Visual signal detection with two-component noise: low-pass spectrum effects.
Detection of signals in natural images and scenes is limited by both noise and structure. The purpose of this study is to investigate phenomenological issues of signal detection in two-component noise. One component had a broadband (white) spectrum designed to simulate image noise. The other component was filtered to simulate two classes of low-pass background structure spectra: Gaussian-filtered noise and power-law noise. Measurements of human and model observer performance are reported for several aperiodic signals and both classes of background spectra. Human results are compared with two classes of observer models and are fitted very well by suboptimal prewhitening matched filter models. The nonprewhitening model with an eye filter does not agree with human results when background-noise-component power spectrum bandwidths are less than signal energy bandwidths.


Function of PCA3 in prostate tissue and clinical research progress on developing a PCA3 score.
Prostate cancer gene 3 (PCA3, also known as DD3) is a new biomarker that could improve the accuracy of prostate cancer diagnosis. It is a great biomarker with fairly high specificity and sensitivity. The incidence of prostate cancer is rising steadily in most countries. The commonly used prostate-specific antigen (PSA) test once gave people hope for early diagnosis of prostate cancer. However, the low specificity of the PSA test has resulted in a large number of unnecessary biopsies and overtreatment. During the past decade, many new prostate cancer biomarkers have been found. Among these, PCA3 is the most promising. Due to its great performance in distinguishing prostate cancer from other prostate conditions, PCA3 could likely be applied for early diagnosis of prostate cancer, patient follow-up, prognosis prediction, and targeted therapy. After years of research, we have obtained some knowledge about the sequence of PCA3 gene. We have also determined the relationship between PCA3 and the proliferation of prostate cancer cells and learned some information about how PCA3 affects tumor-related genes and proteins. A PCA3 score has been created, and it has been used in a variety of studies. Some researchers have even applied PCA3 to targeted therapy and obtained a good effect in vitro. This review describes the current state of research, and explores the future prospects for PCA3.


Small round blue cell tumors of the sinonasal tract: a differential diagnosis approach.
One of the most challenging diagnostic categories within tumors of the sinonasal tract is the small round blue cell tumors. Biopsies are usually small and limited, resulting in considerable diagnostic difficulty for practicing surgical pathologists. These tumors share several overlapping histologic and immunophenotypic findings while also showing considerable variation within and between cases. Specific tumor site of origin, imaging findings, and clinical findings must be combined with the histology and pertinent ancillary studies if the correct diagnosis is to be reached. Discrimination between neoplasms is critical as there are significant differences in therapy and overall outcome. It is important to have a well developed differential diagnosis for this category of tumors, where each of the diagnoses is considered, evaluated, and either confirmed or excluded from further consideration. In an undifferentiated tumor, showing a small round blue cell morphology, using the mnemonic 'MR SLEEP' helps to highlight tumors to consider: melanoma, mesenchymal chondrosarcoma, rhabdomyosarcoma, sinonasal undifferentiated carcinoma, squamous cell carcinoma (including NUT carcinoma), small cell osteosarcoma, lymphoma, esthesioneuroblastoma (olfactory neuroblastoma), Ewing sarcoma/primitive neuroectodermal tumor, pituitary adenoma, and plasmacytoma. A panel of pertinent immunohistochemistry studies, histochemistries and/or molecular tests should aid in reaching a diagnosis, especially when taking the pattern and intensity of reactions into consideration.


Injectable cryogel-based whole-cell cancer vaccines.
A biomaterial-based vaccination system that uses minimal extracorporeal manipulation could provide in situ enhancement of dendritic cell (DC) numbers, a physical space where DCs interface with transplanted tumour cells, and an immunogenic context. Here we encapsulate GM-CSF, serving as a DC enhancement factor, and CpG ODN, serving as a DC activating factor, into sponge-like macroporous cryogels. These cryogels are injected subcutaneously into mice to localize transplanted tumour cells and deliver immunomodulatory factors in a controlled spatio-temporal manner. These vaccines elicit local infiltrates composed of conventional and plasmacytoid DCs, with the subsequent induction of potent, durable and specific anti-tumour T-cell responses in a melanoma model. These cryogels can be delivered in a minimally invasive manner, bypass the need for genetic modification of transplanted cancer cells and provide sustained release of immunomodulators. Altogether, these findings indicate the potential for cryogels to serve as a platform for cancer cell vaccinations.


Measurement of intracellular pH in sea urchin eggs by 31P NMR.
The intracellular pH (pHi) of sea urchin eggs was measured using 31P nuclear magnetic resonance (NMR) spectroscopy. The mean value of pHi of unfertilized eggs was about 6.2 (H. pulcherrimus and A. crassispina) to 6.3 (P. depressus). In contrast to results of other studies, pHi of sea urchin eggs was not changed after fertilization. During exposure of the eggs to NH4Cl or procaine-containing natural sea water (NSW), however, pHi rose about 0.4-0.8 pH units; the pHi fell to its initial value upon washing the eggs with weak base-free NSW. These changes of pHi by weak base treatment agreed well with the data obtained by other workers. In order to understand the discrepancy of pHi changes in fertilized eggs between NMR data and other measuring procedures, we measured acid production and O2 uptake, so that CO2 accumulation and proton release did not result in alkalinization. the invariance of the fertilized eggs under anaerobic conditions; otherwise NMR showed a different answer from other measuring procedures, because of its particular characteristics such as non-destructivity and compartmentation of pH.


Anti-Toxoplasma activities of methanolic extract of Sambucus nigra (Caprifoliaceae) fruits and leaves.
Toxoplasma gondii is an obligatory intracellular parasite that infects a wide range of warm-blooded animals and humans. Considering the severity of toxoplasmosis, side effects of current treatments, and the contribution of the ethnopharmacological knowledge for the treatment of parasitic infections, the aim of the present study was to investigate the efficacy of methanolic extracts from the fruits and leaves of Sambucus nigra against tachyzoite of T gondii. For this, fruits and leaves of S. nigra were collected from Mazandaran province, Iran, were dried under the shade, and powdered using a commercial electrical blender. For extractions, methanol was used as solvent. Virulent RH strain of T. gondii was maintained in mice and macrophages containing tachyzoites were aspirated from the peritoneal cavity. Four concentrations (5, 10, 25 and 50 mg/mL) of S. nigra extract were incubated with infected macrophages for 30, 60, 120 and 180 minutes and the viability of the tachyzoites were evaluated by trypan blue staining. Results showed that S. nigra fruit extracts at the concentrations of 5 and 10 mg/mL killed 100% of T gondii tachyzoites after 60 and 120 minutes, respectively; and concentrations of 25 and 50 mg/mL killed 100% of the tachyzoites after 30 minutes. Additionally, extract of S. nigra leaves, at the concentrations of 5, 10 and 25 mg/mL after 180 minutes, and concentration of 50 mg/mL after 60 minutes, resulted with the highest efficacy. Our results showed that S. nigra has acceptable efficacy in vitro and the parasiticidal effect of fruit extract was significantly better than leaf extract. However, in vivo efficacy of this extract needs further investigation.


Salt cress. A halophyte and cryophyte Arabidopsis relative model system and its applicability to molecular genetic analyses of growth and development of extremophiles.
Salt cress (Thellungiella halophila) is a small winter annual crucifer with a short life cycle. It has a small genome (about 2 x Arabidopsis) with high sequence identity (average 92%) with Arabidopsis, and can be genetically transformed by the simple floral dip procedure. It is capable of copious seed production. Salt cress is an extremophile native to harsh environments and can reproduce after exposure to extreme salinity (500 mm NaCl) or cold to -15 degrees C. It is a typical halophyte that accumulates NaCl at controlled rates and also dramatic levels of Pro (>150 mm) during exposure to high salinity. Stomata of salt cress are distributed on the leaf surface at higher density, but are less open than the stomata of Arabidopsis and respond to salt stress by closing more tightly. Leaves of salt cress are more succulent-like, have a second layer of palisade mesophyll cells, and are frequently shed during extreme salt stress. Roots of salt cress develop both an extra endodermis and cortex cell layer compared to Arabidopsis. Salt cress, although salt and cold tolerant, is not exceptionally tolerant of soil desiccation. We have isolated several ethyl methanesulfonate mutants of salt cress that have reduced salinity tolerance, which provide evidence that salt tolerance in this halophyte can be significantly affected by individual genetic loci. Analysis of salt cress expressed sequence tags provides evidence for the presence of paralogs, missing in the Arabidopsis genome, and for genes with abiotic stress-relevant functions. Hybridizations of salt cress RNA targets to an Arabidopsis whole-genome oligonucleotide array indicate that commonly stress-associated transcripts are expressed at a noticeably higher level in unstressed salt cress plants and are induced rapidly under stress. Efficient transformation of salt cress allows for simple gene exchange between Arabidopsis and salt cress. In addition, the generation of T-DNA-tagged mutant collections of salt cress, already in progress, will open the door to a new era of forward and reverse genetic studies of extremophile plant biology.


The role of anterior insular cortex in social emotions.
Functional neuroimaging investigations in the fields of social neuroscience and neuroeconomics indicate that the anterior insular cortex (AI) is consistently involved in empathy, compassion, and interpersonal phenomena such as fairness and cooperation. These findings suggest that AI plays an important role in social emotions, hereby defined as affective states that arise when we interact with other people and that depend on the social context. After we link the role of AI in social emotions to interoceptive awareness and the representation of current global emotional states, we will present a model suggesting that AI is not only involved in representing current states, but also in predicting emotional states relevant to the self and others. This model also proposes that AI enables us to learn about emotional states as well as about the uncertainty attached to events, and implies that AI plays a dominant role in decision making in complex and uncertain environments. Our review further highlights that dorsal and ventro-central, as well as anterior and posterior subdivisions of AI potentially subserve different functions and guide different aspects of behavioral regulation. We conclude with a section summarizing different routes to understanding other people's actions, feelings and thoughts, emphasizing the notion that the predominant role of AI involves understanding others' feeling and bodily states rather than their action intentions or abstract beliefs.


