An Emergent Research and Policy Framework for Telehealth.
Telehealth is a fast-growing sector in health care, using a variety of technologies to exchange information across locations and to improve access, quality, and outcomes across the continuum of care. Thousands of studies and hundreds of systematic reviews have been done, but their variability leaves many questions about telehealth's effectiveness, implementation priorities, and return on investment. There is an urgent need for a systematic, policy-relevant framework to integrate regulatory, operational, and clinical factors and to guide future investments in telehealth research and practice. An invited multidisciplinary group of 21 experts from AcademyHealth, the American Telemedicine Association (ATA), Kaiser Permanente Institute for Health Policy (KP), and the Physician Insurers Association of America (PIAA) met to review and discuss the components of a draft framework for policy-relevant telehealth research. The framework was revised and presented in a challenge workshop at Concordium 2016, and some additional refinements were made. The current framework encompasses the regulatory and payment policy context for telehealth, delivery system factors, and outcomes of telehealth interventions. Based on the feedback at Concordium 2016, the framework seems to have potential to help educate policymakers, payers, and health systems about the value of telehealth and to frame discussions about implementation barriers, including risk management concerns, technology costs, and organizational culture. However, questions remain about how to disseminate and use the framework to help coordinate policy, research, and implementation efforts in the delivery system.


Rare A360T Mutation Alters GSK3β(Ser9) Binding in the Cytosolic Loop of Presenilin 1, Influencing β-Catenin Nuclear Localization and Pro-Death Gene Expression in Alzheimer's Disease Case.
Presenilin 1 (PS1) forms, via its large cytosolic loop, a trimeric complex with N-cadherin and β-catenin, which is a key component of Wnt signaling. PS1 undergoes phosphorylation at 353 and 357 serines upon enhanced activity and elevated levels of the GSK3β isoform. PS1 mutations surrounding these serines may alter the stability of the β-catenin complex. Such mutations are found in some cases of familial early-onset Alzheimer's disease (fEOAD), but their functional impact remains obscure. One of such variants of PS1, the A360T substitution, is located close to GSK3β-targeted serine residues. This variant was recently demonstrated in the French population, but more detail is needed to understand its biological effects. To assess the significance of this variant, we employed functional studies using a fibroblast cell line from an Alzheimer's disease case (a female proband) carrying the A360T mutation. Based on functional transcriptomic, cellular, and biochemical assays, we demonstrated atypically impaired β-catenin/GSK3β signaling in the A360T patient's fibroblasts. In detail, this was characterized by a decreased level of active cytosolic β-catenin and bound by PS1, an increased level of nuclear β-catenin, an increased level of inhibited GSK3β phosphorylated on Ser9, and enhanced interaction of GSK3β(Ser9) with PS1. Based on the transcriptomic profile of the A360T fibroblasts, we proposed a dysregulated transcriptional activity of β-catenin, exemplified by increased expression of various cyclin-dependent kinases and cyclins, such as cyclin D1, potentially inducing neurons' cell cycle re-entry followed by apoptosis. The A360T cells did not exhibit significant amyloid pathology. Therefore, cell death in this PS1 cytosolic loop mutation may be attributed to impaired β-catenin/GSK3β signaling rather than amyloid deposition per se. We further estimated the biological and clinical relevance of the A360T variant by whole exome sequencing (WES). WES was performed on DNA from the blood of an A360T female proband, as well as an unrelated male patient carrying the A360T mutation and his mutation-free daughter (both unavailable for the derivation of the fibroblast cell lines). WES confirmed the highest-priority AD causality of the A360T variant in PS1 and also profiled the pathways and processes involved in the A360T case, highlighting the greatest importance of altered Wnt signaling.


