Distribution of Batrachochytrium dendrobatidis and pathology in the skin of green tree frogs Litoria caerulea with severe chytridiomycosis.
Although histopathology is used routinely for diagnosis of chytridiomycosis in live and dead amphibians, there are no quantitative data on the distribution of the causative fungus, Batrachochytrium dendrobatidis, in the skin. We performed quantitative histological examinations on 6 sites on the body and 4 toes of 10 free-ranging adult green tree frogs Litoria caerulea found recently dead or dying from chytridiomycosis. Large numbers of sporangia occurred in all areas of ventral skin and toes; on average there were 94.3 sporangia mm(-1) of superficial epidermis. The number of sporangia was highly variable and this appeared to be related to the stage in the cycle of sloughing. The stratum corneum tends to build up with high intensities of infection and then sheds entirely rather than being shed continuously. Very few or no sporangia occurred on dorsal skin. This distribution could be explained by the dryness of the dorsal skin or possibly by the greater number of serous glands, which produce antifungal peptides, on the dorsum. In some frogs, ulceration and erosions occurred on skin on the back in the absence of sporangia. Other pathological changes such as hyperkeratosis and congestion occurred much more frequently on ventral surfaces.


Terminalia bellirica stimulates the secretion and action of insulin and inhibits starch digestion and protein glycation in vitro.
Traditional plant treatments have been used throughout the world for the therapy of diabetes mellitus. The aim of the present study was to investigate the efficacy and mode of action of Terminalia bellirica used traditionally for the treatment of diabetes in India. T. bellirica aqueous extract stimulated basal insulin output and potentiated glucose-stimulated insulin secretion concentration-dependently in the clonal pancreatic beta-cell line, BRIN-BD11 (P < 0.001). The insulin-secretory activity of the plant extract was abolished in the absence of extracellular Ca2+ and by inhibitors of cellular Ca2+ uptake, diazoxide and verapamil (P < 0.001; n 8). Furthermore, the extract did not increase insulin secretion in depolarised cells and did not further augment insulin secretion triggered by tolbutamide or glibenclamide. T. bellirica extract also displayed insulin-mimetic activity and enhanced insulin-stimulated glucose uptake in 3T3-L1 adipocytes by 300 %. At higher concentrations, the extract also produced a 10-50 % (P < 0.001) decrease in starch digestion in vitro and inhibited protein glycation (P < 0.001). The present study has revealed that components in T. bellirica extract stimulate insulin secretion, enhance insulin action and inhibit both protein glycation and starch digestion. The former actions are dependent on the active principle(s) in the plant being absorbed intact. Future work assessing the use of T. bellirica as a dietary adjunct or as a source of active anti-diabetic agents may provide new opportunities for the treatment of diabetes.


Transient sex change in the immature Malabar grouper, Epinephelus malabaricus, androgen treatment.
To clarify the cause of sex change recovery after the withdrawal of androgen treatment, immature female Malabar grouper were fed a diet containing 17alpha-methyltestosterone (MT) at 50 μg/g for 7 mo and then a normal diet for 6 mo. The MT brought about precocious sex change from immature ovaries to mature testes with active spermatogenesis, including the development of spermatozoa, and sex change reversed soon after MT treatment withdrawal. This result indicates that precocious sex change in immature Malabar grouper with oral MT treatment is impermanent. The expression of three steroidogenic enzymes (Cyp11a, Cyp19a1a, and Cyp11b) in the gonads of the Malabar grouper were analyzed immunohistochemically at the end of the 7-mo treatment. No apparent differences were seen in the expression pattern of these enzymes between the mature testes of MT-treated fish and the immature ovaries of control fish. In addition, serum estradiol-17beta and 11-ketotestosterone levels in treated fish were the same as those in control fish. These results indicate that in the case of immature Malabar grouper MT might have little effect on endogenous steroidogenesis during precocious sex change even though it induced active spermatogenesis in the gonads of treated fish. From these results, we also concluded that MT might have little effect on the steroidogenic endocrine pathway, and this is one cause of sex change recovery after treatment withdrawal.


A proposed syntax for Minimotif Semantics, version 1.
One of the most important developments in bioinformatics over the past few decades has been the observation that short linear peptide sequences (minimotifs) mediate many classes of cellular functions such as protein-protein interactions, molecular trafficking and post-translational modifications. As both the creators and curators of a database which catalogues minimotifs, Minimotif Miner, the authors have a unique perspective on the commonalities of the many functional roles of minimotifs. There is an obvious usefulness in standardizing functional annotations both in allowing for the facile exchange of data between various bioinformatics resources, as well as the internal clustering of sets of related data elements. With these two purposes in mind, the authors provide a proposed syntax for minimotif semantics primarily useful for functional annotation. Herein, we present a structured syntax of minimotifs and their functional annotation. A syntax-based model of minimotif function with established minimotif sequence definitions was implemented using a relational database management system (RDBMS). To assess the usefulness of our standardized semantics, a series of database queries and stored procedures were used to classify SH3 domain binding minimotifs into 10 groups spanning 700 unique binding sequences. Our derived minimotif syntax is currently being used to normalize minimotif covalent chemistry and functional definitions within the MnM database. Analysis of SH3 binding minimotif data spanning many different studies within our database reveals unique attributes and frequencies which can be used to classify different types of binding minimotifs. Implementation of the syntax in the relational database enables the application of many different analysis protocols of minimotif data and is an important tool that will help to better understand specificity of minimotif-driven molecular interactions with proteins.


Protective role of propolis in chlorpyrifos-induced changes in the haematological parameters and the oxidative/antioxidative status of Cyprinus carpio carpio.
The protective effect of propolis on haematological parameters and antioxidant status were evaluated in the blood and various tissues of carp exposed to chlorpyrifos (CPF). The fish were exposed to sublethal concentrations of CPF (0.040 and 0.080 mg/L) for 10 days, and propolis (10 mg per kg of fish weight) was simultaneously administered. Samples of the blood and tissue (liver, kidney, and gill) were collected at the end of the experiment and analysed for their oxidant-antioxidant status, including the malondialdehyde (MDA) levels, and the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activity. The samples were also measured for changes in the haematological parameters, such as the red blood cell (RBC) and white blood cell (WBC) counts, the haemoglobin concentration (Hb), the haematocrit (Ht) level, and the erythrocyte indices: the mean corpuscular volume (MCV), the mean corpuscular haemoglobin (MCH) and the mean corpuscular haemoglobin concentration (MCHC). The findings of this study demonstrated that CPF had a negative effect on the haematological parameters and the antioxidant enzyme activities of the fish; this toxic effect was neutralised by the administration of propolis. The present results suggest that propolis can be effective in the protection of CPF-induced toxicity in fish.


Forearm pronation and supination: reliability of absolute torques and nondominant/dominant ratios.
This study examined the reliability of pronation and supination measurements expressed in absolute units (newton-meters [Nm]) and nondominant/dominant ratios (%), and determined isometrically using the BTE (WS20) and the Cybex (340) dynamometers. Twenty-one healthy men and 22 healthy women were tested twice on each machine, within 14 days. Twelve of 16 reliability coefficients for absolute torques were considered acceptable (> 0.75) when determined as the reliability of two repetitions on one occasion, while 14 of 16 coefficients were acceptable when determined as the reliability of two repetitions on each of two occasions. However, reliability coefficients for the nondominant/dominant ratios were not acceptable on one (0 of 8 coefficients > 0.75) or two (2 of 8 coefficients > 0.75) occasions. Ratio data were also characterized by larger standard errors of measurement (SEMs) and wider 95% confidence intervals, relative to the sample mean and standard deviation. Overall, reliability coefficients, SEMs, and 95% confidence intervals were similar for men and women, pronation and supination movements, and the BTE and Cybex dynamometers. The authors suggest that absolute scores be used when possible, as these data tend to provide more reliable measurements--especially when the clinician has only limited test occasions to establish baseline scores.


Ectopic overexpression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative-(BMS 247550) and Apo-2L/TRAIL-induced apoptosis.
Second mitochondria-derived activator of caspases (Smac)/DIABLO is a mitochondrial protein that is released into the cytosol along with cytochrome c (cyt c) during the execution of the intrinsic pathway of apoptosis. Smac/DIABLO promotes apoptosis by neutralizing the inhibitory effect of the inhibitor of apoptosis (IAP) family of proteins on the processing and activities of the effector caspases. Present studies demonstrate that, upon engagement of the mitochondrial pathway of apoptosis, epothilone (Epo) B derivative BMS 247550, a novel nontaxane antimicrotubule agent, as well as the death ligand Apo-2L/TRAIL (tumor necrosis factor-alpha-related apoptosis-inducing ligand) induce the mitochondrial release and cytosolic accumulation of Smac/DIABLO, along with cyt c, in human acute leukemia Jurkat T cells. While it had no activity alone, ectopic overexpression of Smac/DIABLO or treatment with the N-terminus heptapeptide (Smac-7) or tetrapeptide (Smac-4) of Smac/DIABLO significantly increased Epo B- or Apo-2L/TRAIL-induced processing and PARP cleavage activity of caspase-3. This produced a significant increase in apoptosis of Jurkat cells (P <.05). Increased apoptosis was also associated with the down-regulation of XIAP, cIAP1, and survivin. Along with the increased activity of caspase-3, ectopic overexpression of Smac/DIABLO or cotreatment with Smac-4 also increased Epo B- or Apo-2L/TRAIL-induced processing of caspase-8 and Bid, resulting in enhanced cytosolic accumulation of cyt c. This was not due to increased assembly and activity of Apo-2L/TRAIL-induced DISC (death-inducing signaling complex) but dependent on the feedback activity of caspase-3. These findings demonstrate that cotreatment with the N-terminus Smac/DIABLO peptide is an effective strategy to enhance apoptosis triggered by the death receptor or mitochondrial pathway and may improve the antitumor activity of Apo-2L/TRAIL and Epo B.