A non-neuronal cardiac cholinergic system plays a protective role in myocardium salvage during ischemic insults.
In our previous study, we established the novel concept of a non-neuronal cardiac cholinergic system--cardiomyocytes produce ACh in an autocrine and/or paracrine manner. Subsequently, we determined the biological significance of this system--it played a critical role in modulating mitochondrial oxygen consumption. However, its detailed mechanisms and clinical implications have not been fully investigated. We investigated if this non-neuronal cardiac cholinergic system was upregulated by a modality other than drugs and if the activation of the system contributes to favorable outcomes. Choline acetyltransferase knockout (ChAT KO) cells with the lowest cellular ACh levels consumed more oxygen and had increased MTT activity and lower cellular ATP levels compared with the control cells. Cardiac ChAT KO cells with diminished connexin 43 expression formed poor cell-cell communication, evidenced by the blunted dye transfer. Similarly, the ChAT inhibitor hemicholinium-3 decreased ATP levels and increased MTT activity in cardiomyocytes. In the presence of a hypoxia mimetic, ChAT KO viability was reduced. Norepinephrine dose-dependently caused cardiac ChAT KO cell death associated with increased ROS production. In in vivo studies, protein expression of ChAT and the choline transporter CHT1 in the hindlimb were enhanced after ischemia-reperfusion compared with the contralateral non-treated limb. This local effect also remotely influenced the heart to upregulate ChAT and CHT1 expression as well as ACh and ATP levels in the heart compared with the baseline levels, and more intact cardiomyocytes were spared by this remote effect as evidenced by reduced infarction size. In contrast, the upregulated parameters were abrogated by hemicholinium-3. The non-neuronal cholinergic system plays a protective role in both myocardial cells and the entire heart by conserving ATP levels and inhibiting oxygen consumption. Activation of this non-neuronal cardiac cholinergic system by a physiotherapeutic modality may underlie cardioprotection through the remote effect of hindlimb ischemia-reperfusion.


The effect of chemical information on the spatial distribution of fruit flies: I Model results.
Animal aggregation is a general phenomenon in ecological systems. Aggregations are generally considered as an evolutionary advantageous state in which members derive the benefits of protection and mate choice, balanced by the costs of limiting resources and competition. In insects, chemical information conveyance plays an important role in finding conspecifics and forming aggregations. In this study, we describe a spatio-temporal simulation model designed to explore and quantify the effects of these infochemicals, i.e., food odors and an aggregation pheromone, on the spatial distribution of a fruit fly (Drosophila melanogaster) population, where the lower and upper limit of local population size are controlled by an Allee effect and competition. We found that during the spatial expansion and strong growth of the population, the use of infochemicals had a positive effect on population size. The positive effects of reduced mortality at low population numbers outweighed the negative effects of increased mortality due to competition. At low resource densities, attraction toward infochemicals also had a positive effect on population size during recolonization of an area after a local population crash, by decreasing the mortality due to the Allee effect. However, when the whole area was colonized and the population was large, the negative effects of competition on population size were larger than the positive effects of the reduction in mortality due to the Allee effect. The use of infochemicals thus has mainly positive effects on population size and population persistence when the population is small and during the colonization of an area.


Palliative medicine consultation impacts DNR designation and length of stay for terminal medical MICU patients.
The purpose of this study was to assess the impact of a palliative medicine consultation on medical intensive care unit (MICU) and hospital length of stay, Do Not Resuscitate (DNR) designation, and location of death for MICU patients who died during hospitalization. A comparison of two retrospective cohorts in a 17-bed MICU in a tertiary care university-affiliated hospital was conducted. Patients admitted to the MICU between January 1, 2003 and June 30, 2004 (N = 515) were compared to MICU patients who had had a palliative medicine consultation between January 1, 2005 and June 1, 2009 (N = 693). To control for disease severity, only patients in both cohorts who died during their hospitalization were considered for this study. Palliative medicine consultation reduced time until death during the entire hospitalization (log-rank test, p < 0.01). Time from MICU admission until death was also reduced (log-rank test, p < 0.01), further demonstrating the impact of the palliative care consultation on the duration of dying for hospitalized patients. The intervention group contained a significantly higher percentage of patients with a DNR designation at death than did the control group (86% vs. 68%, χ2 test, p < 0.0001). Palliative medicine consultation is associated with an increased rate of DNR designation and reduced time until death. Patients in the intervention group were also more likely to die outside the MICU as compared to controls in the usual care group.


Spectrum and frequency of FZD4 mutations in familial exudative vitreoretinopathy.
Mutations in the frizzled-4 gene (FZD4) have recently been associated with autosomal dominant familial exudative vitreoretinopathy (FEVR) in families linking to the EVR1 locus on the long arm of chromosome 11. The purpose of this study was to screen FZD4 in a panel of 40 patients with FEVR to identify the types and location of mutations and to calculate what proportion of this heterogeneous condition is attributable to FZD4 mutations. PCR products were generated from genomic DNA with primers designed to amplify the coding sequence of FZD4. The PCR products were screened for mutations by single-strand conformational polymorphism-heteroduplex analysis (SSCP-HA) and by direct sequencing. In total, eight mutations were identified, seven of which were novel. Three were deletions (c957delG, c1498delA, and c1501-1502delCT), one was a nonsense mutation (Q505X), and four were missense mutations (G36D, M105T, M157V, and S497F). Eight mutations have been identified in the FZD4 gene in a cohort of 40 unrelated patients with FEVR. This result indicates that FZD4 mutations are responsible for only 20% of FEVR index cases and suggests that the other FEVR loci may account for more cases than previously anticipated.


The effect of COVID rehabilitation for ongoing symptoms Post HOSPitalisation with COVID-19 (PHOSP-R): protocol for a randomised parallel group controlled trial on behalf of the PHOSP consortium.
Many adults hospitalised with COVID-19 have persistent symptoms such as fatigue, breathlessness and brain fog that limit day-to-day activities. These symptoms can last over 2 years. Whilst there is limited controlled studies on interventions that can support those with ongoing symptoms, there has been some promise in rehabilitation interventions in improving function and symptoms either using face-to-face or digital methods, but evidence remains limited and these studies often lack a control group. This is a nested single-blind, parallel group, randomised control trial with embedded qualitative evaluation comparing rehabilitation (face-to-face or digital) to usual care and conducted within the PHOSP-COVID study. The aim of this study is to determine the effectiveness of rehabilitation interventions on exercise capacity, quality of life and symptoms such as breathlessness and fatigue. The primary outcome is the Incremental Shuttle Walking Test following the eight week intervention phase. Secondary outcomes include measures of function, strength and subjective assessment of symptoms. Blood inflammatory markers and muscle biopsies are an exploratory outcome. The interventions last eight weeks and combine symptom-titrated exercise therapy, symptom management and education delivered either in a face-to-face setting or through a digital platform ( www.yourcovidrecovery.nhs.uk ). The proposed sample size is 159 participants, and data will be intention-to-treat analyses comparing rehabilitation (face-to-face or digital) to usual care. Ethical approval was gained as part of the PHOSP-COVID study by Yorkshire and the Humber Leeds West Research NHS Ethics Committee, and the study was prospectively registered on the ISRCTN trial registry (ISRCTN13293865). Results will be disseminated to stakeholders, including patients and members of the public, and published in appropriate journals. Strengths and limitations of this study • This protocol utilises two interventions to support those with ongoing symptoms of COVID-19 • This is a two-centre parallel-group randomised controlled trial • The protocol has been supported by patient and public involvement groups who identified treatments of symptoms and activity limitation as a top priority.


Hodgkin's lymphoma in younger patients: lessons learned on the road to success.
Despite significant improvements in the treatment of Hodgkin's lymphoma over the past 2 decades, physicians continue to face dilemmas in therapy for the disease, and many cured patients live with complications of treatment. Newer therapeutic options are still needed for the disease, to minimize complications and to improve the treatment of patients in relapse. This review considers the treatment of Hodgkin's lymphoma in younger patients, addressing such issues as which patients with early-stage disease may require radiotherapy, what prognostic factors provide information that can affect treatment choices in patients with advanced disease, and what we have learned about treatment complications in this setting.


Flash light detection and ranging range accuracy limits for returns from single opaque surfaces via Cramer-Rao bounds.
A Cramer-Rao lower bound on the range accuracy obtainable by a Flash light detection and ranging (LADAR) system receiving a return from a single surface in the instantaneous field of view of each detector is developed and verified with experimental data. The bound is compared to the performance of a new algorithm and that of a matched filter receiver by using both simulated and measured LADAR data. The simulated data are used to show that the estimator is nearly unbiased and efficient for systems that match the negative paraboloid model used in its derivation. It is found that the achievable range accuracy for the LADAR system and for the target geometry used to collect the measured data is of the order of 2.5 in. while the bound predicts a range accuracy limit of approximately 0.6 in.


Cytogenetic analysis of 63 non-small cell lung carcinomas: recurrent chromosome alterations amid frequent and widespread genomic upheaval.
A detailed cytogenetic analysis of 63 non-small cell lung carcinomas (NSCLCs) was carried out for identification of recurrent chromosomal alterations. Most specimens displayed very complex karyotypes with multiple numerical and structural changes (median number, 31). Losses of chromosomes 9 (65% of cases) and 13 (71%) were the most frequent numerical changes. Loss of the Y was often observed in tumors from males. Gain of chromosome 7 was also frequent (41%). Chromosome arms 1p, 1q, 3p, 3q, 6q, 7q, 8q, 9p, 11q, 17p, and 19q were particularly prone to rearrangement. The chromosome arm most often contributing to losses was 9p (79%). Other arms that were frequently lost included 3p, 6q, 8p, 9q, 13q, 17p, 18q, 19p, 21q, 22q, and the short arm of each acrocentric chromosome. The percentage of cases with loss of 3p was significantly higher in squamous cell carcinomas (94%) than in adenocarcinomas (60%). There was also a statistically significant increase in the proportion of cases with gains of 1q, 7p, and 11q in adenocarcinomas compared to squamous cell carcinomas. Several recurrent isochromosomes and unbalanced exchanges were found. Among these was i(5p), which was observed in nine tumors, eight of which displayed adenomatous features. An i(8q) was identified in six cases, including five adenocarcinomas. Double minutes and/or homogeneously staining regions were seen in seven specimens. These data indicate that numerous chromosome alterations contribute to the pathogenesis of NSCLC and that, amid this widespread genomic disarray, recurrent abnormalities exist that could have biological and clinical implications.