Hypericum perforatum Reduces Paracetamol-Induced Hepatotoxicity and Lethality in Mice by Modulating Inflammation and Oxidative Stress.
Hypericum perforatum is a medicinal plant with anti-inflammatory and antioxidant properties, which is commercially available for therapeutic use in Brazil. Herein the effect of H. perforatum extract on paracetamol (acetaminophen)-induced hepatotoxicity, lethality, inflammation, and oxidative stress in male swiss mice were investigated. HPLC analysis demonstrated the presence of rutin, quercetin, hypericin, pseudohypericin, and hyperforin in H. perforatum extract. Paracetamol (0.15-3.0 g/kg, p.o.) induced dose-dependent mortality. The sub-maximal lethal dose of paracetamol (1.5 g/kg, p.o.) was chosen for the experiments in the study. H. perforatum (30-300 mg/kg, i.p.) dose-dependently reduced paracetamol-induced lethality. Paracetamol-induced increase in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations, and hepatic myeloperoxidase activity, IL-1β, TNF-α, and IFN-γ concentrations as well as decreased reduced glutathione (GSH) concentrations and capacity to reduce 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonate radical cation; ABTS˙(+) ) were inhibited by H. perforatum (300 mg/kg, i.p.) treatment. Therefore, H. perforatum protects mice against paracetamol-induced lethality and liver damage. This effect seems to be related to the reduction of paracetamol-induced cytokine production, neutrophil recruitment, and oxidative stress.


The Apc5 subunit of the anaphase-promoting complex/cyclosome interacts with poly(A) binding protein and represses internal ribosome entry site-mediated translation.
The anaphase-promoting complex/cyclosome (APC/C) is a multisubunit ubiquitin ligase that mediates the proteolysis of cell cycle proteins in mitosis and G(1). We used a yeast three-hybrid screen to identify proteins that interact with the internal ribosome entry site (IRES) of platelet-derived growth factor 2 mRNA. Surprisingly, this screen identified Apc5, although it does not harbor a classical RNA binding domain. We found that Apc5 binds the poly(A) binding protein (PABP), which directly binds the IRES element. PABP was found to enhance IRES-mediated translation, whereas Apc5 overexpression counteracted this effect. In addition to its association with the APC/C complex, Apc5 binds much heavier complexes and cosediments with the ribosomal fraction. In contrast to Apc3, which is associated only with the APC/C and remains intact during differentiation, Apc5 is degraded upon megakaryocytic differentiation in correlation with IRES activation. Expression of Apc5 in differentiated cells abolished IRES activation. This is the first report implying an additional role for an APC/C subunit, apart from its being part of the APC/C complex.


Oxaliplatin-induced peripheral neuropathy's effects on health-related quality of life of colorectal cancer survivors.
Oxaliplatin is a highly neurotoxic chemotherapeutic agent routinely used for the treatment of colorectal cancer. Recent data suggest that oxaliplatin-induced peripheral neuropathy may be long-lasting; however, the effects of persistent neuropathy on colorectal cancer survivors' physical and emotional well-being are not well understood. This cross sectional, descriptive study included persons who had received oxaliplatin-based chemotherapy for treatment of colorectal cancer at Moffitt Cancer Center between 2003 and 2010. Questionnaires including the Chemotherapy-Induced Peripheral Neuropathy Assessment Tool, Center for Epidemiological Studies Depression Scale (CES-D), Insomnia Severity Index, Medical Outcomes Study Short Form 36, and a demographic survey were administered. Pearson's correlations and linear regression analyses were used to examine relationships between neuropathy and depressive symptoms, sleep quality, and health-related quality of life (HRQOL). Eighty-nine percent of participants reported at least one symptom of peripheral neuropathy with a mean of 3.8 (±2.4) neuropathic symptoms. Depressive symptoms on the CES-D were significantly associated with more severe peripheral neuropathy(r = 0.38, p = 0.0001) and interference with activities (r = 0.59, p < 0.0001). Higher degrees of sleep disturbance on the Insomnia Severity Index (ISI) were significantly associated with more severe peripheral neuropathy (r = 0.35, p = 0.0004) and interference with activities(r = 0.52, p < 0.0001). HRQOL was significantly associated with peripheral neuropathy and interference with activities.


