Mortality and clinical outcomes in children treated with antiretroviral therapy in four African vertical programmes during the first decade of paediatric HIV care, 2001-2010.
To assess mortality and clinical outcomes in children treated with antiretroviral therapy (ART) in four African vertical programmes between 2001 and 2010. Cohort analysis of data from HIV-infected children (<15 years old) initiating ART in four sub-Saharan HIV programmes in Kenya, Uganda and Malawi, between December 2001 and December 2010. Rates of mortality, programme attrition and first-line clinico-immunological failure were calculated by age group (<2, 2-4 and 5-14 years), 1 or 2 years after ART initiation, and risk factors were examined. A total of 3949 children, 22.7% aged <2 years, 32.2% 2-4 years and 45.1% 5-14 years, were included. At ART initiation, 60.8% had clinical stage 3 or 4, and 46.5% severe immunosuppression. Overall mortality, attrition and 1-year failure rates were 5.1, 10.8 and 9.0 per 100 person-years, respectively. Immunosuppression, stage 3 or 4, and underweight were associated with increased rates of mortality, attrition and treatment failure. Adjusted estimates showed lower mortality hazard ratios (HR) among children aged 2-4 years (HR = 0.57, 95% CI 0.42-0.77 than children aged 5-14 years). One-year treatment failure incidence rate ratios (IRR) were similar regardless of age (IRR = 0.91, 95% CI 0.67-1.25 for <2 years; 1.01, 95% CI 0.83-1.23 for 2-4 years, vs. 5-14 years). Good treatment outcomes were achieved during the first decade of HIV paediatric care despite the late start of therapy. Encouraging early HIV infant diagnosis in and outside prevention of mother-to-child transmission programmes, and linkage to care services for early ART initiation, is needed to reduce mortality and delay treatment failure.


Global health language and culture competency.
This article presents findings from a survey conducted to examine the availability of foreign language and culture training to Civil Affairs health personnel and the relevance of that training to the tasks they perform. Civil Affairs forces recognize the value of cross-cultural communication competence because their missions involve a significant level of interaction with foreign governments? officials, military, and civilians. Members of the 95th Civil Affairs Brigade (Airborne) who had a health-related military occupational specialty code were invited to participate in the survey. More than 45% of those surveyed were foreign language qualified. Many also received predeployment language and culture training specific to the area of deployment. Significantly more respondents reported receiving cultural training and training on how to work effectively with interpreters than having received foreign language training. Respondents perceived interpreters as important assets and were generally satisfied with their performance. Findings from the survey highlight a need to identify standard requirements for predeployment language training that focuses on medical and health terminology and to determine the best delivery platform(s). Civil Affairs health personnel would benefit from additional cultural training that focuses on health and healthcare in the country or region of deployment. Investing in the development of distance learning capabilities as a platform for delivering health-specific language and culture training may help ease the time and resources constraints that limit the ability of Civil Affairs health personnel to access the training they need.


Pacemaker endocarditis: an important clinical entity.
Pacemaker endocarditis remains a rare but potentially life threatening complication of pacemaker implantation. This case illustrates a rare cause of pacemaker endocarditis, Serratia marcescens, the management difficulties that can be faced with such organisms, and the potential indolent nature of pacemaker lead associated endocarditis. A review of the current data for pacemaker endocarditis management suggests that treatment with antimicrobials alone is unlikely to be curative and explantation of the device is recommended in all cases of confirmed pacemaker endocarditis (by echocardiography, in correlation with the patient's clinical condition and inflammatory markers).


Exercise training effect on obstructive sleep apnea syndrome.
The role, if any, of exercise training in the management of individuals with obstructive sleep apnea syndrome (OSAS) is unclear. Anecdotally, patients have reported improvement in symptoms with regular participation in an exercise regime. In this study, we evaluated the effects of an exercise training program and weight loss on physical and subjective measures associated with OSAS. Nine subjects with mild to moderate OSAS completed a six month supervised exercise program. Pre and post-training measures on polysomnographic testing, physical training, anthropometric measures, quality of life (QOL), daytime somnolence and mood states were assessed. A significant decrease in the AHI (p=0.002) was noted along with improvements (p<0.05) in total sleep time, sleep efficiency, number of awakenings/hour, arousals/hour, apnea index and mean exercise training workloads. Significant decreases (p<.001) in weight (-6.2 kg) and body mass index (-1.6) were observed. Evaluation of QOL measures by the Health Status Questionnaire, Profile of Mood States and Epworth Sleepiness Scale showed significant changes in health status, affective state, and a decrease in daytime somnolence. Regular exercise training had a positive impact on the AHI, aerobic capacity, body mass index and QOL. However, exercise training alone was not an adequate intervention strategy for most individuals with OSAS but may serve well as an adjunct treatment strategy in the conservative management of individuals with mild to moderate OSAS.


Different Components of the RNA Interference Machinery Are Required for Conidiation, Ascosporogenesis, Virulence, Deoxynivalenol Production, and Fungal Inhibition by Exogenous Double-Stranded RNA in the Head Blight Pathogen Fusarium graminearum.
In filamentous fungi, gene silencing through RNA interference (RNAi) shapes many biological processes, including pathogenicity. We explored the requirement of key components of fungal RNAi machineries, including DICER-like 1 and 2 (FgDCL1, FgDCL2), ARGONAUTE 1 and 2 (FgAGO1, FgAGO2), AGO-interacting protein FgQIP (QDE2-interacting protein), RecQ helicase (FgQDE3), and four RNA-dependent RNA polymerases (FgRdRP1, FgRdRP2, FgRdRP3, FgRdRP4), in the ascomycete mycotoxin-producing fungal pathogen Fusarium graminearum (Fg) for sexual and asexual multiplication, pathogenicity, and its sensitivity to double-stranded (ds)RNA. We corroborate and extend earlier findings that conidiation, ascosporogenesis, and Fusarium head blight (FHB) symptom development require an operable RNAi machinery. The involvement of RNAi in conidiation is dependent on environmental conditions as it is detectable only under low light (<2 μmol m-2 s-1). Although both DCLs and AGOs partially share their functions, the sexual ascosporogenesis is mediated primarily by FgDCL1 and FgAGO2, while FgDCL2 and FgAGO1 contribute to asexual conidia formation and germination. FgDCL1 and FgAGO2 also account for pathogenesis as their knockout (KO) results in reduced FHB development. Apart from KO mutants Δdcl2 and Δago1, mutants Δrdrp2, Δrdrp3, Δrdrp4, Δqde3, and Δqip are strongly compromised for conidiation, while KO mutations in all RdPRs, QDE3, and QIP strongly affect ascosporogenesis. Analysis of trichothecenes mycotoxins in wheat kernels showed that the relative amount of deoxynivalenol (DON), calculated as [DON] per amount of fungal genomic DNA was reduced in all spikes infected with RNAi mutants, suggesting the possibility that the fungal RNAi pathways affect Fg's DON production. Moreover, silencing of fungal genes by exogenous target gene-specific double-stranded RNA (dsRNA) (spray-induced gene silencing, SIGS) is dependent on DCLs, AGOs, and QIP, but not on QDE3. Together these data show that in F. graminearum, different key components of the RNAi machinery are crucial in different steps of fungal development and pathogenicity.


Complementary and alternative medicine in pediatric oncology: availability and institutional policies in Canada--a report from the Children's Oncology Group.
Complementary and alternative medicine (CAM) is used frequently by pediatric oncology patients. A survey exploring the institutional practices and policies surrounding CAM use in pediatric oncology patients was completed by 17 pediatric hematology/oncology centers in Canada. We found that CAM was offered in only 18% of the institutions, but 94% of the communities. Only 6% of oncology divisions made direct referrals to community CAM providers, and only 20% of the centers had policies regarding use of CAM therapies for their patients. Despite published widespread use of CAM therapies, our study demonstrates that institutional CAM resources and policies on CAM are present in much lower proportions.


Mitochondrial resequencing arrays detect tumor-specific mutations in salivary rinses of patients with head and neck cancer.
Alterations of the mitochondrial genome have been identified in multiple solid tumors and in many head and neck squamous cell carcinomas (HNSCC). Identification of mitochondrial mutations in the salivary rinses of patients with HNSCC has potential application in disease detection. In this study, we used the MitoChip v2.0 mitochondrial genome resequencing array to detect minor populations of mitochondrial DNA in salivary rinses of patients with HNSCC. Salivary rinses from 13 patients with HNSCC, whose tumors carried mitochondrial mutations, were collected before surgical resection. DNA isolated from salivary rinses and serial dilutions of DNA derived from HNSCC-derived cell lines with known mitochondrial mutations were sequenced using the MitoChip, and analyzed using a quantitative algorithm which we developed to detect minor populations of mitochondrial DNA from MitoChip probe intensity data. We detected heteroplasmic populations of mitochondrial DNA up to a 1:200 dilution using MitoChip v2.0 and our analysis algorithm. A logarithmic relationship between the magnitude of assay intensity and concentration of minor mitochondrial populations was shown. This technique was able to identify tumor-specific mitochondrial mutations in salivary rinses from 10 of 13 (76.9%) patients with head and neck cancer. Minor populations of mitochondrial DNA and disease-specific mitochondrial mutations in salivary rinses of patients with HNSCC can be successfully identified using the MitoChip resequencing array and the algorithm which we have developed. This technique has potential application in the surveillance of patients after resection and may have applicability in the surveillance of body fluids in other tumor types.