Interplay between function and structure in complex networks.
We show that abrupt structural transitions can arise in functionally optimal networks, driven by small changes in the level of transport congestion. Our results offer an explanation as to why so many diverse species of network structure arise in nature (e.g., fungal systems) under essentially the same environmental conditions. Our findings are based on an exactly solvable model system which mimics a variety of biological and social networks. We then extend our analysis by introducing a renormalization scheme involving cost motifs, to describe analytically the average shortest path across multiple-ring-and-hub networks. As a consequence, we uncover a "skin effect" whereby the structure of the inner multi-ring core can cease to play any role in terms of determining the average shortest path across the network.


A Qualitative Case Study of Smartphone-Connected Hearing Aids: Influences on Patients, Clinicians, and Patient-Clinician Interactions.
Innovations in hearing aid technology influence clinicians and individuals who use hearing aids. Little research, to date, explains the innovation adoption experiences and perspectives of clinicians and patients, which matter to a field like audiology, wherein technology innovation is constant. By understanding clinician and patient experiences with such innovations, the field of audiology may develop technologies and ways of practicing in a manner more responsive to patients' needs, and attentive to society's influence. The authors aimed to understand how new innovations influence clinician and patient experiences, through a study focusing on connected hearing aids. "Connected" refers to the wireless functional connection of hearing aids with everyday technologies like mobile phones and tablets. The authors used a qualitative collective case study methodology, borrowing from constructivist grounded theory for data collection and analysis methods. Specifically, the authors designed a collective case study of a connected hearing aid and smartphone application, composed of two cases of experience with the innovation: the case of clinician experiences, and the case of patient experiences. The qualitative sampling methods employed were case sampling, purposive within-case sampling, and theoretical sampling, and culminated in a total collective case n = 19 (clinician case n = 8; patient case n = 11). These data were triangulated with a supplementary sample of ten documents: relevant news and popular media collected during the study time frame. The authors conducted interviews with the patients and clinicians, and analyzed the interview and document data using the constant comparative method. The authors compared their two cases by looking at trends within, between, and across cases. The clinician case highlighted clinicians' heuristic-based candidacy judgments in response to the adoption of the connected hearing aids into their practice. The patient case revealed patients' perceptions of themselves as technologically competent or incompetent, and descriptions of how they learned to use the new technology. Between cases, the study found a difference in the response to how the connected hearing aid changed the clinician-patient relationship. While clinicians valued the increased time they spent "getting to know" their patients, patients experienced some frustration specific to the additional troubleshooting related to Bluetooth connectivity. Across cases, there was a resounding theme of "normalization" of hearing aids via their integration with a "normal" technology (mobile phones) and general lack of concern about privacy in relation to the smartphone application and its tracking and geotagging features. Both audiologists and patients credited the connected hearing aids with increased opportunities to participate more fully in everyday life. The introduction of smartphone-connected hearing aids influenced the identities and candidate profiles of hearing aid users, and the nature of time spent in clinical interactions, in important and interesting ways. The influence of connected hearing aids on patient experience and audiology practice calls for continued research and clinical consideration, with implications for clinical decision-making regarding hearing aid candidacy. Further study should look critically at normalization and possible unintended stigmatizing effects of making hearing aids increasingly discreet.


Seq-Gen: an application for the Monte Carlo simulation of DNA sequence evolution along phylogenetic trees.
Seq-Gen is a program that will simulate the evolution of nucleotide sequences along a phylogeny, using common models of the substitution process. A range of models of molecular evolution are implemented, including the general reversible model. Nucleotide frequencies and other parameters of the model may be given and site-specific rate heterogeneity can also be incorporated in a number of ways. Any number of trees may be read in and the program will produce any number of data sets for each tree. Thus, large sets of replicate simulations can be easily created. This can be used to test phylogenetic hypotheses using the parametric bootstrap. Seq-Gen can be obtained by WWW from http:/(/)evolve.zoo.ox.ac.uk/Seq-Gen/seq-gen.html++ + or by FTP from ftp:/(/)evolve.zoo.ox.ac.uk/packages/Seq-Gen/. The package includes the source code, manual and example files. An Apple Macintosh version is available from the same sites.


A robust structure-adaptive hybrid vector filter for color image restoration.
A robust structure-adaptive hybrid vector filter is proposed for digital color image restoration in this paper. At each pixel location, the image vector (i.e., pixel) is first classified into several different signal activity categories by applying a modified quadtree decomposition to luminance component (image) of the input color image. A weight-adaptive vector filtering operation with an optimal window is then activated to achieve the best tradeoff between noise suppression and detail preservation. Through extensive simulation experiments conducted using a wide range of test color images, the filter has demonstrated superior performance to that of a number of well known benchmark techniques, in terms of both standard objective measurements and perceived image quality, in suppressing several distinct types of noise commonly considered in color image restoration, including Gaussian noise, impulse noise, and mixed noise.


Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia.
Infertility affects around 7% of men worldwide. Idiopathic non-obstructive azoospermia (NOA) is defined as the absence of spermatozoa in the ejaculate due to failed spermatogenesis. There is a high probability that NOA is caused by rare genetic defects. In this study, whole-exome sequencing (WES) was applied to two Estonian brothers diagnosed with NOA and Sertoli cell-only syndrome (SCOS). Compound heterozygous loss-of-function (LoF) variants in FANCM (Fanconi anemia complementation group M) were detected as the most likely cause for their condition. A rare maternally inherited frameshift variant p.Gln498Thrfs∗7 (rs761250416) and a previously undescribed splicing variant (c.4387-10A>G) derived from the father introduce a premature STOP codon leading to a truncated protein. FANCM exhibits enhanced testicular expression. In control subjects, immunohistochemical staining localized FANCM to the Sertoli and spermatogenic cells of seminiferous tubules with increasing intensity through germ cell development. This is consistent with its role in maintaining genomic stability in meiosis and mitosis. In the individual with SCOS carrying bi-allelic FANCM LoF variants, none or only faint expression was detected in the Sertoli cells. As further evidence, we detected two additional NOA-affected case subjects with independent FANCM homozygous nonsense variants, one from Estonia (p.Gln1701∗; rs147021911) and another from Portugal (p.Arg1931∗; rs144567652). The study convincingly demonstrates that bi-allelic recessive LoF variants in FANCM cause azoospermia. FANCM pathogenic variants have also been linked with doubled risk of familial breast and ovarian cancer, providing an example mechanism for the association between infertility and cancer risk, supported by published data on Fancm mutant mouse models.


Concerns and Treatment Satisfaction in Patients Being Treated With Azelaic Acid Foam for Rosacea
Objective: To describe patient characteristics, concerns, side effects, treatment satisfaction, and quality of life (QoL) of rosacea patients currently being treated with monotherapy azelaic acid foam based on patient-reported data. Methods: The study utilized a non-interventional, prospective, observational design. Patients were recruited in the United States and were eligible if the following criteria were met: diagnosed with rosacea by a medical professional, ≥18 years of age, currently receiving monotherapy with azelaic acid foam, and able to provide informed consent. Patients using other topical treatments for rosacea during enrollment were excluded. An online tool administered a survey of 3 questionnaires including the Rosacea Treatment Preference Questionnaire, Treatment Satisfaction with Medicines Questionnaire (SATMED-Q), and Dermatology Life Quality Index (DLQI). The survey collected demographics, clinical characteristics, treatment history, adverse events, and patient-reported outcomes related to treatment with azelaic acid foam and QoL with rosacea. Results: 54 patients met eligibility criteria. Participants were primarily female (90.7%), ranging from 26 to 63 years of age. The most common subtypes reported were erythematotelangiectatic and papulopustular (74.1% each) with 59.3% of participants reporting mild symptoms (16.7% "absent"; 24.1% "moderate") in the 4 weeks before enrollment. The majority reported no concerns (74.1%) with their treatment. The biggest concern was cost (11.1%), with a mean importance score (IS) on a 10-point scale of 9.3. A majority (77.8%) of patients reported no side effects. Side effects reported included dryness (13%; IS: 5.3), stinging (7.4%, IS: 2.5), itching (5.6%; IS: 4.7), or burning (3.7%; IS: 7.0). Global satisfaction (SATMED-Q) mean score was 79.0 and treatment effectiveness mean score was 70.8. QoL impact of rosacea was minimal (mean DLQI score: 2.35). In regression models, increasing dryness was significantly associated with worsening outcomes in SATMED-Q and DLQI. Conclusions: Patient characteristics of the study population closely mirror the distribution of rosacea by gender and subtype as in previous estimates. Findings indicate minimal patient concerns with azelaic acid foam and primarily pertained to cost. Patient-reported side effects were rare. Minor patient-reported side effects and concerns do not appear to affect rosacea-related QoL and medication satisfaction. Compared to a previously conducted study of similar design with patients using metronidazole gel and metronidazole cream, more patients in the current study reported no concerns with their treatment, while the number of patients reporting no side effects, as well as mean SATMED-Q and DLQI scores, were similar. Further research is necessary to directly compare the results of these 2 studies. J Drugs Dermatol. 2019;18(4):381-386.


Inhaled alprazolam rapidly suppresses epileptic activity in photosensitive participants.
Treatment options for seizure clusters are limited; the need for easy-to-administer treatments remains. The Staccato system delivers drug deep into the lung via inhalation. In this phase 2a study, we investigated the ability of three different doses of Staccato alprazolam to suppress the electroencephalographic (EEG) photoparoxysmal response (PPR) compared with placebo in participants with photosensitive seizures. Adults (18-60 years) with a diagnosis and history of PPR on EEG with or without an epilepsy diagnosis were eligible to participate. Participants received Staccato alprazolam 0.5, 1.0, and 2.0 mg, and Staccato placebo (twice) in random order. Intermittent photic stimulation and clinical assessments were performed at one predose and seven postdose time points. The primary endpoint of the study was the change in standardized photosensitivity range (SPR) in participants receiving each dose of Staccato alprazolam. Fifteen participants with a prior epilepsy diagnosis were screened; five were enrolled, randomized, and completed the study. All participants were white females with a mean (SD) age of 27.2 (6.8) years. All doses of Staccato alprazolam reduced the SPR at 2 minutes; the effect was sustained through 4 hours for the 0.5-mg dose and 6 hours for the 1.0- and 2.0-mg doses. The magnitude and duration of sedation and sleepiness were dose-related. Four participants (80%) experienced ≥1 adverse event (AE); none was severe or serious. Cough, diarrhea, dysgeusia, oral dysesthesia, sedation, and somnolence were experienced by two participants (40%) each. This proof-of-concept study demonstrated that Staccato alprazolam 0.5, 1.0, and 2.0 mg rapidly suppressed epileptiform activity in photosensitive participants with epilepsy. The AE profile of Staccato alprazolam was similar to what has been reported for alprazolam for other indications. The results support further development of Staccato alprazolam as a rescue medication for the acute treatment of seizures.


