Neural correlates of preparatory and regulatory control over positive and negative emotion.
This study used functional magnetic resonance imaging to investigate brain activation during preparatory and regulatory control while participants (N = 24) were instructed either to simply view or decrease their emotional response to, pleasant, neutral or unpleasant pictures. A main effect of emotional valence on brain activity was found in the right precentral gyrus, with greater activation during positive than negative emotion regulation. A main effect of regulation phase was evident in the bilateral anterior prefrontal cortex (PFC), precuneus, posterior cingulate cortex, right putamen and temporal and occipital lobes, with greater activity in these regions during preparatory than regulatory control. A valence X regulation interaction was evident in regions of ventromedial PFC and anterior cingulate cortex, reflecting greater activation while regulating negative than positive emotion, but only during active emotion regulation (not preparation). Conjunction analyses revealed common brain regions involved in differing types of emotion regulation including selected areas of left lateral PFC, inferior parietal lobe, temporal lobe, right cerebellum and bilateral dorsomedial PFC. The right lateral PFC was additionally activated during the modulation of both positive and negative valence. Findings demonstrate significant modulation of brain activity during both preparation for, and active regulation of positive and negative emotional states.


Anti-tumoral effect of the non-nucleoside DNMT inhibitor RG108 in human prostate cancer cells.
Current therapeutic strategies for advanced prostate cancer (PCa) are largely ineffective. Because aberrant DNA methylation associated with inappropriate gene-silencing is a common feature of PCa, DNA methylation inhibitors might constitute an alternative therapy. In this study we aimed to evaluate the anti-cancer properties of RG108, a novel non-nucleoside inhibitor of DNA methyltransferases (DNMT), in PCa cell lines. The anti-tumoral impact of RG108 in LNCaP, 22Rv1, DU145 and PC-3 cell lines was assessed through standard cell viability, apoptosis and cell cycle assays. Likewise, DNMT activity, DNMT1 expression and global levels of DNA methylation were evaluated in the same cell lines. The effectiveness of DNA demethylation was further assessed through the determination of promoter methylation and transcript levels of GSTP1, APC and RAR-β2, by quantitative methylation-specific PCR and RT-PCR, respectively. RG108 led to a significant dose and time dependent growth inhibition and apoptosis induction in LNCaP, 22Rv1 and DU145. LNCaP and 22Rv1 also displayed decreased DNMT activity, DNMT1 expression and global DNA methylation. Interestingly, chronic treatment with RG108 significantly decreased GSTP1, APC and RAR-β2 promoter hypermethylation levels, although mRNA reexpression was only attained for GSTP1 and APC. RG108 is an effective tumor growth suppressor in most PCa cell lines tested. This effect is likely mediated by reversion of aberrant DNA methylation affecting cancer related-genes epigenetically silenced in PCa. However, additional mechanism might underlie the anti-tumor effects of RG108. In vivo studies are now mandatory to confirm these promising results and evaluate the potential of this compound for PCa therapy.


Sleeping difficulty, disease and mortality in older women: a latent class analysis and distal survival analysis.
The aim of this study is to identify patterns of sleep difficulty in older women, to investigate whether sleep difficulty is an indicator for poorer survival, and to determine whether sleep difficulty modifies the association between disease and death. Data were from the Australian Longitudinal Study on Women's Health, a 15-year longitudinal cohort study, with 10 721 women aged 70-75 years at baseline. Repeated-measures latent class analysis identified four classes of persistent sleep difficulty: troubled sleepers (N = 2429, 22.7%); early wakers (N = 3083, 28.8%); trouble falling asleep (N = 1767, 16.5%); and untroubled sleepers (N = 3442, 32.1%). Sleep difficulty was an indicator for mortality. Compared with untroubled sleepers, hazard ratios and 95% confidence intervals for troubled sleepers, early wakers, and troubled falling asleep were 1.12 (1.03, 1.23), 0.81 (0.75, 0.91) and 0.89 (0.79, 1.00), respectively. Sleep difficulty may modify the prognosis of women with chronic diseases. Hazard ratios (and 95% confidence intervals) for having three or more diseases (compared with 0 diseases) were enhanced for untroubled sleepers, early wakers and trouble falling asleep [hazard ratio = 1.86 (1.55, 2.22), 1.91 (1.56, 2.35) and 1.98 (1.47, 2.66), respectively], and reduced for troubled sleepers [hazard ratio = 1.57 (1.24, 1.98)]. Sleep difficulty in older women is more complex than the presence or absence of sleep difficulty, and should be considered when assessing the risk of death associated with disease.


Relation of MRI-Detected Features of Patellofemoral Osteoarthritis to Pain, Performance-Based Function, and Daily Walking: The Multicenter Osteoarthritis Study.
The study objective was to determine the relationship of magnetic resonance imaging (MRI)-detected features of patellofemoral joint osteoarthritis to pain and functional outcomes. We sampled 1,099 participants from the 60-month visit of the Multicenter Osteoarthritis Study (mean ± SD age: 66.8 ± 7.5 years; body mass index: 29.6 ± 4.8; 65% female). We determined the prevalence of MRI-detected features of patellofemoral joint osteoarthritis (eg, cartilage damage, bone marrow lesions, and osteophytes) and assessed the relationship between these features and knee pain severity, knee pain on stairs, chair stand time, and walking less than 6,000 steps per day. We evaluated the relationship of MRI features to each outcome using logistic and linear regression, adjusting for potential covariates. Participants with cartilage damage in 3-4 subregions had the highest mean pain severity (22.0/100; 95% confidence interval [CI]: 17.6-26.4 mm). They also showed higher odds of having at least mild pain on stairs (odds ratio [OR]: 3.3; 95% CI: 1.7-6.5) and of walking less than 6,000 steps per day (OR: 2.3; 95% CI: 1.1-4.4) compared with those without cartilage damage. Participants with bone marrow lesions in 3-4 subregions had higher odds of at least mild pain on stairs than those without (OR: 3.3; 95% CI: 2.2-5.2). Participants with osteophytes in 3-4 subregions also had higher odds of walking less than 6,000 steps/day (OR 2.1, 95% CI: 1.3-3.5, respectively). MRI-detected features of osteoarthritis of the patellofemoral joint are related to pain and functional performance. This knowledge highlights the need to develop treatments for those with patellofemoral joint osteoarthritis to improve pain and maximize function.


Quantitative study of [(pF)Phe4,Arg14,Lys15]nociceptin/orphanin FQ-NH2 (UFP-102) at NOP receptors in rat periaqueductal gray slices.
The nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor is a novel member of the opioid receptor family with little affinity for traditional opioids. This receptor and its endogenous ligand, N/OFQ, are widely distributed in the brain and are implicated in many physiological functions including pain regulation. [(pF)Phe(4),Arg(14),Lys(15)]N/OFQ-NH(2) (UFP-102) is a newly developed peptide agonist of NOP receptors. In this study, we quantitatively investigated the effect of UFP-102 at native NOP receptors of the ventrolateral periaqueductal gray (PAG), a crucial midbrain area involved in pain regulation and enriched with NOP receptors, using blind patch-clamp whole-cell recording technique in rat brain slices. UFP-102, like N/OFQ, induced an outward current in ventrolateral PAG neurons and increased the membrane current elicited by a hyperpolarization ramp from -60 to -140 mV. The current induced by UFP-102 was characterized with inward rectification and had a reversal potential near the equilibrium potential of K(+) ions, indicating that UFP-102 activates G-protein coupled inwardly rectifying K(+) channels. The effect of UFP-102 was concentration-dependent with the maximal effect similar to that of N/OFQ. The EC(50) value was 11+/-2 nM, which is 5 fold lower than that of N/OFQ. The effect of UFP-102 was not affected by naloxone while competitively antagonized by UFP-101 ([Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2)), a potent NOP receptor antagonist, with a pA(2) value of 6.7. These results suggest that UFP-102 is a full agonist at the postsynaptic NOP receptors of the midbrain of rats and is 5 fold more potent than N/OFQ.


Designing copper(II) ternary complexes to generate radical cations of peptides in the gas phase: role of the auxiliary ligand.
A series of ternary copper(II) complexes of the type [Cu(II)(L)(M)](2+), where M represents the hexapeptides GGGFLR, YGGFLR and WGGFLR and L a set of 12 nitrogen donor ligands have been evaluated for their ability to form cationic peptide radicals, M(+)*, in the gas phase. Although the fragmentation chemistry of these ions is complex, two main conclusions emerge: (i) Complexes containing a tri- or tetra-dentate ligand were found to be more effective at producing the peptide radical because in these instances competitive loss of the ligand from the complex is inhibited; (ii) The ligands ought not possess any acidic protons in order to prevent competitive loss of the protonated peptide, [M + H](+). There is significant interaction of the N-terminal aromatic residues in YGGFLR and WGGLFR with the copper(ii) ion in several of the complexes as revealed by the formation of [Cu(I)(L)(p-quinomethide)](+) and [Cu(I)(L)(3-methyleneindoline)](+) fragment ions. Following its dissociation from the ternary complex, CID of the YGGFLR(+)* radical cation shows a dependence on the ligand in the complex from which it was formed. This 'memory effect' most likely reflects differences in the coordinated peptide structure induced by the ligand in the precursor complex which are maintained following dissociation.


BRAF mutation testing algorithm for vemurafenib treatment in melanoma: recommendations from an expert panel.
The incidence of melanoma has increased rapidly over the past 30 years, and the disease is now the sixth most common cancer among men and women in the U.K. Many patients are diagnosed with or develop metastatic disease, and survival is substantially reduced in these patients. Mutations in the BRAF gene have been identified as key drivers of melanoma cells and are found in around 50% of cutaneous melanomas. Vemurafenib (Zelboraf(®) ; Roche Molecular Systems Inc., Pleasanton, CA, U.S.A.) is the first licensed inhibitor of mutated BRAF, and offers a new first-line option for patients with unresectable or metastatic melanoma who harbour BRAF mutations. Vemurafenib was developed in conjunction with a companion diagnostic, the cobas(®) 4800 BRAF V600 Mutation Test. The purpose of this paper is to make evidence-based recommendations to facilitate the implementation of BRAF mutation testing and targeted therapy in patients with metastatic melanoma in the U.K. The recommendations are the result of a meeting of an expert panel and have been reviewed by melanoma specialists and representatives of the National Cancer Research Network Clinical Study Group on behalf of the wider melanoma community. This article is intended to be a starting point for practical advice and recommendations, which will no doubt be updated as we gain further experience in personalizing therapy for patients with melanoma.