Time course of changes in the expression of insulin sensitivity-related genes after an acute load of virgin olive oil.
Our aim was to examine whether an acute fat load could induce changes in the expression of insulin sensitivity-related genes in human peripheral blood mononuclear cells. Selection of candidate genes was based on previous studies with sustained virgin olive oil (VOO) consumption and biological plausibility in relation to insulin sensitivity. Eleven healthy volunteers ingested raw VOO (50 mL). Blood samples were collected at 0, 1 and 6 h. Plasma glucose, insulin and hydroxytyrosol increased at 1 h and decreased at 6 h. Lipid oxidative damage increased at 6 h (p < 0.05). Gene expression changes were characterized based on quantification of the samples relative to a reference sample [i.e., relative quantification (RQ) method]. A 1 h downregulation was observed in O-linked-N-acetylglucosamine transferase (OGT, RQ: 0.62 +/- 0.32) and arachidonate-5-lipoxygenase-activating protein (ALOX5AP, RQ: 0.64 +/- 0.31) genes (p < 0.005). OGT was upregulated at 6 h (RQ: 1.88 +/- 0.28, p < 0.05). CD36 (thrombospondin receptor) was upregulated at 1 h (RQ: 1.6 +/- 0.8, p < 0.05) returning to the basal values at 6 h. Lipoic acid synthetase (LIAS), peroxisome proliferator-activated receptor binding protein (PPARBP), a disintegrin and metallopeptidase domain 17 (ADAM17), and adrenergic beta-2-receptor (ADRB2) genes were upregulated at 6 h (range for the mean RQ: 1.33-1.56) following an increasing linear trend (p < 0.05) from baseline to 6 h. ALOX5AP and OGT genes inversely correlated with insulin and glucose levels at 1 h. ADAM17 and ADRB2 inversely correlated with oxLDL at 6 h (p < 0.05). Taken together, these observations may inform the future clinical nutrigenomics study designs and indicate that a single dose of VOO can elicit quantifiable and rapid changes in gene expression in targets that are mechanistically relevant for insulin sensitivity and the metabolic syndrome.


Synchrotron FTIR mapping of mineralization in a microfluidic device.
Fourier transform infrared micro-spectroscopy provides an effective means of performing rapid, non-destructive, and label-free analysis of specimens according to their vibrational modes. However, as water absorbs very strongly in the infrared region, analysis of aqueous solutions in transmission mode can suffer from problems with signal saturation. We here describe the fabrication of a novel microfluidic device that overcomes this problem. Devices with channel depths of just 3 μm were constructed from calcium fluoride using photolithography and hot embossing bonding, where calcium fluoride was selected due to its transparency in the IR region. The utility of this device was then demonstrated by employing it to follow the precipitation pathways of calcium sulfate and calcium carbonate using synchrotron FTIR micro-spectroscopy. Importantly, due to the high brightness provided by synchrotron radiation, and the fact that the reacting ions (HCO3-, CO32- and SO42-) and the different mineral polymorphs all have finger print spectra in the measured IR range, this method can be used to acquire time-resolved, hyperspectral maps of the mineral particles formed within the sample cell, and then study the interaction and evolution of particles. The data provide new insight into the formation pathway of a population of crystals in confined volumes, and demonstrate that this in situ, real-time detection system provides a powerful tool for studying crystallization processes.


Temporal dynamics of stress-induced alternations of intrinsic amygdala connectivity and neuroendocrine levels.
Stress-induced changes in functional brain connectivity have been linked to the etiology of stress-related disorders. Resting state functional connectivity (rsFC) is especially informative in characterizing the temporal trajectory of glucocorticoids during stress adaptation. Using the imaging Maastricht Acute Stress Test (iMAST), we induced acute stress in 39 healthy volunteers and monitored the neuroendocrine stress levels during three runs of resting state functional magnetic resonance imaging (rs-fMRI): before (run 1), immediately following (run 2), and 30 min after acute stress (run 3). The iMAST resulted in strong increases in cortisol levels. Whole-brain analysis revealed that acute stress (run 2 - 1) was characterized by changes in connectivity of the amygdala with the ventrolateral prefrontal cortex (vlPFC), ventral posterior cingulate cortex (PCC), cuneus, parahippocampal gyrus, and culmen. Additionally, cortisol responders were characterized by enhanced amygdala - medial prefrontal cortex (mPFC) connectivity. Stress recovery (run 3 - 2) was characterized by altered amygdala connectivity with the dorsolateral prefrontal cortex (dlPFC), ventral and dorsal anterior cingulate cortex (ACC), anterior hippocampal complex, cuneus, and presupplementary motor area (preSMA). Opposite to non-responders, cortisol responders were characterized by enhanced amygdala connectivity with the anterior hippocampal complex and parahippocampal gyrus, and reduced connectivity with left dlPFC, dACC, and culmen during early recovery. Acute stress responding and recovery are thus associated with changes in the functional connectivity of the amygdala network. Our findings show that these changes may be regulated via stress-induced neuroendocrine levels. Defining stress-induced neuronal network changes is pertinent to developing treatments that target abnormal neuronal activity.


Upconversion multichannel infrared spectrometer.
A multichannel IR spectrometer using a standard silicon CCD array is demonstrated. Sum frequency generation between an ultrafast optical pulse and a frequency-dispersed IR beam generates a spatially extended optical signal that is collected on a generic CCD video camera. This method provides an inexpensive and efficient alternative to conventional multichannel IR arrays.


Effect of a 3'-->5' exonuclease with a proofreading function on the fidelity of error-prone DNA polymerase alpha from regenerating liver of aged rats.
A nuclease that releases noncomplementary nucleotides from the 3'-end of DNA was isolated and highly purified from rat liver extract. The d(T9-C) priming activities for DNA synthesis in vitro by DNA polymerases alpha and beta were recovered by the addition of this enzyme, which itself does not contain a DNA polymerase activity. This nuclease hydrolysed nucleotides from the 3'-end, but did not remove [32P]-labeled nucleotides from the 5'-terminus of specifically labeled DNA. Also, the reaction products released from the 3'-end of DNA were all mononucleotides. These results indicate that the exonuclease is a 3'-->5' exonuclease with properties the same as those of DNase VII from human placenta. Rat DNase VII requires 4 mM MgCl2 or 0.125 mM MnCl2 for maximum activity, and shows a pH optimum of 7.5. These optimal conditions are similar to those of DNA polymerases, and indicate that both rat DNase VII and DNA polymerases are able to act under same conditions. Non-complementary nucleotide incorporation by DNA polymerase alpha from aged rat has been observed during in vitro DNA synthesis on poly dA-dT10. The amount of this mis-incorporation is decreased by the coexistence of the 3'-->5' exonuclease, but not all errors are edited out. Thus, this rat DNase VII is suggested to play an important role in proofreading during DNA synthesis.


Association Between Cumulative Low-Density Lipoprotein Cholesterol Exposure During Young Adulthood and Middle Age and Risk of Cardiovascular Events.
Low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease (CVD). Most observational studies on the association between LDL-C and CVD have focused on LDL-C level at a single time point (usually in middle or older age), and few studies have characterized long-term exposures to LDL-C and their role in CVD risk. To evaluate the associations of cumulative exposure to LDL-C, time-weighted average (TWA) LDL-C, and the LDL-C slope change during young adulthood and middle age with incident CVD later in life. This cohort study analyzed pooled data from 4 prospective cohort studies in the US (Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Framingham Heart Study Offspring Cohort, and Multi-Ethnic Study of Atherosclerosis). Participants were included if they had 2 or more LDL-C measures that were at least 2 years apart between ages 18 and 60 years, with at least 1 of the LDL-C measures occurring during middle age at 40 to 60 years. Data from 1971 to 2017 were collected and analyzed from September 25, 2020, to January 10, 2021. Cumulative exposure to LDL-C, TWA LDL-C, and LDL-C slope from age 18 to 60 years. Incident coronary heart disease (CHD), ischemic stroke, and heart failure (HF). A total of 18 288 participants were included in this study. These participants had a mean (SD) age of 56.4 (3.7) years and consisted of 10 309 women (56.4%). During a median follow-up of 16 years, 1165 CHD, 599 ischemic stroke, and 1145 HF events occurred. In multivariable Cox proportional hazards regression models that adjusted for the most recent LDL-C level measured during middle age and for other CVD risk factors, the hazard ratios for CHD were as follows: 1.57 (95% CI, 1.10-2.23; P for trend = .01) for cumulative LDL-C level, 1.69 (95% CI, 1.23-2.31; P for trend <.001) for TWA LDL-C level, and 0.88 (95% CI, 0.69-1.12; P for trend = .28) for LDL-C slope. No association was found between any of the LDL-C variables and ischemic stroke or HF. This cohort study showed that cumulative LDL-C and TWA LDL-C during young adulthood and middle age were associated with the risk of incident CHD, independent of midlife LDL-C level. These findings suggest that past levels of LDL-C may inform strategies for primary prevention of CHD and that maintaining optimal LDL-C levels at an earlier age may reduce the lifetime risk of developing atherosclerotic CVD.


Hormonal contraceptive use, cervical ectopy, and the acquisition of cervical infections.
Several previous studies have suggested that hormonal contraception could be associated with increased risk of cervical infections. However, few high-quality prospective studies have examined this relationship. The goal of this study was to measure the effect of oral contraceptives (OC) and depot-medroxyprogesterone acetate (DMPA) on the acquisition of cervical chlamydial and gonococcal infections. Women attending 2 reproductive health centers in Baltimore, MD, were enrolled into a prospective cohort study. Participants were 15 to 45 years and were initiating OCs or DMPA or not using hormonal contraception. Interviews, physical examinations, and testing for incident cervical infections were conducted at 3, 6, and 12 months. The analysis included 819 women. Most were single (77%) and nulliparous (75%); 43% were black. Median age was 22 years. During the study, 45 women acquired a chlamydial or gonococcal infection (6.2 per 100 women-years). DMPA use (hazard ratio [HR], 3.6; 95% confidence interval [CI], 1.6-8.5), but not OC use (HR, 1.5; 95% CI, 0.6-3.5), was significantly associated with increased acquisition of cervical infections after adjusting for other risk factors. Cervical ectopy was not an important mediator of cervical infection risk. DMPA use, but not OC use, appeared to be significantly associated with increased acquisition of cervical chlamydial and gonococcal infections.