Variable region gene utilization and mutation in a group of neutralizing murine anti-human immunodeficiency virus type 1 principal neutralizing determinant antibodies.
The heavy (VH) and light (VL) chain variable region nucleotide sequences of four neutralizing anti-human immunodeficiency virus type 1 (HIV-1) murine monoclonal antibodies (mAbs) were determined. These mAbs bind to native gp120, recombinant gp120, and a linear HIV-1 principal neutralizing determinant (PND) peptide that spans amino acid 308-328. Three mAbs that bind to the same linear determinant, 110.3, 110.4, and 110.5, all use the same VL gene elements, a VK21 gene and JK2. These three mAbs also share the same VKJK junctional diversity and specific somatic mutations. They have identical VL immunoglobulin gene rearrangement patterns on Southern blot. Two of the antibodies, 110.4 and 110.5, also use the same VH gene elements, SB32-D-JH4, and have identical VD and DJ junctions and N sequences. Two different anti-HIV-1 PND murine mAbs reported by others, BAT123 and 0.5 beta, also use VK21-JK2, and BAT123 also uses the SB32 VH gene element. Although 110.3 uses the same VL region gene as 110.3 and 110.4, it uses a different VH gene that appears to be a member of the 7183 VH family. 110.6, an mAb that recognizes a discrete, overlapping PND compared to 110.3, 110.4, and 110.5, uses entirely different VH and VL gene elements and has unique immunoglobulin VH and VL rearrangement patterns. Our data, taken together with reports of the BAT123 and 0.5 beta mAb sequences, suggest that the murine antibody response to HIV-1 PND may be restricted to a small subset of VH and VL gene elements.


Clinical Features and Chest CT Manifestations of Coronavirus Disease 2019 (COVID-19) in a Single-Center Study in Shanghai, China.
OBJECTIVE. Confronting the new coronavirus infection known as coronavirus disease 2019 (COVID-19) is challenging and requires excluding patients with suspected COVID-19 who actually have other diseases. The purpose of this study was to assess the clinical features and CT manifestations of COVID-19 by comparing patients with COVID-19 pneumonia with patients with non-COVID-19 pneumonia who presented at a fever observation department in Shanghai, China. MATERIALS AND METHODS. Patients were retrospectively enrolled in the study from January 19 through February 6, 2020. All patients underwent real-time reverse transcription-polymerase chain reaction (RT-PCR) testing. RESULTS. Eleven patients had RT-PCR test results that were positive for severe acute respiratory syndrome coronavirus 2, whereas 22 patients had negative results. No statistical difference in clinical features was observed (p > 0.05), with the exception of leukocyte and platelet counts (p < 0.05). The mean (± SD) interval between onset of symptoms and admission to the fever observation department was 4.40 ± 2.00 and 5.52 ± 4.00 days for patients with positive and negative RT-PCR test results, respectively. The frequency of opacifications in patients with positive results and patients with negative results, respectively, was as follows: ground-glass opacities (GGOs), 100.0% versus 90.9%; mixed GGO, 63.6% versus 72.7%; and consolidation, 54.5% versus 77.3%. In patients with positive RT-PCR results, GGOs were the most commonly observed opacification (seen in 100.0% of patients) and were predominantly located in the peripheral zone (100.0% of patients), compared with patients with negative results (31.8%) (p = 0.05). The median number of affected lung lobes and segments was higher in patients with positive RT-PCR results than in those with negative RT-PCR results (five vs 3.5 affected lobes and 15 vs nine affected segments; p < 0.05). Although the air bronchogram reticular pattern was more frequently seen in patients with positive results, centrilobular nodules were less frequently seen in patients with positive results. CONCLUSION. At the point during the COVID-19 outbreak when this study was performed, imaging patterns of multifocal, peripheral, pure GGO, mixed GGO, or consolidation with slight predominance in the lower lung and findings of more extensive GGO than consolidation on chest CT scans obtained during the first week of illness were considered findings highly suspicious of COVID-19.


Histopathological evaluation of the effects of fiber reinforced acrylic resins on living tissues.
The aim of this study was the histopathological evaluation of the effects of the fiber reinforced acrylic resins on living tissues. The study was performed on 21 rabbits. Three groups, each including seven subjects, were formed. There was no applied plate in the control group. For the second group, heat-polymerized acrylic resin plates were inserted. For the third group, heat-polymerized acrylic resin plates containing proportionally 5% chopped silanated E type glass fiber were inserted. Plates were fixed to the palatine bone of the rabbits with titanium screws. Before the implementation of the plates and 1 month after the plates were applied, soft tissue samples were taken from the buccal mucosa of the rabbits. Also, tissue samples were taken from the control group. All samples were evaluated histopathologically. In the control group, only a focal atrophy was observed. In the acrylic group, large decomposition containing erythrocytes under the parahyperkeratotic region and micro-vesicle like spongiotic tissue reactions were observed. In the fiber reinforced acrylic group, widespread focal atrophy, bulgy look of the epithelium cells similar to apoptosis, over-distension and sub-corneal decomposition had been observed. In terms of atrophy and hyperkeratosis there were no statistically significant differences among groups. However, in respect to sub-corneal decomposition, there was a statistically significant difference in the fiber reinforced group (p < 0.01). The statistically significant difference in the sub-corneal decomposition of the fiber reinforced group had made us think that fiber edges had a traumatic effect on the reaction.


Microvascular decompression of the facial nerve for the treatment of hemifacial spasm: preoperative magnetic resonance imaging related to clinical outcomes.
The objective of this study was to investigate the role of preoperative three dimensional short-range magnetic resonance angiography (3D-TOF MRA) in predicting the clinical outcomes following microvascular decompression for the treatment of hemifacial spasm. Preoperative magnetic resonance (MR) imaging was performed on all patients with hemifacial spasm (564 cases) between January 1992 and September 1998. Of the 564 patients, 440 patients were included in this retrospective study. The presence of vascular contact, offenders, and anomalies in the vertebro-basilar system, were determined by 3D-TOF MRA prior to microvascular decompression of the facial nerve. The preoperative findings were compared with the surgical findings and clinical outcomes. Findings. A correlation was found between the clinical outcome (p < 0.01) and the presence of a vascular indentation at the root entry zone (REZ) of the facial nerve. A shift of the vertebrobasilar system to the symptomatic side was found in 214 (48.6%) patients with hemifacial spasm, compared to only 10 (13.5%) patients in the control group (p < 0.01). The unilateral vertebral artery was observed in 43 (9.8%) patients with hemifacial spasm and in 8 (10.8%) of the control patients. A hypoplasia of the artery was found in 8 (1.8%) patients with hemifacial spasm and in 1 (1.4%) control patient. The compressing offenders in the patients, discovered by MRI in conjunction with MRA, were as follows: 45.9% (202 patients) in the anterior inferior cerebellar artery (AICA), 34.8% (153 patients) in the posterior inferior cerebellar artery (PICA), 12.5% (55 patients) in the vertebral artery (VA) and 6.8% (30 patients) in multiple vessels. In contrast to the compressing offenders seen on the MRA, the offenders confirmed during surgery were as follows: 43% (189 patients) in the AICA, 36.4% (160 patients) in the PICA, 1.4% (6 patients) in the VA, 19% (84 patients) in multiple vessels, and 0.2% (1 patient) in the vein. In our long-term follow-up series of the 440 patients with hemifacial spasm, an excellent surgical outcome was obtained in 86.3% of cases and a good outcome was achieved in 6.4% (mean follow-up duration, 45.5 months). Preoperative 3D-TOF MRA can identify the relationship between the facial nerve and adjacent vessels in patients with a hemifacial spasm and assist in preoperative planning. This study suggests that 3D-TOF MRA is useful for selecting appropriate patients for surgical treatment and, to some extent, as an additional role for predicting the clinical outcome.


A Lyme borreliosis human serosurvey of asymptomatic adults in Ireland.
Blood samples were obtained through the Blood Transfusion Service in Ireland in order to obtain information on the prevalence of asymptomatic B. burgdorferi infections and in an attempt to identify the type of habitat that presents the most risk of infection. Areas in the country were rated as low, medium or high risk based on the availability of suitable tick habitat, access to the public and the distribution of deer, the latter parameter being related to both the occurrence of rodent reservoir hosts and woodland recreational areas. Approximately 100 plasma samples from each of four areas were analysed for IgG anti-Borrelia antibodies by indirect immuno-fluorescence with a titre of 1 :80 indicating a positive reaction in asymptomatic individuals. Prevalence figures of 15, 11, 8 and 5% were obtained for high, high/medium, medium/low and low risk areas respectively. No positive samples were detected in blood from an Icelandic population which is not exposed to I. ricinus bites. The overall subclinical prevalence (9.75%) is surprisingly high in view of the apparent rarity of clinical cases in Ireland, though under-diagnosis probably occurs. These results seem to indicate that farmland is less important than woodland as Lyme borreliosis habitat. If this is so, it is probably due to the presence in woodland of Apodemus sylvaticus, a putative reservoir host, and also to the use of such areas for recreation at certain times of the year.


Hospitalisations and surgery in Crohn's disease.
Hospitalisation and surgery are considered to be markers of more severe disease in Crohn's disease. These are costly events and limiting these costs has emerged as one rationale for the cost of expensive biologic therapies. The authors sought to review the most recent international literature to estimate current hospitalisation and surgery rates for Crohn's disease and place them in the historical context of where they have been, whether they have changed over time, and to compare these rates across different jurisdictions. It is in this context that the authors could set the stage for interpreting some of the early data and studies that will be forthcoming on rates of hospitalisation and surgery in an era of more aggressive biologic therapy. The most recent data from Canada, the United Kingdom and Hungary all suggest that surgical rates were falling prior to the advent of biologic therapy, and continue to fall during this treatment era. The impact of biologic therapy on surgical rates will have to be analysed in the context of evolving reductions in developed regions before biologic therapy was even introduced. Whether more aggressive medical therapy will decrease the requirement for surgery over long periods of time remains to be proven.