Dietary sugars, not lipids, drive hypothalamic inflammation.
The hypothalamus of hypercaloric diet-induced obese animals is featured by a significant increase of microglial reactivity and its associated cytokine production. However, the role of dietary components, in particular fat and carbohydrate, with respect to the hypothalamic inflammatory response and the consequent impact on hypothalamic control of energy homeostasis is yet not clear. We dissected the different effects of high-carbohydrate high-fat (HCHF) diets and low-carbohydrate high-fat (LCHF) diets on hypothalamic inflammatory responses in neurons and non-neuronal cells and tested the hypothesis that HCHF diets induce hypothalamic inflammation via advanced glycation end-products (AGEs) using mice lacking advanced glycation end-products (AGEs) receptor (RAGE) and/or the activated leukocyte cell-adhesion molecule (ALCAM). We found that consumption of HCHF diets, but not of LCHF diets, increases microgliosis as well as the presence of N(ε)-(Carboxymethyl)-Lysine (CML), a major AGE, in POMC and NPY neurons of the arcuate nucleus. Neuron-secreted CML binds to both RAGE and ALCAM, which are expressed on endothelial cells, microglia, and pericytes. On a HCHF diet, mice lacking the RAGE and ALCAM genes displayed less microglial reactivity and less neovasculature formation in the hypothalamic ARC, and this was associated with significant improvements of metabolic disorders induced by the HCHF diet. Combined overconsumption of fat and sugar, but not the overconsumption of fat per se, leads to excessive CML production in hypothalamic neurons, which, in turn, stimulates hypothalamic inflammatory responses such as microgliosis and eventually leads to neuronal dysfunction in the control of energy metabolism.


Ntau-methylhistidine (3-methylhistidine) and muscle protein turnover: an overview.
Actin and myosin, the contractile proteins of skeletal muscle, are methylated following peptide bond synthesis, with production of Ntau-methylhistidine (3-methylhistidine, 3-MeHis). During intracellular breakdown of these proteins, the 3-MeHis is released and excreted in the urine. Studies on tissue distribution of 3-MeHis and on its qunatitative excretion following administration to rats and to man show that urinary output of this amino acid provides a reliable index of the rate of myofibrillar protein breakdown in the musculature of intact rats and human subjects. Estimates of the fractional rate of muscle protein breakdown based on 3-MeHis data are consistent with rates computed by other techniques. By this technique, it has been shown that the fractional rate of muscle protein breakdown is not significantly different in the elderly as compared with young adults. However, since muscle mass is less in the elderly, it makes a smaller contribution to whole body protein breakdown with aging in humans. Output of 3-MeHis diminishes in growing rats and obese human subjects with protein or energy restriction, though the initial response of myofibrillar protein breakdown in growing rats to protein and protein-energy restriction differs. Measurement of 3-MeHis excretion has also proved useful in exploring the effects of physical and thermal trauma on the rate of muscle useful in exploring the effects of physical and thermal trauma on the rate of muscle protein breakdown.


Production and turnover of ectomycorrhizal extramatrical mycelial biomass and necromass under elevated CO2 and nitrogen fertilization.
Extramatrical mycelia (EMM) of ectomycorrhizal fungi are important in carbon (C) and nitrogen (N) cycling in forests, but poor knowledge about EMM biomass and necromass turnovers makes the quantification of their role problematic. We studied the impacts of elevated CO2 and N fertilization on EMM production and turnover in a Pinus taeda forest. EMM C was determined by the analysis of ergosterol (biomass), chitin (total bio- and necromass) and total organic C (TOC) of sand-filled mycelium in-growth bags. The production and turnover of EMM bio- and necromass and total C were estimated by modelling. N fertilization reduced the standing EMM biomass C to 57% and its production to 51% of the control (from 238 to 122 kg C ha(-1) yr(-1) ), whereas elevated CO2 had no detectable effects. Biomass turnover was high (˜13 yr(-1) ) and unchanged by the treatments. Necromass turnover was slow and was reduced from 1.5 yr(-1) in the control to 0.65 yr(-1) in the N-fertilized treatment. However, TOC data did not support an N effect on necromass turnover. An estimated EMM production ranging from 2.5 to 6% of net primary production stresses the importance of its inclusion in C models. A slow EMM necromass turnover indicates an importance in building up forest humus.


SpikeNET: an event-driven simulation package for modelling large networks of spiking neurons.
Many biological neural network models face the problem of scalability because of the limited computational power of today's computers. Thus, it is difficult to assess the efficiency of these models to solve complex problems such as image processing. Here, we describe how this problem can be tackled using event-driven computation. Only the neurons that emit a discharge are processed and, as long as the average spike discharge rate is low, millions of neurons and billions of connections can be modelled. We describe the underlying computation and implementation of such a mechanism in SpikeNET, our neural network simulation package. The type of model one can build is not only biologically compliant, it is also computationally efficient as 400 000 synaptic weights can be propagated per second on a standard desktop computer. In addition, for large networks, we can set very small time steps (< 0.01 ms) without significantly increasing the computation time. As an example, this method is applied to solve complex cognitive tasks such as face recognition in natural images.


MR imaging in Fahr disease.
The calcifications of Fahr disease that are detected by CT in the dentate nuclei of the cerebellum, basal ganglia, and white matter of the cerebral hemispheres displayed three patterns with magnetic resonance imaging using the multiple echo technique: (a) cerebellar calcifications were undetected; (b) basal ganglia calcifications displayed low or no signal and appeared as "black" areas in four echoes; and (c) white matter calcifications displayed a high signal in the four echoes and appeared intensely white. The different behavior of the three calcified sites probably reflects different stages of the disease or different metabolic states with predominance of inert calcium deposits in the basal ganglia. In the white matter there is probably a higher concentration of binding proteins and mucopolysaccharides.


Regulation of neurite outgrowth from differentiated human neuroepithelial cells: a comparison of the activities of prothrombin and thrombin.
The mechanism by which thrombin and prothrombin control neurite retraction was studied in Ad12E1HER10 human neuroepithelial cells. Morphological changes in differentiated cells were apparent within minutes of the addition of very low concentrations of thrombin (3 pM). Higher concentrations (2 nM) of prothrombin were required to elicit a similar response. Doses of thrombin and prothrombin sufficient to cause neurite retraction stimulated protein tyrosine kinase activity. Protein tyrosine kinase activation also correlated positively with thrombin- and prothrombin-induced phosphoinositide 3-kinase activation and InsP6 dephosphorylation. However, thrombin-stimulated Ins(1,4,5)P3 generation and intracellular Ca2+ mobilization only occurred at concentrations in excess of those needed to induce retraction. No fluctuations in Ins(1,4,5)P3 were detected after stimulation with prothrombin, and no rapid synchronized release of Ca2+ was observed, even at very high concentrations. Prothrombin did, however, cause small oscillations in the intracellular Ca2+ concentration, similar to those produced by low concentrations of thrombin, after approximately 30 min. We conclude that prothrombin- and thrombin-induced neurite retractions are not dependent on PtdIns(4,5)P2 and Ca2+ mobilization, but are more probably mediated through an effector mechanism involving protein tyrosine kinase activation. No intracellular Ca2+ mobilization, protein tyrosine kinase activity or neurite retraction was observed after treatment of cells with proteolytically inactive mutant thrombin (S205-->A). Prothrombin-mediated intracellular Ca2+ mobilization and neurite retraction were inhibited by hirudin, which was shown to interact with thrombin but not prothrombin. It is concluded that cleavage of prothrombin to thrombin is a necessary prerequisite for biological activity on differentiated Ad12E1HER10 cells and that differences in agonist concentration are capable of coupling the thrombin receptor to different pathways within the cell.


Stationary intraoral digital tomosynthesis using a carbon nanotube X-ray source array.
Intraoral dental tomosynthesis and closely related tuned-aperture CT (TACT) are low-dose three-dimensional (3D) imaging modalities that have shown improved detection of multiple dental diseases. Clinical interest in implementing these technologies waned owing to their time-consuming nature. Recently developed carbon nanotube (CNT) X-ray sources allow rapid multi-image acquisition without mechanical motion, making tomosynthesis a clinically viable technique. The objective of this investigation was to evaluate the feasibility of and produce high-quality images from a digital tomosynthesis system employing CNT X-ray technology. A test-bed stationary intraoral tomosynthesis unit was constructed using a CNT X-ray source array and a digital intraoral sensor. The source-to-image distance was modified to make the system comparable in image resolution to current two-dimensional intraoral radiography imaging systems. Anthropomorphic phantoms containing teeth with simulated and real caries lesions were imaged using a dose comparable to D-speed film dose with a rectangular collimation. Images were reconstructed and analysed. Tomosynthesis images of the phantom and teeth specimen demonstrated perceived image quality equivalent or superior to standard digital images with the added benefit of 3D information. The ability to "scroll" through slices in a buccal-lingual direction significantly improved visualization of anatomical details. In addition, the subjective visibility of dental caries was increased. Feasibility of the stationary intraoral tomosynthesis is demonstrated. The results show clinical promise and suitability for more robust observer and clinical studies.


Neuromyelitis optica spectrum disorder mimicking stroke: A case report and literature review.
Hemiparesis is a frequently observed manifestation of stroke but exceptionally rare in the context of neuromyelitis optica spectrum disorder (NMOSD). In this case, a 68-year-old woman initially presented with acute right-sided weakness, leading to suspicion of ischemic stroke. However, her symptoms worsened despite treatment with aspirin and statins. Subsequent spinal MRI and aquaporin 4 antibody testing confirmed the diagnosis of NMOSD. The administration of methylprednisolone and immunoglobulin resulted in improved clinical outcomes. This case serves as an illustrative example of the diverse manifestations encountered in NMOSD and underscores the significance of considering this potential etiology in elderly patients to facilitate prompt diagnosis and therapeutic intervention.