When crises collide: how intimate partner violence and poverty intersect to shape women's mental health and coping?
Until recently, the connection between intimate partner violence (IPV) and persistent poverty had been largely ignored. Recent research indicates, however, that the two phenomena cooccur at high rates; produce parallel effects; and, in each other's presence, constrain coping options. Therefore, both external situational, and internal psychological difficulties are missed when women contending with both poverty and IPV are viewed through the lens of just one or just the other. This article describes mental health consequences for women who contend with both partner violence and poverty. It proposes that the stress, powerlessness, and social isolation at the heart of both phenomena combine to produce posttraumatic stress disorder, depression, and other emotional difficulties. The article also introduces the term ''survival-focused coping'' to describe women's methods of coping with IPV in the context of poverty and highlights the role that domestic violence advocates, mental health providers, and researchers can play in addressing these tightly intertwined phenomena.


Subject matter expert and public evaluations of a veterinary toxicology course brochure-writing assignment.
Veterinary schools are increasingly developing students' communication skills, with an emphasis placed on practice conveying medical and scientific knowledge to different audiences. We describe how patient-centered written communication has been integrated into the training of veterinary students using toxicology-related preventive materials. Third-year veterinary students were given an assignment to prepare a client-focused brochure related to veterinary toxicology. Since 2010, 148 students have completed this assignment, with an average score of 93.4%. Use of a grading rubric was instituted in 2011 and resulted in a more rigorous assessment of the brochures by the course instructors. In this study, we evaluated a sample (n=6) selected from 10 brochures volunteered for further public and expert assessment. Each brochure was measured for readability and assessed with a rubric for perceived usefulness and acceptability by 12 veterinary toxicologists and 10 or 11 adult members of the public attending a college of veterinary medicine open house. Veterinary toxicologist review anticipated that the brochures would be useful for most clients, and the public reviewers confirmed this assessment. Evaluation of the brochures using set marking criteria and readability indexes showed that students had successfully targeted the chosen audiences. Feedback showed that the general public rated the sample brochures highly in terms of quality, usefulness, and interest. Completion of this study has resulted in revision of the grading rubric, an increased use of brochure examples, and additional instruction in readability assessment and brochure development, thereby improving the assignment as a learning exercise.


Development and Pilot Testing of an Encounter Tool for Shared Decision Making About the Treatment of Graves' Disease.
The best treatment option for patients with Graves' disease (GD) depends on each person's situation and how the differences between the treatment options matter to them in bringing resolution to their illness. The objective of this study was to develop and test an encounter decision tool (GD Choice) for patients and clinicians to engage in shared decision making about the treatment of GD. GD Choice was developed using an iterative process based on the principles of interaction design and participatory action research. To evaluate the impact of the tool, a controlled before-after study was conducted, assessing the use of GD Choice versus usual care (UC). Sixty-eight patients were enrolled, 37 to UC and 31 to GD Choice. At baseline, the groups were similar. Treatment discussion length was similar in both arms. After their visit, patients in both groups had similar knowledge about the options, except for GD Choice patients knowing significantly more about the complications of treatment (correctly answered by 83% vs. 55%; p = 0.04). Compared with UC, patients in the GD Choice arm had greater involvement in decision making observed on video recordings of clinical encounters (mean OPTION scale score, 35% vs. 30%; p = 0.02), but reported similar levels of decisional comfort and participation in shared decision making. GD Choice increases engagement in the decision-making process and knowledge regarding intervention complications without increasing the length of consultation. These promising results support the conduct of a randomized trial of GD Choice versus UC in a large multicenter trial.


Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma.
Pachyonychia congenita type 1 (PC-1) is an autosomal dominant ectodermal dysplasia characterized by nail dystrophy, focal non-epidermolytic palmoplantar keratoderma (FNEPPK) and oral lesions. We have previously shown that mutations in keratin 16 (K16) cause fragility of specific epithelia resulting in phenotypes of PC-1 or FNEPPK alone. Here, we report 2 novel mutations in K16 causing distinct phenotypes. A heterozygous missense mutation (L124R) was detected in a kindred with PC-1. In a family where mild FNEPPK was the only phenotype, a 23 bp deletion and a separate 1 bp deletion downstream were found in exon 6: [1244-1266del; 1270delG]. At the protein level, these mutations remove 8 residues and substitute 2 residues in the helix termination motif (HTM) of the K16 polypeptide. The HTM sequence is conserved in all known intermediate filament proteins and for convenience, this complex mutation was designated deltaHTM. Transient expression of K16 cDNAs carrying either the L124R or the deltaHTM mutation in epithelial cell line PtK2 produced aggregation of the keratin cytoskeleton. However, the aggregates observed with the deltaHTM mutation were morphologically different and appeared to be less disruptive to the endogenous cytoskeleton. Therefore, loss of the HTM sequence may render this mutant K16 less capable of contributing to filament assembly and decrease its dominant-negative effect, resulting in the milder FNEPPK phenotype.


Dehydration-Triggered Ionic Channel Engineering in Potassium Niobate for Li/K-Ion Storage.
Boosting charge transfer in materials is critical for applications involving charge carriers. Engineering ionic channels in electrode materials can create a skeleton to manipulate their ion and electron behaviors with favorable parameters to promote their capacity and stability. Here, tailoring of the atomic structure in layered potassium niobate (K4 Nb6 O17 ) nanosheets and facilitating their application in lithium and potassium storage by dehydration-triggered lattice rearrangement is reported. The spectroscopy results reveal that the interatomic distances of the NbO coordination in the engineered K4 Nb6 O17 are slightly elongated with increased degrees of disorder. Specifically, the engineered K4 Nb6 O17 shows enhanced electrical and ionic conductivity, which can be attributed to the enlarged interlamellar spacing and subtle distortions in the fine atomic arrangements. Moreover, subsequent experimental results and calculations demonstrate that the energy barrier for Li+ /K+ diffusion is significantly lower than that in pristine K4 Nb6 O17 . Interestingly, the diffusion coefficient of K+ is one order of magnitude higher than that of Li+ , and the engineered K4 Nb6 O17 presents superior electrochemical performance for K+ to Li+ . This work offers an ionic engineering strategy to enable fast and durable charge transfer in materials, holding great promise for providing guidance for the material design of related energy storage systems.


An inexpensive and reliable new haemoglobin colour scale for assessing anaemia.
To describe a new inexpensive method (the WHO Colour Scale) for estimating haemoglobin concentration from a drop of blood by means of a colour scale, and to compare its reliability with a standard laboratory method of measuring haemoglobin, and its clinical usefulness in field trials. The new colour scale method was used to measure haemoglobin concentration in 1213 random venous blood samples from routine work in four laboratories (one each in the UK, South Africa, Thailand, and Switzerland). Limited field trials of the method for assessing clinical usefulness were done in a rural hospital (in South Africa) staffed by nurses, at two blood donor sessions (one each in South Africa and Thailand), and by nonlaboratory personnel in malaria clinics (in Thailand), following training and a short practice session. In the laboratory based comparability study the presence of anaemia was reliably detected using the new method with 91% sensitivity and 86% specificity. Clinically relevant levels of anaemia (mild to moderate, pronounced, and severe) were graded and serious anaemia (< 8 g/dl) was identified with an efficiency of 89%. The clinical trials showed the ease and reliability with which the colour scale could be used by non-laboratory persons after brief training. The blood donor trials showed it to be at least as reliable as the copper sulphate method with the advantage of being more convenient. The preliminary studies have shown that the WHO Colour Scale is a reliable screening method for detecting anaemia, especially for diagnosing serious anaemia. Following a brief training session health workers found it simple to use and, at a cost of about 1/10th that for traditional photometric analysis, it should be of value in "countries in need" for primary health centres, obstetrical management, paediatric clinics, tropical disease control programmes, blood transfusion donor selection, as well as for industrial health checks and epidemiological studies.


Photoswitchable Inhibitors of Microtubule Dynamics Optically Control Mitosis and Cell Death.
Small molecules that interfere with microtubule dynamics, such as Taxol and the Vinca alkaloids, are widely used in cell biology research and as clinical anticancer drugs. However, their activity cannot be restricted to specific target cells, which also causes severe side effects in chemotherapy. Here, we introduce the photostatins, inhibitors that can be switched on and off in vivo by visible light, to optically control microtubule dynamics. Photostatins modulate microtubule dynamics with a subsecond response time and control mitosis in living organisms with single-cell spatial precision. In longer-term applications in cell culture, photostatins are up to 250 times more cytotoxic when switched on with blue light than when kept in the dark. Therefore, photostatins are both valuable tools for cell biology, and are promising as a new class of precision chemotherapeutics whose toxicity may be spatiotemporally constrained using light.


Live-cell visualization of dynamics of HIV budding site interactions with an ESCRT component.
HIV (human immunodeficiency virus) diverts the cellular ESCRT (endosomal sorting complex required for transport) machinery to promote virion release from infected cells. The ESCRT consists of four heteromeric complexes (ESCRT-0 to ESCRT-III), which mediate different membrane abscission processes, most importantly formation of intralumenal vesicles at multivesicular bodies. The ATPase VPS4 (vacuolar protein sorting 4) acts at a late stage of ESCRT function, providing energy for ESCRT dissociation. Recruitment of ESCRT by late-domain motifs in the viral Gag polyprotein and a role of ESCRT in HIV release are firmly established, but the order of events, their kinetics and the mechanism of action of individual ESCRT components in HIV budding are unclear at present. Using live-cell imaging, we show late-domain-dependent recruitment of VPS4A to nascent HIV particles at the host cell plasma membrane. Recruitment of VPS4A was transient, resulting in a single or a few bursts of at least two to five VPS4 dodecamers assembling at HIV budding sites. Bursts lasted for ∼35 s and appeared with variable delay before particle release. These results indicate that VPS4A has a direct role in membrane scission leading to HIV-1 release.