Effect of ezetimibe on plasma adipokines: a systematic review and meta-analysis.
Statins are known to influence the status of adipokines, which play a key role in the pathophysiology of cardiometabolic diseases. As the effect of ezetimibe as an add-on to statin therapy on the impact of statins on plasma adipokines levels is currently unclear, the aim of the present study was to investigate this through a meta-analysis of controlled trials. A systematic review was performed, followed by a bibliographic search in PubMed, Medline, SCOPUS, Web of Science and Google Scholar databases. Quantitative data synthesis was performed using a fixed- or random-effects model (based on the level of interstudy heterogeneity) and the generic inverse variance weighting method. Effect sizes were expressed as standardized mean difference (SMD) and 95% confidence interval (CI). Meta-analysis of 23 controlled trials did not suggest any significant effect of adding ezetimibe on top of statin therapy on plasma concentrations of adiponectin (SMD 0.34, 95% CI -0.28, 0.96; P = 0.288), leptin (SMD -0.75, 95% CI: -2.35, 0.85; P = 0.360), plasminogen activator inhibitor 1 (SMD -1.06, 95% CI: -2.81, 0.69; P = 0.236) and interleukin 6 (SMD 0.30, 95% CI: -0.08, 0.67; P = 0.124). However, significantly greater reductions in plasma concentrations of tumour necrosis factor α (TNF-α) (SMD -0.48, 95% CI -0.87, -0.08; P = 0.018) were achieved with ezetimibe/statin combination therapy. The results suggested that ezetimibe add-on to statin therapy is associated with an enhanced TNF-α-lowering effect compared with statin monotherapy. Owing to the emerging role of TNF-α in the pathogenesis of metabolic disorders, further investigations are required to unveil the translational relevance of this TNF-α-lowering effect.


Immunocytochemical localization of group III metabotropic glutamate receptors in the hippocampus with subtype-specific antibodies.
The metabotropic glutamate receptors (mGluRs) mGluR4 and mGluR7 have been postulated to serve as presynaptic autoreceptors in the hippocampal formation. The cellular and synaptic localization of these proteins in the hippocampus, however, is not known. Polyclonal antibodies that specifically react with mGluR4a or mGluR7 were produced and used for immunocytochemical localization of these receptor proteins. Immunoblot analysis with mGluRs expressed in stably transfected baby hamster kidney cells suggests that each of the antibodies reacts specifically with the appropriate mGluR subtype but not with other mGluRs. Both antibodies recognized native proteins in rat brain with molecular weights similar to the molecular weights of the bands in mGluR-transfected cell lines. The distribution of mGluR4a immunoreactivity was fairly uniform in all brain regions. Immunoreactivity for mGluR7 was variable in different brain regions and closely paralleled the previously reported distribution of mGluR7 mRNA. Immunocytochemistry with light and electron microscopy (EM) revealed that immunoreactivities for mGluR4a and mGluR7 are widely but differentially distributed throughout the hippocampal formation. Staining with antibodies directed against mGluR4a was intense in cell bodies and dendrites of pyramidal cells, granule cells, and scattered interneurons. Analysis at the EM level revealed postsynaptic mGluR4a localization at asymmetrical (presumably glutamatergic) synapses and presynaptic localization at both asymmetrical and symmetrical synapses. Immunoreactivity for mGluR7 revealed largely presynaptic localization of this receptor at asymmetrical but not symmetrical synapses. These data are consistent with a largely presynaptic role of mGluR7 in the hippocampus and suggest that mGluR4 may have both presynaptic and postsynaptic functions.


Update on the role of genetics in the onset of age-related macular degeneration.
Age-related macular degeneration (AMD), akin to other common age-related diseases, has a complex pathogenesis and arises from the interplay of genes, environmental factors, and personal characteristics. The past decade has seen very significant strides towards identification of those precise genetic variants associated with disease. That genes encoding proteins of the (alternative) complement pathway (CFH, C2, CFB, C3, CFI) are major players in etiology came as a surprise to many but has already lead to the development of therapies entering human clinical trials. Other genes replicated in many populations ARMS2, APOE, variants near TIMP3, and genes involved in lipid metabolism have also been implicated in disease pathogenesis. The genes discovered to date can be estimated to account for approximately 50% of the genetic variance of AMD and have been discovered by candidate gene approaches, pathway analysis, and latterly genome-wide association studies. Next generation sequencing modalities and meta-analysis techniques are being employed with the aim of identifying the remaining rarer but, perhaps, individually more significant sequence variations, linked to disease status. Complementary studies have also begun to utilize this genetic information to develop clinically useful algorithms to predict AMD risk and evaluate pharmacogenetics. In this article, contemporary commentary is provided on rapidly progressing efforts to elucidate the genetic pathogenesis of AMD as the field stands at the end of the first decade of the 21st century.


The burden of chronic spontaneous urticaria: unsatisfactory treatment and healthcare resource utilization in France (the ASSURE-CSU study).
Data on the clinical burden of chronic spontaneous urticaria (CSU) and economic consequences are lacking in France. To characterize the clinical and economic burden of CSU in symptomatic patients despite treatment by analysing data of French patients from the ASSURE-CSU study. ASSURE-CSU was an international observational study that included CSU patients with symptoms that lasted for 12 months or more despite treatment. Disease characteristics and healthcare resource use were obtained from medical records. Data on disease history, health-related quality of life (HR-QoL), and work productivity were collected from a patient survey. A total of 101 patients were analysed (76.2% female; mean age: 48.9 years) with moderate to severe disease (UAS7 score ≥16) in 43.4% and angioedema in 72.3%. The mean (S.D.) total scores of Chronic Urticaria Quality of Life (CU-Q2oL) and Dermatology Life Quality Index (DLQI) were 37.7 (22.3) and 9.7 (6.9), respectively, thus indicating a significant impact of the disease on HR-QoL. Mean absenteeism and presenteeism were 6.4% and 20.8%, respectively, with a mean loss of work productivity estimated at 20.7%. The mean (S.D.) total direct cost of CSU was €2,397 per patient per year and was mainly driven by therapies (€1,435) and inpatient costs (€859). The indirect costs for four weeks were mainly presenteeism (€421) and loss of work productivity (€420). CSU significantly impairs HR-QoL, which increases with the severity of the disease. The direct and indirect costs for the management of symptomatic CSU are an important economic burden.


Association of fasting glucagon and proinsulin concentrations with insulin resistance.
Hyperproinsulinaemia and relative hyperglucagonaemia are features of type 2 diabetes. We hypothesised that raised fasting glucagon and proinsulin concentrations may be associated with insulin resistance (IR) in non-diabetic individuals. We measured IR [by a euglycaemic-hyperinsulinaemic (240 pmol min(-1) m(-2)) clamp technique] in 1,296 non-diabetic (on a 75 g OGTT) individuals [716 women and 579 men, mean age 44 years, BMI 26 kg/m(2) (range 18-44 kg/m(2))] recruited at 19 centres in 14 European countries. IR was related to fasting proinsulin or pancreatic glucagon concentrations in univariate and multivariate analyses. Given its known relationship to IR, serum adiponectin was used as a positive control. In either sex, both glucagon and proinsulin were directly related to IR, while adiponectin was negatively associated with it (all p < 0.0001). In multivariate models, controlling for known determinants of insulin sensitivity (i.e. sex, age, BMI and glucose tolerance) as well as factors potentially affecting glucagon and proinsulin (i.e. fasting plasma glucose and C-peptide concentrations), glucagon and proinsulin were still positively associated, and adiponectin was negatively associated, with IR. Finally, when these associations were tested as the probability that individuals in the top IR quartile would have hormone levels in the top quartile of their distribution independently of covariates, the odds ratio was approximately 2 for both glucagon (p = 0.05) and proinsulin (p = 0.02) and 0.36 for adiponectin (p < 0.0001). Whole-body IR is independently associated with raised fasting plasma glucagon and proinsulin concentrations, possibly as a result of IR at the level of alpha cells and beta cells in pancreatic islets.


VALGENT: A protocol for clinical validation of human papillomavirus assays.
Testing for high-risk HPV is more effective in primary cervical cancer screening than the cytological examination of a Pap smear. Separate genotyping may be useful for triage in both HPV-based and cytology-based screening. Only clinically validated tests should be used in clinical practice. VALGENT is a study framework for test comparison and validation of HPV assays in general and HPV genotyping tests in particular according to clinically relevant outcomes and for clinical applications endorsed by scientific evidence. VALGENT involves the collation of fresh or archived cervical cell specimen from women attending routine screening supplemented with cytologically abnormal samples. Multiple aliquots of residual material are sent from a central laboratory to participating laboratories for testing with novel HPV assays with limited, extended or full genotyping capacity. Outcomes are derived from screening and pathology registries. Each VALGENT panel includes an assay already validated for screening. A series of accuracy and concordance statistics were generated. Currently, two VALGENT study rounds, originated from laboratories in Antwerp (Belgium) and Edinburgh (Scotland), were completed. Two new assays (G5+/6+ PCR-LMNX and Xpert HPV) were validated for screening by showing similar accuracy for cervical precancer as the standard comparator test. For two other tests (BD Onclarity, PapilloCheck) validation was confirmed. Inter-test agreement was high although certain type-specific discordances were observed which warrant further analysis. VALGENT extends current guidelines for high-risk HPV test validation in cervical cancer screening and has produced a large study resource for test comparison. More robust procedures of sample selection and handling and integration with the global WHO reference laboratory network focusing on analytical accuracy, may result in the generation of an international standard and a formalized system for clinical validation of HPV assays and quality control in HPV-based screening.


Clinical and molecular study of Corynebacterium diphtheriae systemic infections in France. Coryne Study Group.
Diphtheria is a disease with a long history that almost completely disappeared from developed countries. In addition, until 1987, systemic infections involving Corynebacterium diphtheriae were rare. However, in 1990, an epidemic occurred in Russia. These two circumstances have provided the stimulus to gain insight into the situation in France. In fact, between 1987 and 1993, a total of 59 C. diphtheriae strains were isolated. Epidemiological data were collected for patients from whom 40 strains were isolated from normally sterile sites, including 34 from blood cultures, and half of the bacteremic patients developed endocarditis. Osteoarticular involvement was noted in 11 of these 40 patients, including 5 bacteremic patients. The fatality rate following bacteremia was 36%, despite specific antibiotic treatment (beta-lactams and aminoglycosides). The mean age of the participants was 38 years, with half of the patients subsisting under low socioeconomic conditions and suffering from homelessness or alcoholism. Apparently, the skin turned out to be the major route of transmission in this reemerging disease. Eighty-eight percent of the isolates belonged to the C. diphtheriae biotype mitis. These were found predominantly in the Paris area, and most were of the same ribotype. Those isolates originating from the overseas territories (Guyana and New Caledonia) belonged to C. diphtheriae biotype gravis. No strains were positive for the tox gene by PCR. This study attests to the persistent circulation in France of C. diphtheriae in the form of systemic infections. The matter is especially significant since these strains are nontoxigenic and are of a unique ribotype. The strains are, however, sensitive to most antibiotics, although 20% are rifampin resistant.