Purification and structural characterization of insulin and glucagon from the bichir Polypterus senegalis (Actinopterygii: Polypteriformes).
The Polypteriformes (bichirs and reedfish) are a family of ray-finned fishes of ancient lineage. Insulin has been isolated from an extract of the pancreas and upper gastrointestinal tract of the bichir Polypterus senegalis and its primary structure established as A-chain: Gly-Ile-Val-Glu-Gln-Cys-Cys-Asp-Thr-Pro10-Cys-Ser- Leu-Tyr-Asp-Leu-Glu-Asn-Tyr-Cys20-Asn: B-chain: Ala-Ala-Asn-Arg-His-Leu-Cys-Gly-Ser-His10-Leu-Val- Glu-Ala-Leu-Tyr-Leu-Val-Cys-Gly20-Asn-Arg-Gly-Phe- Phe-Tyr-Ile-Pro-Ser-Lys30-Met. Despite the fact that Polypterus insulin contains several unusual structural features that are not found in insulins from other jawed fish (Asp at A-8, Thr at A-9, Arg at B-4, Asn at B-21, Ile at B-27, Met at B-31), all the residues in human insulin that are involved in receptor binding, dimerization, and hexamerization have been conserved. A comparison of the structures of insulins from a range of species indicates that Polypterus insulin most closely resembles paddlefish insulin II (seven amino acid substitutions). In contrast, Polypterus glucagon (His-Ser- Gln-Gly-Thr-Phe-Thr-Asn-Asp-Tyr10-Thr-Lys-Tyr- Gln-Asp-Ser-Arg-Arg-Ala-Gln20-Asp-Phe-Val-Gln- Trp-Leu-Met-Ser-Asn) most closely resembles the glucagons from the gar Lepisosteus spatula and the bowfin Amia calva (four amino acid substitutions). The data are consistent with the conclusion based on comparison of morphological characteristics that the Polypterids are the most basal living group of the Actinopterygians with evolutionary connections to both the Acipenserids and the Neopterygians.


[Interhemispheric relationships of electrical activity in the blinking dominant in rabbits].
The study of intercentral and interhemispheric relations of the electrical activity of the cerebral cortex during formation and functioning of winking dominant, by the method of spectral-correlation analysis, has shown that the dominant focus is characterized by an increase of spectrum power in the range of delta-frequencies and a raise of coherence level of potentials in the same range that leads to the appearance of interhemispheric asymmetry according to these parameters. Appearance of the dominant state in the opposite hemisphere is accompanied by a reconstruction of the electrical activity characteristic of dominant focus.


An Experimental Test of How Selfies Change Social Judgments on Facebook.
Selfies are everywhere on social media. Research has focused only on who is posting selfies and has not addressed the audience members viewing selfies. This study aims to fill this gap by analyzing the judgments people make of selfies posted on Facebook. Using an online experiment, we test how including a selfie on a Facebook status update changes people's appraisals of narcissism, message appropriateness, and social attraction. We also consider how the valence and intimacy of the status update text interplay with the selfie to change social judgments. Participants rated posts with selfies as more narcissistic and inappropriate, and less socially attractive. Selfie evaluations also depended upon the valence and intimacy of the status update text. Gender of the selfie poster did not influence evaluation of posts. One implication from these results is that posting selfies on social media may lead to negative judgments about the poster.


Formative dialogues in teaching nonthreatening peer coaching.
Teaching universities, while claiming to value good teaching, do little to help individual faculty members improve learning in their classrooms. One effective way to help teachers reflect on their teaching and improve their teaching skills is to have a colleague observe and discuss the teaching episode, yet these dialogues seem to be rare. Visits to the classroom, if they occur at all, are usually summative, with little or no discussion, and typically used for the purposes of evaluation. The formative dialogues program, however, provides opportunities for faculty members to request a collegial, nonthreatening observation and discussion of a teaching session. The program is easy to administer and promises to provide opportunities to enhance the learning environment of the health professional classroom.


Improving antiepileptic drug tolerability among patients living with epilepsy: the impact of pharmaceutical care services.
Therapeutic management of epilepsy is usually long term; thus, patient tolerability of prescribed antiepileptic drugs should be a major consideration as it affects compliance to therapy. The aim of this study was to determine the impact of pharmaceutical care services on antiepileptic drug tolerability among patients living with epilepsy. This study was an open, randomized, controlled, longitudinal and two-arm parallel prospective study with a 6-month patient follow-up period. Patients were recruited from the neurology and medical out-patient clinics of two selected epilepsy referral centres. Recruited patients were randomized into one of the two study groups: pharmaceutical care (PC) or usual care (UC) groups. Patients in the UC group received the usual care provided in the hospitals, while patients in the PC group received PC services in addition to the usual care provided in the hospitals. The impact of PC on patient tolerability of antiepileptic drugs was evaluated using a patient judged antiepileptic drug tolerabiltity scale. The evaluation was done at baseline (pre-intervention), 3 months and 6 months post-intervention. Patients in the PC group had a significantly lower antiepileptic drug tolerability score than those of the UC group at 3 months and 6 months - (Pre-intervention: 0.97 versus 1.13; t = -1.081; p = 0.281), (3 months: 1.13 versus 0.71; t = 3.084; p = 0.001), (6 months: 1.00 versus 0.60; t = 3.083; p = 0.001), indicating a significant improvement in the tolerability of antiepileptic drugs among those in the PC group over time. Pharmaceutical care interventions that included education and counseling services significantly improved tolerability of antiepileptic drugs among patients living with epilepsy.


Evaluation of National Anaesthetics Teaching in Undergraduate Medicine (ENATUM).
During a global pandemic where anaesthetists play a pertinent role in treating coronavirus 2019 (COVID-19), it is crucial to inspire medical students to consider a career in anaesthetics and perioperative care. Where anaesthetic skills are vital for all surgical foundation doctors, regardless of whether they have a rotation in anaesthetics, this study seeks to establish the current level of exposure to anaesthetics in the UK medical schools' curriculum and evaluate if the current anaesthetic undergraduate curriculum is sufficient to prepare students to pass their exams and perform the duties expected of them as future junior doctors. A 35-item structured questionnaire, registered at University College London Hospital Research & Development (R&D), was distributed amongst foundation doctors who had graduated from UK universities within the previous 3 years between August and October 2020. In total, 239 participants completed the questionnaire from 34 UK medical schools. Despite 90.0% of participants being allocated an 'anaesthesia' placement, 54.0% spent <15 hours shadowing an anaesthetist throughout their medical school. Of participants, 38.5% agreed that their anaesthetic teaching was sufficient compared to teaching of other specialities, with 48.6% of students not satisfied with the teaching provided to meet anaesthetic learning outcomes set by The Royal College of Surgeons of England; 72.4% said they would have benefited from additional anaesthetic teaching, with 80.7% stating it would have increased understanding into the speciality; and 71.5% stated a short course in anaesthetics alongside undergraduate training would have been beneficial. Our results demonstrate that there is a lack of standardization in undergraduate anaesthetics teaching nationally and an additional undergraduate anaesthetic teaching programme is required to increase understanding and provide further insight into anaesthetics. Key messages: The emergence of the coronavirus 2019 (COVID-19) pandemic has halted undergraduate medical education, in particular perioperative medicine and surgery.Exposure to anaesthesia is already limited in the medical undergraduate curriculum, with a limited number of anaesthesia-themed foundation rotations available for junior doctors.Recent UK graduates feel that undergraduate anaesthetics education is inadequate at medical school, reporting a lack of confidence in applying undergraduate anaesthesia learning outcomes.Additional anaesthetic teaching and online teaching methods are suggested ways of improving the delivery of undergraduate anaesthetic education.Can a national, standardized anaesthetics teaching curriculum improve the undergraduate knowledge base of anaesthesia?


Treatment of Isolated Zygomatic Arch Fracture: Improved Outcomes with External Splinting.
The various approaches to reduction and fixation of isolated displaced zygomatic arch fractures have not been well studied. The authors compared established treatment methods for zygomatic arch fractures for both aesthetic and functional outcomes. Consecutive patients with isolated zygomatic arch fractures with a minimum of 6 months' follow-up were studied in five groups: group 1, intraoral approach (no fixation); group 2, temporal approach (no fixation); group 3, coronal flap plate fixation; group 4, external splint fixation; and group 5, no surgery. Perioperative complications, facial contour symmetry (aesthetic outcome), improvement in mouth opening (functional outcome), and reoperations were compared. Patients undergoing external splint fixation had no perioperative complications. Coronal flap plate fixation had the highest rate of perioperative complications (46 percent), with facial nerve injury (4 percent), hematoma (8 percent), and persistent hyperesthesia (8 percent). Reoperations (fat grafting or bony reconstruction) were highest with coronal flap plate fixation (23 percent) and the temporal approach (7.7 percent); external splint fixation and the intraoral approach required no reinterventions. Patients treated with external splint fixation had the largest improvement in mean interincisor mouth opening. Mean postoperative interincisor opening in decreasing order was as follows: external splint fixation (51.6 mm), coronal flap plate fixation (47.1 mm), no surgery (39.8 mm), intraoral approach (39.6 mm), and temporal approach (38.9 mm). The highest volumetric symmetry was seen in external splint fixation (97.9 percent), followed by coronal flap plate fixation (94 percent), temporal approach (76.2 percent), intraoral approach (73 percent), and no surgery (68.3 percent). For isolated zygomatic arch fracture, patients undergoing external splint fixation had the lowest risk of perioperative complications and the greatest improvement in functional and aesthetic outcomes compared with the intraoral approach (no fixation), the temporal approach (no fixation), coronal flap plate fixation, and no surgery. Therapeutic, II.


[Mineral elements content in smoked fish].
The content of macroelements (phosphorus, calcium, magnesium potassium and sodium) and microelements (copper, zinc, iron, manganese, chromium, selenium, fluorine and iodine) in the following smoked fish: sprat, mackerel, salmon, smoked herring and trout were determined. The most of calcium, phosphorus, iron, zinc, copper and manganese contain smoked sprat. The amount of calcium in fish's remaining species is considerably lower, and phosphorus approximated to his content in sprat. The selenium and the fluorine occur on approximate level in all examined fish, however the amount of iodine was diverse but high. Smoked salmon and trout contain the most iodine, and the least smoked herring, sprat and mackerel. Contribution of fish in the recommended daily intake for mineral elements was estimated.


Intratumoral chemotherapy.
In an effort to improve survival from malignant gliomas, investigators have used intratumoral chemotherapy protocols to deliver high doses of tumoricidal agents directly to the brain. Theoretically, these infusions bypass the blood-brain barrier, minimize systemic drug levels and the side effects of chemotherapy, and achieve prolonged elevations of intracerebral chemotherapeutic agents relative to those obtainable by systemic administration. Almost all major classes of chemotherapeutic agents have been examined as possible intratumoral therapies via delivery approaches ranging from simple intratumoral injections to implantable computer-driven constant infusion pumps and biodegradable polymer matrices. In this review, we summarize the major clinical trials and experimental investigations underlying the development of intratumoral chemotherapy as a treatment for gliomas.


