLD: results of longitudinal analysis from the UK Biobank.
This study aimed to investigate the association between the intake of different dietary carbohydrate components and the long-term outcomes of non-alcoholic fatty liver disease (NAFLD). We used prospective data from 26,729 NAFLD participants from the UK Biobank cohort study. Dietary information was recorded by online 24-hour questionnaires (Oxford WebQ). Consumption of different carbohydrate components was calculated by the UK Nutrient Databank Food Composition Table. Cox proportional hazards models were used to estimate the adjusted hazard ratio (HR) and 95% confidence interval (CI). A substitution model was used to estimate the associations of hypothetical substitution for free sugars. During a median of 10.5 (IQR: 10.2-11.2) years and a total of 280,135 person-years of follow-up, 310 incident end-stage liver disease (ESLD) and 1750 deaths were recorded. Compared with the lowest quartile, the multi-adjusted HRs (95% CI) of incident ESLD in the highest quartile were 1.65 (1.14-2.39) for free sugars, 0.51 (0.35-0.74) for non-free sugars, and 0.55 (0.36-0.83) for fiber. For overall mortality, the multi-adjusted HRs (95% CI) in the highest quartile were 1.21 (1.04-1.39) for free sugars, 0.79 (0.68-0.92) for non-free sugars, and 0.79 (0.67-0.94) for fiber. Substituting free sugars with equal amounts of non-free sugars, starch or fiber was associated with a lower risk of incident ESLD and overall mortality. A lower intake of free sugars and a higher intake of fiber are associated with a lower incidence of ESLD and overall mortality in NAFLD patients. These findings support the important role of the quality of dietary carbohydrates in preventing ESLD and overall mortality in NAFLD patients.


Evidence for granulosa-theca interaction in the secretion of oxytocin by bovine ovarian tissue.
We have examined the ability of granulosa cells, from carefully selected preovulatory bovine follicles, to secrete oxytocin in vitro. Although cells from 83% of follicles underwent functional luteinization (greatly increased progesterone secretion) in serum-supplemented culture, only 69% had cells capable of oxytocin secretion. Secretion followed a similar time course in all cultures, with the peak appearing on day 3. Oxytocin, but not progesterone, output could be consistently increased by addition of pieces of theca interna tissue, or theca conditioned medium, to the cultures. The effect could be achieved by exposure to theca tissue at any time prior to peak output without altering the time course of secretion. Oxytocin could not be detected in follicular fluid from any of the selected follicles, nor in medium from theca cultured alone. We conclude that the potential for oxytocin secretion is a feature of follicular maturation which is lost during atresia and that the stimulus to secretion is associated with luteinization but not with progesterone output. Finally, the intermixing of follicular cells during corpus luteum formation may provide a mechanism for the enhancement of oxytocin secretion within a predetermined time frame.


Efavirenz-induced hypersensitivity reaction manifesting in rash and hepatitis in a Latino male.
To report a case of hypersensitivity manifesting in a rash, fever, and life-threatening hepatitis in a patient initiated on efavirenz therapy. A 30-year-old Latino male newly diagnosed with HIV was started on efavirenz-based highly active antiretroviral therapy (HAART) using tenofovir 300 mg, emtricitabine 200 mg, and efavirenz 600 mg once daily. Eleven days after beginning therapy, he developed a hypersensitivity reaction manifesting in rash and fever preceding severe drug-induced hepatitis. Liver enzyme peak values were aspartate transaminase 3410 U/L and alanine transaminase 2132 U/L. Hepatitis resolved with discontinuation of the HAART. The patient was rechallenged with tenofovir and emtricitabine one year later; no adverse reactions occurred. The Naranjo probability scale demonstrated a probable relationship between this adverse reaction and efavirenz. A MEDLINE search (2004 to September 2007) revealed 2 cases of rash preceding hepatitis with the initiation of efavirenz. Both cases were in women; there were no prior reported cases of efavirenz hypersensitivity in men. Although the mechanism of this reaction is unknown, a few factors may have contributed to this reaction. The half-life and the auto-induction of efavirenz may explain the continued rise in liver enzymes and severe hepatitis that continued to occur once the drug was discontinued. Another cause that may have contributed is the metabolism of the medication. CYP2B6 is responsible for almost 90% of the clearance of efavirenz. Data from a recent pharmacokinetic study showed that efavirenz concentrations were higher in both black and Latino patients when compared with those of white patients. In addition, it is highly probable that this patient's liver function was impaired when transaminase levels peaked, resulting in decreased clearance of efavirenz. Although such a hypersensitivity reaction is rare, efavirenz is the most probable cause of the erythematous maculopapular rash and acute hepatitis in this patient. Monitoring of liver function in patients who present with a rash following initiation of efavirenz-based HAART is recommended. In addition, clinicians should exercise caution in patients presenting with rash, fever, and increased liver enzymes (> 3 times the upper limit of normal or patient baseline). It is strongly recommended that efavirenz therapy be withheld in such cases and reevaluated once liver enzyme levels stabilize.