Mimicking electrodeposition in the gas phase: a programmable concept for selected-area fabrication of multimaterial nanostructures.
An in situ gas-phase process that produces charged streams of Au, Si, TiO(2), ZnO, and Ge nanoparticles/clusters is reported together with a programmable concept for selected-area assembly/printing of more than one material type. The gas-phase process mimics solution electrodeposition whereby ions in the liquid phase are replaced with charged clusters in the gas phase. The pressure range in which the analogy applies is discussed and it is demonstrated that particles can be plated into pores vertically (minimum resolution 60 nm) or laterally to form low-resistivity (48 microOmega cm) interconnects. The process is applied to the formation of multimaterial nanoparticle films and sensors. The system works at atmospheric pressure and deposits material at room temperature onto electrically biased substrate regions. The combination of pumpless operation and parallel nozzle-free deposition provides a scalable tool for printable flexible electronics and the capability to mix and match materials.


Surgical treatment for chronic pelvic pain.
The source of chronic pelvic pain may be reproductive organ, urological, musculoskeletal-neurological, gastrointestinal, or myofascial. A psychological component almost always is a factor, whether as an antecedent event or presenting as depression as result of the pain. Surgical interventions for chronic pelvic pain include: 1) resection or vaporization of vulvar/vestibular tissue for human papillion virus (HPV) induced or chronic vulvodynia/vestibulitis; 2) cervical dilation for cervix stenosis; 3) hysteroscopic resection for intracavitary or submucous myomas or intracavitary polyps; 4) myomectomy or myolysis for symptomatic intramural, subserosal or pedunculated myomas; 5) adhesiolysis for peritubular and periovarian adhesions, and enterolysis for bowel adhesions, adhesiolysis for all thick adhesions in areas of pain as well as thin ahesions affecting critical structures such as ovaries and tubes; 6) salpingectomy or neosalpingostomy for symptomatic hydrosalpinx; 7) ovarian treatment for symptomatic ovarian pain; 8) uterosacral nerve vaporization for dysmenorrhea; 9) presacral neurectomy for disabling central pain primarily of uterine but also of bladder origin; 10) resection of endometriosis from all surfaces including removal from bladder and bowel as well as from the rectovaginal septal space. Complete resection of all disease in a debulking operation is essential; 11) appendectomy for symptoms of chronic appendicitis, and chronic right lower quadrant pain; 12) uterine suspension for symptoms of collision dyspareunia, pelvic congestion, severe dysmenorrhea, cul-desac endometriosis; 13) repair of all hernia defects whether sciatic, inguinal, femoral, Spigelian, ventral or incisional; 14) hysterectomy if relief has not been achieved by organ-preserving surgery such as resection of all endometriosis and presacral neurectomy, or the central pain continues to be disabling. Before such a radical step is taken, MRI of the uterus to confirm presence of adenomyosis may be helpful; 15) trigger point injection therapy for myofascial pain and dysfunction in pelvic and abdominal muscles. With application of all currently available laparoscopic modalities, 80% of women with chronic pelvic pain will report a decrease of pain to tolerable levels, a significant average reduction which is maintained in 3-year follow-up. Individual factors contributing to pain cannot be determined, although the frequency of endometriosis dictates that its complete treatment be attempted. The beneficial effect of uterosacral nerve ablation may be as much due to treatment of occult endometriosis in the uterosacral ligaments as to transection of the nerve fibers themselves. The benefit of the presacral neurectomy appears to be definite but strictly limited to midline pain. Appendectomy, herniorraphy, and even hysterectomy are all appropriate therapies for patients with chronic pelvic pain. Even with all laparoscopic procedures employed, fully 20% of patients experience unsatisfactory results. In addition, these patients are often depressed. Whether the pain contributes to the depression or the depression to the pain is irrelevant to them. Selected referrals to an integrated pain center with psychologic assistance together with judicious prescription of antidepressant drugs will likely benefit both women who respond to surgical intervention and those who do not. A maximum surgical effort must be expended to resect all endometriosis, restore normal pelvic anatomy, resect nerve fibers, and treat surgically accessible disease. In addition, it is important to provide patients with chronic pelvic pain sufficient psychologic support to overcome the effects of the condition, and to assist them with underlying psychologic disorders.