Assessment of deoxyuridine suppression test in diagnosis of vitamin B12 or folate deficiency.
Deoxyuridine (dU) suppression tests have been performed on virtually all marrow samples aspirated at this hospital over the past 12 months. Of the 110 samples studied 26 gave abnormal results, and these 26 samples came from patients deficient in either vitamin B(12) or folate. The dU suppression test was found to be of particular value in the diagnosis of vitamin B(12) or folate deficiency in non-anaemic patients with macrocytosis and equivocal changes in marrow morphology and in patients in whom the serum vitamin B(12) or red cell folate levels were within the normal range.


Recurrent inference machines as inverse problem solvers for MR relaxometry.
In this paper, we propose the use of Recurrent Inference Machines (RIMs) to perform T1 and T2 mapping. The RIM is a neural network framework that learns an iterative inference process based on the signal model, similar to conventional statistical methods for quantitative MRI (QMRI), such as the Maximum Likelihood Estimator (MLE). This framework combines the advantages of both data-driven and model-based methods, and, we hypothesize, is a promising tool for QMRI. Previously, RIMs were used to solve linear inverse reconstruction problems. Here, we show that they can also be used to optimize non-linear problems and estimate relaxometry maps with high precision and accuracy. The developed RIM framework is evaluated in terms of accuracy and precision and compared to an MLE method and an implementation of the Residual Neural Network (ResNet). The results show that the RIM improves the quality of estimates compared to the other techniques in Monte Carlo experiments with simulated data, test-retest analysis of a system phantom, and in-vivo scans. Additionally, inference with the RIM is 150 times faster than the MLE, and robustness to (slight) variations of scanning parameters is demonstrated. Hence, the RIM is a promising and flexible method for QMRI. Coupled with an open-source training data generation tool, it presents a compelling alternative to previous methods.


Paediatric hypoglycaemia; are we investigating appropriately and adequately?
Paediatric hypoglycaemia is a relatively common medical emergency. To allow identification of the underlying cause, investigations need to be performed urgently prior to treatment being given. Careful consideration is needed to ensure correct patient selection, as inadequate investigations have further cost and patient safety implications. 49 cases of proven or suspected hypoglycaemia (glucose ≤2.6 mmol/L) were identified via the laboratory. Clinical notes, laboratory investigations and results were reviewed. Only 41% of patients (15 neonates, 5 children) required investigation with a 'Hyposcreen'. Of these 20 patients, 3 had no investigations performed. In the remaining patients the cause for hypoglycaemia was identifiable, but 6 had investigations regardless. In total 23 patients had 'Hyposcreen' but only 2 were complete. Intermediary metabolites (96%), lactate (100%), cortisol (100%), insulin (83%) and growth hormone (87%) were taken most commonly with urine samples (52%) and ammonia (30%) taken least often. 40% cortisol, 29% insulin and 56% intermediary metabolite results were abnormal affecting 10 patients, but only 5 had follow-up. A total of £6977 was spent on investigations, of which £1630 has subsequently been found to be unnecessary. If investigations in the 23 children had been complete, this would have totalled £2700 of unnecessary expenditure. Investigations for hypoglycaemia are generally incomplete (91%) or inappropriate (21%). This has major cost implications for both the National Health Service and the individual who is investigated inadequately or incorrectly. We need national evidence-based guidance for investigation thresholds and normal ranges to help avoid inappropriate investigations and delay in diagnosis.


[Evaluation of antimicrobial sensitivity of 87 clinical isolates of vancomycin-resistant enterococci].
1) To evaluate the antimicrobial susceptibility pattern of vancomycin-resistant enterococci to the antimicrobial agents that are commonly used to treat enterococci infections and to some alternative drugs. 2) To evaluate the accuracy of E test for susceptibility testing enterococci. We evaluated 87 clinical VRE isolates that were selected from a previous study which analyzed 1936 clinical isolates collected and processed in 97 US medical centers in the last quarter of 1992. The isolates were identified to the species level by using the API 20S System, the Vitek gram-positive identification cards and a modified version of the conventional method proposed by Facklam and Collins. The in vitro susceptibility testing was performed by broth microdilution, E test and disk diffusion methods, following the criteria described by the National Committee for Clinical Laboratory Standards (NCCLS). The VRE isolates were tested against antimicrobial agents commonly used to treat enterococci infections (vancomycin, teicoplanin, ampicillin, penicillin, gentamicin and streptomycin) and against ten potential alternative drugs (chloramphenicol, doxycycline, sparfloxacin, ciprofloxacin, clinafloxacin, erythromycin, spectinomycin, trospectomycin, trimetoprim-sulfametoxazol and novobiocin). Our results showed a high rate of resistance to ampicillin and penicillin (86%). High level resistance to gentamicin and streptomycin was demonstrated by 82% and 85% respectively. Although teicoplanin and vancomycin belong to the same antibiotic group (glycopeptide), 29% of VRE were susceptible to teicoplanin. Among the alternative drugs, trospectomycin, doxycyclin and chloramphenicol showed the highest in vitro activity, with 94%, 92% and 82% susceptibility respectively. In addition, erythromycin, trimetoprim-sulfametoxazol and ciprofloxacin showed the highest rates of resistance (98%, 83% and 69%, respectively). The treatment options for infections caused by vancomycin-resistant enterococci seem to be very narrow since a small percentage of those isolates were susceptible to the other antimicrobial agents commonly used to treat these infections and only a few of the alternative drugs tested showed good in vitro activity. Many regimens using various antibiotic combinations have been tested against VRE, most of them with fluoroquinolones. However further studies are necessary to evaluate the clinical role of these antibiotic combinations.


Micronuclei in neonates and children: effects of environmental, genetic, demographic and disease variables.
Children may be more susceptible to the effects of the environmental exposure and medical treatments than adults; however, limited information is available about the differences in genotoxic effects in children by age, sex and health status. Micronucleus (MN) assay is a well established method of monitoring genotoxicity, and this approach is thoroughly validated for adult lymphocytes by the Human Micronucleus Biomonitoring project (HUMN.org). Similar international undertaking is in progress for exfoliated buccal cells. Most of the MN studies in children are focused on analyses of lymphocytes but in the recent years, more investigators are interested in using exfoliated cells from the oral cavity and other cell types that can be collected non-invasively, which is particularly important in paediatric cohorts. The baseline MN frequency is relatively low in newborns and its assessment requires large cohorts and cell sample counts. Available results are mostly consistent in conclusion that environmental pollutants and radiation exposures lead to the increase in the MN frequency in children. Effects of medical treatments are less clear, and more studies are needed to optimise the doses and minimise genotoxicity without compromising therapy outcomes. Despite the recent progress in MN assay in children, more studies are warranted to establish the relationship between MN in lymphocytes and exfoliated cells, to clarify sex, age and genotype differences in baseline MN levels and the changes in response to genotoxicants. One of the most important types of MN studies in children are prospective cohorts that will help to clarify the predictive value of MN and other cytome end points for cancer and other chronic diseases of childhood and adulthood. Emerging 'omic' and other novel molecular technologies may shed light on the molecular mechanisms and biological pathways associated with the MN levels in children.


Validation of computed tomographic middle cerebral artery "dot"sign: an angiographic correlation study.
The middle cerebral artery (MCA) "dot" sign consists of hyperdensity of an arterial structure, seen as a dot in the sylvian fissure. The MCA dot sign has been proposed to indicate thrombosis of M2 or M3 MCA branches, analogous to the hyperdense middle cerebral artery (HMCA) sign indicating M1 thrombosis. The MCA dot sign has not been validated previously against the gold standard of conventional cerebral angiography. Noncontrast CT scans and immediately subsequent cerebral angiograms from 54 acute stroke patients within 8 hours of symptom onset were analyzed. CT films were inspected for the MCA dot sign and HMCA sign. Vascular findings on CT were compared with findings at angiography. Mean patient age was 71 years; median National Institutes of Health Stroke Scale score was 16.5. Mean time from symptom onset to CT was 125 minutes, and that from CT to angiography was 117 minutes. All patients had arterial occlusion at angiography. Of the anterior circulation occlusions, M1 occlusions were noted in 28 patients, isolated M2 in 15, and isolated M3 in 4. One definite MCA dot sign was observed in 16.7% of patients, and an HMCA sign was observed in 13.9%. MCA dot sign performance in predicting the presence of M2 or M3 clot at angiography was as follows: sensitivity 38%, specificity 100%, positive predictive value 100%, negative predictive value 68%, and overall accuracy 73%. The MCA dot sign is a highly specific and moderately sensitive indicator of acute thrombus in the M2/M3 MCA branches, as validated by catheter angiography. The MCA dot sign is a useful additional acute stroke CT marker.


Spontaneous zygogenesis in Escherichia coli, a form of true sexuality in prokaryotes.
A new type of mating, differing from classic conjugation and previously observed in a certain strain of Escherichia coli K-12, has also been found in strains derived from ordinary F- cells of E. coli K-12 exposed to an exogenous factor originating in an E. coli clinical isolate. Immunofluorescence and electron microscopy after single and double labelling of DNA were used to produce evidence in favour of a novel mating mechanism by cell contact at the poles of the bacterial rod. These findings are supported by genetic analyses indicating complete genetic mixing. Unstable complementing diploids were formed, which throw off phenotypically haploid cells, of which some showed a parental phenotype and some were true genetic recombinants. Recombination was observed even when one parent was a UV-inactivated F- RecA- strain. The name 'spontaneous zygogenesis' (Z-mating, for short) is proposed for this kind of mating.