Identification and Simultaneous Determination of the Main Toxical Pyrrolizidine Alkaloids in a Compound Prescription of Traditional Chinese Medicine: Qianbai Biyan Tablet.
Qianbai biyan tablet (QT) is a compound prescription of traditional Chinese medicine which is used to treat nasal congestion, rhinitis, and nasosinusitis, with Senecio scandens as its main plant material. Several pyrrolizidine alkaloids (PAs) were reported in Senecio scandens and others of Senecio species. Although Senecio scandens is assigned as the legal plant material of QT, whether replaced use of it by other Senecio plants can bring toxicity is unknown because of the lack of quantitative data about toxic PAs between different Senecio species. In the present study, adonifoline, senkirkine, and another PA presumed as emiline have been identified in QT; however, there was no senecionine detected in all tablets. PA contents in QTs varied in different companies and different batches. Adonifoline existed only in Senecio scandens, and senecionine was detected in all eight Senecio plants investigated in the present study. Data showed that replaced use of Senecio scandens with a low level of senecionine by other Senecio plants such as Senecio vulgaris containing a high level of senecionine is advertised to be forbidden. Data of the present study may be used as a reference to make new drug quality regularity and recommendation guideline for the safety of QT.


High Sensitivity Monitoring of VOCs in Air through FTIR Spectroscopy Using a Multipass Gas Cell Setup.
Human exposure to Volatile Organic Compounds (VOCs) and their presence in indoor and working environments is recognized as a serious health risk, causing impairments of varying severities. Different detecting systems able to monitor VOCs are available in the market; however, they have significant limitations for both sensitivity and chemical discrimination capability. During the last years we studied systematically the use of Fourier Transform Infrared (FTIR) spectroscopy as an alternative, powerful tool for quantifying VOCs in air. We calibrated the method for a set of compounds (styrene, acetone, ethanol and isopropanol) by using both laboratory and portable infrared spectrometers. The aim was to develop a new, and highly sensitive sensor system for VOCs monitoring. In this paper, we improved the setup performance, testing the feasibility of using a multipass cell with the aim of extending the sensitivity of our system down to the part per million (ppm) level. Considering that multipass cells are now also available for portable instruments, this study opens the road for the design of new high-resolution devices for environmental monitoring.


15-LOX-1 has diverse roles in the resensitization of resistant cancer cell lines to doxorubicin.
Lipoxygenases (LOXs) are a family of enzymes that can oxygenate polyunsaturated fatty acids. As a member of the family, 15-lipoxygenase-1 (15-LOX-1) specifically metabolizes arachidonic acid and linoleic acid. 15-LOX-1 can affect physiological and pathophysiological events via regulation of the protein-lipid interactome, alterations in intracellular redox state and production of lipid metabolites that are involved in the induction and resolution of inflammation. Although several studies have shown that 15-LOX-1 has an antitumorigenic role in many different cancer models, including breast cancer, the role of the protein in cancer drug resistance has not been established yet. In this study, we, for the first time, aimed to show the potential role of 15-LOX-1 in acquired doxorubicin (DOX) resistance in MCF7 and HeLa cancer cell lines. Our results show that ALOX15 was transcriptionally downregulated in DOX-resistant cells compared with their drug-sensitive counterparts. Moreover, overexpression of ALOX15 in the drug-resistant cells resulted in resensitization of those cells to DOX in a cell-dependent manner. 15-LOX-1 expression could induce apoptosis by activating PPARγ and enhance the accumulation of DOX in drug-resistant MCF7 cells by altering cellular motility properties, and membrane dynamics. However, HeLa DOX cells did not show any of these effects but were susceptible to cell death when treated with 13(S)-HODE. These results underline the role and importance of 15-LOX-1 in cancer drug resistance, and points to novel mechanisms as a therapeutic approach to overcome cancer drug resistance.


