Menstrual irregularity and bone mass in premenopausal women: Cross-sectional associations with testosterone and SHBG

Background. There have been few studies examining the associations between menstrual irregularity, androgens and bone mass in population-based samples of premenopausal women. This study aimed to describe the associations between menstrual pattern, testosterone, sex hormone binding globulin (SHBG) and bone mass in a population-based sample of premenopausal women. Methods. Cross-sectional study (N = 382, mean age 31.5 years). Menstrual pattern was assessed by questionnaire, bone mass measured by quantitative ultrasound (QUS) and androgen status was assessed by levels of serum testosterone, SHBG and the free androgen index (FAI). Results. Women with irregular cycles (n = 41, 11%) had higher free androgen index (FAI, P = 0.01) and higher QUS measurements including speed of sound (SOS, 1%, P < 0.05), quantitative ultrasound index (QUI, 7%, p < 0.05), and broadband ultrasound attenuation (BUA, 7%, p = 0.10). These associations persisted after adjustment for age and body mass index (BMI). After further adjustment for hormonal factors (either testosterone, SHBG or FAI), the strength of the associations was moderately attenuated, however, women with irregular cycles still had a 6% increase in mean QUS. Total testosterone, FAI and SHBG were also associated with QUS measures (testosterone and FAI, r +0.11 to +0.21, all p < 0.05; SHBG r -0.14 to -0.16, all p < 0.05) and the associations remained significant after adjustment. Conclusion. Irregular menstrual cycles were associated with higher bone mass in this population-based sample of premenopausal women suggesting menstrual disturbance should continue to be evaluated but may be less harmful for bone mass. The association between menstrual irregularity and bone mass was partially mediated by markers of androgen status especially free testosterone

Targeting RNA Polymerase Primary σ70 as a Therapeutic Strategy against Methicillin-Resistant Staphylococcus aureus by Antisense Peptide Nucleic Acid

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) causes threatening infection-related mortality worldwide. Currently, spread of multi-drug resistance (MDR) MRSA limits therapeutic options and requires new approaches to "druggable" target discovery, as well as development of novel MRSA-active antibiotics. RNA polymerase primary σ⁷⁰ (encoded by gene rpoD) is a highly conserved prokaryotic factor essential for transcription initiation in exponentially growing cells of diverse S. aureus, implying potential for antisense inhibition. METHODOLOGY/PRINCIPAL FINDINGS: By synthesizing a serial of cell penetrating peptide conjugated peptide nucleic acids (PPNAs) based on software predicted parameters and further design optimization, we identified a target sequence (234 to 243 nt) within rpoD mRNA conserved region 3.0 being more sensitive to antisense inhibition. A (KFF)₃K peptide conjugated 10-mer complementary PNA (PPNA2332) was developed for potent micromolar-range growth inhibitory effects against four pathogenic S. aureus strains with different resistance phenotypes, including clinical vancomycin-intermediate resistance S. aureus and MDR-MRSA isolates. PPNA2332 showed bacteriocidal antisense effect at 3.2 fold of MIC value against MRSA/VISA Mu50, and its sequence specificity was demonstrated in that PPNA with scrambled PNA sequence (Scr PPNA2332) exhibited no growth inhibitory effect at higher concentrations. Also, PPNA2332 specifically interferes with rpoD mRNA, inhibiting translation of its protein product σ⁷⁰ in a concentration-dependent manner. Full decay of mRNA and suppressed expression of σ⁷⁰ were observed for 40 µM or 12.5 µM PPNA2332 treatment, respectively, but not for 40 µM Scr PPNA2332 treatment in pure culture of MRSA/VISA Mu50 strain. PPNA2332 (≥1 µM) essentially cleared lethal MRSA/VISA Mu50 infection in epithelial cell cultures, and eliminated viable bacterial cells in a time- and concentration- dependent manner, without showing any apparent toxicity at 10 µM. CONCLUSIONS: The present result suggested that RNAP primary σ⁷⁰ is a very promising candidate target for developing novel antisense antibiotic to treat severe MRSA infections