Molecular, cellular, morphological, physiological and behavioral aspects of gonadotropin-inhibitory hormone.
Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that was isolated from the brains of Japanese quail in 2000, which inhibited luteinizing hormone release from the anterior pituitary gland. Here, we summarize the following fifteen years of researches that investigated on the mechanism of GnIH actions at molecular, cellular, morphological, physiological, and behavioral levels. The unique molecular structure of GnIH peptide is in its LPXRFamide (X=L or Q) motif at its C-terminal. The primary receptor for GnIH is GPR147. The cell signaling pathway triggered by GnIH is initiated by inhibiting adenylate cyclase and decreasing cAMP production in the target cell. GnIH neurons regulate not only gonadotropin synthesis and release in the pituitary, but also regulate various neurons in the brain, such as GnRH1, GnRH2, dopamine, POMC, NPY, orexin, MCH, CRH, oxytocin, and kisspeptin neurons. GnIH and GPR147 are also expressed in gonads and they may regulate steroidogenesis and germ cell maturation in an autocrine/paracrine manner. GnIH regulates reproductive development and activity. In female mammals, GnIH may regulate estrous or menstrual cycle. GnIH is also involved in the regulation of seasonal reproduction, but GnIH may finely tune reproductive activities in the breeding seasons. It is involved in stress responses not only in the brain but also in gonads. GnIH may inhibit male socio-sexual behavior by stimulating the activity of cytochrome P450 aromatase in the brain and stimulates feeding behavior by modulating the activities of hypothalamic and central amygdala neurons.


Entire-Dataset Analysis of NMR Fast-Exchange Titration Spectra: A Mg2+ Titration Analysis for HIV-1 Ribonuclease H Domain.
This article communicates our study to elucidate the molecular determinants of weak Mg2+ interaction with the ribonuclease H (RNH) domain of HIV-1 reverse transcriptase in solution. As the interaction is weak (a ligand-dissociation constant >1 mM), nonspecific Mg2+ interaction with the protein or interaction of the protein with other solutes that are present in the buffer solution can confound the observed Mg2+-titration data. To investigate these indirect effects, we monitored changes in the chemical shifts of backbone amides of RNH by recording NMR 1H-15N heteronuclear single-quantum coherence spectra upon titration of Mg2+ into an RNH solution. We performed the titration under three different conditions: (1) in the absence of NaCl, (2) in the presence of 50 mM NaCl, and (3) at a constant 160 mM Cl- concentration. Careful analysis of these three sets of titration data, along with molecular dynamics simulation data of RNH with Na+ and Cl- ions, demonstrates two characteristic phenomena distinct from the specific Mg2+ interaction with the active site: (1) weak interaction of Mg2+, as a salt, with the substrate-handle region of the protein and (2) overall apparent lower Mg2+ affinity in the absence of NaCl compared to that in the presence of 50 mM NaCl. A possible explanation may be that the titrated MgCl2 is consumed as a salt and interacts with RNH in the absence of NaCl. In addition, our data suggest that Na+ increases the kinetic rate of the specific Mg2+ interaction at the active site of RNH. Taken together, our study provides biophysical insight into the mechanism of weak metal interaction on a protein.


A clinical audit of the management of patients with a tracheostomy in an Australian tertiary hospital intensive care unit: Focus on speech-language pathology.
Speech-language pathologists manage communication and swallowing disorders, both of which can occur in patients after tracheostomy insertion. An audit on the incidence and timing of speech-language pathology intervention for adults with tracheostomies has not previously been published. Data were retrospectively extracted from the medical records of all patients who were tracheostomized at Royal Prince Alfred Hospital, NSW, Australia, from October 2007 for 1 year. Extracted data included diagnosis, date and type of tracheostomy, time to speech-language pathologist involvement, time to phonation, and time to oral intake. Among the 140 patients (mean age 58 years, range 16-85), diagnoses were neurological (32%), head and neck (25%), cardiothoracic (24%), respiratory (6%), and other (13%). Speech-language pathology was involved with 78% of patients, with initial assessment on average 14 days after tracheostomy insertion (14 days to 166 days). Median time from tracheostomy insertion to phonation was 12 days (range 1-103). Median time from tracheostomy insertion to oral intake was 15 days (range 1-142). Only 20% of patients returned to verbal communication within 1 week after tracheostomy insertion. Further research into access to and timing of speech-language pathology intervention in the critical care setting is warranted.


Host-Pathogen Adhesion as the Basis of Innovative Diagnostics for Emerging Pathogens.
Infectious diseases are an existential health threat, potentiated by emerging and re-emerging viruses and increasing bacterial antibiotic resistance. Targeted treatment of infectious diseases requires precision diagnostics, especially in cases where broad-range therapeutics such as antibiotics fail. There is thus an increasing need for new approaches to develop sensitive and specific in vitro diagnostic (IVD) tests. Basic science and translational research are needed to identify key microbial molecules as diagnostic targets, to identify relevant host counterparts, and to use this knowledge in developing or improving IVD. In this regard, an overlooked feature is the capacity of pathogens to adhere specifically to host cells and tissues. The molecular entities relevant for pathogen-surface interaction are the so-called adhesins. Adhesins vary from protein compounds to (poly-)saccharides or lipid structures that interact with eukaryotic host cell matrix molecules and receptors. Such interactions co-define the specificity and sensitivity of a diagnostic test. Currently, adhesin-receptor binding is typically used in the pre-analytical phase of IVD tests, focusing on pathogen enrichment. Further exploration of adhesin-ligand interaction, supported by present high-throughput "omics" technologies, might stimulate a new generation of broadly applicable pathogen detection and characterization tools. This review describes recent results of novel structure-defining technologies allowing for detailed molecular analysis of adhesins, their receptors and complexes. Since the host ligands evolve slowly, the corresponding adhesin interaction is under selective pressure to maintain a constant receptor binding domain. IVD should exploit such conserved binding sites and, in particular, use the human ligand to enrich the pathogen. We provide an inventory of methods based on adhesion factors and pathogen attachment mechanisms, which can also be of relevance to currently emerging pathogens, including SARS-CoV-2, the causative agent of COVID-19.


Source modeling sleep slow waves.
Slow waves are the most prominent electroencephalographic (EEG) feature of sleep. These waves arise from the synchronization of slow oscillations in the membrane potentials of millions of neurons. Scalp-level studies have indicated that slow waves are not instantaneous events, but rather they travel across the brain. Previous studies of EEG slow waves were limited by the poor spatial resolution of EEGs and by the difficulty of relating scalp potentials to the activity of the underlying cortex. Here we use high-density EEG (hd-EEG) source modeling to show that individual spontaneous slow waves have distinct cortical origins, propagate uniquely across the cortex, and involve unique subsets of cortical structures. However, when the waves are examined en masse, we find that there are diffuse hot spots of slow wave origins centered on the lateral sulci. Furthermore, slow wave propagation along the anterior-posterior axis of the brain is largely mediated by a cingulate highway. As a group, slow waves are associated with large currents in the medial frontal gyrus, the middle frontal gyrus, the inferior frontal gyrus, the anterior cingulate, the precuneus, and the posterior cingulate. These areas overlap with the major connectional backbone of the cortex and with many parts of the default network.


The domain management model--a tool for teaching and management of older adults in emergency departments.
Older adults in emergency departments (EDs) can have complicated health problems that defy straightforward diagnosis and management. Implementation of the 11 core principles in the geriatric emergency care model requires changes in care processes. The Domain Management Model (DMM) is one solution to organize care efficiently using a standard language. Its use is consistent with the geriatric model. Patients' problems are organized into one of four domains: I. Medical/Surgical Issues; II. Mental Status/Emotions/Coping; III. Physical Function; and IV. Living Environment (A. Physical, B. Social, and C. Financial). Specific geriatric cases illustrate improved communication using these standard domains. This model can educate health care staff, facilitate team care, improve flow of relevant information, improve decision making, and facilitate more meaningful interactions with patients.


Surface plasmon polariton detection discriminating the polarization reversal image dipole effects.
Image dipole effects are highly dependent on the polarization direction, constructive (destructive) interference between real and image dipoles for the vertically (horizontally) aligned one in the vicinity of metal surfaces, respectively. This polarization-reversal of the image dipole effects is quantitatively investigated by using a gold nanoparticle functionalized tip as a local dipolar scatterer and a propagating surface plasmon polariton as an excitation source of dipoles. The polarization-resolved detection technique is applied to separate the radiations of the vertical and the horizontal dipoles from each other. In our study, the image dipole effects on the far-field detected signals are fully explained by the Fabry-Perot like interference between the radiations from the real and the image dipoles, and by considering the finite size effects of the gold nanoparticle.


Exceptional preservation of tiny embryos documents seed dormancy in early angiosperms.
The rapid diversification of angiosperms through the Early Cretaceous period, between about 130-100 million years ago, initiated fundamental changes in the composition of terrestrial vegetation and is increasingly well understood on the basis of a wealth of palaeobotanical discoveries over the past four decades and their integration with improved knowledge of living angiosperms. Prevailing hypotheses, based on evidence both from living and from fossil plants, emphasize that the earliest angiosperms were plants of small stature with rapid life cycles that exploited disturbed habitats in open, or perhaps understorey, conditions. However, direct palaeontogical data relevant to understanding the seed biology and germination ecology of Early Cretaceous angiosperms are sparse. Here we report the discovery of embryos and their associated nutrient storage tissues in exceptionally well-preserved angiosperm seeds from the Early Cretaceous. Synchrotron radiation X-ray tomographic microscopy of the fossil embryos from many taxa reveals that all were tiny at the time of dispersal. These results support hypotheses based on extant plants that tiny embryos and seed dormancy are basic for angiosperms as a whole. The minute size of the fossil embryos, and the modest nutrient storage tissues dictated by the overall small seed size, is also consistent with the interpretation that many early angiosperms were opportunistic, early successional colonizers of disturbance-prone habitats.