Association Between Daily Worry, Pathological Worry, and Fear of Progression in Patients With Cancer.
Background: Fear of progression (FoP), or fear of cancer recurrence (FCR), is characterized by worries or concerns about negative illness-related future events. Actually, to worry is a common cognitive process that, in its non-pathological form, belongs to daily life. However, worry can also become pathological appearing as a symptom of mental disorders. This study aimed at investigating the associations among daily worry, pathological worry, and FoP in patients with cancer. Methods: This is a cross-sectional study that includes 328 hospitalized patients with cancer. Patients filled out the FoP Questionnaire (FoP-Q), the Worry Domains Questionnaire (WDQ) for the assessment of daily worry, and the Penn State Worry Questionnaire (PSWQ) for the assessment of pathological worry. Depressive, anxiety, and somatic symptoms were measured with modules of the Patient Health Questionnaire [Patient Health Questionnaire-Depressive Symptoms (PHQ-2), Generalized Anxiety Disorder-2 (GAD-2), and Patient Health Questionnaire-Somatic Symptoms (PHQ-15)]. Furthermore, a structured clinical interview was conducted for the assessment of anxiety disorders. The hierarchical multiple linear regression analysis was used to identify factors independently associated with FoP. Results: Mean age of the participants was M = 58.5 years (SD = 12.8), and 64.6% were men. FoP and worry were significantly intercorrelated (r = 0.58-0.78). The level of FoP was most strongly associated with daily worry (β = 0.514, p < 0.001), followed by pathological worry (β = 0.221, p < 0.001). Further significant determinants were younger age and depressive and anxiety symptoms. Clinical variables were not independently associated with FoP. The final model explained 74% of the variance. Discussion: Fear of progression is strongly associated with daily worry and pathological worry. These results bring up the question of whether FoP is an expression of a general tendency to worry. Whether a general tendency to worry, in fact, represents an independent vulnerability factor for experiencing FCR/FoP needs to be investigated in a longitudinal research design.


Radius margin bounds for support vector machines with the RBF kernel.
An important approach for efficient support vector machine (SVM) model selection is to use differentiable bounds of the leave-one-out (loo) error. Past efforts focused on finding tight bounds of loo (e.g., radius margin bounds, span bounds). However, their practical viability is still not very satisfactory. Duan, Keerthi, and Poo (2003) showed that radius margin bound gives good prediction for L2-SVM, one of the cases we look at. In this letter, through analyses about why this bound performs well for L2-SVM, we show that finding a bound whose minima are in a region with small loo values may be more important than its tightness. Based on this principle, we propose modified radius margin bounds for L1-SVM (the other case) where the original bound is applicable only to the hard-margin case. Our modification for L1-SVM achieves comparable performance to L2-SVM. To study whether L1- or L2-SVM should be used, we analyze other properties, such as their differentiability, number of support vectors, and number of free support vectors. In this aspect, L1-SVM possesses the advantage of having fewer support vectors. Their implementations are also different, so we discuss related issues in detail.