Micellar drug nanocarriers and biomembranes: how do they interact?
Pluronic based formulations are among the most successful nanomedicines and block-copolymer micelles including drugs that are undergoing phase I/II studies as anticancer agents. Using coarse-grained models, molecular dynamics simulations of large-scale systems, modeling Pluronic micelles interacting with DPPC lipid bilayers, on the μs timescale have been performed. Simulations show, in agreement with experiments, the release of Pluronic chains from the micelle to the bilayer. This release changes the size of the micelle. Moreover, the presence of drug molecules inside the core of the micelle has a strong influence on this process. The picture emerging from the simulations is that the micelle stability is a result of an interplay of drug-micelle core and block-copolymer-bilayer interactions. The equilibrium size of the drug vector shows a strong dependency on the hydrophobicity of the drug molecules embedded in the core of the micelle. In particular, the radius of the micelle shows an abrupt increase in a very narrow range of drug molecule hydrophobicity.


Expression and use of human immunodeficiency virus type 1 coreceptors by human alveolar macrophages.
Human immunodeficiency virus type 1 (HIV-1) requires, in addition to CD4, coreceptors of the CC or CXC chemokine families for productive infection of T cells and cells of the monocyte-macrophage lineage. Based on the hypothesis that coreceptor expression on alveolar macrophages (AM) may influence HIV-1 infection of AM in the lung, this study analyzes the expression and utilization of HIV-1 coreceptors on AM of healthy individuals. AM were productively infected with five different primary isolates of HIV-1. Levels of surface expression of CCR5, CXCR4, and CD4 were low compared to those of blood monocytes, but CCR3 was not detectable. mRNA for CCR5, CXCR4, CCR2, and CCR3 were all detectable, but to varying degrees and with variability among donors. Expression of CCR5, CXCR4, and CCR2 mRNA was downregulated following stimulation with lipopolysaccharide (LPS). In contrast, secretion of the chemokines RANTES, MIP-1alpha, and MIP-1beta was upregulated with LPS stimulation. Interestingly, HIV-1 replication was diminished following LPS stimulation. Infection of AM with HIV-1 in the presence of the CC chemokines demonstrated blocking of infection. Together, these studies demonstrate that AM can be infected by a variety of primary HIV-1 isolates, AM express a variety of chemokine receptors, the dominant coreceptor used for HIV entry into AM is CCR5, the expression of these receptors is dependent on the state of activation of AM, and the ability of HIV-1 to infect AM may be modulated by expression of the chemokine receptors and by chemokines per se.


The use of dietary supplements in a community hospital comprehensive cancer center: implications for conventional cancer care.
There is little data on the prevalence of use of dietary supplements in cancer, especially in light of the growing evidence that some dietary supplements can have adverse interactions with conventional cancer treatment. The purpose of this study was to investigate the use of dietary supplements among adult cancer patients in a community hospital comprehensive cancer center. A survey of 227 new adult cancer patients presenting for treatment for the first time at Cancer Treatment Centers of America at Midwestern Regional Medical Center, between November 2001 and October 2003. Patients completed the McCune Questionnaire, a validated instrument that captures information on the use of 56 dietary supplements in cancer, at admission to the hospital. Of the 227 patients, 73% used some form of dietary supplements during the 30 day period before the survey was conducted. Dietary supplement use was significantly higher (p = 0.04) in patients with colorectal (80%) and breast (75%) cancer as compared to patients with lung cancer (53%). Patients with stage II (86%) and III (76%) disease at diagnosis were more likely (p = 0.02) to use dietary supplements as compared to those with stage I (71%) disease at diagnosis, while those with stage IV (61%) disease at diagnosis were least likely to use them. Of the 80 patients who had received chemotherapy within the last 30 days, 71% had also used dietary supplements in that timeframe and 25% had consumed one or more herbal therapies that are suspected to have adverse interactions with chemotherapy. Of the 57 patients combining chemotherapy with dietary supplements, 52.6% did not consult a healthcare professional. In our study, twenty-five percent of patients receiving chemotherapy were concurrently using dietary supplements suspected to have adverse interactions with chemotherapy, usually relying on information sources other than healthcare professionals. Given the prevalence rates of these agents, healthcare providers should systematically inquire about them, and consider the potential for drug-dietary supplement interactions in treatment planning.


Lysis of inducer T cell clones by activated macrophages and macrophage-like cell lines.
We describe a sequence of reciprocal interactions between cloned inducer T cells and antigen-presenting cells (APC) that results in selective depletion of the antigen-reactive inducer cells. We show that corecognition of antigen and I-A by hapten-reactive inducer T cell clones results in (a) release of macrophage-activating factor (MAF) and other lymphokines, (b) expression of lytic activity by a subset of MAF-sensitized APC after triggering, and (3) lysis (mediated by the activated and triggered macrophage) of the inducer T cell clone and other cells in the vicinity. We suggest that this sequence of steps may limit the extent of macrophage-mediated tissue destruction by depleting the specific inducer T cell clones that initiate the response.


Downregulated NPAS4 in multiple brain regions is associated with major depressive disorder.
Major Depressive Disorder (MDD) is a commonly observed psychiatric disorder that affects more than 2% of the world population with a rising trend. However, disease-associated pathways and biomarkers are yet to be fully comprehended. In this study, we analyzed previously generated RNA-seq data across seven different brain regions from three distinct studies to identify differentially and co-expressed genes for patients with MDD. Differential gene expression (DGE) analysis revealed that NPAS4 is the only gene downregulated in three different brain regions. Furthermore, co-expressing gene modules responsible for glutamatergic signaling are negatively enriched in these regions. We used the results of both DGE and co-expression analyses to construct a novel MDD-associated pathway. In our model, we propose that disruption in glutamatergic signaling-related pathways might be associated with the downregulation of NPAS4 and many other immediate-early genes (IEGs) that control synaptic plasticity. In addition to DGE analysis, we identified the relative importance of KEGG pathways in discriminating MDD phenotype using a machine learning-based approach. We anticipate that our study will open doors to developing better therapeutic approaches targeting glutamatergic receptors in the treatment of MDD.


Fluid resuscitation in septic shock: the effect of increasing fluid balance on mortality.
To determine whether progressively increasing fluid balance after initial fluid resuscitation for septic shock is associated with increased mortality. A retrospective review of the use of intravenous fluids in patients with septic shock in a large university affiliated hospital with 56 medical-surgical intensive care unit beds. We analyzed the data of 350 patients with septic shock who were managed according to the Surviving Sepsis Campaign guidelines. Based on net fluid balance at 24 hours, we examined the results of increase in positive fluid balance on the risk of in-hospital mortality. Patients were divided into 4 groups based on the amount of fluid balance by 24 hours, based on 6-L aliquots. At 24 hours, the average fluid balance was +6.5 L. After correcting for age and sequential organ failure assessment score, a more positive fluid balance at 24 hours significantly increased the risk of in-hospital mortality. Using Cox proportional hazard analysis, excess 12-, 18-, and 24-L positive fluid balance had higher risk of mortality than those patients with a neutral to positive 6-L fluid balance (reference group). Adjusted hazard ratios, 1.519 (95% confidence interval [CI], 1.353-1.685), 1.740 (95% CI, 1.467-2.013), and 1.620 (95% CI, 1.197-2.043), respectively, P < .05. In patients with septic shock resuscitated according to current guidelines, a more positive fluid balance at 24 hours is associated with an increase in the risk of mortality. Optimal survival occurred at neutral fluid balance and up to 6-L positive fluid balance at 24 hours after the development of septic shock.


Good Liars Are Neither 'Dark' Nor Self-Deceptive.
Deception is a central component of the personality 'Dark Triad' (Machiavellianism, Psychopathy and Narcissism). However, whether individuals exhibiting high scores on Dark Triad measures have a heightened deceptive ability has received little experimental attention. The present study tested whether the ability to lie effectively, and to detect lies told by others, was related to Dark Triad, Lie Acceptability, or Self-Deceptive measures of personality using an interactive group-based deception task. At a group level, lie detection accuracy was correlated with the ability to deceive others-replicating previous work. No evidence was found to suggest that Dark Triad traits confer any advantage either to deceive others, or to detect deception in others. Participants who considered lying to be more acceptable were more skilled at lying, while self-deceptive individuals were generally less credible and less confident when lying. Results are interpreted within a framework in which repeated practice results in enhanced deceptive ability.


The effect of emotional and attentional load on attentional startle modulation.
The interactive effects of emotion and attention on attentional startle modulation were investigated in two experiments. Participants performed a discrimination and counting task with two visual stimuli during which acoustic eyeblink startle-eliciting probes were presented at long lead intervals. In Experiment 1, this task was combined with aversive Pavlovian conditioning. In Group Attend CS+, the attended stimulus was followed by an aversive unconditional stimulus (US) and the ignored stimulus was presented alone whereas the ignored stimulus was paired with the US in Group Attend CS-. In Experiment 2, a non-aversive reaction time task US replaced the aversive US. Regardless of the conditioning manipulation and consistent with a modality non-specific account of attentional startle modulation, startle magnitude was larger during attended than ignored stimuli in both experiments. Blink latency shortening was differentially affected by the conditioning manipulations suggesting additive effects of conditioning and discrimination and counting task on blink startle.


Electrophysiological demonstration of mu, delta and kappa opioid receptors in the ventral pallidum.
Opioid mu, kappa and delta receptors are present in significant densities in the ventral pallidum (VP). To examine their contribution to VP neuronal activity, changes in firing rate during microiontophoresis of the receptor-selective agonists [D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin (DAMGO) (mu), [D-Pen2,5]-enkephalin (DPDPE) (delta) and trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cy-clohexyl]-benzene-acetamide methane sulfonate (U50488H) (kappa), and the antagonists D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) (mu) and norbinaltorphimine (kappa) were determined in chloral hydrate-anesthetized rats. A majority of the neurons demonstrated ejection current-dependent decreases in neuronal activity to DAMGO and U50488H. The rate suppressions were attenuated by coiontophoresis of the homotypic antagonist, indicating receptor subtype-specificity of the responses. In contrast, DPDPE decreased firing in only 24% of the recorded neurons. In those neurons tested with all three agonists, nearly 70% were sensitive to at least one. Among responding neurons, approximately one-quarter was influenced by activation of all three receptor subtypes while another quarter was sensitive to only mu activation. Thus, subpopulations of VP neurons may exist according to the influence of particular opioid receptor subtypes. These findings were compared to the nonselective opioid, morphine. Morphine iontophoresis elicited both excitations and inhibitions whereas DAMGO exclusively inhibited the same VP neurons. Responses to both were antagonized by naloxone and CTOP, indicating mu receptor-specific actions. The results are discussed in terms of differential direct and indirect effects of morphine and DAMGO. In summary, mu, delta and kappa opioid receptors can independently alter neuronal activity within the VP, and direct and indirect effects are most likely involved.