Effect of allopurinol on myocardial oxygen free radical production in coronary bypass surgery.
Allopurinol protects the heart from reperfusion injury. The aim of this study was to investigate myocardial free radical production during reperfusion with and without allopurinol treatment in coronary artery bypass grafting patients randomized into allopurinol (n = 14) or placebo (n = 13) groups. Allopurinol (1 g) was given blind prior to cardiopulmonary bypass and prior to opening the aorta. Oxygen free radicals were measured before anesthesia in arterial blood, before cross-clamping and 1 and 10 min after reperfusion in arterial and coronary sinus blood. Levels were measured as relative concentrations by the electron spin resonance method. One minute after reperfusion the level of spin-trapped radicals in arterial blood was elevated significantly (p = 0.016) in the allopurinol group, from 7.7 (SE: 0.8) to 8.6 (1.4) and non-significantly (p = 0.074) in the placebo group, from 7.3 (0.7) to 8.3 (0.8). Ten minutes after reperfusion the arterial values were 8.6 (1.5) in the allopurinol and 7.6 (0.7) in the placebo group, the sinus values being 7.6 (1.3) and 8.3 (0.8), respectively. Myocardial free radical production was -0.94 (1.21) in the allopurinol and +0.79 (0.96) in the placebo group after 10 min reperfusion, the difference being significant (p = 0.043). All patients in both groups had an increasing tendency to free radical production during early reperfusion. Patients treated with allopurinol showed less myocardial production of free radicals, indicating that its protective effect may be due to its antioxidative properties.


Distinctive populations of basement membrane and cell membrane heparan sulfate proteoglycans are produced by cultured cell lines.
We have investigated the nature and distribution of different populations of heparan sulfate proteoglycans (HSPGs) in several cell lines in culture. Clone 9 hepatocytes and NRK and CHO cells were biosynthetically labeled with 35SO4, and proteoglycans were isolated by DEAE-Sephacel chromatography. Heterogeneous populations of HSPGs and chondroitin/dermatan proteoglycans (CSPGs) were found in the media and cell layer extracts of all cultures. HSPGs were further purified from the media and cell layers and separated from CSPGs by ion exchange chromatography after chondroitinase ABC digestion. In all cell types, HSPGs were found both in the cell layers (20-70% of the total) as well as the medium. When the purified HSPG fractions were further separated by octyl-Sepharose chromatography, very little HSPG in the incubation media bound to the octyl-Sepharose, whereas 40-55% of that in the cell layers bound and could be eluted with 1% Triton X-100. This hydrophobic population most likely consists of membrane-intercalated HSPGs. Basement membrane-type HSPGs were identified by immunoprecipitation as a component (30-80%) of the unbound (nonhydrophobic) HSPG fraction. By immunofluorescence, basement membrane-type HSPGs were distributed in a reticular network in Clone 9 and NRK cell monolayers; by immunoelectron microscopy, these HSPGs were localized to irregular clumps of extracellular matrix located beneath and between cells. The cells did not produce a morphologically recognizable basement membrane layer under these culture conditions. When membrane-associated HSPGs were localized by immunoelectron microscopy, they were found in a continuous layer along the cell membrane of all cell types. The results demonstrate that two antigenically distinct populations of HSPG--an extracellular matrix and a membrane-intercalated population--are found at the surface of several different cultured cells lines; these populations can be distinguished from one another by differences in their distribution in the monolayers by immunocytochemistry and can be separated by hydrophobic chromatography; and basement membrane-type HSPGs are secreted and deposited in the extracellular matrix by cultured cells even though they do not produce a bona fide basement membrane-like layer.


Reporting of Harms in Randomized Controlled Trials Published in Urology Journals: An Updated Analysis.
Harms are often overlooked, but important, outcomes of randomized controlled trial reporting. Our goal was to determine if harms reporting has improved in high-impact urology journals. Randomized controlled trials published in The Journal of Urology®, Urology, European Urology, and BJU International in 2012 and 2020 were analyzed. Each randomized controlled trial was evaluated by 2 authors in a masked-duplicate fashion to evaluate for adherence to harms reporting guidelines recommended by the Consolidated Standards of Reporting Trials (CONSORT) group. One hundred and thirty-two published studies met inclusion criteria. Between 2012 and 2020, there was a statistically significant increase in the median number of harms criteria reported between 2012 and 2020 (5.3 vs 7.2; P = .01). Methods criteria demonstrating the greatest improvements included item #3 "which harms were assessed," item #4a "when harm information was collected," and item #4b "methods to attribute harm to intervention." Results sections with the most improvement in reporting include item #6 "reasons for patient withdrawal," item #8a "effect size for harms," and item #8b "stratified serious + minor harms." Reporting of adverse events in randomized trials published in several top urology journals has demonstrated marked improvement. Studies published in 2020 reported approximately 70% of CONSORT-Harms criteria-an increase of nearly 40% since 2004. While these improvements mark significant change, deficits remain present and should be addressed to provide clinicians with the most complete perspective possible.


Choline and betaine intake and the risk of colorectal cancer in men.
Dietary choline and betaine have been hypothesized to decrease the risk of cancer because of their role as methyl donors in the one-carbon metabolism. However, it remains unknown whether dietary intake of choline and betaine is associated with colorectal cancer risk. We prospectively examined the associations between dietary choline and betaine intake and risk of colorectal cancer in men in the Health Professionals Follow-up Study. We followed 47,302 men and identified a total of 987 incident colorectal cancer cases from 1986 to 2004. We assessed dietary and supplemental choline and betaine intake every 4 years using a validated semiquantitative food frequency questionnaire. The Cox proportional hazards model was used to estimate multivariate relative risks and 95% confidence intervals. All statistical tests were two-sided. We did not find any statistically significant associations between choline intake or betaine intake and risk of colorectal cancer. Comparing the top quintile with bottom quintile, multivariate relative risks (95% confidence interval) were 0.97 (0.79-1.20; P(trend) = 0.87) for choline intake and 0.94 (0.77-1.16; P(trend) = 0.79) for betaine intake. Similarly, we observed no associations between colorectal cancer risk and choline from free choline, glycerophosphocholine, phosphocholine, phosphatidylcholine, or sphingomyelin. Our data do not support the hypothesis that choline and betaine intake is inversely associated with colorectal cancer risk.


Switchable inteins for conditional protein splicing.
Synthetic biologists aim at engineering controllable biological parts such as DNA, RNA and proteins in order to steer biological activities using external inputs. Proteins can be controlled in several ways, for instance by regulating the expression of their encoding genes with small molecules or light. However, post-translationally modifying pre-existing proteins to regulate their function or localization leads to faster responses. Conditional splicing of internal protein domains, termed inteins, is an attractive methodology for this purpose. Here we discuss methods to control intein activity with a focus on those compatible with applications in living cells.


Newborn screening in the developing countries.
We review newborn screening (NBS) publications from the developing countries to identify global progress in improving child health. Many developing countries do not yet have national NBS. As infant mortality rates decline, NBS gains in public health priority. Local incidence and outcome data are used to persuade health officials to include screening in priority health spending. Congenital hypothyroidism is the most cost-effective screened condition in most countries. In sub-Saharan Africa, India and some parts of Asia, screening for hemoglobinopathies and glucose-6-dehydrogenase deficiency are also important. Expanded screening for metabolic conditions is most needed in areas of high consanguinity. Screening for hearing disorders and critical congenital heart defects is increasing globally. The largest birth cohorts are India and China, but only China has successful NBS. Reports from completed government research projects in India support initiation of NBS. Government activities around NBS are increasing in India and there is increased emphasis on pilot programs for sickle cell NBS in sub-Saharan Africa. Genetic counseling training in Asia and Africa is increasing and will be helpful as part of NBS. To build successful screening programs, partnerships among health professionals, parents, policy makers and industry stakeholders are essential.


KIR reconstitution is altered by T cells in the graft and correlates with clinical outcomes after unrelated donor transplantation.
Although unrelated hematopoietic cell transplantation (HCT) is curative for many hematologic malignancies, complications and relapse remain challenging obstacles. Natural killer (NK) cells, which recover quickly after transplantation, produce cytokines and express killer immunoglobulin-like receptors (KIRs) that regulate their cytotoxicity. Some clinical trials based on a KIR ligand mismatch strategy are associated with less relapse and increased survival, but results are mixed. We hypothesized that T cells in the graft may affect NK cell function and KIR expression after unrelated transplantation and that these differences correlate with clinical outcomes. NK cell function was evaluated using 77 paired samples from the National Marrow Donor Program Research Repository. Recipient NK cells at 100 days after both unmanipulated bone marrow (UBM) and T-cell depleted (TCD) transplants were compared with NK cells from their healthy donors. NK cells expressed fewer KIRs and produced more interferon gamma (IFN-gamma) after UBM compared to TCD transplants. Multivariate models showed that increased NK cell IFN-gamma production correlated with more acute graft-versus-host disease (GVHD), and decreased KIR expression correlated with inferior survival. These results support the notion that T cells in the graft affect NK cell reconstitution in vivo. Understanding these mechanisms may result in strategies to improve clinical outcomes from unrelated HCT.


Breathing better: A tech-monitored study of positive expiratory pressure and reading aloud for chronic obstructive pulmonary disease.
Breathing exercises, such as diaphragmatic breathing and positive expiratory pressure (PEP), relieve breathlessness in people with chronic obstructive pulmonary disease (COPD). This study aimed to investigate the effects of breathing exercises with PEP and reading aloud on vital signs, fatigue level, severity of dyspnoea and respiratory function parameters in patients with COPD. The study followed a randomized controlled trial of COPD patients from a single hospital in eastern Turkey. The study included 103 patients who were randomly assigned to receive pre-reading exercises, breathing exercises with a PEP device or no intervention for 8 weeks. The use of a PEP device improved oxygen saturation, forced expiratory volume in 1 s (FEV1 ) and FEV1 /forced vital capacity (FVC) values and reduced fatigue and dyspnoea severity. Reading aloud lowered the mean arterial pressure and reduced fatigue and dyspnoea severity. The study concludes that PEP devices and reading aloud can improve respiratory function in patients with COPD. Additionally, reading aloud is an accessible, easy-to-implement and economically feasible method for treating COPD symptoms.


Trioctylphosphine as self-assembly inducer.
Nickel nanoparticles (NPs) of different shapes and sizes in polydispersed as well as monodispersed forms were synthesized using trioctylphosphine (TOP), triphenylphosphine (TPP), oleylamine (OA) and their combinations as surfactants to study their self-assembly inducing capabilities. Randomly agglomerated polydispersed NPs were found for TPP and OA, and TPP or OA separately. However, in consolidation with the earlier report of Singh et al., J. Mater. Chem. C, 2014, 2, 8918, NPs formed using TOP only and a combination of TOP with OA naturally exhibited monodispersed NPs associated with natural nanolattice formation without any other external force or surfactants, demonstrating clearly the self-inducing capacity of TOP into monodispersed NPs and their self-assembled nanolattices. Fourier-transformed infra-red (FTIR) data clearly indicated the capping of these surfactants along with acetylacetonate ligands from nickel acetylacetonate precursor on the surface of the NPs. Remarkably, the narrowest zeta potential (ζ) base-widths were observed for samples possessing a self-assembled nanolattice, compared to the broader ones for randomly agglomerated particles.