Neurocognitive Performance of 425 Top-Level Football Players: Sport-specific Norm Values and Implications.
Concussion diagnosis and management in sports largely relies on neurocognitive testing. In the absence of baseline assessment, only norm values of the general population are available for comparison with scores of concussed athletes. To evaluate whether (elite) sport specific norm values are needed, cognitive performance was compared between top-level football players and the general population. Cognitive performance of 425 top-level football players was evaluated using the computerized test battery CNS Vital Signs. Players were split into two age groups (15-19 and 20-29 years) and test results were compared with a norm sample (n = 268) by means of age-standardized scores using Cohen's d effect size statistics. The younger age group outperformed the norm sample in all domains, with small to moderate effects on tests of processing speed (d = 0.58, 95% CI = 0.31,0.85), cognitive flexibility (d = 0.27, 95% CI = 0.01,0.53) and psychomotor speed (d = 0.97, 95% CI = 0.69,1.24). In the older age group, no differences were found on four out of six domains; a moderate positive effect was found for psychomotor speed (d = 0.74, 95% CI = 0.54,0.93), a small negative effect for reaction time (d = -0.47, 95% CI = -0.66,-0.28). Relative to the norm, older football players scored lower than younger football players on all test domains. Cognitive performance of elite football players may be different from the general population. It is recommended to use football-specific norm scores for comparison with test results of concussed players, and to choose an adequate control group when investigating effects of contact sport on cognition. Studies with older/retired football players are needed to further analyze potential sport-specific age effects.


Nutrient timing revisited: is there a post-exercise anabolic window?
Nutrient timing is a popular nutritional strategy that involves the consumption of combinations of nutrients--primarily protein and carbohydrate--in and around an exercise session. Some have claimed that this approach can produce dramatic improvements in body composition. It has even been postulated that the timing of nutritional consumption may be more important than the absolute daily intake of nutrients. The post-exercise period is widely considered the most critical part of nutrient timing. Theoretically, consuming the proper ratio of nutrients during this time not only initiates the rebuilding of damaged muscle tissue and restoration of energy reserves, but it Does So in a supercompensated fashion that enhances both body composition and exercise performance. Several researchers have made reference to an anabolic "window of opportunity" whereby a limited time exists after training to optimize training-related muscular adaptations. However, the importance - and even the existence - of a post-exercise 'window' can vary according to a number of factors. Not only is nutrient timing research open to question in terms of applicability, but recent evidence has directly challenged the classical view of the relevance of post-exercise nutritional intake with respect to anabolism. Therefore, the purpose of this paper will be twofold: 1) to review the existing literature on the effects of nutrient timing with respect to post-exercise muscular adaptations, and; 2) to draw relevant conclusions that allow practical, evidence-based nutritional recommendations to be made for maximizing the anabolic response to exercise.


When Doing Wrong Feels So Right: Normalization of Deviance.
Normalization of deviance is a term first coined by sociologist Diane Vaughan when reviewing the Challenger disaster. Vaughan noted that the root cause of the Challenger disaster was related to the repeated choice of NASA officials to fly the space shuttle despite a dangerous design flaw with the O-rings. Vaughan describes this phenomenon as occurring when people within an organization become so insensitive to deviant practice that it no longer feels wrong. Insensitivity occurs insidiously and sometimes over years because disaster does not happen until other critical factors line up. In clinical practice, failing to do time outs before procedures, shutting off alarms, and breaches of infection control are deviances from evidence-based practice. As in other industries, health care workers do not make these choices intending to set into motion a cascade toward disaster and harm. Deviation occurs because of barriers to using the correct process or drivers such as time, cost, and peer pressure. As in other industries, operators will often adamantly defend their actions as necessary and justified. Although many other high-risk industries have embraced the normalization of deviance concept, it is relatively new to health care. It is urgent that we explore the impact of this concept on patient harm. We can borrow this concept from other industries and also the steps these other high-risk organizations have found to prevent it.


A global sensitivity tool for cardiac cell modeling: Application to ionic current balance and hypertrophic signaling.
Cardiovascular diseases are the major cause of death in the developed countries. Identifying key cellular processes involved in generation of the electrical signal and in regulation of signal transduction pathways is essential for unraveling the underlying mechanisms of heart rhythm behavior. Computational cardiac models provide important insights into cardiovascular function and disease. Sensitivity analysis presents a key tool for exploring the large parameter space of such models, in order to determine the key factors determining and controlling the underlying physiological processes. We developed a new global sensitivity analysis tool which implements the Morris method, a global sensitivity screening algorithm, onto a Nimrod platform, which is a distributed resources software toolkit. The newly developed tool has been validated using the model of IP3-calcineurin signal transduction pathway model which has 30 parameters. The key driving factors of the IP3 transient behaviour have been calculated and confirmed to agree with previously published data. We next demonstrated the use of this method as an assessment tool for characterizing the structure of cardiac ionic models. In three latest human ventricular myocyte models, we examined the contribution of transmembrane currents to the shape of the electrical signal (i.e. on the action potential duration). The resulting profiles of the ionic current balance demonstrated the highly nonlinear nature of cardiac ionic models and identified key players in different models. Such profiling suggests new avenues for development of methodologies to predict drug action effects in cardiac cells.


Hydrogen-rich water protects against ischemic brain injury in rats by regulating calcium buffering proteins.
Hydrogen-rich water (HRW) has anti-oxidant activities, and it exerts neuroprotective effects during ischemia-reperfusion brain injury. Parvalbumin and hippocalcin are two calcium buffering proteins, which are involved in neuronal differentiation, maturation and apoptosis. The aim of this study was to investigate whether HRW could moderate parvalbumin and hippocalcin expression during ischemic brain injury and glutamate toxicity-induced neuronal cell death. Focal brain ischemia was induced in male Sprague-Dawley rats by middle cerebral artery occlusion (MCAO). Rats were treated with H2O or HRW (6 ml/kg per rat) before and after MCAO, and cerebral cortical tissues were collected 1, 7 and 14 days after MCAO. Based on our results, HRW treatment was able to reduce brain infarct volume and improve neurological function following ischemic brain injury. In addition, HRW prevented the ischemia-induced reduction of parvalbumin and hippocalcin levels in vivo and also reduced the glutamate toxicity-induced death of neurons, including the dose-dependent reduction of glutamate toxicity-associated proteins in vitro. Moreover, HRW attenuated the glutamate toxicity-induced elevate in intracellular Ca(2+) levels. All these results suggest that HRW could protect against ischemic brain injury and that the maintenance of parvalbumin and hippocalcin levels by HRW during ischemic brain injury might contribute to the neuroprotective effects against neuron damage.


Dynamic switch of negative feedback regulation in Drosophila Akt-TOR signaling.
Akt represents a nodal point between the Insulin receptor and TOR signaling, and its activation by phosphorylation controls cell proliferation, cell size, and metabolism. The activity of Akt must be carefully balanced, as increased Akt signaling is frequently associated with cancer and as insufficient Akt signaling is linked to metabolic disease and diabetes mellitus. Using a genome-wide RNAi screen in Drosophila cells in culture, and in vivo analyses in the third instar wing imaginal disc, we studied the regulatory circuitries that define dAkt activation. We provide evidence that negative feedback regulation of dAkt occurs during normal Drosophila development in vivo. Whereas in cell culture dAkt is regulated by S6 Kinase (S6K)-dependent negative feedback, this feedback inhibition only plays a minor role in vivo. In contrast, dAkt activation under wild-type conditions is defined by feedback inhibition that depends on TOR Complex 1 (TORC1), but is S6K-independent. This feedback inhibition is switched from TORC1 to S6K only in the context of enhanced TORC1 activity, as triggered by mutations in tsc2. These results illustrate how the Akt-TOR pathway dynamically adapts the routing of negative feedback in response to the activity load of its signaling circuit in vivo.


Cerebral infarction and ventricular septal defect.
With the availability of contrast echocardiography, patent foramen ovale is frequently detected in patients with stroke, especially in those with no clear etiology and/or the young patient with stroke. Before this report, an association of stroke with ventricular septal defect had not been reported. In this communication, we describe a 38-year-old patient who developed an occipital lobe infarction and who, on investigation, was found to have a ventricular septal defect. Other investigations, which included four-vessel cerebral angiography, collagen disease workup, and coagulation profile, were all normal. We believe this case further extends the spectrum of cerebral ischemic events that may occur with intracardiac shunts.


Frequency of expression of prostate-specific antigen mRNA in lung tumors.
The presence of prostate-specific antigen (PSA) protein and messenger RNA (mRNA) was studied in 52 primary lung tumor tissues. The PSA protein was detected more frequently and at higher levels in lung tumor extracts from men. The levels of PSA protein in tumor extracts correlated with preoperative and postoperative serum PSA levels, suggesting a possible contamination of the tumor extracts with PSA from residual blood in the tumor vasculature. The PSA mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot hybridization in 24 (68%) of 35 tumors from men, in 9 (53%) of 17 tumors from women, and in 5 (71%) of 7 adjacent normal lung tissue specimens. The levels of PSA protein did not associate with patient age, the tumor stage, grade, or histologic type, or the nodal status. Similarly, PSA mRNA was not associated with any clinicopathologic variables, but squamous cell carcinomas, especially in men, were more frequently positive. A by-product of the RT-PCR procedure was cloned and sequenced and found to be a 450-base pair sequence not previously deposited in the data bank. We conclude that PSA mRNA and protein frequently can be detected in lung tumors and normal tissues from men and women but at levels much lower than those seen in breast carcinomas in women. The significance of the new 450-base pair sequence remains to be determined.