Assisted suicide and the killing of people? Maybe. Physician-assisted suicide and the killing of patients? No: the rejection of Shaw's new perspective on euthanasia.
David Shaw presents a new argument to support the old claim that there is not a significant moral difference between killing and letting die and, by implication, between active and passive euthanasia. He concludes that doctors should not make a distinction between them. However, whether or not killing and letting die are morally equivalent is not as important a question as he suggests. One can justify legal distinctions on non-moral grounds. One might oppose physician-assisted suicide and active euthanasia when performed by doctors on patients whether or not one is in favour of the legalisation of assisted suicide and active euthanasia. Furthermore, one can consider particular actions to be contrary to appropriate professional conduct even in the absence of legal and ethical objections to them. Someone who wants to die might want only a doctor to kill him or to help him to kill himself. However, we are not entitled to everything that we want in life or death. A doctor cannot always fittingly provide all that a patient wants or needs. It is appropriate that doctors provide their expert advice with regard to the performance of active euthanasia but they can and should do so while, qua doctors, they remain hors de combat.


Psychosocial and mental health challenges faced by emerging adults living with HIV and support systems aiding their positive coping: a qualitative study from the Kenyan coast.
In sub-Saharan Africa, there is little data on the challenges faced by young people living with HIV transitioning into adult life. Adapting the socio-ecological framework, this qualitative study investigated the challenges faced by emerging adults living with HIV from a rural Kenyan setting. Additionally, the study explored support systems that aid positive coping among these young adults. In April 2018, in-depth interviews were conducted with a convenience sample of 22 young adults living with HIV (12 females), 18-24 years old, from rural Kilifi, coast of Kenya. Data were analyzed thematically using NVIVO 11 software. Young adults living with HIV from this setting face various challenges at different levels of the social ecosystem. At the individual level, key challenges they reported included acceptance of HIV positive status, antiretroviral adherence, economic burden associated with access to healthcare, building an intimate relationship, mental health problems, and HIV status disclosure. At the family level, death of parents, poverty, and being unaccepted were the commonly mentioned challenges. At the community level, socialization difficulties and long waiting time at the HIV clinic were highlighted. HIV stigma and discrimination were frequently reported across the different levels. Economic independence, social support (from families, friends, organizations, healthcare providers and peer meetings), and reliance on spirituality aided positive coping among these young adults amidst the challenges of living with HIV. In this rural setting, emerging adults living with HIV face various challenges at the individual, family, and community level, some of which are cross-cutting. Our findings underscore the need for designing multi-level youth-friendly interventions that can address modifiable challenges encountered by emerging adults living with HIV in this and similar settings. Such interventions should incorporate appropriate context-specific support structures that may help these young people smoothly transit into adult life.


In situ hybridization and monoclonal antibody analysis of plasma membrane Ca-pump mRNA and protein in submandibular glands of rabbit, rat and man.
The degree of supersaturation of saliva with calcium (Ca) is related to the mineral phase of enamel in erupted teeth, the incidence of caries, and the formation of calculus. The mechanisms for regulating salivary Ca concentration are therefore of relevance to dentistry. Sections of rabbit, rat and human submandibular gland (SMG) were processed for immuno-histochemistry with a specific anti-plasma membrane Ca-pump antibody, 5F10. Western blots confirm that the molecular weight of the proteins identified by our antibody (135 kDa) is consistent with an appropriate molecular weight for PMCA antigen (135-150 kDa). Tissue sections were also processed for in situ hybridization to study the distribution of the PMCA mRNA isoforms. In mammals, the PMCA1 gene is reported to code for a PMCA protein with a role in maintaining the intracellular Ca levels in both epithelial and non-epithelial cells. Other genes including the PMCA2 and PMCA4 genes may code for PMCA proteins specific to Ca transporting tissues. Our studies demonstrate cytoplasmic labeling of PMCA mRNA with hPMCA-1 and hPMCA-4 specific cDNA probes in humans, and rPMCA-1 and rPMCA-2 specific oligonucleotide probes in rats. Labeling of PMCA protein and all mRNA isoforms was found in the cytoplasm of the interlobular and intralobular ducts (except for intercalated ducts). The demonstrated presence of PMCA in SMGs of rabbit, rat, and man, may suggest a role for PMCA in the regulation of intracellular Ca and in a mechanism for regulating and maintaining the high concentration of Ca in salvia.


Trajectories of adherence to home-based exercise programs among people with knee osteoarthritis.
To investigate the presence of different trajectories of self-reported adherence to home exercise programs among people with knee osteoarthritis (OA), and to compare baseline characteristics across identified groups. Pooled analysis of data from three randomised controlled trials involving exercise interventions for people aged ≥50 years with clinical knee OA (n = 341). Exercise adherence was self-reported on an 11-point numerical rating scale (NRS; 0 = not at all-10 = completely as instructed). Latent class growth analysis was used to identify distinct trajectories of adherence, at intervals from 12 to 78 weeks from baseline. Baseline characteristics of these groups were compared using chi-squared tests, one-way analysis of variance (ANOVA) and Kruskal Wallis tests where appropriate. Three distinct adherence trajectories were identified: a "Rapidly declining adherence" group (n = 157, 47.4%) whose adherence was 7.7 ± 1.6 (/10) at 12 weeks, declined to 4.2 ± 2.2 by 22 weeks and remained low thereafter; a "Gradually declining adherence" group (n = 153, 45.1%) whose adherence declined from 8.5 ± 1.5 to 7.8 ± 1.5 over the same period, and continued to decline slowly, and a "Low adherence" group (n = 21, 6.3%) whose adherence was 2.2 ± 1.4 at 12 weeks and remained low. At baseline the "Rapidly declining adherence" group reported significantly lower Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain (mean difference (95% Confidence Interval (CI)) -0.8 (-1.4, -0.2)) and better WOMAC function compared to the "Gradually declining adherence" group (-3.1 (-5.2, -1.1)). Three trajectories of self-reported adherence to home exercises were found among people with knee OA. Findings highlight the need for close monitoring of adherence from initiation of a home exercise program in order to identify and intervene when low or rapidly declining adherence is identified.


Alcohol consumption and the risk of coronary heart disease in postmenopausal women with diabetes: Women's Health Initiative Observational Study.
Although several observational studies have consistently reported an inverse association between moderate alcohol consumption and risk of coronary heart disease (CHD), it is yet not well established if this association also exists among people with type 2 diabetes. The aim of this study is to evaluate the association between the frequency and quantity of alcohol intake and the risk of developing CHD among postmenopausal women with diabetes. We conducted a prospective cohort study, which included 3,198 women with self-reported diabetes and without any history of cardiovascular disease at baseline, in the Women's Health Initiative Observational Study. Alcohol intake was assessed by a semiquantitative food frequency questionnaire. The primary outcome of this study was CHD, which was validated by medical record review. Cox proportional hazards regression was used to estimate the hazard ratio (HR) for the association of alcohol intake and risk of incident CHD while adjusting for several potential confounders. During the 22,546 person-years of follow-up, there were 336 incident cases of CHD. Both frequency and quantity of alcohol intake were inversely associated with the risk of developing CHD. Compared to nondrinkers, the multivariable HRs across categories of frequency of alcohol consumption (<or=0.5, 0.5-2 and >or=2 drinks/week) were 0.89 (95% confidence intervals [CI]: 0.63, 1.26), 0.84 (95% CI: 0.56, 1.25) and 0.65 (95% CI: 0.43, 0.99), respectively (p for trend: 0.04). This association did not appear to differ based on the type of the alcoholic beverage consumed. Moderate alcohol consumption of postmenopausal women with type 2 diabetes may have a benefit on CHD similar to that seen in postmenopausal nondiabetic women. The potential risks of alcohol on noncardiac outcomes may need consideration when recommending alcohol to women with diabetes.


Impact of placement type on the development of clinical competency in speech-language pathology students.
Speech-language pathology students gain experience and clinical competency through clinical education placements. However, currently little empirical information exists regarding how competency develops. Existing research about the effectiveness of placement types and models in developing competency is generally descriptive and based on opinions and perceptions. The changing nature of education of speech-language pathology students, diverse student cohorts, and the crisis in finding sufficient clinical education placements mean that establishing the most effective and efficient methods for developing clinical competency in students is needed. To gather empirical information regarding the development of competence in speech-language pathology students; and to determine if growth of competency differs in groups of students completing placements that differ in terms of caseload, intensity and setting. Participants were students in the third year of a four-year undergraduate speech-language pathology degree who completed three clinical placements across the year and were assessed with the COMPASS® competency assessment tool. Competency development for the whole group across the three placements is described. Growth of competency in groups of students completing different placement types is compared. Interval-level data generated from the students' COMPASS® results were subjected to parametric statistical analyses. The whole group of students increased significantly in competency from placement to placement across different placement settings, intensities and client age groups. Groups completing child placements achieved significantly higher growth in competency when compared with the competency growth of students completing adult placements. Growth of competency was not significantly different for students experiencing different intensity of placements, or different placement settings. These results confirm that the competency of speech-language pathology students develops across three clinical placements over a one-year period regardless of placement type or context, indicating that there may be a transfer of learning between placements types. Further research investigating patterns of competency development in speech-language pathology students is warranted to ensure that assumptions used to design clinical learning opportunities are based on valid evidence.