Identification and characterization of microRNAs and endogenous siRNAs in Schistosoma japonicum.
Small endogenous non-coding RNAs (sncRNAs) such as small interfering RNA (siRNA), microRNA and other small RNA transcripts are derived from distinct loci in the genome and play critical roles in RNA-mediated gene silencing mechanisms in plants and metazoa. They are approximately 22 nucleotides long; regulate mRNA stability through perfect or imperfect match to the targets. The biological activities of sncRNAs have been related to many biological events, from resistance to microbe infections to cellular differentiation. The development of the zoonotic parasite Schistosoma japonicum parasite includes multiple steps of morphological alterations and biological differentiations, which provide a unique model for studies on the functions of small RNAs. Characterization of the genome-wide transcription of the sncRNAs will be a major step in understanding of the parasite biology. The objective of this study is to investigate the transcriptional profile and potential function of the small non-coding RNAs in the development of S. japanicum. The endogenous siRNAs were found mainly derived from transposable elements (TE) or transposons and the natural antisense transcripts (NAT). In contrast to other organisms, the TE-derived siRNAs in S. japonicum were more predominant than other sncRNAs including microRNAs (miRNAs). Further, there were distinct length and 3'end variations in the sncRNAs, which were associated with the developmental differentiation of the parasite. Among the identified miRNA transcripts, there were 38 unique to S. japonicum and 16 that belonged to 13 miRNA families are common to other metazoan lineages. These miRNAs were either ubiquitously expressed, or they exhibited specific expression patterns related to the developmental stages or sex. Genes that encoded miRNAs are mainly located in clusters within the genome of S. japonicum. However, genes within one cluster could be differentially transcribed, which suggested that individual genes might be regulated by distinct mechanisms during parasite development. Many miRNA and endogenous siRNA transcripts were identified in S. japonicum and the amount of siRNA was at least 4.4 and 1.6 times more than that of miRNA in both schistosomulum and adult worm stages respectively. SiRNAs are mainly derived from transposable elements (or transposons); while natural antisense transcripts (NAT)-derived siRNAs were much less. A majority of miRNA transcripts identified in the parasite were species-specific and the expression of certain miRNAs was found developmentally regulated. Both miRNA and siRNAs are potentially important regulators in the development of schistosomal parasites.


Defects in cell-mediated immunity affect chronic, but not innate, resistance of mice to Mycobacterium avium infection.
To investigate the role of cell-mediated immunity in the control of Mycobacterium avium infection, we studied the effects of targeted gene disruptions in components of the T lymphocyte-dependent, macrophage-mediated response on resistance of mice to this pathogen. Normal mice developed a chronic, asymptomatic infection, with rapid induction of mRNAs for IFN-gamma, IL-12, and TNF-alpha in spleen, liver, and lung. Bacterial loads in gene knockout, scid, and wild-type mice were indistinguishable for the first 4 wk of infection. However, by 8 wk postinfection, scid mice as well as animals with a targeted disruption of the IFN-gamma gene showed enhanced bacterial growth compared with wild-type controls. In contrast, knockout mice lacking the genes for the TNF-alpha p55/p75 receptors or inducible nitric oxide synthase not only developed comparable bacterial loads to wild-type animals, they also failed to display the splenomegaly and profound suppression of mitogen-induced lymphocyte proliferative responses evident in infected wild-type controls. Thus, M. avium is clearly distinct from other intracellular pathogens (e.g., Leishmania monocytogenes, Toxoplasma gondii, and Mycobacterium tuberculosis) whose initial replication in the host is tightly controlled by Th1-dependent effector mechanisms. Instead, the major effect of host cell-mediated immunity is to limit bacterial growth during the chronic phase of infection. Surprisingly, inducible nitric oxide appears to be more important for the immunopathology than for the host resistance induced by this bacterial pathogen.


Clinically evident fat necrosis in women treated with high-dose-rate brachytherapy alone for early-stage breast cancer.
To investigate the incidence of and variables associated with clinically evident fat necrosis in women treated on a protocol of high-dose-rate (HDR) brachytherapy alone without external-beam whole-breast irradiation for early-stage breast carcinoma. From 6/1997 until 8/1999, 30 women diagnosed with Stage I or II breast carcinoma underwent surgical excision and postoperative irradiation via HDR brachytherapy implant as part of a multi-institutional clinical Phase I/II protocol. Patients eligible included those with T1, T2, N0, N1 (< or = 3 nodes positive), M0 tumors of nonlobular histology with negative surgical margins, no extracapsular lymph-node extension, and a negative postexcision mammogram. Brachytherapy catheters were placed at the initial excision, re-excision, or at the time of axillary sampling. Direct visualization, surgical clips, ultrasound, or CT scans assisted in delineating the target volume defined as the excision cavity plus 2-cm margin. High activity (192)Ir (3-10 Ci) was used to deliver 340 cGy per fraction, 2 fractions per day, for 5 consecutive days to a total dose of 34 Gy to the target volume. Source position and dwell times were calculated using standard volume optimization techniques. Dosimetric analyses were performed with three-dimensional postimplant dose and volume reconstructions. The median follow-up of all patients was 24 months (range, 12-36 months). Eight patients (crude incidence of 27%) developed clinically evident fat necrosis postimplant in the treated breast. Fat necrosis was determined by clinical presentation including pain and swelling in the treated volume, computed tomography, and/or biopsy. All symptomatic patients (7 of 8 cases) were successfully treated with 3 to 12 months of conservative management. Continuous variables that were found to be associated significantly with fat necrosis included the number of source dwell positions (p = 0.04), and the volume of tissue which received fractional doses of 340 cGy, 510 cGy, and 680 cGy (p = 0.03, p = 0.01, and p = 0.01, respectively). Other continuous variables including patient age, total excised tissue volume, tumor size, number of catheters, number of days the catheters were in place, planar separation, dose homogeneity index (DHI), and uniformity index (UI) were not significant. Discrete variables including the presence/absence of DCIS, sentinel versus full axillary nodal assessment, receptor status, presence/absence of diabetes, and the use of chemotherapy or hormone therapy were not found to have a significant association with the risk of fat necrosis. In this study of HDR brachytherapy of the breast tumor excision cavity plus margin, treatment was planned and delivered in accordance with the dosimetric parameters of the protocol resulting in a high degree of target volume dose homogeneity. Nonetheless, at a median follow-up of 24 months, a high rate of clinically definable fat necrosis occurred. The overall implant volume as reflected in the number of source dwell positions and the volume of breast tissue receiving fractional doses of 340, 510, and 680 cGy were significantly associated with fat necrosis. Future dosimetric optimization algorithms for HDR breast brachytherapy will need to include these factors to minimize the risk of fat necrosis.


'Friends with benefits': how tobacco companies influence sales through the provision of incentives and benefits to retailers.
In countries banning advertising and display of tobacco at point-of-sale, little is known about tobacco companies' continuing promotion of products through incentives and benefits to retailers. A telephone survey of 4527 randomly selected Australian retailers was conducted in August 2018, and identified 800 current tobacco retailers (response rate: 72.4%) who were asked a series of questions about benefits offered to them by tobacco companies and what retailers agreed to in return. 41.1% of retailers reported being provided with a tobacco cabinet and 38.3% reported having a price list supplied by a tobacco company. One-third (33.3%) reported being offered at least one benefit from a tobacco company for doing something in return. Price discounts were the most frequently reported benefit (19.0%), followed by rebates (8.4%) and gifts (3.0%). Retailers also reported offers of prizes and incentives for increasing sales or demonstrating product knowledge. In return, retailers reported giving companies benefits such as prominence on the price list and/or in the tobacco cabinet and/or influence over the product range and stock levels. Tobacco companies are continuing to market tobacco and influence sales through provision of incentives and benefits to retailers. Laws that ban the supply of benefits to consumers should be extended to also prohibit the provision of benefits to tobacco retailers.


Potassium channels in cardiac cells activated by arachidonic acid and phospholipids.
Two types of potassium-selective channels activated by intracellular arachidonic acid or phosphatidylcholine have been found in neonatal rat atrial cells. In inside-out patches, arachidonic acid and phosphatidylcholine each opened outwardly rectifying potassium-selective channels with conductances of 160 picosiemens (IK.AA) and 68 picosiemens (IK.PC), respectively. These potassium channels were not sensitive to internally applied adenosine triphosphate (ATP), magnesium, or calcium. Lowering the intracellular pH from 7.2 to 6.8 or 6.4 reversibly increased IK.AA channel activity three- or tenfold, respectively. A number of fatty acid derivatives were tested for their ability to activate IK.AA. These potassium-selective channels may help explain the increase in potassium conductance observed in ischemic cells and raise the possibility that fatty acid derivatives act as second messengers.


Effect on rates of breast feeding of training for the baby friendly hospital initiative.
Breastfeeding rates and related hospital practices need improvement in Italy and elsewhere. Training of staff is necessary, but its effectiveness needs assessment. Eight hospitals in different regions of Italy. Controlled, non-randomised study. Data collected in three phases. Training after the first phase in group 1 hospitals and after the second phase in group 2. Training of trainers and subsequent training of health workers with a slightly adapted version of the 18 hour Unicef course on breastfeeding management and promotion. Hospital practices, knowledge of 571 health workers, and breastfeeding rates at discharge, three, and six months in 2669 mother and baby pairs. After training hospitals improved their compliance with the "ten steps to successful breast feeding," from an average of 2.4 steps at phase one to 7.7 at phase three. Knowledge scores of health professionals increased from 0.41 to 0.72 in group 1 (training after phase one) and from 0.53 to 0.75 in group 2 (after phase two). The rate of exclusive breast feeding at discharge increased significantly after training: 41% to 77% in group 1 and 23% to 73% in group 2, as did the rates of full (exclusive plus predominant) breast feeding at three months (37% to 50% in group 1 v 40% to 59% in group 2) and any breast feeding at six months (43% to 62% in group 1 v 41% to 64% in group 2). Training for at least three days with a course including practical sessions and counselling skills is effective in changing hospital practices, knowledge of health workers, and breastfeeding rates.