Variant surface glycoprotein RNA interference triggers a precytokinesis cell cycle arrest in African trypanosomes.
Trypanosoma brucei is a protozoan parasite that causes African sleeping sickness. T. brucei multiplies extracellularly in the bloodstream, relying on antigenic variation of a dense variant surface glycoprotein (VSG) coat to escape antibody-mediated lysis. We investigated the role of VSG in proliferation and pathogenicity by using inducible RNA interference to ablate VSG transcript down to 1-2% normal levels. Inhibiting VSG synthesis in vitro triggers a rapid and specific cell cycle checkpoint blocking cell division. Parasites arrest at a discrete precytokinesis stage with two full-length flagella and opposing flagellar pockets, without undergoing additional rounds of S phase and mitosis. A subset (<10%) of the stalled cells have internal flagella, indicating that the progenitors of these cells were already committed to cytokinesis when VSG restriction was sensed. Although there was no obvious VSG depletion in vitro after 24-h induction of VSG RNA interference, there was rapid clearance of these cells in vivo. We propose that a stringent block in VSG synthesis produces stalled trypanosomes with a minimally compromised VSG coat, which can be targeted by the immune system. Our data indicate that VSG protein or transcript is monitored during cell cycle progression in bloodstream-form T. brucei and describes precise precytokinesis cell cycle arrest. This checkpoint before cell division provides a link between the protective VSG coat and cell cycle progression and could function as a novel parasite safety mechanism, preventing extensive dilution of the protective VSG coat in the absence of VSG synthesis.


Formation of bubbles and droplets in parallel, coupled flow-focusing geometries.
This paper describes the mechanism of formation of bubbles of nitrogen in water containing Tween 20 as a surfactant, and of droplets of water in hexadecane containing Span 80 as a surfactant. The study of these microfluidic systems compares two or four flow-focusing generators coupled through shared inlets, supplying the continuous phase, and through a common outlet channel. The processes that form bubbles in neighboring generators interact for a wide range of flow parameters; the formation of bubbles alternates in time and space, and the bubbles assemble into complex patterns in the outlet channel. The dynamics of formation of bubbles in these systems are stable for long time (at least 10 min). For a certain range of flow parameters, the coupled flow-focusing generators exhibit two stable modes of operation for a single set of flow parameters. The dynamics of formation of droplets of water in hexadecane by the coupled flow-focusing generators are simpler--the adjacent generators produce only monodisperse droplets over the entire range of flow parameters that are explored. These observations suggest that the mechanism of interaction between coupled flow-focusing generators relies on the compressibility of the dispersed phase (e.g., the gas or liquid), and on variations in pressure at the flow-focusing orifices induced by the breakup of bubbles or droplets.


Multiple accessory pathways in the young: the impact of structural heart disease.
The presence of multiple accessory pathways (MultAP) is described in structural heart disease (SHD) such as Ebstein's anomaly and cardiomyopathies. Structural defects can impact the tolerability of tachyarrhythmia and can complicate both medical management and ablation. In a large cohort of pediatric patients with and without SHD undergoing invasive electrophysiology study, we examined the prevalence of MultAP and the effect of both MultAP and SHD on ablation outcomes. Accessory pathway number and location, presence of SHD, ablation success, and recurrence were analyzed in consecutive patients from our center over a 16-year period. In 1088 patients, 1228 pathways (36% retrograde only) were mapped to the right side (TV) in 18%, septum (S) in 39%, and left side (MV) in 43%. MultAP were present in 111 pts (10%), involving 250 distinct pathways. SHD tripled the risk of MultAP (26% SHD vs 8% no SHD, P < .001). Multivariable adjusted risk factors for MultAP included Ebstein's (OR 8.7[4.4-17.5], P < .001) and cardiomyopathy (OR 13.3[5.1-34.5], P < .001). Of 1306 ablation attempts, 94% were acutely successful with an 8% recurrence rate. Ablation success was affected by SHD (85% vs 95% for no SHD, P < .01) but not by MultAP (91% vs 94% for single, P = .24). Recurrence rate was higher for SHD (17% SHD vs 8% no SHD, P < .05) and MultAP (19% MultAP vs 8% single, P < .001). MultAP are found in 10% of pediatric patients, and are more common in SHD compared to those with normal hearts. Both the presence of MultAP and SHD negatively influence ablation outcomes.


Frequency and Effect of Access-Related Vascular Injury and Subsequent Vascular Intervention After Transcatheter Aortic Valve Replacement.
Vascular access and closure remain a challenge in transcatheter aortic valve replacement (TAVR). This single-center study aimed to report the incidence, predictive factors, and clinical outcomes of access-related vascular injury and subsequent vascular intervention. During a 30-month period, 365 patients underwent TAVR and 333 patients (94%) were treated by true percutaneous transfemoral approach. Of this latter group, 83 patients (25%) had an access-related vascular injury that was managed by the use of a covered self-expanding stent (n = 49), balloon angioplasty (n = 33), or by surgical intervention (n = 1). In 16 patients (5%), the vascular injury was classified as a major vascular complication. Absence of a preprocedural computed tomography angiography (CTA) of the iliofemoral arteries (OR 2.04, p = 0.007) and female gender (OR 2.18, p = 0.004) were independent predictors of the need for access-related vascular intervention. In addition, a high sheath/common femoral artery ratio as measured on preoperative CTA was associated with a higher rate of post-TAVR vascular intervention. The radiation dose, iodine contrast volume, transfusion need, length of hospitalization, and 30-day mortality were not significantly different between patients with versus without access-related vascular intervention. In conclusion, access-related vascular intervention in patients who underwent transfemoral-TAVR is not uncommon. Female gender and a high sheath/common femoral artery ratio are risk factors for access-related vascular injury, whereas preprocedural planning with CTA of the access vessels may reduce the risk of vascular injury. Importantly, most access-related vascular injuries may be treated by percutaneous techniques with similar clinical outcomes to patients without vascular injuries.


Diagnosing childhood tuberculosis in rural clinics in Mpumalanga Province, South Africa.
Tuberculosis is a major global public health challenge and disease in young children is particularly severe. Diagnosing tuberculosis in children is complex as clinical presentation is often atypical and available diagnostic modalities are imperfect. Diagnosis is particularly challenging in developing countries where resources and access to sophisticated facilities are limited. The South African primary health care system requires frontline nurses to be equipped to suspect, diagnose and treat children with tuberculosis, but their capacity to diagnose childhood tuberculosis is unknown. Relatively low rates of childhood tuberculosis notification suggested that tuberculosis may have been under-diagnosed in Mpumalanga Province. To determine the ability of the primary health care nurses to diagnose childhood tuberculosis in primary care public health facilities in Gert Sibande District, Mpumalanga Province. Within-method triangulation by means of a self-completed questionnaire and a facility audit of records and diagnostic aids, was used to assess nurses' knowledge and determine whether primary health care facilities were adequately equipped to facilitate the diagnosis of childhood tuberculosis. There was a limited appreciation of the need to use complementary clinical and epidemiological features and diagnostic approaches to diagnose childhood tuberculosis. Child contacts had only been screened in 22.6% (111/491) of confirmed smear positive adult tuberculosis cases reviewed. The diagnostic score chart advocated by the World Health Organization and South African Department of Health was only used by 16% (10/62) of the facilities. Nurses who had been specifically trained on tuberculosis were more knowledgeable about diagnostic approaches and all respondents who were using the score chart had received specific tuberculosis training. The deficiencies in knowledge and practice evident during this survey and practice audit could at least partially explain the relatively low detection rates of childhood tuberculosis in Gert Sibande district, Mpumalanga Province. There is a need to equip primary health care nurses with the knowledge, support and access to diagnostic tests required to ensure a high index of suspicion and early, effective, diagnosis of tuberculosis in children.


Modelling biocompatible ionic liquids based on organic acids and amino acids: challenges for computational models and future perspectives.
In this short review I shall highlight the basic principle and the difficulties that arise in attempting the computational modeling of seemingly simple systems which hide an unexpected complexity. Biocompatible ionic liquids which are based on the coupling of organic or amino acid anions with metabolic cations such as cholinium are the target of this review. These substances have been the subject of intense research activities in the last few years and have attracted the attention of computational chemists. I shall show that the computational description of these substances is far from trivial and requires the use of sophisticated techniques in order to account for a surprisingly rich chemistry that is due to several phenomena such as polarization, charge transfer, proton transfer equilibria and tautomerization reactions.


Concurrence of chromosome 3 and 4 aberrations in human uveal melanoma.
Uveal melanoma (UM) is the most common primary intraocular malignancy with a very poor prognosis. The most frequent chromosome aberration in UM is the monosomy of chromosome 3. Previously, we demonstrated that ~50% of UMs express type-I receptor for luteinizing hormone‑releasing hormone (LH-RH-R). The gene encoding LH-RH-R is located in chromosome 4 (location: 4q21.2); however, the occurrence of numerical aberrations of chromosome 4 have never been studied in UM. In the present study, we investigated the abnormalities of chromosome 3 and 4, and the possible correlation between them, as well as with LH-RH-R expression. Forty-six specimens of UM were obtained after enucleation. Numerical aberrations of chromosome 3 and 4 were studied by fluorescence in situ hybridization (FISH). Chromosome 4 was detected in normal biparental disomy only in 14 (30%) samples; however, 32 cases (70%) showed more than 2 signals/nucleus. Monosomy of chromosome 3 could be found in 16 (35%) samples. In 6 specimens (13%), more than 2 copies of chromosome 3 were found, while normal biparental disomy was detected in 24 (52%) samples. Statistical analysis indicated a statistically significant (p<0.05) correlation between the copy number of chromosome 3 and 4. Moreover, moderate difference was revealed in the survival rate of the UM patients with various pathological profiles. No correlation was found between chromosome aberrations and LH-RH-R expression. Our results clearly demonstrate abnormalities in chromosome 3 and 4 and the incidence of the monosomy of chromosome 3 in human UM. In summary, our results provide new incite concerning the genetic background of this tumor. Our findings could contribute to a more precise determination of the prognosis of human UM and to the development of new therapeutic approaches to this malignancy.