Genetic Analysis of Genome-Scale Recombination Rate Evolution in House Mice

The rate of meiotic recombination varies markedly between species and among individuals. Classical genetic experiments demonstrated a heritable component to population variation in recombination rate, and specific sequence variants that contribute to recombination rate differences between individuals have recently been identified. Despite these advances, the genetic basis of species divergence in recombination rate remains unexplored. Using a cytological assay that allows direct in situ imaging of recombination events in spermatocytes, we report a large (∼30%) difference in global recombination rate between males of two closely related house mouse subspecies (Mus musculus musculus and M. m. castaneus). To characterize the genetic basis of this recombination rate divergence, we generated an F2 panel of inter-subspecific hybrid males (n = 276) from an intercross between wild-derived inbred strains CAST/EiJ (M. m. castaneus) and PWD/PhJ (M. m. musculus). We uncover considerable heritable variation for recombination rate among males from this mapping population. Much of the F2 variance for recombination rate and a substantial portion of the difference in recombination rate between the parental strains is explained by eight moderate- to large-effect quantitative trait loci, including two transgressive loci on the X chromosome. In contrast to the rapid evolution observed in males, female CAST/EiJ and PWD/PhJ animals show minimal divergence in recombination rate (∼5%). The existence of loci on the X chromosome suggests a genetic mechanism to explain this male-biased evolution. Our results provide an initial map of the genetic changes underlying subspecies differences in genome-scale recombination rate and underscore the power of the house mouse system for understanding the evolution of this trait

Costs of treating patients with schizophrenia who have illness-related crisis events

<p>Abstract</p> <p>Background</p> <p>Relatively little is known about the relationship between psychosocial crises and treatment costs for persons with schizophrenia. This naturalistic prospective study assessed the association of recent crises with mental health treatment costs among persons receiving treatment for schizophrenia.</p> <p>Methods</p> <p>Data were drawn from a large multi-site, non-interventional study of schizophrenia patients in the United States, conducted between 1997 and 2003. Participants were treated at mental health treatment systems, including the Department of Veterans Affairs (VA) hospitals, community mental health centers, community and state hospitals, and university health care service systems. Total costs over a 1-year period for mental health services and component costs (psychiatric hospitalizations, antipsychotic medications, other psychotropic medications, day treatment, emergency psychiatric services, psychosocial/rehabilitation group therapy, individual therapy, medication management, and case management) were calculated for 1557 patients with complete medical information. Direct mental health treatment costs for patients who had experienced 1 or more of 5 recent crisis events were compared to propensity-matched samples of persons who had not experienced a crisis event. The 5 non-mutually exclusive crisis event subgroups were: suicide attempt in the past 4 weeks (n = 18), psychiatric hospitalization in the past 6 months (n = 240), arrest in the past 6 months (n = 56), violent behaviors in the past 4 weeks (n = 62), and diagnosis of a co-occurring substance use disorder (n = 413).</p> <p>Results</p> <p>Across all 5 categories of crisis events, patients who had a recent crisis had higher average annual mental health treatment costs than patients in propensity-score matched comparison samples. Average annual mental health treatment costs were significantly higher for persons who attempted suicide ($46,024), followed by persons with psychiatric hospitalization in the past 6 months ($37,329), persons with prior arrests ($31,081), and persons with violent behaviors ($18,778). Total cost was not significantly higher for those with co-occurring substance use disorder ($19,034).</p> <p>Conclusion</p> <p>Recent crises, particularly suicide attempts, psychiatric hospitalizations, and criminal arrests, are predictive of higher mental health treatment costs in schizophrenia patients.</p

Kihi-to, a herbal traditional medicine, improves Abeta(25–35)-induced memory impairment and losses of neurites and synapses

<p>Abstract</p> <p>Background</p> <p>We previously hypothesized that achievement of recovery of brain function after the injury requires the reconstruction of neuronal networks, including neurite regeneration and synapse reformation. Kihi-to is composed of twelve crude drugs, some of which have already been shown to possess neurite extension properties in our previous studies. The effect of Kihi-to on memory deficit has not been examined. Thus, the goal of the present study is to determine the <it>in vivo </it>and <it>in vitro </it>effects of Kihi-to on memory, neurite growth and synapse reconstruction.</p> <p>Methods</p> <p>Effects of Kihi-to, a traditional Japanese-Chinese traditional medicine, on memory deficits and losses of neurites and synapses were examined using Alzheimer's disease model mice. Improvements of Aβ(25–35)-induced neuritic atrophy by Kihi-to and the mechanism were investigated in cultured cortical neurons.</p> <p>Results</p> <p>Administration of Kihi-to for consecutive 3 days resulted in marked improvements of Aβ(25–35)-induced impairments in memory acquisition, memory retention, and object recognition memory in mice. Immunohistochemical comparisons suggested that Kihi-to attenuated neuritic, synaptic and myelin losses in the cerebral cortex, hippocampus and striatum. Kihi-to also attenuated the calpain increase in the cerebral cortex and hippocampus. When Kihi-to was added to cells 4 days after Aβ(25–35) treatment, axonal and dendritic outgrowths in cultured cortical neurons were restored as demonstrated by extended lengths of phosphorylated neurofilament-H (P-NF-H) and microtubule-associated protein (MAP)2-positive neurites. Aβ(25–35)-induced cell death in cortical culture was also markedly inhibited by Kihi-to. Since NF-H, MAP2 and myelin basic protein (MBP) are substrates of calpain, and calpain is known to be involved in Aβ-induced axonal atrophy, expression levels of calpain and calpastatin were measured. Treatment with Kihi-to inhibited the Aβ(25–35)-evoked increase in the calpain level and decrease in the calpastatin level. In addition, Kihi-to inhibited Aβ(25–35)-induced calcium entry.</p> <p>Conclusion</p> <p>In conclusion Kihi-to clearly improved the memory impairment and losses of neurites and synapses.</p