Trypanosoma brucei Orc1 is essential for nuclear DNA replication and affects both VSG silencing and VSG switching.
Binding of the Origin Recognition Complex (ORC) to replication origins is essential for initiation of DNA replication, but ORC has non-essential functions outside of DNA replication, including in heterochromatic gene silencing and telomere maintenance. Trypanosoma brucei, a protozoan parasite that causes human African trypanosomiasis, uses antigenic variation as a major virulence mechanism to evade the host's immune attack by expressing its major surface antigen, the Variant Surface Glycoprotein (VSG), in a monoallelic manner. An Orc1/Cdc6 homologue has been identified in T. brucei, but its role in DNA replication has not been directly confirmed and its potential involvement in VSG repression or switching has not been thoroughly investigated. In this study, we show that TbOrc1 is essential for nuclear DNA replication in mammalian-infectious bloodstream and tsetse procyclic forms (BF and PF). Depletion of TbOrc1 resulted in derepression of telomere-linked silent VSGs in both BF and PF, and increased VSG switching particularly through the in situ transcriptional switching mechanism. TbOrc1 associates with telomere repeats but appears to do so independently of two known T. brucei telomere proteins, TbRAP1 and TbTRF. We conclude that TbOrc1 has conserved functions in DNA replication and is also required to control telomere-linked VSG expression and VSG switching.


Varicella-zoster virus at relapses of multiple sclerosis.
The possible participation of different herpes viruses was studied during exacerbations of multiple sclerosis (MS). We searched for the presence of DNA from the following herpes viruses: varicella zoster virus (VZV), herpes-simplex viruses 1 and 2; Epstein-Barr virus (EBV) and human herpes-virus-6 (HHV6) in mononuclear cells from patients with MS during relapse (n = 40), MS during remission (n = 131) and controls (n = 125). Additionally, immune cells containing viral antigens were quantified by flow cytometry, and VZV load was determined by real time PCR in 2 MS patients at various times during relapse and remission. DNA from VZV was found in 95% of MS patients during relapse and in 17% during remission; all controls were negative; by contrast, DNA from HHV6 was found in 24% of MS patients during relapse and in 2% during remission; DNA from herpes simplex viruses was not found in any subject; and DNA from EBV was found in a similar percentage of subjects from all groups. Sequential quantification of VZV-load showed a curve that increased during relapse and disappeared at remission. Also, VZV antigens were found inside a large number of immune cells from MS patients during relapse as compared with MS patients on remission and controls. In the typical forms of VZV infection, varicella and herpes-zoster, DNA from VZV is found in mononuclear cells exclusively during brief periods at the beginning of the active infection, but not during latency; thus, the conspicuous presence of VZV during relapses of MS may indicate a period of active infection and suggests the participation of VZV in the pathogenesis of MS.


Auditory P300 and eye tracking dysfunction in schizophrenic pedigrees.
Several psychophysiological abnormalities associated with schizophrenia have been proposed as genetic trait markers of vulnerability to the disorder. Smooth pursuit eye tracking dysfunction and abnormal long latency event-related potentials are the most promising candidates. Both are independent of the effects of psychotropic medication or mental state at the time of testing, and twin studies demonstrate that each has a high level of heritability. Having recorded smooth pursuit eye tracking and event-related potentials in 20 high-density schizophrenic families, we find abnormalities in one or both measures in most of the families studied. The abnormalities, when present, occur in the family members with schizophrenia and other forms of functional psychosis, and they have a bimodal distribution with approximately half the nonschizophrenic relatives also showing eye tracking dysfunction and/or abnormal event-related potentials. Some of these relatives had psychiatric symptoms; others were normal. Our results suggest that psychophysiological examination can help to clarify the boundaries of schizophrenia spectrum disorder. By helping to decide the phenotypic status of nonschizophrenic family members, this should increase the power of DNA linkage studies.


Program effectiveness of a Restorative Whole-school Approach for tackling school bullying in Hong Kong.
With bullying in schools high on policy makers' agendas, researchers are looking for effective strategies to tackle its disruptive effects. The present study sets out to address this issue. First, the prevalence of bullying is examined in Hong Kong High Schools, and second, the effectiveness of a Restorative Whole-school Approach (RWsA) in reducing bullying is examined in a quasi-experimental design. The RWsA emphasizes the setting up of restorative goals, clear instructions, team building, and good relationships among students, parents, and teachers. Over the course of 2 years, and across four schools, the effectiveness of this program was observed by comparing an intervention group with a partial intervention group (which did not receive the full treatment) and a control group (which received no treatment whatsoever). The group that received the RWsA treatment exhibited a significant reduction of bullying, higher empathic attitudes, and higher self-esteem in comparison to the partial intervention and the control group.


Renal tubular transport of morphine, morphine-6-glucuronide, and morphine-3-glucuronide in the isolated perfused rat kidney.
The isolated perfused rat kidney was used to examine the renal handling of morphine and its inactive metabolite morphine-3-glucuronide (M3G), and active metabolite morphine-6-glucuronide (M6G). The kidneys were perfused with Krebs-Henseleit buffer (pH 7.4) containing albumin, glucose, and amino acids, and drug concentrations were measured by high performance liquid chromatography. There was no conversion of morphine to the glucuronides or deconjugation of M3G or M6G. At an initial morphine concentration of 100 ng/ml, the unbound renal clearance to glomerular filtration rate ratio (CLur/GFR) was 5.5 +/- 3.2 (mean +/- SD), indicating that net tubular secretion of morphine occurred. In the presence of M3G (2000 ng/ml) and M6G (500 ng/ml) this Clur/GFR ratio was elevated to 17.3 +/- 4.8 (p less than .001), which implicates an interaction between these compounds at an active reabsorption transport system. The CLur/GFR ratio for M3G at 2000 ng/ml was 0.90 +/- 0.04, indicating the possibility of a small component of tubular reabsorption, and this ratio was not significantly altered in the presence of morphine and M6G. M6G was reabsorbed, probably actively, to a greater extent than M3G, with an initial CLur/GFR ratio of 0.67 +/- 0.04, which was not affected when morphine and M3G were coadministered. These data demonstrate an unusual phenomenon in that the glucuronide metabolites, which are larger and less lipophilic than the parent drug morphine, undergo net tubular reabsorption. The renal handling of morphine is a complex combination of glomerular filtration, active tubular secretion, and possibly active reabsorption.


Technical aspects of neurostimulation: Focus on equipment, electric field modeling, and stimulation protocols.
Neuromodulation is a field of science, medicine, and bioengineering that encompasses implantable and non-implantable technologies for the purpose of improving quality of life and functioning of humans. Brain neuromodulation involves different neurostimulation techniques: transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS), which are being used both to study their effects on cognitive brain functions and to treat neuropsychiatric disorders. The mechanisms of action of neurostimulation remain incompletely understood. Insight into the technical basis of neurostimulation might be a first step towards a more profound understanding of these mechanisms, which might lead to improved clinical outcome and therapeutic potential. This review provides an overview of the technical basis of neurostimulation focusing on the equipment, the present understanding of induced electric fields, and the stimulation protocols. The review is written from a technical perspective aimed at supporting the use of neurostimulation in clinical practice.


Isolation and genome sequencing of four Arctic marine Psychrobacter strains exhibiting multicopper oxidase activity.
Marine cold-temperature environments are an invaluable source of psychrophilic microbial life for new biodiscoveries. An Arctic marine bacterial strain collection was established consisting of 1448 individual isolates originating from biota, water and sediment samples taken at a various depth in the Barents Sea, North of mainland Norway, with an all year round seawater temperature of 4 °C. The entire collection was subjected to high-throughput screening for detection of extracellular laccase activity with guaiacol as a substrate. In total, 13 laccase-positive isolates were identified, all belonging to the Psychrobacter genus. From the most diverse four strains, based on 16S rRNA gene sequence analysis, all originating from the same Botryllus sp. colonial ascidian tunicate sample, genomic DNA was isolated and genome sequenced using a combined approach of whole genome shotgun and 8 kb mate-pair library sequencing on an Illumina MiSeq platform. The genomes were assembled and revealed genome sizes between 3.29 and 3.52 Mbp with an average G + C content of around 42%, with one to seven plasmids present in the four strains. Bioinformatics based genome mining was performed to describe the metabolic potential of these four strains and to identify gene candidates potentially responsible for the observed laccase-positive phenotype. Up to two different laccase-like multicopper oxidase (LMCO) encoding gene candidates were identified in each of the four strains. Heterologous expression of P11F6-LMCO and P11G5-LMCO2 in Escherichia coli BL21 (DE3) resulted in recombinant proteins exhibiting 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS) and guaiacol oxidizing activity. Thirteen Psychrobacter species with laccase-positive phenotype were isolated from a collection of Arctic marine bacteria. Four of the isolates were genome sequenced. The overall genome features were similar to other publicly available Psychrobacter genome sequences except for P11G5 harboring seven plasmids. However, there were differences at the pathway level as genes associated with degradation of phenolic compounds, nicotine, phenylalanine, styrene, ethylbenzene, and ethanolamine were detected only in the Psychrobacter strains reported in this study while they were absent among the other publicly available Psychrobacter genomes. In addition, six gene candidates were identified by genome mining and shown to possess T1, T2 and T3 copper binding sites as the main signature of the three-domain laccases. P11F6-LMCO and P11G5-LMCO2 were recombinantly expressed and shown to be active when ABTS and guaiacol were used as substrates.


PAH biomarkers for human health risk assessment: a review of the state-of-the-art.
Polycyclic aromatic hydrocarbons (PAH) are widely distributed in the environment, and some are carcinogenic to human beings. The study of biomarkers has helped clarify the nature and magnitude of the human health risks posed by such substances. This article provides a review of the state-of-the-art on PAH biomarkers for human health risk assessment and also discusses their applicability within the context of environmental management in Brazil. The article discusses the methodologies for determination of some biomarkers such as 1-hydroxypyrene and PAH-DNA adducts. Cytogenetic markers, frequency of chromosomal aberrations, and micronucleus induction were considered for the evaluation of cancer risk. The current stage of studies on validation of such biomarkers was also approached.