HIV infection among injecting drug users in north-east Malaysia, 1992.
Human immunodeficiency virus (HIV) has spread widely among injecting drug users (IDUs) in countries to the north and west of the 'Golden Triangle' region of South-East Asia; it is likely to have spread southwards to Malaysia as well. In order to assess HIV seroprevalence among IDUs in north-east Malaysia and describe risk factors for HIV infection in this population, we performed a cross-sectional seroepidemiological study among 210 IDUs recruited at the detoxification ward of the General Hospital in the capital city of the north-eastern Malaysian state, Kelantan. Subjects were sequential entrants to the detoxification ward, interviewed about HIV risk behaviour, and tested for antibody to HIV and to syphilis. Nearly a third (62/210, 30%) of these IDUs were HIV seropositive. Three-quarters (159/210) had travelled to Thailand in the preceding 5 years, of whom 32% (51/159) were HIV seropositive; this was associated with injecting in Thailand, but not with sexual contact there. Of those who had not left Malaysia in the preceding 5 years, 26% (11/43) were HIV seropositive, a rate not significantly different from those who had travelled. Travel within Malaysia was common (144/210, 69%) among IDUs interviewed, as was unsafe injecting and unsafe sexual behaviour (20% had shared injecting equipment and 21% had had unprotected intercourse) in other states. In every locale, rates of unsafe injecting behaviour were high (55% sharing in last month), even among those who knew they were HIV infected, and rates of condom usage were low (93% of 160 sexually active IDUs had never used a condom). Syphilis was not associated with HIV infection, but with contact with Thai prostitutes.(ABSTRACT TRUNCATED AT 250 WORDS)


Absence of lactobacilli containing glycolipids with the α-galactose epitope and the enhanced fucosylation of a receptor glycolipid GA1 in the digestive tracts of immune-deficient scid mice.
The Lactobacillus species in the digestive tracts of immune-deficient scid mice was distinct from that in control mice, i.e. Lactobacillus murinus in scid and L. johnsonii in control mice, according to their 16S-rRNA, indicating that a symbiotic relationship between lactobacilli and a host is established under pressure from the immune system. The caecal and colonal contents rich in L. murinus of scid mice were loose with a strong sour smell, resulting in diarrhoea, and those with L. johnsonii in control mice included abundant solid materials. Lactobacillus glycolipids were revealed to be recognized by the immune system, and by TLC-immunostaining, LacTetH-DG (Galα1-6Galα1-6Galα1-2Glcα1-3'DG) of L. johnsonii was detected in the stomach, caecum and colon of control mice, but not in those of scid ones, in which fucosylation of a receptor GA1 for L. johnsonii was enhanced more than 4-fold compared with in the control mice. Thus, structural modification of receptor glycolipids was revealed to occur in the process of establishment of a symbiotic relationship between lactobacilli and a host. LacTetH-DG was also immunogenic to human, because of the presence of natural antibodies against it, and the antibody binding to it was comparable to that of blood group- and species-related glycosphingolipids.


Fitting of calibration-free scanned-wavelength-modulation spectroscopy spectra for determination of gas properties and absorption lineshapes.
The development and initial demonstration of a scanned-wavelength, first-harmonic-normalized, wavelength-modulation spectroscopy with nf detection (scanned-WMS-nf/1f) strategy for calibration-free measurements of gas conditions are presented. In this technique, the nominal wavelength of a modulated tunable diode laser (TDL) is scanned over an absorption transition to measure the corresponding scanned-WMS-nf/1f spectrum. Gas conditions are then inferred from least-squares fitting the simulated scanned-WMS-nf/1f spectrum to the measured scanned-WMS-nf/1f spectrum, in a manner that is analogous to widely used scanned-wavelength direct-absorption techniques. This scanned-WMS-nf/1f technique does not require prior knowledge of the transition linewidth for determination of gas properties. Furthermore, this technique can be used with any higher harmonic (i.e., n>1), modulation depth, and optical depth. Selection of the laser modulation index to maximize both signal strength and sensitivity to spectroscopic parameters (i.e., gas conditions), while mitigating distortion, is described. Last, this technique is demonstrated with two-color measurements in a well-characterized supersonic flow within the Stanford Expansion Tube. In this demonstration, two frequency-multiplexed telecommunication-grade TDLs near 1.4 μm were scanned at 12.5 kHz (i.e., measurement repetition rate of 25 kHz) and modulated at 637.5 and 825 kHz to determine the gas temperature, pressure, H2O mole fraction, velocity, and absorption transition lineshape. Measurements are shown to agree within uncertainty (1%-5%) of expected values.


Considering Cannabis: The Effects of Regular Cannabis Use on Neurocognition in Adolescents and Young Adults.
Thirty-six percent of high school seniors have used cannabis in the past year, and an alarming 6.5% smoked cannabis daily, up from 2.4% in 1993 (Johnston et al., 2013). Adolescents and emerging adults are undergoing significant neurodevelopment and animal studies suggest they may be particularly vulnerable to negative drug effects. In this review, we will provide a detailed overview of studies outlining the effects of regular (at least weekly) cannabis use on neurocognition, including studies outlining cognitive, structural and functional findings. We will also explore the public health impact of this research.


Use of carotid ultrasound to stratify risk.
B-mode carotid ultrasound is a well validated imaging technique for evaluating the anatomical extent of subclinical atherosclerosis. It is used to measure arterial carotid intima-media thickness (IMT), and there is clear evidence that carotid IMT measurements can be used to identify individuals at increased risk for coronary events and stroke. The validity and the usefulness of the technique - primarily as a research tool but also in the assessment of clinical cardiovascular risk - have been shown in a number of studies.


Recurrence Rate after Endoscopic vs. Open Approaches for Juvenile Nasopharyngeal Angiofibroma: A Meta-analysis.
Context The effect on recurrence rate between patients with juvenile nasopharyngeal angiofibroma (JNA), treated by an endoscopic versus open approach, has not been well established. Objective A meta-analysis of the available literature concerning recurrence rate in patients who underwent surgery for JNA. Methods A retrospective meta-analysis of studies analyzing recurrence rate after endoscopic or open surgery for patients with JNA was performed using the DerSimonian-Laird random-effects method. English and non-English articles were reviewed using Embase, Medline, and Cochrane databases. Results Among nine studies, including 362 patients from 1981 to 2015, with a mean follow-up of 49.4 months, a total of 89 patients (24.5%) had recurrence. Our analysis revealed a total effect size of -0.16 in favor of endoscopic approach (-0.25 to -0.06, CI [confidence interval] 95%). When analyzing tumor by stage (Radkowski's IA-IIIB n = 299), the endoscopic approach proved to be superior independent of tumor stage (2 vs. 17% for tumors stage IA-IIA, and 26 vs. 32% for tumor stage IIB-IIIB for endoscopic and open approaches respectively; p < 0.05). The endoscopic approach has a statistical significant lower recurrence rate in patients without intracranial compromise when compared with the open approach (13 vs. 28%; p < 0.02). No statistical difference was seen in patients with intracranial compromise ( p = 0.5) Conclusion The use of an endoscopic approach to treat JNA has a significantly lower recurrence rate when compared with open approaches. Independent of disease stage, an endoscopic approach should be the standard of care to surgically treat JNA. For cases with intracranial compromise, either approach can be used for surgical resection.


Self-organization in the basal ganglia with modulation of reinforcement signals.
Self-organization is one of fundamental brain computations for forming efficient representations of information. Experimental support for this idea has been largely limited to the developmental and reorganizational formation of neural circuits in the sensory cortices. We now propose that self-organization may also play an important role in short-term synaptic changes in reward-driven voluntary behaviors. It has recently been shown that many neurons in the basal ganglia change their sensory responses flexibly in relation to rewards. Our computational model proposes that the rapid changes in striatal projection neurons depend on the subtle balance between the Hebb-type mechanisms of excitation and inhibition, which are modulated by reinforcement signals. Simulations based on the model are shown to produce various types of neural activity similar to those found in experiments.


Coordinate replication of members of the multigene family of core and H1 human histone genes.
Cells of the K562 human erythroleukemia cell line were obtained in different stages of the cell cycle by centrifugal elutriation. The cells had been previously labeled for 2 hr with BrdUrd so that BrdUrd-DNA synthesized during four different selected intervals of the S phase could be isolated. This DNA was used to determine the temporal replication during S phase of EcoRI segments containing histone genes. Cloned human genomic segments containing the core histone genes (H2A, H2B, H3, and H4), H2A and H2B pseudogenes, and the H1 gene were prepared. The genomic inserts were excised from these plasmids, nick-translated, and used as hybridization probes. The results with different probes compared on the same and on independently prepared DBM-paper transfers indicate that all of these histone genes replicate during the first half of the S phase. These genes were not among the earliest to replicate in the K562 cell line. Similar studies were carried out with HeLa cells in which EcoRI segments containing the H4 histone and H2A and H2B pseudogenes were found to replicate during the first half of the S phase. These histone genes replicate during the interval of the S phase when histone mRNA appears in the cytoplasm at the maximal rate. The possible relationship between these events is discussed.


Impact of Percoll purification on isolation of primary human hepatocytes.
Research and therapeutic applications create a high demand for primary human hepatocytes. The limiting factor for their utilization is the availability of metabolically active hepatocytes in large quantities. Centrifugation through Percoll, which is commonly performed during hepatocyte isolation, has so far not been systematically evaluated in the scientific literature. 27 hepatocyte isolations were performed using a two-step perfusion technique on tissue obtained from partial liver resections. Cells were seeded with or without having undergone the centrifugation step through 25% Percoll. Cell yield, function, purity, viability and rate of bacterial contamination were assessed over a period of 6 days. Viable yield without Percoll purification was 42.4 × 106 (SEM ± 4.6 × 106) cells/g tissue. An average of 59% of cells were recovered after Percoll treatment. There were neither significant differences in the functional performance of cells, nor regarding presence of non-parenchymal liver cells. In five cases with initial viability of <80%, viability was significantly increased by Percoll purification (71.6 to 87.7%, p = 0.03). Considering our data and the massive cell loss due to Percoll purification, we suggest that this step can be omitted if the initial viability is high, whereas low viabilities can be improved by Percoll centrifugation.