Molecular evolution of the MAGUK family in metazoan genomes.
Development, differentiation and physiology of metazoans all depend on cell to cell communication and subsequent intracellular signal transduction. Often, these processes are orchestrated via sites of specialized cell-cell contact and involve receptors, adhesion molecules and scaffolding proteins. Several of these scaffolding proteins important for synaptic and cellular junctions belong to the large family of membrane-associated guanylate kinases (MAGUK). In order to elucidate the origin and the evolutionary history of the MAGUKs we investigated full-length cDNA, EST and genomic sequences of species in major phyla. Our results indicate that at least four of the seven MAGUK subfamilies were present in early metazoan lineages, such as Porifera. We employed domain sequence and structure based methods to infer a model for the evolutionary history of the MAGUKs. Notably, the phylogenetic trees for the guanylate kinase (GK)-, the PDZ- and the SH3-domains all suggested a matching evolutionary model which was further supported by molecular modeling of the 3D structures of different GK domains. We found no MAGUK in plants, fungi or other unicellular organisms, which suggests that the MAGUK core structure originated early in metazoan history. In summary, we have characterized here the molecular and structural evolution of the large MAGUK family. Using the MAGUKs as an example, our results show that it is possible to derive a highly supported evolutionary model for important multidomain families by analyzing encoded protein domains. It further suggests that larger superfamilies encoded in the different genomes can be analyzed in a similar manner.


Mnemonic construction and representation of temporal structure in the hippocampal formation.
The hippocampal-entorhinal region supports memory for episodic details, such as temporal relations of sequential events, and mnemonic constructions combining experiences for inferential reasoning. However, it is unclear whether hippocampal event memories reflect temporal relations derived from mnemonic constructions, event order, or elapsing time, and whether these sequence representations generalize temporal relations across similar sequences. Here, participants mnemonically constructed times of events from multiple sequences using infrequent cues and their experience of passing time. After learning, event representations in the anterior hippocampus reflected temporal relations based on constructed times. Temporal relations were generalized across sequences, revealing distinct representational formats for events from the same or different sequences. Structural knowledge about time patterns, abstracted from different sequences, biased the construction of specific event times. These findings demonstrate that mnemonic construction and the generalization of relational knowledge combine in the hippocampus, consistent with the simulation of scenarios from episodic details and structural knowledge.


Influence of pranayamas and yoga-asanas on serum insulin, blood glucose and lipid profile in type 2 diabetes.
A distinguishable feature of type 2 diabetes besides hyperglycemia and deranged lipid profile is an impaired insulin secretion, peripheral insulin resistance and obesity which has become a major health concern worldwide. India with an estimated 31million diabetics in 2000 and 79mllions by the yr 2030 has the highest number of type 2 diabetics in the world. In this study, we aimed to see if yoga-asanas and pranayamas have any influence in modifying certain biochemical parameters. Sixty patients of uncomplicated type 2 diabetes (age 35-60 yrs of 1-10 yrs duration) were divided into two groups: Group 1 (n=30): performed yoga along with the conventional hypoglycemic medicines and group 2 (n=30): patients who only received conventional medicines. Duration of the study was 45 days. Basal recordings of blood glucose (fasting and post-prandial), lipid profile and serum insulin were taken at the time of recruitment and the second reading after forty five days. Results showed a significant improvement in all the biochemical parameters in group 1 while group 2 showed significant improvement in only few parameters, thus suggesting a beneficial effect of yoga regimen on these parameters in diabetic patients.


Topical treatment of nonhealing venous leg ulcer with propolis ointment.
An investigation of effectiveness of topical treatment of nonhealing chronic venous leg ulcers with propolis ointment was conducted. 56 patients were included in the study and randomized into two groups. In group 1, there were 28 patients (ulceration area: 6.9-9.78 cm(2)) treated by means of topical propolis ointment application and short stretch bandage compression. In group 2, there were 29 patients (ulceration area: 7.2-9.4 cm(2)) treated by means of Unna boot leg compression without topical propolis treatment. In the study, the efficacy of both treatment methods in patients with resistive venous leg ulcers was compared. The ulceration of patients from group 1 healed completely after 6 weeks of therapy in all cases. In all patients from group 2, the process of healing was longer but successfully completed after 16 weeks of the therapy. We found that an adjunctive propolis ointment treatment increases the efficacy of the short stretch bandage compression stocking, and this combined treatment is more effective than Unna's boot compression alone.


Optical performance of frequency-selective bolometers.
Frequency-selective bolometers (FSBs) are a new type of detector for millimeter and submillimeter wavelengths that are transparent to all but a narrow range of frequencies as set by characteristics of the absorber itself. Therefore stacks of FSBs tuned to different frequencies provide a low-loss compact method for utilizing a large fraction of the light collected by a telescope. Tests of prototype FSBs indicate that the absorption spectra are well predicted by models, that peak absolute absorption efficiencies of the order of 50% are attainable, and that their out-of-band transmission is high.


Are Desensitizing Toothpastes Equally Biocompatible and Effective Against Microorganisms?
The aims of this study were evaluate cytotoxicity, genotoxicity, antimicrobial activity of desensitizing toothpastes compared to a common one and the surface roughness of tooth enamel submitted to brushing with these toothpastes. Samples of three desensitizing toothpastes (Colgate Sensitive, Sensodyne and Oral B Sensitive) and common toothpaste (Colgate) were placed in contact with gingival human fibroblasts. Cytotoxicity and genotoxocity were measured by MTT assay and micronucleus test. Antimicrobial activity of the toothpastes extracts against C. albicans, S. mutans and S. aureus were assessed. For surface roughness evaluation, bovine teeth were submitted to 10.000 brushing cycles. The results were analyzed statically using Mann-Whitney U, ANOVA and Z tests (p<0.05). All toothpastes caused cytotoxic effect to the cells (p<0.05), except Colgate Sensitive. The toothpastes did not increase the number of micronuclei compared to the untreated control group. Colgate eliminated all the evaluated microorganisms at lower concentrations compared to Colgate Sensitive and Oral B Sensitive, which were not able to eliminate S. aureus. Sensodyne did not reach the minimum microbicidal concentration. The surface roughness of tooth enamel increased after brushing with Colgate Sensitive and Oral B Sensitive, however the comparison between groups showed no difference on the enamel surface roughness presented by desensitizing toothpastes when compared with the common one (p>0.05). Based on these results, we can conclude that although none toothpaste has induced genotoxicity, Colgate Sensitive was also not cytotoxic. Colgate was the most effective against the microorganisms, and there were no differences on the enamel surface roughness between the groups.


Human metapneumovirus-associated respiratory tract infections in the Republic of Ireland during the influenza season of 2003-2004.
Human metapneumovirus (hMPV) is a newly identified paramyxovirus that has been associated with respiratory tract illness in children aged < 5 years, the elderly, and immunocompromised patients. This study determined the frequency of respiratory tract infections (RTIs) associated with hMPV in the Republic of Ireland. Bronchoalveolar lavage (BAL) samples from 168 adult patients and respiratory specimens from 122 children aged < 5 years were collected between September 2003 and May 2004. The virus was detected by reverse-transcription (RT)-PCR using hMPV polymerase (L) and matrix (M)-specific primers in four (2.4%) of 171 BAL specimens obtained from 168 adults. No other respiratory virus was detected in these specimens, and no hMPV RNA was detected in respiratory specimens from children during the same time period. In all four adult cases, two of whom had underlying disease, hMPV was associated with mild, self-limiting upper RTIs. The most common clinical findings included fever (3/4 patients), cough (4/4) and rhinorrhoea (3/4). No patient died as a result of these RTI episodes. Phylogenetic analysis was performed using the amplified regions of the M and fusion (F) genes of hMPV. The Irish isolates belonged to cluster 1B, and did not show a separate Irish sub-lineage.


Hierarchical porous carbon by ultrasonic spray pyrolysis yields stable cycling in lithium-sulfur battery.
Utilizing the unparalleled theoretical capacity of sulfur reaching 1675 mAh/g, lithium-sulfur (Li-S) batteries have been counted as promising enablers of future lithium ion battery (LIB) applications requiring high energy densities. Nevertheless, most sulfur electrodes suffer from insufficient cycle lives originating from dissolution of lithium polysulfides. As a fundamental solution to this chronic shortcoming, herein, we introduce a hierarchical porous carbon structure in which meso- and macropores are surrounded by outer micropores. Sulfur was infiltrated mainly into the inner meso- and macropores, while the outer micropores remained empty, thus serving as a "barricade" against outward dissolution of long-chain lithium polysulfides. On the basis of this systematic design, the sulfur electrode delivered 1412 mAh/g sulfur with excellent capacity retention of 77% after 500 cycles. Also, a control study suggests that even when sulfur is loaded into the outer micropores, the robust cycling performance is preserved by engaging small sulfur crystal structures (S2-4). Furthermore, the hierarchical porous carbon was produced in ultrahigh speed by scalable spray pyrolysis. Each porous carbon particle was synthesized through 5 s of carrier gas flow in a reaction tube.


Rethinking the history of common walnut (Juglans regia L.) in Europe: Its origins and human interactions.
Common walnut (Juglans regia L) is an economically important species cultivated worldwide for its high-quality wood and nuts. It is generally accepted that after the last glaciation J. regia survived and grew in almost completely isolated stands in Asia, and that ancient humans dispersed walnuts across Asia and into new habitats via trade and cultural expansion. The history of walnut in Europe is a matter of debate, however. In this study, we estimated the genetic diversity and structure of 91 Eurasian walnut populations using 14 neutral microsatellites. By integrating fossil pollen, cultural, and historical data with population genetics, and approximate Bayesian analysis, we reconstructed the demographic history of walnut and its routes of dispersal across Europe. The genetic data confirmed the presence of walnut in glacial refugia in the Balkans and western Europe. We conclude that human-mediated admixture between Anatolian and Balkan walnut germplasm started in the Early Bronze Age, and between western Europe and the Balkans in eastern Europe during the Roman Empire. A population size expansion and subsequent decline in northeastern and western Europe was detected in the last five centuries. The actual distribution of walnut in Europe resulted from the combined effects of expansion/contraction from multiple refugia after the Last Glacial Maximum and its human exploitation over the last 5,000 years.