Exploring posttraumatic outcomes as a function of childhood sexual abuse.
There is sparse systematic examination of the potential for growth as well as distress that may occur for some adult survivors of childhood sexual abuse. The presented study explored posttraumatic growth and its relationship with negative posttrauma outcomes within the specific population of survivors of childhood sexual abuse (N = 40). Results showed that 95% of the participants experienced clinically significant post-traumatic stress disorder symptomatology related to their childhood sexual abuse. In conjunction with these high levels of negative symptoms, the population evidenced posttraumatic growth levels that were comparable to other trauma samples. This research has clinical relevance in terms of adding to the knowledge base on sexual abuse and the usefulness of this knowledge in therapeutic interventions and relationships.


Priority effects alter interaction outcomes in a legume-rhizobium mutualism.
Priority effects occur when the order of species arrival affects the final community structure. Mutualists often interact with multiple partners in different orders, but if or how priority effects alter interaction outcomes is an open question. In the field, we paired the legume Medicago lupulina with two nodulating strains of Ensifer bacteria that vary in nitrogen-fixing ability. We inoculated plants with strains in different orders and measured interaction outcomes. The first strain to arrive primarily determined plant performance and final relative abundances of rhizobia on roots. Plants that received effective microbes first and ineffective microbes second grew larger than plants inoculated with the same microbes in the opposite order. Our results show that mutualism outcomes can be influenced not just by partner identity, but by the interaction order. Furthermore, hosts receiving high-quality mutualists early can better tolerate low-quality symbionts later, indicating that priority effects may help explain the persistence of ineffective symbionts.


Prevention of hip fractures by exposure to sunlight and pharmacotherapy in patients with Alzheimer's disease.
Hypovitaminosis D and K due to malnutrition or sunlight deprivation, compensatory hyperparathyroidism, increased bone resorption, low bone mineral density (BMD), and an increased risk of falls may contribute to an increased risk of hip fractures in patients with Alzheimer's disease. The purpose of the present study was to clarify the efficacy of interventions against hip fractures in patients with Alzheimer's disease. With respect to randomized controlled trials (RCTs) regarding Alzheimer's disease and hip fractures, the literature was searched with PubMed. Three RCTs were identified, and the relative risk (RR) and 95% confidence interval (CI) were calculated for individual RCTs. Exposure to sunlight with calcium supplementation, menatetrenone (vitamin K2) plus calcium and vitamin D supplementation, and risedronate plus calcium and vitamin D supplementation improved hypovitaminosis D and hyperparathyroidism, contributing to a reduction in bone resorption. Risedronate itself strongly decreased bone resorption. Menatetrenone also decreased the serum level of undercarboxylated osteocalcin. The three interventions increased metacarpal BMD and reduced the incidence of hip fractures. The respective RRs (95% CI) were 0.22 (0.049-0.999), 0.13 (0.031-0.554), and 0.26 (0.100- 0.690). The present study clarified the efficacy of three interventions, including exposure to sunlight, menatetrenone, and risedronate with calcium and/or vitamin D supplementation against hip fractures in patients with Alzheimer's disease.


ggMOB: Elucidation of genomic conjugative features and associated cargo genes across bacterial genera using genus-genus mobilization networks.
Horizontal gene transfer mediated by conjugation is considered an important evolutionary mechanism of bacteria. It allows organisms to quickly evolve new phenotypic properties including antimicrobial resistance (AMR) and virulence. The frequency of conjugation-mediated cargo gene exchange has not yet been comprehensively studied within and between bacterial taxa. We developed a frequency-based network of genus-genus conjugation features and candidate cargo genes from whole-genome sequence data of over 180,000 bacterial genomes, representing 1,345 genera. Using our method, which we refer to as ggMOB, we revealed that over half of the bacterial genomes contained one or more known conjugation features that matched exactly to at least one other genome. Moreover, the proportion of genomes containing these conjugation features varied substantially by genus and conjugation feature. These results and the genus-level network structure can be viewed interactively in the ggMOB interface, which allows for user-defined filtering of conjugation features and candidate cargo genes. Using the network data, we observed that the ratio of AMR gene representation in conjugative versus non-conjugative genomes exceeded 5:1, confirming that conjugation is a critical force for AMR spread across genera. Finally, we demonstrated that clustering genomes by conjugation profile sometimes correlated well with classical phylogenetic structuring; but that in some cases the clustering was highly discordant, suggesting that the importance of the accessory genome in driving bacterial evolution may be highly variable across both time and taxonomy. These results can advance scientific understanding of bacterial evolution, and can be used as a starting point for probing genus-genus gene exchange within complex microbial communities that include unculturable bacteria. ggMOB is publicly available under the GNU licence at https://ruiz-hci-lab.github.io/ggMOB/.


The effect of agency on women's mental distress: A prospective cohort study from rural Rajasthan, India.
Agency, the ability to identify goals and then act upon them, is a core component of women's empowerment and has important implications for the rights and well-being of women and girls. However, inadequate measurement of agency impedes empirical investigation, and few studies have investigated the relation between agency and health. Using a theory-based measure of women's agency, we investigated the longitudinal association between agency and mental distress among women living in rural Rajasthan, India. Women completed baseline interviews between June and October 2016 and follow-up interviews between June and November 2017 (n = 2859). We measured mental distress with the Hindi version of the 12 item General Health Questionnaire, which asked women 12 questions about symptoms of mental distress (score range: 0-12). We measured agency using a measurement model which was composed of 23 indicators tapping into four domains of agency and validated in a prior research study. We modeled the relation between women's agency and mental distress using Poisson regression and an individual-level fixed effects approach to account for time-fixed characteristics of individuals. In models that controlled for time-varying confounding (e.g., household wealth, number of sons), a one standard deviation increase in agency was associated with a reduction of 0.21 distress symptoms (95% CI: -0.32, -0.09), which corresponds to a 7% reduction (95% CI: 3%, 11%) relative to the mean. We found that specific domains of agency varied in their association with mental distress; namely, an increase in women's agency regarding her attitudes about gender norms corresponded to a reduction in mental distress, whereas an increase in women's agency regarding speaking up in public corresponded to an increase in mental distress. Our research demonstrates that agency may be a determinant of mental health and that comprehensive measurement can reveal nuanced relationships.


Sarcoidosis of the upper respiratory tract and its association with lupus pernio.
In a series of 34 patients with sarcoidosis affecting the upper respiratory tract and nose, 26 had lupus pernio (LP) and 17 had sarcoidosis of the upper respiratory tract (SURT). In nine patients these features coexisted. A patient presenting with SURT carried a 50% risk of developing LP although one feature could be present without the other. Both were disorders of women of the child-bearing years of life. SURT, like LP, was an indicator of chronic fibrotic sarcoidosis, developing insidiously and progressing indolently over the years. It was complicated by ulceration, septal perforation, and LP. Three patients had nasal septal perforations, in two instances following submucous resection. This operation is contraindicated in patients with active sarcoidosis, particularly when granulomas are found on nasal biopsy. The Kveim-Siltzbach skin test was positive in all patients with SURT, making it invaluable in the differential diagnosis of granuloma of the nasal cavity.


Corticosteroids for treatment of sore throat: systematic review and meta-analysis of randomised trials.
Objective To estimate the benefits and harms of using corticosteroids as an adjunct treatment for sore throat.Design Systematic review and meta-analysis of randomised control trials.Data sources Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), trial registries up to May 2017, reference lists of eligible trials, related reviews.Study selection Randomised controlled trials of the addition of corticosteroids to standard clinical care for patients aged 5 or older in emergency department and primary care settings with clinical signs of acute tonsillitis, pharyngitis, or the clinical syndrome of sore throat. Trials were included irrespective of language or publication status.Review methods Reviewers identified studies, extracted data, and assessed the quality of the evidence, independently and in duplicate. A parallel guideline committee (BMJ Rapid Recommendation) provided input on the design and interpretation of the systematic review, including the selection of outcomes important to patients. Random effects model was used for meta-analyses. Quality of evidence was assessed with the GRADE approach.Results 10 eligible trials enrolled 1426 individuals. Patients who received single low dose corticosteroids (the most common intervention was oral dexamethasone with a maximum dose of 10 mg) were twice as likely to experience pain relief after 24 hours (relative risk 2.2, 95% confidence interval 1.2 to 4.3; risk difference 12.4%; moderate quality evidence) and 1.5 times more likely to have no pain at 48 hours (1.5, 1.3 to 1.8; risk difference 18.3%; high quality). The mean time to onset of pain relief in patients treated with corticosteroids was 4.8 hours earlier (95% confidence interval -1.9 to -7.8; moderate quality) and the mean time to complete resolution of pain was 11.1 hours earlier (-0.4 to -21.8; low quality) than in those treated with placebo. The absolute pain reduction at 24 hours (visual analogue scale 0-10) was greater in patients treated with corticosteroids (mean difference 1.3, 95% confidence interval 0.7 to 1.9; moderate quality). Nine of the 10 trials sought information regarding adverse events. Six studies reported no adverse effects, and three studies reported few adverse events, which were mostly complications related to disease, with a similar incidence in both groups.Conclusion Single low dose corticosteroids can provide pain relief in patients with sore throat, with no increase in serious adverse effects. Included trials did not assess the potential risks of larger cumulative doses in patients with recurrent episodes of acute sore throat.Systematic review registration PROSPERO CRD42017067808.


Material approaches to stretchable strain sensors.
With the recent progress made in wearable electronics, devices now require high flexibility and stretchability up to large strain levels (typically larger than 30 % strain). Wearable strain sensors or deformable strain sensors have been gaining increasing research interest because of the rapid development of electronic skins and robotics and because of their biomedical applications. Conventional brittle strain sensors made of metals and piezoresistors are not applicable for such stretchable sensors. This Review summarizes recent advances in stretchable sensors and focuses on material aspects for high stretchability and sensitivity. It begins with a brief introduction to the Wheatstone bridge circuit of conventional resistive strain sensors. Then, studies on the manipulation of materials are reviewed, including waved structural approaches for making metals and semiconductors stretchable, the use of liquid metals, and conductive filler/elastomer composites by using percolation among the fillers. For capacitive strain sensors, the constant conductivity of the electrode is a key factor in obtaining reliable sensors. Possible approaches to developing capacitive strain sensors are presented. This Review concludes with a discussion on the major challenges and perspectives related to stretchable strain sensors.