Using community level strategies to reduce asthma attacks triggered by outdoor air pollution: a case crossover analysis.
Evidence indicates that asthma attacks can be triggered by exposure to ambient air pollutants, however, detailed pollution information is missing from asthma action plans. Asthma is commonly associated with four criteria pollutants with standards derived by the United States Environmental Protection Agency. Since multiple pollutants trigger attacks and risks depend upon city-specific mixtures of pollutants, there is lack of specific guidance to reduce exposure. Until multi-pollutant statistical modeling fully addresses this gap, some guidance on pollutant attack risk is required. This study examines the risks from exposure to the asthma-related pollutants in a large metropolitan city and defines the city-specific association between attacks and pollutant mixtures. Our goal is that city-specific pollution risks be incorporated into individual asthma action plans as additional guidance to prevent attacks. Case-crossover analysis and conditional logistic regression were used to measure the association between ozone, fine particulate matter, nitrogen dioxide, sulfur dioxide and carbon monoxide pollution and 11,754 emergency medical service ambulance treated asthma attacks in Houston, Texas from 2004-2011. Both single and multi-pollutant models are presented. In Houston, ozone and nitrogen dioxide are important triggers (RR = 1.05; 95% CI: 1.00, 1.09), (RR = 1.10; 95% CI: 1.05, 1.15) with 20 and 8 ppb increase in ozone and nitrogen dioxide, respectively, in a multi-pollutant model. Both pollutants are simultaneously high at certain times of the year. The risk attributed to these pollutants differs when they are considered together, especially as concentrations increase. Cumulative exposure for ozone (0-2 day lag) is of concern, whereas for nitrogen dioxide the concern is with single day exposure. Persons at highest risk are aged 46-66, African Americans, and males. Accounting for cumulative and concomitant outdoor pollutant exposure is important to effectively attribute risk for triggering of an asthma attack, especially as concentrations increase. Improved asthma action plans for Houston individuals should warn of these pollutants, their trends, correlation and cumulative effects. Our Houston based study identifies nitrogen dioxide levels and the three-day exposure to ozone to be of concern whereas current single pollutant based national standards do not.


Adenosine induces cell-cycle arrest and apoptosis in androgen-dependent and -independent prostate cancer cell lines, LNcap-FGC-10, DU-145, and PC3.
Adenosine has been shown to inhibit cell growth and induce apoptosis in the several cancer cells via intrinsic and extrinsic pathway. The present study was designed to understand the mechanism underlying adenosine-induced apoptosis in the DU-145, PC3, and LNcap-FGC10 human prostate cancer cells. To observe cell viability and proliferation, MTT assay, cell counting, and BrdU assay were carried out in DU-145, PC3, and LNcap-FGC10 cells. Apoptosis was assessed with the analysis of cell cycle, Hoechst 33258 staining, propidium iodide and annexin-V staining, reactive oxygen species (ROS) formation, mitochondrial membrane potential (ΔΨM) measurement, caspase-3 activity assay, Bcl-2 and Bax protein expression. Moreover, the expression of adenosine receptors and the effects of adenosine receptor (A(1) , A(2a) , and A(3) ) antagonists were examined. Adenosine significantly reduced cell proliferation in a dose-dependent manner in DU-145, PC3, and LNcap-FGC10 cell lines. Adenosine induced arrest in the cell-cycle progression in G0/G1 phase through Cdk4/cyclinD1-mediated pathway. Adenosine induced apoptosis, which was determined by morphological changes and increased sub-G1 population. Furthermore, increase of ROS, loss of MMP, activation of caspase-3, and down-regulation of Bcl-2 expression was observed. A(1) , A(2a) , A(2b) , and A(3) adenosine receptors mRNA are expressed in the cell lines. Moreover, adenosine-induced apoptosis was inhibited by MRS1220, A(3) adenosine receptor antagonist. Our results suggest that adenosine induced apoptosis in prostate cancer cells via the mitochondrial pathway and is related to the adenosine receptors. These data might suggest that adenosine could be used as an agent for the treatment of prostate cancer.


Bioaccumulation of total mercury in the earthworm Eisenia andrei.
Earthworms are a major part of the total biomass of soil fauna and play a vital role in soil maintenance. They process large amounts of plant and soil material and can accumulate many pollutants that may be present in the soil. Earthworms have been explored as bioaccumulators for many heavy metal species such as Pb, Cu and Zn but limited information is available for mercury uptake and bioaccumulation in earthworms and very few report on the factors that influence the kinetics of Hg uptake by earthworms. It is known however that the uptake of Hg is strongly influenced by the presence of organic matter, hence the influence of ligands are a major factor contributing to the kinetics of mercury uptake in biosystems. In this work we have focused on the uptake of mercury by earthworms (Eisenia andrei) in the presence of humic acid (HA) under varying physical conditions of pH and temperature, done to assess the role of humic acid in the bioaccumulation of mercury by earthworms from soils. The study was conducted over a 5-day uptake period and all earthworm samples were analysed by direct mercury analysis. Mercury distribution profiles as a function of time, bioaccumulation factors (BAFs), first order rate constants and body burden constants for mercury uptake under selected conditions of temperature, pH as well as via the dermal and gut route were evaluated in one comprehensive approach. The results showed that the uptake of Hg was influenced by pH, temperature and the presence of HA. Uptake of Hg(2+) was improved at low pH and temperature when the earthworms in soil were in contact with a saturating aqueous phase. The total amount of Hg(2+) uptake decreased from 75 to 48 % as a function of pH. For earthworms in dry soil, the uptake was strongly influenced by the presence of the ligand. Calculated BAF values ranged from 0.1 to 0.8. Mercury uptake typically followed first order kinetics with rate constants determined as 0.2 to 1 h(-1).


Functional consequences of Kir2.1/Kir2.2 subunit heteromerization.
Kir2 subunits form channels that underlie classical strongly inwardly rectifying potassium currents. While homomeric Kir2 channels display a number of distinct and physiologically important properties, the functional properties of heteromeric Kir2 assemblies, as well as the stoichiometries and the arrangements of Kir2 subunits in native channels, remain largely unknown. Therefore, we have implemented a concatemeric approach, whereby all four cloned Kir2 subunits were linked in tandem, in order to study the effects of Kir2.1 and Kir2.2 heteromerization on properties of the resulting channels. Kir2.2 subunits contributed stronger to single-channel conductance than Kir2.1 subunits, and channels containing two or more Kir2.2 subunits displayed conductances indistinguishable from that of a Kir2.2 homomeric channel. In contrast, single-channel kinetics was a more discriminating property. The open times were significantly shorter in Kir2.2 channels compared with Kir2.1 channels and decreased nearly proportionally to the number of Kir2.2 subunits in the heteromeric channel. Similarly, the sensitivity to block by barium also depended on the proportions of Kir2.1 to Kir2.2 subunits. Overall, the results showed that Kir2.1 and Kir2.2 subunits exert neither a dominant nor an anomalous effect on any of the properties of heteromeric channels. The data highlight opportunities and challenges of using differential properties of Kir2 channels in deciphering the subunit composition of native inwardly rectifying potassium currents.


Effect of winter cover crops on soil nitrogen availability, corn yield, and nitrate leaching.
Biculture of nonlegumes and legumes could serve as cover crops for increasing main crop yield, while reducing NO3 leaching. This study, conducted from 1994 to 1999, determined the effect of monocultured cereal rye (Secale cereale L.), annual ryegrass (Lolium multiflorum), and hairy vetch (Vicia villosa), and bicultured rye/vetch and ryegrass/vetch on N availability in soil, corn (Zea mays L.) yield, and NO3-N leaching in a silt loam soil. The field had been in corn and cover crop rotation since 1987. In addition to the cover crop treatments, there were four N fertilizer rates (0, 67, 134, and 201 kg N ha(-1), referred to as N0, N1, N2, and N3, respectively) applied to corn. The experiment was a randomized split-block design with three replications for each treatment. Lysimeters were installed in 1987 at 0.75 m below the soil surface for leachate collection for the N 0, N 2, and N 3 treatments. The result showed that vetch monoculture had the most influence on soil N availability and corn yield, followed by the bicultures. Rye or ryegrass monoculture had either no effect or an adverse effect on corn yield and soil N availability. Leachate NO3-N concentration was highest where vetch cover crop was planted regardless of N rates, which suggests that N mineralization of vetch N continued well into the fall and winter. Leachate NO3-N concentration increased with increasing N fertilizer rates and exceeded the U.S. Environmental Protection Agency's drinking water standard of 10 mg N l(-1) even at recommended N rate for corn in this region (coastal Pacific Northwest). In comparisons of the average NO3-N concentration during the period of high N leaching, monocultured rye and ryegrass or bicultured rye/vetch and ryegrass/vetch very effectively decreased N leaching in 1998 with dry fall weather. The amount of N available for leaching (determined based on the presidedress nitrate test, the amount of N fertilizer applied, and N uptake) correlated well with average NO3-N during the high N leaching period for vetch cover crop treatment and for the control without the cover crops. The correlation, however, failed for other cover crops largely because of variable effectiveness of the cover crops in reducing NO3 leaching during the 5 years of this study. Further research is needed to determine if relay cover crops planted into standing summer crops is a more appropriate approach than fall seeding in this region to gain sufficient growth of the cover crop by fall. Testing with other main crops that have earlier harvest dates than corn is also needed to further validate the effectiveness of the bicultures to increase soil N availability while protecting the water quality.


Comparing spiro-OMeTAD and P3HT hole conductors in efficient solid state dye-sensitized solar cells.
Two hole conductor materials, spiro-OMeTAD and P3HT, were compared in solid-state dye-sensitized solar cells. Two organic dyes containing one anchor unit (D35) or two anchor units (M3) were used in the comparison. Absorbed photon to current conversion efficiency close to unity was obtained for the devices with spiro-OMeTAD. Energy conversion efficiencies of 4.7% and 4.9% were measured for the devices with spiro-OMeTAD and the dyes D35 and M3, respectively. For the devices using the P3HT hole conductor the results were rather different comparing the two dye molecules, with energy conversion efficiencies of 3.2% and 0.5% for D35 and M3, respectively. Photo-induced absorption measurements suggest that the regeneration of the dyes, and the polymer infiltration, is not complete using P3HT, while spiro-OMeTAD regenerates the dyes efficiently. However, the TiO(2)/D35/P3HT system shows rather high energy conversion efficiency and electrochemical oxidation of the dyes on TiO(2) indicates that D35 have a more efficient dye to dye hole conduction than M3, which thereby might explain the higher performance. The dye hole conduction may therefore be of significant importance for optimizing the energy conversion in such hybrid TiO(2)/dye/polymer systems.