Carcinogenesis of Male Oral Submucous Fibrosis Alters Salivary Microbiomes.
Most oral squamous cell carcinoma (OSCC) tumors arise from oral premalignant lesions. Oral submucous fibrosis (OSF), usually occurring in male chewers of betel quid, is a premalignant stromal disease characterized by a high malignant transformation rate and high prevalence. Although a relationship between the inhabited microbiome and carcinogenesis has been proposed, no detailed information regarding the oral microbiome of patients with OSF exists; the changes of the salivary microbiome during cancer formation remain unclear. This study compared the salivary microbiomes of male patients with OSCC and a predisposing OSF background (OSCC-OSF group) and those with OSF only (OSF group). The results of high-throughput sequencing of the bacterial 16S rRNA gene indicated that OSF-related carcinogenesis and smoking status significantly contributed to phylogenetic composition variations in the salivary microbiome, leading to considerable reductions in species richness and phylogenetic diversity. The microbiome profile of OSF-related malignancy was associated with increased microbial stochastic fluctuation, which dominated the salivary microbiome assembly and caused species co-occurrence network collapse. Artificial intelligence selection algorithms consistently identified 5 key species in the OSCC-OSF group: Porphyromonas catoniae, Prevotella multisaccharivorax, Prevotella sp. HMT-300, Mitsuokella sp. HMT-131, and Treponema sp. HMT-927. Robust accuracy in predicting oral carcinogenesis was obtained with our exploratory and validation data sets. In functional analysis, the microbiome of the OSCC-OSF group had greater potential for S-adenosyl-l-methionine and norspermidine synthesis but lower potential for l-ornithine and pyrimidine deoxyribonucleotide synthesis and formaldehyde metabolism. These findings indicated that the salivary microbiome plays important roles in modulating microbial metabolites during oral carcinogenesis. In conclusion, our results provided new insights into salivary microbiome alterations during the malignant transformation of OSF.


Functional Impairment and Changes in Depression Subtypes for Women in STAR*D: A Latent Transition Analysis.
To characterize the association between functional impairment and major depression subtypes at baseline and to characterize changes in subtypes by functional impairment level in women receiving citalopram in level 1 of the Sequenced Treatment Alternatives to Relieve Depression trial. Women who completed baseline and week 12 study visits were included. Items from the self-reported Quick Inventory of Depressive Symptomatology were used to define the latent depression subtypes. The Work and Social Adjustment Scale was used to classify baseline functional impairment. A latent transition analysis model provided estimates of the prevalence of subtype membership and transition probabilities by functional impairment level. Of the 755 women included, 69% had major functional impairment at baseline. Regardless of functional impairment level, the subtypes were differentiated by depression severity, appetite changes, psychomotor disturbances, and insomnia. Sixty-seven percent of women with normal/significant functional impairment and 60% of women with major impairment were likely to transition to a symptom resolution subtype at week 12. Women with baseline major impairment who were in the severe with psychomotor agitation subtype at the beginning of the study were least likely to transition to the symptom resolution subtype (4% chance). Functional impairment level was related to both the baseline depression subtype and the likelihood of moving to a different subtype. These results underscore the need to incorporate not only depression symptoms but also functioning in the assessment and treatment of depression.


Clinical and MRI features of Japanese patients with multiple sclerosis positive for NMO-IgG.
This study investigates the relation between the serological status of NMO (neuromyelitis optica)-IgG and the clinical and MRI features in Japanese patients with multiple sclerosis. Serum NMO-IgG was tested in 35 Japanese patients diagnosed with multiple sclerosis, including 19 with the optic-spinal form of multiple sclerosis (OSMS), three with the spinal form of multiple sclerosis (SMS), and 13 with the conventional form of multiple sclerosis (CMS), which affects the brain. NMO-IgG was detected in 14 patients, 12 with OSMS and 2 with CMS. In these patients, longitudinally extensive (> 3 vertebral segments) spinal cord lesions (93% v 57%) and permanent, complete blindness (no perception of light) in at least one eye (50% v 0%) were the noticeable features as compared with NMO-IgG-negative OSMS. The two patients having CMS with NMO-IgG had unusual brain lesions, but in other respects had features suggesting OSMS. NMO-IgG was detected in more than half the number of patients with OSMS and in some patients with CMS. This newly discovered serum autoantibody was markedly associated with longitudinally extensive spinal cord lesions and with complete blindness, suggesting severe optic-spinal disease.


Transforming growth factor-beta1 (509 C/T, 915 G/C, 869 T/C) polymorphisms are not related to obesity in Turkish children.
Increasing expression of transforming growth factor-beta 1 (TGF-beta1) from fatty tissue affects the serum level and hence may stimulate expression of the other cytokines. The studies concerning the relation between TGF-beta1 polymorphisms and obesity have been performed in adults, and diverse results have been reported. In this study, we aimed to investigate the association of TGF-beta1 509 C/T, 915 G/C, 869 T/C polymorphisms in childhood obesity and related pathologies. Two hundred and seventy-one children and adolescents were included in the study. One hundred and twenty-one of these cases were in the Obese Group and 150 were in the Control Group. In the Obesity Group, we searched the carbohydrate and lipid metabolism disorders such as insulin resistance, dyslipidemia and hepatosteatosis. The results of this study revealed the lack of an association between TGF-beta1 509 C/T, 915 G/C and 869 T/C polymorphisms and obesity. There were no relations between the polymorphism genotypes and obesity-related metabolic disturbances.


Droplet microfluidics for producing functional microparticles.
Isotropic microparticles prepared from a suspension that undergoes polymerization have long been used for a variety of applications. Bulk emulsification procedures produce polydisperse emulsion droplets that are transformed into spherical microparticles through chemical or physical consolidation. Recent advances in droplet microfluidics have enabled the production of monodisperse emulsions that yield highly uniform microparticles, albeit only on a drop-by-drop basis. In addition, microfluidic devices have provided a variety of means for particle functionalization through shaping, compartmentalizing, and microstructuring. These functionalized particles have significant potential for practical applications as a new class of colloidal materials. This feature article describes the current state of the art in the microfluidic-based synthesis of monodisperse functional microparticles. The three main sections of this feature article discuss the formation of isotropic microparticles, engineered microparticles, and hybrid microparticles. The complexities of the shape, compartment, and microstructure of these microparticles increase systematically from the isotropic to the hybrid types. Each section discusses the key idea underlying the design of the particles, their functionalities, and their applications. Finally, we outline the current limitations and future perspectives on microfluidic techniques used to produce microparticles.


Water desorption from a confined biopolymer.
We study desorption of water from a confined biopolymer (chitosan thin films) by employing temperature dependent specular X-ray reflectivity and spectroscopic ellipsometry. The water desorption is found to occur via three distinct stages with significantly different desorption rates. The distinct rates of water desorption are attributed to the presence of different kinds of water with disparate mobilities inside the biopolymer film. We identify two characteristic temperatures (Tc1 and Tc2) at which the water desorption rate changes abruptly. Interestingly, the characteristic temperatures decrease with decreasing the film thickness. The thickness dependence of the characteristic temperature is interpreted in the context of a higher mobility of polymer chains at the free surface for polymers under one-dimensional confinement.


Ascitic fluid cytology and flow cytometry in the primary diagnosis of lymphoma - a case report.
Primary diagnosis of lymphomas from ascitic fluid is rare. We report a case in which a patient being worked up as a case of carcinoma head of pancreas turned out to be a lymphoma on routine ascitic fluid examination and was further sub-classified as a CD 10+ B-cell lymphoma on flow cytometric analysis.


Radioactive Iodine Therapy and Glucose Tolerance.
Radioactive iodine therapy is commonly used as an adjuvant therapy in follicular and papillary thyroid carcinoma (PTC) and in the treatment of Graves' disease (GD). The basis of this therapy is the accumulation of radioactive iodine by the sodium-iodide symporter (NIS) in the thyroid gland. Expression of NIS by extrathyroidal tissues such as islets of pancreas has been reported. Radioactive iodine uptake by pancreatic beta-cells can potentially damage these cells. In this study, we discuss the possible associations between radioactive iodine and glucose intolerance. Overall, radioactive iodine uptake by the pancreas may damage beta-cells and predispose patients to glucose intolerance or type 2 diabetes, particularly in patients exposed to radioactive iodine therapy following total thyroidectomy. Further studies are needed to clarify and confirm this association.


Magnetic-force-induced long-period fiber gratings.
A novel formation method of a long-period fiber grating (LPFG) based on a magnetic-force-induced microbend is proposed and experimentally demonstrated. The LPFG employs a permanent magnet that exerts transversal force to the fiber by attracting a steel coil spring. The transversal force causes periodic microbending to the fiber, and therefore the transmission wave attenuates at the core-to-cladding mode resonance. This device has advantages of ease of fabrication, reconfigurability, and available for any type of fiber.


How residents and interns utilise and perceive the personal digital assistant and UpToDate.
In this era of evidence-based medicine, doctors are increasingly using information technology to acquire medical knowledge. This study evaluates how residents and interns utilise and perceive the personal digital assistant (PDA) and the online resource UpToDate. This is a questionnaire survey of all residents and interns in a tertiary teaching hospital. Out of 168 doctors, 134 (79.8%) responded to the questionnaire. Only 54 doctors (40.3%) owned a PDA. Although these owners perceived that the PDA was most useful for providing drug information, followed by medical references, scheduling and medical calculators, the majority of them did not actually have medical software applications downloaded on their PDAs. The greatest concerns highlighted for the PDA were the fear of loss and breakage, and the preference for working with desktop computers and paper. Meanwhile, only 76 doctors (56.7%) used UpToDate, even though the hospital had an institutional subscription for it. Although 93.4% of these users would recommend UpToDate to a colleague, only 57.9% stated that the use of UpToDate had led to a change in their management of patients. Although UpToDate and various PDA software applications were deemed useful by some of the residents and interns in our study, both digital tools were under-utilised. More should be done to facilitate the use of medical software applications on PDAs, to promote awareness of tools for evidence-based medicine such as UpToDate, and to facilitate the application of evidence-based medicine in daily clinical practice.


A Variational approach to thin film hydrodynamics of binary mixtures.
In order to model the dynamics of thin films of mixtures, solutions, and suspensions, a thermodynamically consistent formulation is needed such that various coexisting dissipative processes with cross couplings can be correctly described in the presence of capillarity, wettability, and mixing effects. In the present work, we apply Onsager's variational principle to the formulation of thin film hydrodynamics for binary fluid mixtures. We first derive the dynamic equations in two spatial dimensions, one along the substrate and the other normal to the substrate. Then, using long-wave asymptotics, we derive the thin film equations in one spatial dimension along the substrate. This enables us to establish the connection between the present variational approach and the gradient dynamics formulation for thin films. It is shown that for the mobility matrix in the gradient dynamics description, Onsager's reciprocal symmetry is automatically preserved by the variational derivation. Furthermore, using local hydrodynamic variables, our variational approach is capable of introducing diffusive dissipation beyond the limit of dilute solute. Supplemented with a Flory-Huggins-type mixing free energy, our variational approach leads to a thin film model that treats solvent and solute in a symmetric manner. Our approach can be further generalized to include more complicated free energy and additional dissipative processes.