MicroRNA dysregulation in cancer: opportunities for the development of microRNA-based drugs.
MicroRNAs (miRNAs) are 19- to 24-nucleotide, non-coding RNAs that have been implicated in both solid and hematological malignancies. Given the ability of miRNAs to target multiple genes and key biological processes, these molecules have received intensive research interest both as biomarkers and as therapeutic agents. The prospect of leveraging miRNAs to complement current therapeutic strategies in cancer is appealing, but is also complex. Simultaneously targeting multiple genes has both advantages and disadvantages for miRNA therapeutic delivery, and achieving target organ specificity while limiting off-target effects remains a major challenge in the translation of novel discoveries in research to the successful therapeutic delivery of miRNA in the clinic. This feature review discusses the current status of therapeutic approaches for miRNA in cancer, as well as potential challenges and future strategies.


Soy Isoflavones Inhibit Both GPIb-IX Signaling and αIIbβ3 Outside-In Signaling via 14-3-3ζ in Platelet.
Soy diet is thought to help prevent cardiovascular diseases in humans. Isoflavone, which is abundant in soybean and other legumes, has been reported to possess antiplatelet activity and potential antithrombotic effect. Our study aims to elucidate the potential target of soy isoflavone in platelet. The anti-thrombosis formation effect of genistein and daidzein was evaluated in ex vivo perfusion chamber model under low (300 s-1) and high (1800 s-1) shear forces. The effect of genistein and daidzein on platelet aggregation and spreading was evaluated with platelets from both wildtype and GPIbα deficient mice. The interaction of these soy isoflavone with 14-3-3ζ was detected by surface plasmon resonance (SPR) and co-immunoprecipitation, and the effect of αIIbβ3-mediated outside-in signaling transduction was evaluated by western blot. We found both genistein and daidzein showed inhibitory effect on thrombosis formation in perfusion chamber, especially under high shear force (1800 s-1). These soy isoflavone interact with 14-3-3ζ and inhibited both GPIb-IX and αIIbβ3-mediated platelet aggregation, integrin-mediated platelet spreading and outside-in signaling transduction. Our findings indicate that 14-3-3ζ is a novel target of genistein and daidzein. 14-3-3ζ, an adaptor protein that regulates both GPIb-IX and αIIbβ3-mediated platelet activation is involved in soy isoflavone mediated platelet inhibition.


Rabbit lung indolethylamine N-methyltransferase. cDNA and gene cloning and characterization.
Indolethylamine N-methyltransferase (INMT) catalyzes the N-methylation of tryptamine and structurally related compounds. This reaction has been studied because of its possible role in the in vivo synthesis of psychoactive compounds or neurotoxins and has been characterized biochemically in preparations of rabbit lung. Therefore, we set out to purify rabbit lung INMT, to clone and express its cDNA, and to clone and structurally characterize its gene as steps toward understanding the function and regulation of this enzyme. Rabbit lung INMT was purified and partial amino acid sequence was obtained. A polymerase chain reaction-based approach was then used to clone a rabbit lung INMT cDNA with a 792-base pair open reading frame that encoded a 263-amino acid protein with a predicted molecular mass of 29 kDa. When the cDNA was expressed in COS-1 cells, the encoded protein catalyzed the methylation of tryptamine and structurally related compounds, and was inhibited by two products of the reaction, S-adenosyl-L-homocysteine (AdoHcy) and N,N-dimethyltryptamine, as well as antimigraine drugs that are structurally related to N,N-dimethyltryptamine. Northern blot analysis demonstrated the presence of 2.0-kilobase mRNA species in rabbit lung, liver and, at lower levels, in brain. The cDNA was then used to clone the rabbit INMT gene. That gene had three exons and was structurally similar to the genes for nicotinamide N-methyltransferase and phenylethanolamine N-methyltransferase in several species. Cloning and expression of a rabbit lung INMT cDNA and cloning of the rabbit INMT gene represent important steps toward determination of the function and regulation of this mammalian methyltransferase enzyme.