Differences in human cervical spine kinematics for active and passive motions of symptomatic and asymptomatic subject groups.
Most musculoskeletal disorders of the head and neck regions cannot be identified through imaging techniques; therefore clinician-conducted assessments (passive motions) are used to evaluate the functional ability of these regions. Although active motions do not require interaction with a clinician, these movements can also provide diagnostic indicators of dysfunction. The purpose of this research was to determine whether kinematic measures differed between active and passive movements of participants in symptomatic and asymptomatic groups. Data obtained on cervical lateral flexion range of motion (ROM), coupled axial rotation, and the angular velocity of lateral flexion were statistically analyzed and demonstrated differences between active and passive motions for symptomatic and asymptomatic subjects. Active motions had higher angular velocities (P < .001) and larger ROMs, with greater lateral flexions (P < .05). The asymptomatic group produced a larger average lateral flexion of 7.9° at an average angular velocity of 2 deg/s greater than the symptomatic group. Trends with regard to group assignment were the same for active and passive motions. This work demonstrates the potential for using kinematic measures of active and passive motions to develop an objective standard for diagnoses of cervical dysfunction and supports validity of the clinician-based analysis to distinguish between participant groups.


The use of minoxidil in the treatment of severe essential hypertension: a report on 100 patients.
1. One hundred patients with severe essential hypertension have been treated with minoxidil for a mean period of 8-4 months in a study involving eleven European centres. Seventy-two males and twenty-eight females were included in the group; the mean age was 55 years and the initial supine systolic and diastolic pressures averaged 212 (range 150-270) and 125 (range 90-150) mmHg respectively. 2. Reduction of supine diastolic pressure to less than 100 mmHg occurred in 94% of patients within 4 weeks. After the average follow-up period of 8-4 months the mean pressures were 151/91 mmHg. Concomitant therapy with beta-receptor-blocking agents and diuretics resulted in satisfactory control of heart rate and weight gain. 3. Side effects included increased hair growth, nausea, fatigue, rash and darkening of the skin. ECG showed mainly T-wave changes and echocardiographic examination indicated improved ventricular emptying.


Chronic Hepatitis E Viral Infection After Liver Transplantation: A Regression of Fibrosis After Antiviral Therapy.
Hepatitis E virus (HEV) infection is increasingly being reported in immunocompromised patients and particularly organ transplant recipients. In this context, HEV infection frequently evolves to chronic infection with a rapid progression of fibrosis to cirrhosis. Ribavirin monotherapy and a minimization of immunosuppression represent the treatment of choice, with a good response rate. However, no data are available on whether treatment can achieve a regression of liver fibrosis in chronic HEV patients. A 57-year-old male patient received a liver transplant for alcoholic cirrhosis and, 6 years later, developed biopsy-proven chronic HEV infection. The patient received different antiviral therapy regimens (pegylated interferon alpha 2b and ribavirin different dosages, and long-term treatment with ribavirin monotherapy still ongoing) but without achieving a sustained virological response. Liver function parameters normalized after 1 month of treatment but without the clearance of HEV. Hepatitis E virus RNA levels also remained detectable in the serum and stools throughout ribavirin monotherapy. No serious adverse events were reported. A gradual regression of liver fibrosis was reported (Metavir A0/F1 in 2015 versus A3/F4 in 2008). Long-term treatment with ribavirin is safe in liver transplant recipients, without achieving HEV sustained virological response, and may induce a biopsy-proven regression of liver fibrosis in a liver transplant recipient with cirrhosis after chronic HEV infection.


Ca2+/calmodulin-dependent protein kinase regulates GABA-activated Cl- current in cockroach dorsal unpaired median neurons.
We studied gamma-aminobutyric acid (GABA)-mediated currents in short-term cultured dorsal unpaired median (DUM) neurons of cockroach Periplaneta americana using the whole cell patch-clamp technique in symmetrical chloride solutions. All DUM neurons voltage-clamped at -50 mV displayed inward currents (I(GABA)) when 10(-4) M of GABA was applied by pneumatic pressure-ejection pulses. The semi-logarithmic curve of I(GABA) amplitude versus the ejection time yielded a Hill coefficient of 4.0. I(GABA) was chloride (Cl-) because the reversal potential given by the current-voltage (I-V) curve varied according to the value predicted by the Nernst equation for Cl- dependence. In addition, I(GABA) was almost completely blocked by bath application of the chloride channel blockers picrotoxin (PTX) or 3,3-bis(trifluoromethyl)bicyclo-[2,2,1]heptane-2,2-diacarbonitrile (BIDN). The I-V curve for I(GABA) displayed a unexpected biphasic aspect and was best fitted by two linear regressions giving two slope conductances of 35.6 +/- 2.1 and 80.9 +/- 4.1 nS for potentials ranging from 0 to -30 and -30 to -70 mV, respectively. At -50 mV, the current amplitude was decreased by cadmium chloride (CdCl2, 10(-3) M) and calcium-free solution. The semi-logarithmic curve for CdCl2-resistant I(GABA) gave a Hill coefficient of 2.4. Hyperpolarizing voltage step from -50 to -80 mV was known to increase calcium influx through calcium-resting channels. According to this protocol, a significant increase of I(GABA) amplitude was observed. However, this effect was never obtained when the same protocol was applied on cell body pretreated with CdCl2. When the calmodulin blocker N-(6-aminohexyl)-5-chloro-1-naphtalene-sulfonamide or the calcium-calmodulin-dependent protein kinase blocker 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62) was added in the pipette solution, I(GABA) amplitude was decreased. Pressure ejection application of the cis-4-aminocrotonic acid (CACA) on DUM neuron cell body held at -50 mV, evoked a Cl- inward current which was insensitive to CdCl2. The Hill plot yielded a Hill coefficient of 2.3, and the I-V curve was always linear in the negative potential range with a slope conductance of 32.4 +/- 1.1 nS. These results, similar to those obtained with GABA in the presence of CdCl2 and KN-62, indicated that CACA activated one subtype of GABA receptor. Our study demonstrated that at least two distinct subtypes of Cl--dependent GABA receptors were expressed in DUM neurons, one of which is regulated by an intracellular Ca2+-dependent mechanism via a calcium-dependent protein kinase. The consequences of the modulatory action of Ca2+ in GABA receptors function and their sensitivity to insecticide are discussed.


Engaging male partners in women's microbicide use: evidence from clinical trials and implications for future research and microbicide introduction.
Constructively engaging male partners in women-centred health programs such as family planning and prevention of mother-to-child HIV transmission has resulted in both improved health outcomes and stronger relationships. Concerted efforts to engage men in microbicide use could make it easier for women to access and use microbicides in the future. This paper synthesizes findings from studies that investigated men's role in their partners' microbicide use during clinical trials to inform recommendations for male engagement in women's microbicide use. We conducted primary and secondary analyses of data from six qualitative studies implemented in conjunction with microbicide clinical trials in South Africa, Kenya, and Tanzania. The analyses included data from 535 interviews and 107 focus groups with trial participants, male partners, and community members to answer research questions on partner communication about microbicides, men's role in women's microbicide use, and potential strategies for engaging men in future microbicide introduction. We synthesized the findings across the studies and developed recommendations. The majority of women in steady partnerships wanted agreement from their partners to use microbicides. Women used various strategies to obtain their agreement, including using the product for a while before telling their partners, giving men information gradually, and continuing to bring up microbicides until resistant partners acquiesced. Among men who were aware their partners were participating in a trial and using microbicides, involvement ranged from opposition to agreement/non-interference to active support. Both men and women expressed a desire for men to have access to information about microbicides and to be able to talk with a healthcare provider about microbicides. We recommend counselling women on whether and how to involve their partners including strategies for gaining partner approval; providing couples' counselling on microbicides so men have the opportunity to talk with providers; and targeting men with community education and mass media to increase their awareness and acceptance of microbicides. These strategies should be tested in microbicide trials, open-label studies, and demonstration projects to identify effective male engagement approaches to include in eventual microbicide introduction. Efforts to engage men must take care not to diminish women's agency to decide whether to use the product and inform their partners.


Enhanced anxiety in the male offspring of sires that self-administered cocaine.
We previously showed that paternal cocaine exposure reduced the reinforcing efficacy of cocaine in male offspring. Here, we sought to determine whether paternal cocaine experience could also influence anxiety levels in offspring. Male rats were allowed to self-administer cocaine (controls received saline passively) for 60 days and then were bred with naïve females. Measures of anxiety and cocaine-induced anxiogenic effects were assessed in the adult offspring. Cocaine-sired male offspring exhibited increased anxiety-like behaviors, as measured using the novelty-induced hypophagia and defensive burying tasks, relative to saline-sired males. In contrast, sire cocaine experience had no effect on anxiety-like behaviors in female offspring. When challenged with an anxiogenic (but not anorectic) dose of cocaine (2.5 mg/kg, i.p.), anxiety-like behavior was enhanced in all animals to an equal degree regardless of sire drug experience. Since anxiety and depression are often co-morbid, we also assessed measures of depressive-like behavior. Sire cocaine experience had no effect on depression-like behaviors, as measured by the forced swim task, among male offspring. In a separate group of naïve littermates, select neuronal correlates of anxiety were measured. Male offspring of cocaine-experienced sires showed increased mRNA and protein expression of corticotropin-releasing factor receptor 2 in the hippocampus. Together, these results indicate that cocaine-experienced sires produce male progeny that have increased baseline anxiety, which is unaltered by subsequent cocaine exposure.


Subunit architecture of the conserved oligomeric Golgi complex.
The conserved oligomeric Golgi (COG) complex is thought to function in intra-Golgi retrograde trafficking mediated by coat protein I vesicles, a pathway essential for the proper structure and function of the Golgi apparatus. Previous work suggested that COG might act as a tethering factor to mediate the initial attachment between coat protein I vesicles and Golgi membranes. Here, we present extensive in vitro co-translation and immunoprecipitation experiments leading to a new model for the overall architecture of the mammalian COG complex. The eight COG subunits (Cog1-8) are found to form two heterotrimeric subassemblies (Cog2/3/4 and Cog5/6/7) linked by a heterodimer composed of the remaining subunits (Cog1/8). This model is in excellent agreement with in vivo data presented in an accompanying paper (Oka, T., Vasile, E., Penman, M., Novina, C. D., Dykxhoorn, D. M., Ungar, D., Hughson, F. M., and Krieger, M. (2005) J. Biol. Chem. 280, 32736-32745).