Study protocol of the iMPaCT project: a longitudinal cohort study assessing psychological determinants, sexual behaviour and chlamydia (re)infections in heterosexual STI clinic visitors.
Chlamydia trachomatis (chlamydia), the most commonly reported sexually transmitted infection (STI) in the Netherlands, can lead to severe reproductive complications. Reasons for the sustained chlamydia prevalence in young individuals, even in countries with chlamydia screening programs, might be the asymptomatic nature of chlamydia infections, and high reinfection rates after treatment. When individuals are unaware of their infection, preventive behaviour or health-care seeking behaviour mostly depends on psychological determinants, such as risk perception. Furthermore, behaviour change after a diagnosis might be vital to reduce reinfection rates. This makes the incorporation of psychological determinants and behaviour change in mathematical models estimating the impact of interventions on chlamydia transmission especially important. Therefore, quantitative real-life data to inform these models is needed. A longitudinal cohort study will be conducted to explore the link between psychological and behavioural determinants and chlamydia (re)infection among heterosexual STI clinic visitors aged 18-24 years. Participants will be recruited at the STI clinics of the public health services of Amsterdam, Hollands Noorden, Kennemerland, and Twente. Participants are enrolled for a year, and questionnaires are administrated at four time points: baseline (before an STI consultation), three-week, six-month and at one-year follow-up. To be able to link psychological and behavioural determinants to (re)infections, participants will be tested for chlamydia at enrolment and at six-month follow-up. Data from the longitudinal cohort study will be used to develop mathematical models for curable STI incorporating these determinants to be able to better estimate the impact of interventions. This study will provide insights into the link between psychological and behavioural determinants, including short-term and long-term changes after diagnosis, and chlamydia (re)infections. Our mathematical model, informed by data from the longitudinal cohort study, will be able to estimate the impact of interventions on chlamydia prevalence, and identify and prioritise successful interventions for the future. These interventions could be implemented at STI clinics tailored to psychological and behavioural characteristics of individuals. Dutch Trial Register NTR-6307 . Retrospectively registered 11-nov-2016.


Avoiding false positives: zones of rarity, the threshold problem, and the DSM clinical significance criterion.
False positives arise when people without disorders are diagnosed as having disorders. Various approaches for avoiding false positives have been suggested. This review critically assesses the roles of zones of rarity, the threshold problem (the problem of determining the boundary of disorder in cases that shade into normality), and the Diagnostic and Statistical Manual of Mental Disorders (DSM) criterion that requires that a disorder cause clinically significant impairment or distress (the harm criterion). The lack of zones of rarity in much of psychiatry gives rise to the threshold problem. The DSM harm criterion is frequently presented as offering a solution to the threshold problem. However, I argue that the harm criterion cannot offer a general solution to the threshold problem, as harm is not always correlated with the intensity and frequency of symptoms. Still, the harm criterion is essential to ensure that people who are merely different are not diagnosed as having a disorder. The threshold problem can be addressed by selecting symptom-based cut-off points to distinguish between disorder and normality. These cut-off points are frequently arbitrary in the sense that they often reflect no natural division between disorder and normal, but they may be more or less wisely chosen. Where possible, the thresholds should be set so that the advantages of diagnosis can be expected to outweigh the disadvantages.


Antibiotic regimens for management of intra-amniotic infection.
Chorioamnionitis is a common infection that affects both mother and infant. Infant complications associated with chorioamnionitis include early neonatal sepsis, pneumonia, and meningitis. Chorioamnionitis can also result in maternal morbidity such as pelvic infection and septic shock.Clinical chorioamnionitis is estimated to occur in 1% to 2% of term births and in 5% to 10% of preterm births; histologic chorioamnionitis is found in nearly 20% of term births and in 50% of preterm births. Women with chorioamnionitis have a two to three times higher risk for cesarean delivery and a three to four times greater risk for endomyometritis, wound infection, pelvic abscess, bacteremia, and postpartum hemorrhage. To assess the effects of administering antibiotic regimens for intra-amniotic infection on maternal and perinatal morbidity and mortality and on infection-related complications. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 October 2014), CENTRAL, MEDLINE, Embase, LILACS, and the WHO ICTRP (September 2014). We also searched reference lists of retrieved studies and contacted experts in the field. Randomized controlled trials (RCTs) that included women who experienced intra-amniotic infection. Trials were included if they compared antibiotic treatment with placebo or no treatment (if applicable), treatment with different antibiotic regimens, or timing of antibiotic therapy (intrapartum and/or postpartum). Therefore, this review assesses trials evaluating intrapartum antibiotics, intrapartum and postpartum antibiotic regimens, and postpartum antibiotics. Diagnosis of intra-amniotic infection was based on standard criteria (clinical/test), and no limit was placed on gestational age. Two review authors independently assessed trials for inclusion and trial quality. Two review authors independently extracted data and checked them for accuracy. We assessed the quality of the evidence using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach and included a 'Summary of findings' table. Our prespecified primary outcomes were maternal and neonatal mortality, maternal and neonatal severe infection, and duration of maternal and neonatal hospital stay.We included 11 studies (involving 1296 women) and assessed them as having low to moderate risk of bias - mainly because allocation concealment methods were not adequately reported, most studies were open, and outcome reporting was incomplete. The quality of the evidence was low to very low for most outcomes, as per the GRADE approach. The following antibiotics were assessed in the included trials: ampicillin, ampicillin/sulbactam, gentamicin, clindamycin, and cefotetan. During labor: meta-analysis of two studies found no clear differences in rates of neonatal sepsis (163 neonates; risk ratio (RR) 1.07, 95% confidence interval (CI) 0.40 to 2.86; I² = 9%; low quality of evidence), treatment failure (endometritis) (163 participants; RR 0.86, 95% CI 0.27 to 2.70; I² = 0%; low quality of evidence), and postpartum hemorrhage (RR 1.39, 95% CI 0.76 to 2.56; I² = 0%; low quality of evidence) when two different dosages/regimens of gentamicin were assessed. No clear differences between groups were found for any reported maternal or neonatal outcomes. The review did not identify data for a comparison of antibiotics versus no treatment/placebo. Postpartum: meta-analysis of two studies that evaluated use of antibiotics versus placebo after vaginal delivery showed no significant differences between groups in rates of treatment failure or postpartum endometritis. No significant differences were found in rates of neonatal death and postpartum endometritis when use of antibiotics was compared with no treatment. Four trials assessing two different dosages/regimens of gentamicin or dual-agent therapy versus triple-agent therapy, or comparing antibiotics, found no significant differences in most reported neonatal or maternal outcomes; the duration of hospital stay showed a difference in favor of the group of women who received short-duration antibiotics (one study, 292 women; mean difference (MD) -0.90 days, 95% CI -1.64 to -0.16; moderate quality of evidence). Intrapartum versus postpartum: one small study (45 women) evaluating use of ampicillin/gentamicin during intrapartum versus immediate postpartum treatment found significant differences favoring the intrapartum group in the mean number of days of maternal postpartum hospital stay (one trial, 45 women; MD -1.00 days, 95% CI -1.94 to - 0.06; very low quality of evidence) and the mean number of neonatal hospital stay days (one trial, 45 neonates; MD -1.90 days, 95% CI -3.91 to -0.49; very low quality of evidence). Although no significant differences were found in the rate of maternal bacteremia or early neonatal sepsis, for the outcome of neonatal pneumonia or sepsis we observed a significant difference favoring intrapartum treatment (one trial, 45 neonates; RR 0.06, 95% CI 0.00 to 0.95; very low quality of evidence). This review included 11 studies (having low to moderate risk of bias). The quality of the evidence was low to very low for most outcomes, as per the GRADE approach. Only one outcome (duration of hospital stay) was considered to provide moderate quality of evidence when antibiotics (short duration) were compared with antibiotics (long duration) during postpartum management of intra-amniotic infection. Our main reasons for downgrading the quality of evidence were limitations in study design or execution (risk of bias), imprecision, and inconsistency of results.Currently, limited evidence is available to reveal the most appropriate antimicrobial regimen for the treatment of patients with intra-amniotic infection; whether antibiotics should be continued during the postpartum period; and which antibiotic regimen or what treatment duration should be used. Also, no evidence was found on adverse effects of the intervention (not reported in any of the included studies). One small RCT showed that use of antibiotics during the intrapartum period is superior to their use during the postpartum period in reducing the number of days of maternal and neonatal hospital stay.


CROI 2017: Neurologic Complications of HIV Infection.
The brain is a major target for HIV infection and is a potential viral reservoir even in virologically well-controlled HIV-infected individuals. Data presented at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI) suggested that during early HIV infection, CD4+ T cells in the meninges and choroid plexus serve as an important early site of HIV infection in the central nervous system (CNS), with brain macrophages and microglial cells becoming an important source of viral replication with advancing disease. Longitudinal evaluations of HIV-associated neurocognitive disorder (HAND) demonstrated that cognitive changes occur during early HIV infection and may remain during chronic infection despite virologic control by antiretroviral therapy. Cerebrospinal fluid escape during treatment was noted in numerous cohorts and pathogenetically evaluated as a state of persistent CNS HIV infection despite antiretroviral therapy. Non-HIV risk factors identified for cognitive impairment were depression and frailty. Questions remain concerning appropriate cognitive screening tests to evaluate for HAND. Additional studies highlighted the increasing role of neuroimaging to longitudinally assess potential changes in brain integrity in individuals on systemically suppressive therapy, and provided new CNS considerations in antiretroviral regimens.


Turning off the majority-rules effect in two-dimensional hierarchical chiral assembly by introducing a chiral mismatch.
Understanding the mechanism in chiral transmission from a single molecule to a supramolecular level is fundamentally important to decipher the nonlinear amplification effect in the two-dimensional (2D) chiral assembly process. In this contribution, we report on the dramatically different nonlinear amplification effect in the chiral co-adsorber induced homochiral assemblies constructed by a series of homologous achiral building blocks on the graphite surface under control of the majority-rules principle. Homologous hexagonal networks are formed for 5-(benzyloxy)-isophthalic acid (BIC) derivatives with different alkyl lengths. While globally homochiral monolayers of BIC-C6 or BIC-C16 can be obtained by using a mixture of chiral co-adsorber 2-octanol with a small enantiomeric excess, such majority-rules principle based nonlinear chiral amplification is inoperative for the assembly of BIC-C10. Molecular mechanistic analysis indicates that BIC-C10 assembly can accommodate a chiral mismatched motif to form long-range ordered but short-range disordered crystalline networks, leading to the co-adsorption of enantiomers without enantioselectivity. The present results shed important insights into the significance of chirality mismatch during chiral transmission and benefit the understanding of chiral communication in a surface monolayer.