Nationwide Actions Against Heart Failure Pandemic in Japan - What Should We Do From Academia?
Heart failure pandemic is rapidly approaching in Japan, requiring nationwide actions. In particular, the Japanese Circulation Society and related societies launched the Stroke and Cardiovascular Disease Control Act, which was passed by the National Diet, as the first ever legislative policy measure against stroke and cardiovascular disease. In association with this, actions against heart failure pandemic from the scientific field are also important. Because heart failure pandemic is a critical problem not only in Japan but also in many developed countries, we believe the nationwide approach, as summarized here, will greatly contribute to the development of cardiovascular medicine, particularly the management and treatment of heart failure worldwide.


Compassionate communities: end-of-life care as everyone's responsibility.
In early 2013, an online survey of over 200 UK palliative care services published in the British Medical Journal found that most of these services were prioritizing 'community engagement' initiatives, most commonly adopting a 'compassionate community' model. Later this same year, a report released by the National Council for Palliative Care and the charity Murray Hall Community Trust, described the increasing uptake of compassionate communities by palliative care services in England. This review examines this new policy and practice development in British end-of-life care explaining its conceptual origins and describing its policy importance to current practice. Why services are increasingly turning to community partnerships and the reasons they believe that this approach might enhance the effectiveness and reach of their clinical work are described.


Fabricating an intelligent cell-like nano-prodrug via hierarchical self-assembly based on the DNA skeleton for suppressing lung metastasis of breast cancer.
Cancer metastasis is a major cause of high mortality in breast cancer. Despite the progress achieved in nanomaterial-based treatments, the cure rate remains unsatisfactory, owing to their poor biocompatibility and non-specific recognition. Inspired by the cell-mimetic strategy, in this work, we fabricated an intelligent cell-like nano-prodrug (Dox-MPK@MDL) for lung metastasis of breast cancer. Specifically, a DNA tetrahedron dendrimer was selected to act as a rigid internal cytoskeleton, and then sequentially coated with a liposome and macrophage membrane to form cell-like Dox-MPK@MDL via hierarchical self-assembly. Here, it should be noted that pH-sensitive Dox-MPK prodrugs were synthesized and inserted into the DNA-based cytoskeleton (the Dox group is an intercalator of double stranded DNA) in advance for the next anti-metastatic therapy. Our results show that Dox-MPK@MDL specifically targeted the sites of lung metastasis via the biomimetic metastasis-homing effects and intelligently triggered Dox release at the metastatic cancer cells, thereby leading to the significant inhibition of lung metastasis. All these features help to enhance the anti-metastatic therapy efficiency of Dox while maximally reducing side-effects.


The efficacy of topical betamethasone for treating phimosis: a comparison of two treatment regimens.
To compare the efficacy of two different topical betamethasone treatment regimens with respect to outcome and untoward effects in boys with phimosis. Boys with phimosis whose parents opted for medical management were treated with topical betamethasone (0.05%) and manual retraction. One author (J.S.P.) prescribed betamethasone twice daily (BID) for 30 days (60 doses), and the other author (L.S.P.) prescribed betamethasone thrice daily (TID) for 21 days (63 doses). All boys had severe phimosis (prepuce unretractable to evaluate meatus) before treatment. The degree of phimosis was graded 1 month after treatment as severe, moderate (prepuce retractable to less than 50% glanular exposure), or mild (penile adhesions). Chi-square analysis (P <0.05) was used to compare the two groups. Treatment failure was defined as persistent severe phimosis. A total of 200 consecutive patients from each treatment group were included. The median patient ages were similar between the groups (3.8 years BID, 4.4 years TID). One child had an untoward effect (candidal dermatitis, TID regimen). There was an 84.5% response rate (moderate to no phimosis) with the BID regimen and an 87% response rate with the TID regimen (P = nonsignificant). Two patients with severe phimosis before treatment were diagnosed with congenital urethral malformations (hypospadias and epispadias) after treatment. The topical application of betamethasone is a highly efficacious, safe, and well-tolerated treatment of phimosis in this large series of boys. The 21-day TID and 30-day BID regimens in conjunction with manual retraction are equally efficacious and can be offered to parents requesting nonsurgical management of phimosis. Untoward effects are rare with either regimen. Important urethral anomalies can occasionally be revealed.


Multiple aphthoid syphilitic chancres of the oral cavity.
We describe the case of a 31-year-old man who was affected by three asymptomatic, aphthoid, syphilitic chancres of the oral cavity. These lesions were accompanied by right latero-cervical and chin lymphadenopathy. The infection was previously diagnosed as aphthous stomatitis. The search for Treponema pallidum by means of darkfield microscope examination was positive. The patient was successfully treated with oral erythromycin ethylsuccinate. To our knowledge, this is the first case of multiple aphthoid syphilitic chancres of the oral cavity reported in the literature. We suggest that all patients with a recent history of painless ulcers in the oral cavity, accompanied by regional lymphadenopathy in which the clinical diagnosis has not been confirmed, should undergo a darkfield microscope examination.


When to control endemic infections by focusing on high-risk groups.
For nontransmissible diseases, decisions between interventions focused on high-risk groups and unfocused interventions can be based on attributable-risk calculations. The assumptions of those calculations, however, are violated for infectious diseases. We used deterministic compartmental models of infection transmission having both high- and low-risk groups and both susceptible and infected states to examine intervention effects on endemic infection levels. High risk is generated by increased susceptibility or contagiousness-factors that can be reduced by interventions. Population effects of focused and unfocused interventions are compared at settings where these would be equal if there were no transmission. In the most likely range of mixing between high- and low-risk groups, focused interventions have considerably larger effects than unfocused interventions. At all mixing levels, both interventions have greater effects on infectious than noninfectious diseases because a change in risk factor for one individual alters risk in others. Interventions on contagiousness in high-risk groups have greater effects than comparable interventions on susceptibility. Risk assessment for infectious disease requires analysis of the population system that is circulating the infection. Vaccine trials on individuals will miss important effects that trials on transmission units will detect. Focusing HIV control on contagiousness factors in high-risk groups will be especially productive.


Review of 120 biopsies performed on the balanopreputial sac. from zoon's balanitis to the concept of a wider spectrum of inflammatory non-cicatricial balanoposthitis.
Long-lasting erythematous lesions involving the balanopreputial sac may be clinically difficult to classify, and biopsies may be performed in order to clarify the nature of the disease. However, our previous experience led us to consider several cases as histopathologically unclassifiable. To establish the causes of such unsatisfactory findings. We reviewed 120 balanopreputial sac biopsies performed at the surgical unit of our institute from January 1999 to December 2002 examining also the patients' clinical records. We found that a small group of previously unclassified cases showed common clinical and histopathological features. Clinically, all patients were uncircumcised and had long-lasting asymptomatic erythematous plaques on the balanopreputial sac with no erythroplastic or lichenoid features and no correlation with sexual intercourse. Histologically, all specimens showed a thinned and spongiotic epithelium, a band-like infiltrate of lymphocytes and histiocytes with a variable number of plasma cells in the upper part of the chorion and further signs of acute, subacute or chronic inflammation. In our view, these cases fall within a spectrum of inflammatory non-cicatricial disorders, ranging from almost pure lymphohistiocytic forms to forms which fulfil all criteria to be classified as balanitis circumscripta plasmacellularis of Zoon. We propose to classify these cases histologically as inflammatory non-cicatricial balanoposthitis and clinically as idiopathic inflammatory non-cicatricial balanoposthitis.


Problems encountered with the use of simulation in an attempt to enhance interpretation of a secondary data source in epidemiologic mental health research.
The longitudinal epidemiology of major depressive episodes (MDE) is poorly characterized in most countries. Some potentially relevant data sources may be underutilized because they are not conducive to estimating the most salient epidemiologic parameters. An available data source in Canada provides estimates that are potentially valuable, but that are difficult to apply in clinical or public health practice. For example, weeks depressed in the past year is assessed in this data source whereas episode duration would be of more interest. The goal of this project was to derive, using simulation, more readily interpretable parameter values from the available data. The data source was a Canadian longitudinal study called the National Population Health Survey (NPHS). A simulation model representing the course of depressive episodes was used to reshape estimates deriving from binary and ordinal logistic models (fit to the NPHS data) into equations more capable of informing clinical and public health decisions. Discrete event simulation was used for this purpose. Whereas the intention was to clarify a complex epidemiology, the models themselves needed to become excessively complex in order to provide an accurate description of the data. Simulation methods are useful in circumstances where a representation of a real-world system has practical value. In this particular scenario, the usefulness of simulation was limited both by problems with the data source and by inherent complexity of the underlying epidemiology.


T2-PROPELLER Compared to T2-FRFSE for Image Quality and Lesion Detection at Prostate MRI.
The primary objective was to compare T2-FRFSE and T2-PROPELLER sequences for image quality. The secondary objective was to compare the ability to detect prostate lesions at MRI in the presence and absence of motion artefact using the 2 sequences. 99 patients underwent 3 T MRI examination of the prostate, including T2-FRFSE and T2-PROPELLER sequences. All patients underwent prostate biopsy. Two independent readers rated overall image quality, presence of motion artefact, and blurring for both sequences using a 5-point Likert scale. Scores were compared for the whole group and for subgroups with and without significant motion artefact. Outcome for lesion detection at an MRI threshold of PI-RADS score ≥3 was compared between T2-FRFSE and T2-PROPELLER. The overall image quality was not significantly different between T2-FRFSE and T2-PROPELLER sequences (3.74 vs. 3.93, p = 0.275). T2-PROPELLER recorded a lesser degree of motion artefact (score 4.53 vs. 3.78, p <0.0001), but demonstrated greater image blurring (score 3.29 vs. 3.73, p <0.001). However, in a subgroup of patients with significant motion artefact on T2-FRFSE, the T2-PROPELLER sequence demonstrated significantly higher image quality (3.46 vs. 2.49, p <0.001). T2-FRFSE and T2-PROPELLER showed comparable positive predictive values for lesion detection at 93.2% and 97.7%, respectively. T2-PROPELLER provides higher quality imaging in the presence of motion artefact, but T2-FRFSE is preferred in the absence of motion. T2-PROPELLER is therefore recommended as a secondary T2 sequence when imaging requires repeat acquisition due to motion artefact.