Molecular determinants of acidic pH-dependent transport of human equilibrative nucleoside transporter 3.
Equilibrative nucleoside transporters (ENTs) translocate hydrophilic nucleosides across cellular membranes and are essential for salvage nucleotide synthesis and purinergic signaling. Unlike the prototypic human ENT members hENT1 and hENT2, which mediate plasma membrane nucleoside transport at pH 7.4, hENT3 is an acidic pH-activated lysosomal transporter partially localized to mitochondria. Recent studies demonstrate that hENT3 is indispensable for lysosomal homeostasis, and that mutations in hENT3 can result in a spectrum of lysosomal storage-like disorders. However, despite hENT3's prominent role in lysosome pathophysiology, the molecular basis of hENT3-mediated transport is unknown. Therefore, we sought to examine the mechanistic basis of acidic pH-driven hENT3 nucleoside transport with site-directed mutagenesis, homology modeling, and [3H]adenosine flux measurements in mutant RNA-injected Xenopus oocytes. Scanning mutagenesis of putative residues responsible for pH-dependent transport via hENT3 revealed that the ionization states of Asp-219 and Glu-447, and not His, strongly determined the pH-dependent transport permissible-impermissible states of the transporter. Except for substitution with certain isosteric and polar residues, substitution of either Asp-219 or Glu-447 with any other residues resulted in robust activity that was pH-independent. Dual substitution of Asp-219 and Glu-447 to Ala sustained pH-independent activity over a broad range of physiological pH (pH 5.5-7.4), which also maintained stringent substrate selectivity toward endogenous nucleosides and clinically used nucleoside drugs. Our results suggest a putative pH-sensing role for Asp-219 and Glu-447 in hENT3 and that the size, ionization state, or electronegative polarity at these positions is crucial for obligate acidic pH-dependent activity.


New Findings on Biological Actions and Clinical Applications of Royal Jelly: A Review.
Royal jelly (RJ) is a natural bee product with great potential for use in medicine. The chemical composition of RJ indicates the presence of various bioactive substances including 10-hydroxydecanoic acid and 24-methylenecholesterol. In addition, a number of biological and pharmacological activities of RJ have been documented. The aim of this study was to review the biological and medical effects of RJ. The search was conducted in articles from electronic and scientific literature databases such as Pub Med, Science Direct, Scopus, Medline, and ISI Web of Science published from 1990 to 2017 using keywords of pharmacological, biological, and clinical effects and royal jelly. Data were chosen after the primary survey of all abstracts and selected full articles. Comparison among related data was done by the authors. Literature has shown that RJ possesses many beneficial effects on biological systems. For example, the therapeutic uses of RJ have been reported in several diseases such as hypercholesterolemia, diabetes, hypertension, and cancers. It was also found to possess neurotrophic, hypotensive, immunomodulatory, antimicrobial, antioxidant, antidiabetic, antihypercholesterolemic, antitumor, and anti-inflammatory effects. Owing to the broad spectrum of biological effects and valuable clinical trials, evaluating the beneficial pharmaceutical effects of RJ in animal and human models seems to be important.


L-prolyl-l-leucyl-glycinamide and its peptidomimetic analog 3(R)-[(2(S)-pyrrolidylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide (PAOPA) attenuate haloperidol-induced c-fos expression in the striatum.
Acute treatment of rats with haloperidol results in a rapid and transient increase in striatal c-fos mRNA and Fos immunoreactivity. The induction of immediate early genes by haloperidol may be involved in the development of extrapyramidal side effects. L-Prolyl-L-leucyl-glycinamide (PLG, or MIF-1) has been observed to antagonize the development of haloperidol-induced D(2) receptor supersensitivity in rats. We investigated the modulatory effects of PLG on haloperidol-induced c-fos and Fos protein expression in the rat striatum. We report that coadministration of either PLG or the potent analog of PLG, 3(R)-[(2(S)-pyrrolidylcarbonyl)amino]-2-oxo-1-pyrrolidineacetam ide (PAOPA), attenuated haloperidol-induced c-fos and Fos expression. Haloperidol induced [2 mg/kg, intraperitoneally (i.p.)] c-fos and Fos expression by 500% and 100%, respectively. These responses were attenuated by 170% and 75%, respectively, when coadministered with PLG (20 mg/kg, i.p.) or by 79% by PAOPA (10 microg/kg, i.p.).