Near-patient tests and the clinical gaze in decision-making of Swedish GPs not following current guidelines for sore throat - a qualitative interview study.
Excessive antibiotics use increases the risk of resistance. Previous studies have shown that the Centor score combined with Rapid Antigen Detection Test (RADT) for Group A Streptococci can reduce unnecessary antibiotic prescribing in patients with sore throat. According to the former Swedish guidelines RADT was recommended with 2-4 Centor criteria present and antibiotics were recommended if the test was positive. C- reactive protein (CRP) was not recommended for sore throats. Inappropriate use of RADT and CRP has been reported in several studies. From a larger project 16 general practitioners (GPs) who stated management of sore throats not according to the guidelines were identified. Half-hour long semi-structured interviews were conducted. The topics were the management of sore throats and the use of near-patient tests. Qualitative content analysis was used. The use of the near-patient test interplayed with the clinical assessment and the perception that all infections caused by bacteria should be treated with antibiotics. The GPs expressed a belief that the clinical picture was sufficient for diagnosis in typical cases. RADT was not believed to be relevant since it detects only one bacterium, while CRP was considered as a reliable numerical measure of bacterial infection. Inappropriate use of near-patient test can partly be understood as remnants of outdated knowledge. When new guidelines are introduced the differences between them and the former need to be discussed more explicitly.


[Omentopexy in Peritoneal Catheter Malfunction].
Among the various problems associated with peritoneal dialysis, besides infectious causes, the risk of catheter malfunction plays a significant role in conditioning the continuation of the method, accounting for up to 15-18% of the total causes of dialysis drop-out. When non-invasive maneuvers, such as the use of laxatives to stimulate intestinal peristalsis or heparin and/or urokinase have no effect, videolaparoscopy is the only method that directly detects the precise causes of peritoneal catheter malfunction. Those found are, with decreasing frequency, the winding of the catheter between the intestinal loops and the omentum (wrapping), the dislocation of the catheter, the combination of wrapping and dislocation, the occlusion of the catheter by a fibrin plug, the adhesions between the intestine and abdominal wall, the occlusion of the catheter by epiploic appendages or adnexal tissue and, occasionally, the presence of a new formation of endoperitoneal tissue enveloping and obstructing the peritoneal catheter. We report the case of a young patient of African ethnicity who, only five days after catheter placement, experienced malfunction. A videolaparoscopy revealed wrapping with invagination of omental tissue inside the catheter. After omental debridement, a proper peritoneal cavity washout with heparin was resumed, and after a couple of weeks, APD was initiated. About a month later, a new malfunction without signs of coprostasis or problems with the abdominal radiogram was observed. However, a subsequent catheterography confirmed the blockage of drainage. This was followed by another catheterography and omentopexy, with definitive solution of the Tenckhoff malfunction.


What does the broken brain say to the neuroscientist? Oscillations and connectivity in schizophrenia, Alzheimer's disease, and bipolar disorder.
The application of the concept and methods of brain oscillations has been an important research area in neurosciences. In the last decades, besides the application in cognitive processes, the study of changes in brain oscillations in diseases has also become an important focal point of research. In the present paper, some remarkable examples in three different diseases are taken into consideration: 1) schizophrenia (SZ), 2) Alzheimer's disease (AD), 3) bipolar disorders (BD). In the current literature, decreased oscillations in cortical recordings are observed in most of the pathologies. For example, decrease of gamma activity in SZ, decrease of delta activity in almost all diseases, as well as frequency shifts in alpha and the lower frequencies were recorded. However, there are also paradoxical cases in which an increase of oscillatory activities is observed. In BD, whereas alpha activity is greatly decreased, a huge increase of beta activity is observed. Or, in SZ, a paradoxical increase of gamma activity can be observed during cognitive loading. We also observed paradoxical changes in the analysis of connectivity. In AD, we find that alpha, delta, and theta coherences between distant parts of the cortex are greatly decreased, whereas in the gamma band, event-related coherences attain very high values. The comparison of the results and paradoxical changes in diseases may lead to important conclusions related to the web of oscillations and neurotransmitters. In turn, we could gain new insights to approach "brain function", in general.


Administered dose and tumor dose of bleomycin labeled with cobalt-57 in mice and men.
Tumor concentrations of the chemotherapeutic drug, bleomycin, labeled with cobalt-57 (Co-bleo) were compared in mouse tumor models and in human lung tumors using quantitative single-photon emission computed tomography. Drug concentrations in histologically similar human tumors showed marked variability for the same injected dose (ID). Small cell carcinomas showed concentrations between 1.09 and 8.85 %ID/cc x 10(-3) while non-small cell lung tumors showed a concentration variation between 0.36 and 6.75 %ID/cc x 10(-3). In contrast to the situation in human tumors, uptake in mouse tumors showed only slight variability in animals with the same tumor model. EMT-6 tumors in mice showed at 6 hr significantly higher uptake of Co-bleo (p less than 0.001) and significantly higher tumor-to-lung ratio (p less than 0.001) when compared to murine fibrosarcomas. The EMT-6 tumors in contrast to the fibrosarcomas responded to bleomycin treatment in a dose dependent manner. The results indicate that while in mice the tumor dose closely follows the administered dose, in humans, the tumor dose and the tumor-to-lung ratio in the individual patient cannot be predicted from the administered dose.


Comparison of direct and indirect measures of systemic arterial pressure during weightlifting in coronary artery disease.
Based on auscultation measurements after exercise, circuit weight training in cardiac patients has been reported to provoke minimal increases in systolic pressure. Direct (brachial artery catheter) and indirect (sphygmomanometry) measures of blood pressure were compared at rest, during lifting with the legs (approximately the fourth, ninth and fourteenth repetition) and during 2 minutes of recovery after lifting with the arms and legs. Subjects performed 15 repetitions of single-arm curl, single-arm military press and single- and double-leg press exercises at 40 and 60% of the maximum load that could be lifted once on a multistation weightlifting apparatus. Indirect measures of systolic pressure at rest were 13% less than those recorded directly (130 +/- 7 vs 149 +/- 8 torr; p less than 0.01); diastolic pressures were similar using either method. This pattern was maintained during lifting with the legs at both intensities, and after exercise with both the legs and the arms. The mean systolic pressure recorded indirectly immediately after exercise was 63 torr (31%) and 76 torr (34%) less than the average peak intraarterial value recorded during leg and arm exercises, respectively. The highest intraarterial pressures were generated during the final repetitions of the set; immediately after the last repetition, both systolic and diastolic pressures rapidly decreased. It is concluded that indirect estimates of systolic pressure are significantly less than true arterial values at rest, and during and after lifting. Moreover, indirect measurements after lifting do not allow accurate conclusions to be drawn about the arterial pressures generated during lifting because of the rapid decrease in pressure that occurs after exercise.


Assessment of coronary sinus anatomy between normal and insufficient mitral valves by multi-slice computertomography for mitral annuloplasty device implantation.
Latest techniques enable positioning of devices into the coronary sinus (CS) for mitral valve (MV) annuloplasty. We evaluate the feasibility of non-invasive assessment to determine CS anatomy and its relation to MV annulus and coronary arteries by multi-slice CT (MSCT) in normal and insufficient MV. Fifty patients (33 males, 17 females, age 67+/-11 years) were studied retrospectively by 64-MSCT scans for anatomical criteria regarding CS and its relation to MV annulus and circumflex artery (CX). We included 24 patients with severe mitral insufficiency and 26 with no MV disease. Diameter of MV, of proximal and distal ostium of CS, length and volume of CS, angle between anterior interventricular vein (AIV) and CS, caliber change of CX before, under/over and after CS were analysed. Different anatomical correlations were demonstrated: distance of MV annulus to CS, CX to CS. Diameter of proximal CS ostium was significantly larger in insufficient MV compared to normal MV (11+/-2.8 mm vs 9.9+/-2.5 mm; p<0.024). CS was significantly longer in patients with insufficient MV (125.4+/-17 mm vs 108.9+/-18 mm; p<0.003) with also significant differences in volume of CS (p<0.039). Significant difference in annulus diameter, 46.1+/-6mm (insufficient MV) versus 39.5+/-7.5 mm, p<0.004 was observed. Angle CS-AIV was 103.5+/-29 degrees (range 52 degrees -144 degrees ) in insufficient valves versus 118.2+/-24.5 degrees (range 73 degrees -166 degrees ) in normal valves with a tendency to higher angles in normal valves (p=0.06). Distance of MV annulus to CS measured 16+/-4.1/14.2+/-3.6 mm (insufficient/normal MV) without significant difference between groups. In 15 patients CX ran under CS. Eighty-four percent of these patients (13/15) show a decrease in CS caliber in the area of intersection. In 14 patients CS ran over and in one patient the diameter of the CS at intersecting region was smaller. In 16 patients no direct point of contact was visible, in five patients CX to CS positioning was not evaluable. There is a significant anatomic difference between normal and insufficient MV, which might be the basis for any interventional approaches through the CS. Exact measurements of all structures and its anatomic correlations are possible with MSCT, which allows pre-interventional planning.


APRIL modulates B and T cell immunity.
The TNF-like ligands APRIL and BLyS are close relatives and share the capacity to bind the receptors TACI and BCMA. BLyS has been shown to play an important role in B cell homeostasis and autoimmunity, but the biological role of APRIL remains less well defined. Analysis of T cells revealed an activation-dependent increase in APRIL mRNA expression. We therefore generated mice expressing APRIL as a transgene in T cells. These mice appeared normal and showed no signs of B cell hyperplasia. Transgenic T cells revealed a greatly enhanced survival in vitro as well as enhanced survival of staphylococcal enterotoxin B-reactive CD4+ T cells in vivo, which both directly correlate with elevated Bcl-2 levels. Analysis of humoral responses to T cell-dependent antigens in the transgenic mice indicated that APRIL affects only IgM but not IgG responses. In contrast, T cell-independent type 2 (TI-2) humoral response was enhanced in APRIL transgenic mice. As TACI was previously reported to be indispensable for TI-2 antibody formation, these results suggest a role for APRIL/TACI interactions in the generation of this response. Taken together, our data indicate that APRIL is involved in the induction and/or maintenance of T and B cell responses.