The Wistar-Kyoto rat model of endogenous depression: A tool for exploring treatment resistance with an urgent need to focus on sex differences.
Major depressive disorder (MDD) is one of the leading causes of years lived with disability and contributor to the burden of disease worldwide. The incidence of MDD has increased by ~20% in the last decade. Currently antidepressant drugs such as the popular selective serotonin reuptake inhibitors (SSRIs) are the leading form of pharmaceutical intervention for the treatment of MDD. SSRIs however, are inefficient in ameliorating depressive symptoms in ~50% of patients and exhibit a prolonged latency of efficacy. Due to the burden of disease, there is an increasing need to understand the neurobiology underpinning MDD and to discover effective treatment strategies. Endogenous models of MDD, such as the Wistar-Kyoto (WKY) rat provide a valuable tool for investigating the pathophysiology of MDD. The WKY rat displays behavioural and neurobiological phenotypes similar to that observed in clinical cases of MDD, as well as resistance to common antidepressants. Specifically, the WKY strain exhibits increased anxiety- and depressive-like behaviours, as well as alterations in Hypothalamic Pituitary Adrenal (HPA) axis, serotonergic, dopaminergic and neurotrophic systems with emerging studies suggesting an involvement of neuroinflammation. More recent investigations have shown evidence for reduced cortical and hippocampal volumes and altered glutamatergic signalling in the WKY strain. Given the growing interest in therapeutics targeting the glutamatergic system, the WKY strain presents itself as a potentially useful tool for screening novel antidepressant drugs and their efficacy against treatment resistant depression. However, despite the sexual dimorphism present in the pathophysiology and aetiology of MDD, sex differences in the WKY model are rarely investigated, with most studies focusing on males. Accordingly, this review highlights what is known regarding sex differences and where further research is needed. Whilst acknowledging that investigation into a range of depression models is required to fully elucidate the underlying mechanisms of MDD, here we review the WKY strain, and its relevance to the clinic.


What role for genetics in the prediction of multiple sclerosis?
For most of us, the foundations of our understanding of genetics were laid by considering Mendelian diseases in which familial recurrence risks are high, and mutant alleles are both necessary and sufficient. One consequence of this deterministic teaching is that our conceptualization of genetics tends to be dominated by the notion that the genetic aspects of disease are caused by rare alleles exerting large effects. Unfortunately, the preconceptions that flow from this training are frequently erroneous and misleading in the context of common traits, where familial recurrence risks are modest, and for the most part the relevant alleles are neither rare, necessary, nor sufficient. For these common traits, the genetic architecture is far more complex, with susceptibility rather than causality resulting from the combined effects of many alleles, each exerting only a modest effect on risk. None of these alleles is sufficient to cause disease on its own, and none is essential for the development of disease. Furthermore, most are carried by large sections of the population, the vast majority of which does not develop the disease. One consequence of our innate belief in the Mendelian paradigm is that we have an inherent expectation that knowledge about the genetic basis for a disease should allow genetic testing and thereby accurate risk prediction. There is an inevitable feeling that the same should be true in complex disease, but is it?


Neuroticism Delays Detection of Facial Expressions.
The rapid detection of emotional signals from facial expressions is fundamental for human social interaction. The personality factor of neuroticism modulates the processing of various types of emotional facial expressions; however, its effect on the detection of emotional facial expressions remains unclear. In this study, participants with high- and low-neuroticism scores performed a visual search task to detect normal expressions of anger and happiness, and their anti-expressions within a crowd of neutral expressions. Anti-expressions contained an amount of visual changes equivalent to those found in normal expressions compared to neutral expressions, but they were usually recognized as neutral expressions. Subjective emotional ratings in response to each facial expression stimulus were also obtained. Participants with high-neuroticism showed an overall delay in the detection of target facial expressions compared to participants with low-neuroticism. Additionally, the high-neuroticism group showed higher levels of arousal to facial expressions compared to the low-neuroticism group. These data suggest that neuroticism modulates the detection of emotional facial expressions in healthy participants; high levels of neuroticism delay overall detection of facial expressions and enhance emotional arousal in response to facial expressions.