Impact of HIV/simian immunodeficiency virus infection and viral proteins on adipose tissue fibrosis and adipogenesis.
HIV-infected patients receiving antiretroviral treatment (ART) often present adipose tissue accumulation and/or redistribution. adipose tissue has been shown to be an HIV/SIV reservoir and viral proteins as Tat or Nef can be released by infected immune cells and exert a bystander effect on adipocytes or precursors. Our aim was to demonstrate that SIV/HIV infection per se could alter adipose tissue structure and/or function. Morphological and functional alterations of subcutaneous (SCAT) and visceral adipose tissue (VAT) were studied in SIV-infected macaques and HIV-infected ART-controlled patients. To analyze the effect of Tat or Nef, we used human adipose stem cells (ASCs) issued from healthy donors, and analyzed adipogenesis and extracellular matrix component production using two dimensional (2D) and three-dimensional (3D) culture models. Adipocyte size and index of fibrosis were determined on Sirius red-stained adipose tissue samples. Proliferating and adipocyte 2D-differentiating or 3D-differentiating ASCs were treated chronically with Tat or Nef. mRNA, protein expression and secretion were examined by RT-PCR, western-blot and ELISA. SCAT and VAT from SIV-infected macaques displayed small adipocytes, decreased adipogenesis and severe fibrosis with collagen deposition. SCAT and VAT from HIV-infected ART-controlled patients presented similar alterations. In vitro, Tat and/or Nef induced a profibrotic phenotype in undifferentiated ASCs and altered adipogenesis and collagen production in adipocyte-differentiating ASCs. We demonstrate here a specific role for HIV/SIV infection per se on adipose tissue fibrosis and adipogenesis, probably through the release of viral proteins, which could be involved in adipose tissue dysfunction contributing to cardiometabolic alterations of HIV-infected individuals.


Costs of potentially inappropriate medication use in residential aged care facilities.
The potential harms of some medications may outweigh their potential benefits (inappropriate medication use). Despite recommendations to avoid the use of potentially inappropriate medications (PIMs) in older adults, the prevalence of PIM use is high in different settings including residential aged care. However, it remains unclear what the costs of these medications are in this setting. The main objective of this study was to determine the costs of PIMs in older adults living in residential care. A secondary objective was to examine if there was a difference in costs of PIMs in a home-like model of residential care compared to an Australian standard model of care. Participants included 541 participants from the Investigation Services Provided in the Residential Environment for Dementia (INSPIRED) Study. The INSPIRED study is a cross-sectional study of 17 residential aged care facilities in Australia. 12 month medication costs were determined for the participants and PIMs were identified using the 2015 updated Beers Criteria for older adults. Of all of the medications dispensed in 1 year, 15.9% were PIMs and 81.4% of the participants had been exposed to a PIM. Log-linear models showed exposure to a PIM was associated with higher total medication costs (Adjusted β = 0.307, 95% CI 0.235 to 0.379, p < 0.001). The mean proportion (±SD) of medication costs that were spent on PIMs in 1 year was 17.5% (±17.8) (AUD$410.89 ± 479.45 per participant exposed to a PIM). The largest PIM costs arose from proton-pump inhibitors (34.4%), antipsychotics (21.0%) and benzodiazepines (18.7%). The odds of incurring costs from PIMs were 52% lower for those residing in a home-like model of care compared to a standard model of care. The use of PIMs for older adults in residential care facilities is high and these medications represent a substantial cost which has the potential to be lowered. Further research should investigate whether medication reviews in this population could lead to potential cost savings and improvement in clinical outcomes. Adopting a home-like model of residential care may be associated with reduced prevalence and costs of PIMs.


Surface crystallization of ionic liquid crystals.
The evidence for surface crystallization in ionic liquids is scarce. The existing reports seem to be contradictory as for its driving forces, since in the two compounds investigated in the literature, the contribution of coloumbic and van der Waals forces is very different. In this work 1-dodecyl-3-methylimidazolium tetrafluoroborate was studied and its surface crystallization characterized by surface tension, ellipsometry and optical microscopy. The results obtained seem to reconcile previous observations, and it was further shown, using the same techniques, that this phenomenon is prevalent in other ionic liquids. MD simulation results illustrate the different possibilities of organization, providing reasonable models to rationalize the experimental observations.


Endocytosis of GPI-linked membrane folate receptor-alpha.
GPI-linked membrane folate receptors (MFRs) have been implicated in the receptor-mediated uptake of reduced folate cofactors and folate-based chemotherapeutic drugs. We have studied the biosynthetic transport to and internalization of MFR isoform alpha in KB-cells. MFR-alpha was synthesized as a 32-kD protein and converted in a maturely glycosylated 36-38-kD protein 1 h after synthesis. 32-kD MFR-alpha was completely soluble in Triton X-100 at 0 degree C. In contrast, only 33% of the 36-38-kD species could be solubilized at these conditions whereas complete solubilization was obtained in Triton X-100 at 37 degrees C or in the presence of saponin at 0 degree C. Similar solubilization characteristics were found when MFR-alpha at the plasma membrane was labeled with a crosslinkable 125I-labeled photoaffinity-analog of folic acid as a ligand. Triton X-100-insoluble membrane domains containing MFR-alpha could be separated from soluble MFR-alpha on sucrose flotation gradients. Only Triton X-100 soluble MFR-alpha was internalized from the plasma membrane. The reduced-folate-carrier, an integral membrane protein capable of translocating (anti-)folates across membranes, was completely excluded from the Triton X-100-resistant membrane domains. Internalized MFR-alpha recycled slowly to the cell surface during which it remained soluble in Triton X-100 at 0 degree C. Using immunoelectron microscopy, we found MFR-alpha along the entire endocytic pathway: in clathrin-coated buds and vesicles, and in small and large endosomal vacuoles. In conclusion, our data indicate that a large fraction, if not all, of internalizing MFR-alpha bypasses caveolae.


Evidence supporting radiation hormesis in atomic bomb survivor cancer mortality data.
A recent update on the atomic bomb survivor cancer mortality data has concluded that excess relative risk (ERR) for solid cancers increases linearly with dose and that zero dose is the best estimate for the threshold, apparently validating the present use of the linear no threshold (LNT) model for estimating the cancer risk from low dose radiation. A major flaw in the standard ERR formalism for estimating cancer risk from radiation (and other carcinogens) is that it ignores the potential for a large systematic bias in the measured baseline cancer mortality rate, which can have a major effect on the ERR values. Cancer rates are highly variable from year to year and between adjacent regions and so the likelihood of such a bias is high. Calculations show that a correction for such a bias can lower the ERRs in the atomic bomb survivor data to negative values for intermediate doses. This is consistent with the phenomenon of radiation hormesis, providing a rational explanation for the decreased risk of cancer observed at intermediate doses for which there is no explanation based on the LNT model. The recent atomic bomb survivor data provides additional evidence for radiation hormesis in humans.


How does the effectiveness of strategies to improve healthcare provider practices in low-income and middle-income countries change after implementation? Secondary analysis of a systematic review.
A recent systematic review evaluated the effectiveness of strategies to improve healthcare provider (HCP) performance in low-income and middle-income countries. The review identified strategies with varying effects, including in-service training, supervision and group problem-solving. However, whether their effectiveness changed over time remained unclear. In particular, understanding whether effects decay over time is crucial to improve sustainability. We conducted a secondary analysis of data from the aforementioned review to explore associations between time and effectiveness. We calculated effect sizes (defined as percentage-point (%-point) changes) for HCP practice outcomes (eg, percentage of patients correctly treated) at each follow-up time point after the strategy was implemented. We estimated the association between time and effectiveness using random-intercept linear regression models with time-specific effect sizes clustered within studies and adjusted for baseline performance. The primary analysis included 37 studies, and a sensitivity analysis included 77 additional studies. For training, every additional month of follow-up was associated with a 0.19 %-point decrease in effectiveness (95% CI: -0.36 to -0.03). For training combined with supervision, every additional month was associated with a 0.40 %-point decrease in effectiveness (95% CI: -0.68 to -0.12). Time trend results for supervision were inconclusive. For group problem-solving alone, time was positively associated with effectiveness, with a 0.50 %-point increase in effect per month (95% CI: 0.37 to 0.64). Group problem-solving combined with training was associated with large improvements, and its effect was not associated with time. Time trends in the effectiveness of different strategies to improve HCP practices vary among strategies. Programmes relying solely on in-service training might need periodical refresher training or, better still, consider combining training with group problem-solving. Although more high-quality research is needed, these results, which are important for decision-makers as they choose which strategies to use, underscore the utility of studies with multiple post-implementation measurements so sustainability of the impact on HCP practices can be assessed.


Molecular phylogenetics and species limits in a cryptically coloured radiation of Australo-Papuan passerine birds (Pachycephalidae: Colluricincla).
Detailed knowledge of species limits is an essential component of the study of biodiversity. Although accurate species delimitation usually requires detailed knowledge of both genetic and phenotypic variation, such variation may be limited or unavailable for some groups. In this study, we reconstruct a molecular phylogeny for all currently recognized species and subspecies of Australasian shrikethrushes (Colluricincla), including the first sequences of the poorly known C. tenebrosa. Using a novel method for species delimitation, the multi-rate Poisson Tree Process (mPTP), in concordance with the phylogenetic data, we estimate species limits in this genetically diverse, but phenotypically subtly differentiated complex of birds. In line with previous studies, we find that one species, the little shrikethrush (C. megarhyncha) is characterized by deep divergences among populations. Delimitation results suggest that these clades represent distinct species and we consequently propose a new classification. Furthermore, our findings suggest that C. megarhyncha melanorhyncha of Biak Island does not belong in this genus, but is nested within the whistlers (Pachycephala) as sister to P. phaionota. This study represents a useful example of species delimitation when phenotypic variation is limited or poorly defined.