Burden of Chronic and Acute Conditions and Symptoms in People With Epilepsy.
People with epilepsy, one-third of whom in the United States are on Medicaid, experience a wide range of chronic and physical comorbidities that influence their care and outcomes. In this study, we examine the burden and racial/ethnic disparities of chronic and acute conditions, injuries, and symptoms in a large and diverse group of people with epilepsy on Medicaid. Using 5 years of Medicaid claims data, we identified adults with epilepsy and used all available claims and diagnoses to identify each person's Clinical Classification Codes groups diagnosed during the study period. Using association rule mining, we identified the top combinations of conditions and stratified these by race/ethnicity to identify potential prevalence disparities. We examined the top combinations of conditions in high utilizers; that is, individuals in the top quartile of hospitalizations and emergency department visits. Among 81,963 patients, the most common conditions were anxiety and mood disorders (46.5%), hypertension (36.9%), back problems (35.2%), developmental disorders (31.6%), and headache (29.5%). When examining combinations of conditions, anxiety and mood disorders continued to have an outsized prevalence, appearing in nearly every combination. There were notable disparities in disease burden, with American Indians and Alaskan Natives having a substantially higher prevalence of developmental disorders, while Black individuals had a higher prevalence of hypertension. These disparities persisted to the higher-order combinations that included these conditions. High utilizers had a much higher disease burden, with 75.8% having an anxiety or mood disorder, as well as a higher burden of injuries. This study shows a high prevalence of psychiatric and physical conditions and identifies racial and ethnic disparities affecting people with epilepsy. Targeting interventions to consider the comorbidities, race, and ethnicity has potential to improve clinical care and reduce disparities.


Epidemic disease decimates amphibian abundance, species diversity, and evolutionary history in the highlands of central Panama.
Amphibian populations around the world are experiencing unprecedented declines attributed to a chytrid fungal pathogen, Batrachochytrium dendrobatidis. Despite the severity of the crisis, quantitative analyses of the effects of the epidemic on amphibian abundance and diversity have been unavailable as a result of the lack of equivalent data collected before and following disease outbreak. We present a community-level assessment combining long-term field surveys and DNA barcode data describing changes in abundance and evolutionary diversity within the amphibian community of El Copé, Panama, following a disease epidemic and mass-mortality event. The epidemic reduced taxonomic, lineage, and phylogenetic diversity similarly. We discovered that 30 species were lost, including five undescribed species, representing 41% of total amphibian lineage diversity in El Copé. These extirpations represented 33% of the evolutionary history of amphibians within the community, and variation in the degree of population loss and decline among species was random with respect to the community phylogeny. Our approach provides a fast, economical, and informative analysis of loss in a community whether measured by species or phylogenetic diversity.


When a child dies the world should stop spinning: an autoethnography exploring the impact of family loss on occupation.
The death of a loved one disrupts family-members' occupational lives. This paper explores the role and course of occupation during a time when my nephew died. A qualitative research methodology, autoethnography, is used to develop the narrative. I found that familiar occupations lost meaning during this time and even seemed absurd. Paradoxically, occupation helped forge a vital pathway back to health and reconstruction of meaning. Four stages of occupation during a family crisis are proposed: maintenance, dissolution, ambivalence, and restoration and adaptation. Reflections on occupational therapists' role during family crises are discussed, as are implications for further research.


A population response analysis approach to assign class II HLA-epitope restrictions.
Identification of the specific HLA locus and allele presenting an epitope for recognition by specific TCRs (HLA restriction) is necessary to fully characterize the immune response to Ags. Experimental determination of HLA restriction is complex and technically challenging. As an alternative, the restricting HLA locus and allele can be inferred by genetic association, using response data in an HLA-typed population. However, simple odds ratio (OR) calculations can be problematic when dealing with large numbers of subjects and Ags, and because the same epitope can be presented by multiple alleles (epitope promiscuity). In this study, we develop a tool, denominated Restrictor Analysis Tool for Epitopes, to extract inferred restriction from HLA class II-typed epitope responses. This automated method infers HLA class II restriction from large datasets of T cell responses in HLA class II-typed subjects by calculating ORs and relative frequencies from simple data tables. The program is validated by: 1) analyzing data of previously determined HLA restrictions; 2) experimentally determining in selected individuals new HLA restrictions using HLA-transfected cell lines; and 3) predicting HLA restriction of particular peptides and showing that corresponding HLA class II tetramers efficiently bind to epitope-specific T cells. We further design a specific iterative algorithm to account for promiscuous recognition by calculation of OR values for combinations of different HLA molecules while incorporating predicted HLA binding affinity. The Restrictor Analysis Tool for Epitopes program streamlines the prediction of HLA class II restriction across multiple T cell epitopes and HLA types.


Social predictors of psychotic experiences: specificity and psychological mechanisms.
It has become widely accepted that the psychotic disorders are endpoints of atypical developmental trajectories indexed by abnormal emotional and cognitive development early in life. However, the role of environmental factors in determining these trajectories has received relatively little attention. In this article, we argue that (1) the influence of environment on psychosis can best be understood if we focus on specific types of psychotic experiences such as hallucinations and delusions, (2) these symptoms are the products of specific cognitive biases and deficits, and (3) the development of these particular patterns of cognitive functioning is influenced by specific kinds of environmental adversity. This approach is at variance with more conventional approaches because it suggests that each type of experience, rather than being the manifestation of a common underlying illness process, is a product of a specific set of causal variables. Importantly, these variables include environmental determinants, although not to the exclusion of endogenous factors such as neurodevelopmental impairment or genetic vulnerability. We discuss the implications of this approach for neurobiological and genetic research into psychosis, as well as clinical practice.


Effects of acute and chronic ethanol administration and its withdrawal on the level and binding of somatostatin in rat brain.
1. Acute ethanol administration resulted in an increase in the total number of specific somatostatin receptors in rat frontoparietal cortex and hippocampus, and a decrease in the level of somatostatin-like immunoreactivity in the hippocampus but not in the frontoparietal cortex. 2. Chronic administration of ethanol caused a decrease in the number of somatostatin receptors in the frontoparietal cortex but not in the hippocampus, although the level of somatostatin-like immunoreactivity was unchanged in both brain areas. 3. A week after suppressing ethanol the value for specific binding of tracer to somatostatin receptors in the frontoparietal cortex was not significantly different from that of the control rats, although the actual number of receptors was slightly lower. 4. These results suggest a possible role for somatostatin in the nervous system during alcoholism and the post-withdrawal reaction.


Intergenerational relations and elder care preferences of Asian Indians in North Carolina.
The US older population is growing in ethnic diversity. Persistent ethnic disparities in service use among seniors are linked to structural barriers to access, and also to family processes such as cultural preferences and intergenerational relations. There is sparse information on the latter issue for immigrant ethnic minority seniors. Information on the Asian group (the fastest growing senior sub-population) is extremely scarce, due to this group's diversity in national, linguistic, and cultural origins. We conducted a qualitative study among community-dwelling Asian Indian families (including at least one member aged 60 years and older) in North Carolina to examine preferences of seniors and the midlife generation regarding elder care, and the role of intergenerational relations in desired care for elders, exploring the theoretical perspective of intergenerational relationship ambivalence. Our results suggest that cultural preferences, ambivalence in intergenerational relations, and regulations on health service eligibility among immigrant/transnational seniors and midlife adults influence preferences for elder care.


[Ginsenoside Rg3 induces apoptosis of human lung squamous cell carcinoma SK-MES-1 cell line].
To investigate the effect of ginsenoside Rg3 on the apoptosis and survivin expression in human lung squamous cell carcinoma cell line SK-MES-1. SK-MES-1 cells were divided into Rg3 treatment group, blank control group and positive control (arsenic trioxide) group. The apoptotic rate of the cells in each group was determined using flow cytometry, and the expression of survivin protein and mRNA was detected by immunocytochemistry and RT-PCR, respectively. A 48-h treatment with Ginsenoside Rg3 induced increased apoptotic rate of SK-MES-1 cells in a dose-dependent manner. Ginsenoside Rg3 significantly downregulated the expressions of survivin protein and mRNA as compared with the expression levels in the blank control group (P<0.05). Ginsenoside Rg3 can induce the apoptosis of SK-MES-1 cells, the mechanism of which may involve inhibited survivin expression.


More than Smoke and Patches: The Quest for Pharmacotherapies to Treat Tobacco Use Disorder.
Tobacco use is a persistent public health issue. It kills up to half its users and is the cause of nearly 90% of all lung cancers. The main psychoactive component of tobacco is nicotine, primarily responsible for its abuse-related effects. Accordingly, most pharmacotherapies for smoking cessation target nicotinic acetylcholine receptors (nAChRs), nicotine's major site of action in the brain. The goal of the current review is twofold: first, to provide a brief overview of the most commonly used behavioral procedures for evaluating smoking cessation pharmacotherapies and an introduction to pharmacokinetic and pharmacodynamic properties of nicotine important for consideration in the development of new pharmacotherapies; and second, to discuss current and potential future pharmacological interventions aimed at decreasing tobacco use. Attention will focus on the potential for allosteric modulators of nAChRs to offer an improvement over currently approved pharmacotherapies. Additionally, given increasing public concern for the potential health consequences of using electronic nicotine delivery systems, which allow users to inhale aerosolized solutions as an alternative to smoking tobacco, an effort will be made throughout this review to address the implications of this relatively new form of nicotine delivery, specifically as it relates to smoking cessation. SIGNIFICANCE STATEMENT: Despite decades of research that have vastly improved our understanding of nicotine and its effects on the body, only a handful of pharmacotherapies have been successfully developed for use in smoking cessation. Thus, investigation of alternative pharmacological strategies for treating tobacco use disorder remains active; allosteric modulators of nicotinic acetylcholine receptors represent one class of compounds currently under development for this purpose.