Neuronal Nogo-A upregulation does not contribute to ER stress-associated apoptosis but participates in the regenerative response in the axotomized adult retina.
Nogo-A, an axonal growth inhibitory protein known to be mostly present in CNS myelin, was upregulated in retinal ganglion cells (RGCs) after optic nerve injury in adult mice. Nogo-A increased concomitantly with the endoplasmic reticulum stress (ER stress) marker C/EBP homologous protein (CHOP), but CHOP immunostaining and the apoptosis marker annexin V did not co-localize with Nogo-A in individual RGC cell bodies, suggesting that injury-induced Nogo-A upregulation is not involved in axotomy-induced cell death. Silencing Nogo-A with an adeno-associated virus serotype 2 containing a short hairpin RNA (AAV2.shRNA-Nogo-A) or Nogo-A gene ablation in knock-out (KO) animals had little effect on the lesion-induced cell stress or death. On the other hand, Nogo-A overexpression mediated by AAV2.Nogo-A exacerbated RGC cell death after injury. Strikingly, however, injury-induced sprouting of the cut axons and the expression of growth-associated molecules were markedly reduced by AAV2.shRNA-Nogo-A. The axonal growth in the optic nerve activated by the intraocular injection of the inflammatory molecule Pam3Cys tended to be lower in Nogo-A KO mice than in WT mice. Nogo-A overexpression in RGCs in vivo or in the neuronal cell line F11 in vitro promoted regeneration, demonstrating a positive, cell-autonomous role for neuronal Nogo-A in the modulation of axonal regeneration.


Electrospun polyvinyl alcohol membranes incorporated with green synthesized silver nanoparticles for wound dressing applications.
Electrospun membranes have the potential to act as an effective barrier for wounds from the external environment to prevent pathogens. In addition, materials with good antibacterial properties can effectively fight off the invading pathogens. In this paper, we report the development of a novel electrospun polyvinyl alcohol (PVA) membrane containing biosynthesized silver nanoparticle (bAg) for wound dressing applications. Plant extract from a medicinal plant Mimosa pudica was utilized for the synthesis of bAg. Synthesized bAg were characterized by Ultraviolet-Visible (UV) Spectroscopy and Fourier Transform Infrared Spectroscopy (FTIR). The morphology of bAg was obtained from Transmission Electron Microscopy (TEM) and found that they were spherical in morphology with average particle size 7.63 ± 1.2 nm. bAg nanoparticles incorporated PVA membranes were characterized using several physicochemical techniques such as Scanning Electron Microscopy (SEM), Energy Dispersive X-Ray Spectroscopy (EDS) and X-Ray Diffraction (XRD) analysis. Experimental results confirmed the successful incorporation of bAg in PVA fibers. PVA nanofiber membranes incorporated with bAg showed good mechanical strength, excellent exudate uptake capacity, antibacterial activity, blood compatibility and cytocompatibility.


Click chemistry at the microscale.
Click chemistry has attracted tremendous attention for the fabrication of novel microscale systems based on its high reaction efficiency, satisfactory versatility and simple processing. Meanwhile, microscale systems also provide desirable analytical platforms for click reaction study. Herein, we review the employment of click reactions for developing state-of-the-art microchip-based and capillary-based systems. The advantages of innovative off-stoichiometry thiol-ene (OSTE)-microchips, bio-functionalized microchips and monolithic microsystems for chemical and biological assays are highlighted. Moreover, the potential of microscale systems applied for click reaction investigation is indicated as well. This article presents an overview of the recent developments in the combination of microscale systems and click chemistry.


Genes required for mycobacterial growth defined by high density mutagenesis.
Despite over a century of research, tuberculosis remains a leading cause of infectious death worldwide. Faced with increasing rates of drug resistance, the identification of genes that are required for the growth of this organism should provide new targets for the design of antimycobacterial agents. Here, we describe the use of transposon site hybridization (TraSH) to comprehensively identify the genes required by the causative agent, Mycobacterium tuberculosis, for optimal growth. These genes include those that can be assigned to essential pathways as well as many of unknown function. The genes important for the growth of M. tuberculosis are largely conserved in the degenerate genome of the leprosy bacillus, Mycobacterium leprae, indicating that non-essential functions have been selectively lost since this bacterium diverged from other mycobacteria. In contrast, a surprisingly high proportion of these genes lack identifiable orthologues in other bacteria, suggesting that the minimal gene set required for survival varies greatly between organisms with different evolutionary histories.