The importance of social and collaborative learning for online continuing medical education (OCME): directions for future development and research.
There is an increasing use of online continuing medical education (OCME), but the potential use of social and collaborative learning to change professional performance and improve patient care has yet to be fully realised. The integration of the main themes from the presentations and comments from participants at a symposium at AMEE 2011. Sociological perspectives on change in professional performance highlight the need for social and collaborative learning in OCME so that learners can share information (explicit knowledge) and opinion (tacit knowledge). The educational topic should be relevant to the complexity of professional practice and use iterative cycles of implementation and critical reflection in social networks so that proposed solutions can be tested in actual practice. The challenge of developing effective online discussions for collaborative learning is recognised. The provision of OCME requires a shift in both policy and practice to emphasise the importance of social and collaborative learning. Further research is recommended, especially to evaluate the implementation and impact of social and collaborative learning for OCME on patient care and the use of newer Web 2.0 approaches.


The Role of Poly(Methyl Methacrylate) in Management of Bone Loss and Infection in Revision Total Knee Arthroplasty: A Review.
Poly(methyl methacrylate) (PMMA) is widely used in joint arthroplasty to secure an implant to the host bone. Complications including fracture, bone loss and infection might cause failure of total knee arthroplasty (TKA), resulting in the need for revision total knee arthroplasty (rTKA). The goals of this paper are: (1) to identify the most common complications, outside of sepsis, arising from the application of PMMA following rTKA, (2) to discuss the current applications and drawbacks of employing PMMA in managing bone loss, (3) to review the role of PMMA in addressing bone infection following complications in rTKA. Papers published between 1970 to 2018 have been considered through searching in Springer, Google Scholar, IEEE Xplore, Engineering village, PubMed and weblinks. This review considers the use of PMMA as both a bone void filler and as a spacer material in two-stage revision. To manage bone loss, PMMA is widely used to fill peripheral bone defects whose depth is less than 5 mm and covers less than 50% of the bone surface. Treatment of bone infections with PMMA is mainly for two-stage rTKA where antibiotic-loaded PMMA is inserted as a spacer. This review also shows that using antibiotic-loaded PMMA might cause complications such as toxicity to surrounding tissue, incomplete antibiotic agent release from the PMMA, roughness and bacterial colonization on the surface of PMMA. Although PMMA is the only commercial bone cement used in rTKA, there are concerns associated with using PMMA following rTKA. More research and clinical studies are needed to address these complications.


Yeast 5-aminolevulinate synthase provides additional chlorophyll precursor in transgenic tobacco.
Synthesis of the tetrapyrrole precursor 5-aminolevulinate (ALA) in plants starts with glutamate and is a tRNA-dependent pathway consisting of three enzymatic steps localized in plastids. In animals and yeast, ALA is formed in a single step from succinyl CoA and glycine by aminolevulinate synthase (ALA-S) in mitochondria. A gene encoding a fusion protein of yeast ALA-S with an aminoterminal transit sequence for the small subunit of ribulose bisphosphate carboxylase was introduced into the genome of wild-type tobacco and a chlorophyll-deficient transgenic line expressing glutamate 1-semi-aldehyde aminotransferase (GSA-AT) antisense RNA. Expression of ALA-S in the GSA-AT antisense transgenic line provided green-pigmented co-transformants similar to wild-type in chlorophyll content, while transformants derived from wild-type plants did not show phenotypical changes. The capacity to synthesize ALA and chlorophyll was increased in transformed plants, indicating a contribution of ALA-S to the ALA supply for chlorophyll synthesis. ALA-S activity was detected in plastids of the transformants. Preliminary evidence is presented that succinyl CoA, the substrate for ALA-S, can be synthesized and metabolized in plastids. The transgenic plants formed chlorophyll in the presence of gabaculine, an inhibitor of GSA-AT. Steady-state RNA and protein levels and consequently, the enzyme activity of GSA-AT were reduced in plants expressing ALA-S. In analogy to the light-dependent ALA synthesis attributed to feedback regulation, a mechanism at the level of intermediates or tetrapyrrole end-products is proposed, which co-ordinates the need for heme and chlorophyll precursors and restricts synthesis of ALA by regulating GSA-AT gene expression. The genetically engineered tobacco plants containing the yeast ALA-S activity demonstrate functional complementation of the catalytic activity of the plant ALA-synthesizing pathway and open strategies for producing tolerance against inhibitors of the C5 pathway.