Topological Cluster Analysis Reveals the Systemic Organization of the Caenorhabditis elegans Connectome

The modular organization of networks of individual neurons interwoven through synapses has not been fully explored due to the incredible complexity of the connectivity architecture. Here we use the modularity-based community detection method for directed, weighted networks to examine hierarchically organized modules in the complete wiring diagram (connectome) of Caenorhabditis elegans (C. elegans) and to investigate their topological properties. Incorporating bilateral symmetry of the network as an important cue for proper cluster assignment, we identified anatomical clusters in the C. elegans connectome, including a body-spanning cluster, which correspond to experimentally identified functional circuits. Moreover, the hierarchical organization of the five clusters explains the systemic cooperation (e.g., mechanosensation, chemosensation, and navigation) that occurs among the structurally segregated biological circuits to produce higher-order complex behaviors

Image perception and interpretation of abnormalities; can we believe our eyes? Can we do something about it?

The radiologist’s visual impression of images is transmitted, via non-visual means (the report), to the clinician. There are several complex steps from the perception of the images by the radiologist to the understanding of the impression by the clinician. With a process as complex as this, it is no wonder that errors in perception, cognition, interpretation, transmission and understanding are very common. This paper reviews the processes of perception and error generation and possible strategies for minimising them

Prothymosin alpha: a ubiquitous polypeptide with potential use in cancer diagnosis and therapy

The thymus is a central lymphoid organ with crucial role in generating T cells and maintaining homeostasis of the immune system. More than 30 peptides, initially referred to as “thymic hormones,” are produced by this gland. Although the majority of them have not been proven to be thymus-speciWc, thymic peptides comprise an eVective group of regulators, mediating important immune functions. Thymosin fraction Wve (TFV) was the Wrst thymic extract shown to stimulate lymphocyte proliferation and diVerentiation. Subsequent fractionation of TFV led to the isolation and characterization of a series of immunoactive peptides/polypeptides, members of the thymosin family. Extensive research on prothymosin (proT) and thymosin 1 (T1) showed that they are of clinical signiWcance and potential medical use. They may serve as molecular markers for cancer prognosis and/or as therapeutic agents for treating immunodeWciencies, autoimmune diseases and malignancies. Although the molecular mechanisms underlying their eVect are yet not fully elucidated proT and T1 could be considered as candidates for cancer immunotherapy. In this review, we will focus in principle on the eventual clinical utility of proT, both as a tumor biomarker and in triggering anticancer immune responses. Considering the experience acquired via the use of T1 to treat cancer patients, we will also discuss potential approaches for the future introduction of proT into the clinical setting

Regulation of Oxidative Stress Response by CosR, an Essential Response Regulator in Campylobacter jejuni

CosR (Campylobacter oxidative stress regulator; Cj0355c) is an OmpR-type response regulator essential for the viability of Campylobacter jejuni, a leading foodborne pathogen causing human gastroenteritis worldwide. Despite importance, the function of CosR remains completely unknown mainly because of cell death caused by its knockout mutation. To overcome this technical limitation, in this study, antisense technology was used to investigate the regulatory function of CosR by modulating the level of CosR expression. Two-dimensional gel electrophoresis (2DGE) was performed to identify the CosR regulon either by suppressing CosR expression with antisense peptide nucleic acid (PNA) or by overexpressing CosR in C. jejuni. According to the results of 2DGE, CosR regulated 32 proteins involved in various cellular processes. Notably, CosR negatively regulated a few key proteins of the oxidative stress response of C. jejuni, such as SodB, Dps, Rrc and LuxS, whereas CosR positively controlled AhpC. Electrophoretic mobility shift assay showed that CosR directly bound to the promoter region of the oxidative stress genes. DNase I footprinting assays identified 21-bp CosR binding sequences in the sodB and ahpC promoters, suggesting CosR specifically recognizes and binds to the regulated genes. Interestingly, the level of CosR protein was significantly reduced by paraquat (a superoxide generator) but not by hydrogen peroxide. Consistent with the overall negative regulation of oxidative stress defense proteins by CosR, the CosR knockdown by antisense rendered C. jejuni more resistant to oxidative stress compared to the wild type. Overall, this study reveals the important role played by the essential response regulator CosR in the oxidative stress defense of C. jejuni