Prevalence of abnormal anal cytology in women infected with HIV.
Anal cancer is a rare disease. Nevertheless, it may be a reason for concern among groups in which its incidence is increasing: those who engage in anoreceptive intercourse, promiscuous persons, and those with sexually transmitted infections (HPV and HIV). The aim of this study was to evaluate the prevalence of abnormal anal cytology in women infected with HIV seen at Hospital de Clínicas de Porto Alegre, Brazil. A cross-sectional design was used. Anal smear screening was offered to all women infected with HIV seen at the hospital's outpatient sexually transmitted infections clinic from March 2006 to March 2008. A total of 184 patients were thus enrolled. Only patients who gave written consent were included in the study. The prevalence of abnormal anal cytology was 14.1% (26 patients). Twenty-two patients presented atypical squamous cells of undetermined significance, and four exhibited low-grade intraepithelial neoplasia. Initially, abnormal anal cytology was significantly associated with age, number of pregnancies, smoking, abnormal cervical cytology, CD4⁺ < 200 cells/mm³ and hepatitis C co-infection. After adjustment, only CD4⁺ < 200 cells/mm³ and smoking were found to increase the risk of altered anal cytology. The anal Pap method described is simple and can be used for screening in cohorts of HIV-positive women who are at risk of developing anal carcinoma, mainly those with CD4⁺ counts <200 cells/mm³ and smokers.


Therapeutic applications of PARP inhibitors: anticancer therapy and beyond.
The aim of this article is to describe the current and potential clinical translation of pharmacological inhibitors of poly(ADP-ribose) polymerase (PARP) for the therapy of various diseases. The first section of the present review summarizes the available preclinical and clinical data with PARP inhibitors in various forms of cancer. In this context, the role of PARP in single-strand DNA break repair is relevant, leading to replication-associated lesions that cannot be repaired if homologous recombination repair (HRR) is defective, and the synthetic lethality of PARP inhibitors in HRR-defective cancer. HRR defects are classically associated with BRCA1 and 2 mutations associated with familial breast and ovarian cancer, but there may be many other causes of HRR defects. Thus, PARP inhibitors may be the drugs of choice for BRCA mutant breast and ovarian cancers, and extend beyond these tumors if appropriate biomarkers can be developed to identify HRR defects. Multiple lines of preclinical data demonstrate that PARP inhibition increases cytotoxicity and tumor growth delay in combination with temozolomide, topoisomerase inhibitors and ionizing radiation. Both single agent and combination clinical trials are underway. The final part of the first section of the present review summarizes the current status of the various PARP inhibitors that are in various stages of clinical development. The second section of the present review summarizes the role of PARP in selected non-oncologic indications. In a number of severe, acute diseases (such as stroke, neurotrauma, circulatory shock and acute myocardial infarction) the clinical translatability of PARP inhibition is supported by multiple lines of preclinical data, as well as observational data demonstrating PARP activation in human tissue samples. In these disease indications, PARP overactivation due to oxidative and nitrative stress drives cell necrosis and pro-inflammatory gene expression, which contributes to disease pathology. Accordingly, multiple lines of preclinical data indicate the efficacy of PARP inhibitors to preserve viable tissue and to down-regulate inflammatory responses. As the clinical trials with PARP inhibitors in various forms of cancer progress, it is hoped that a second line of clinical investigations, aimed at testing of PARP inhibitors for various non-oncologic indications, will be initiated, as well.


Inosine attenuates 3-nitropropionic acid-induced Huntington's disease-like symptoms in rats via the activation of the A2AR/BDNF/TrKB/ERK/CREB signaling pathway.
Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by involuntary bizarre movements, psychiatric symptoms, dementia, and early death. Several studies suggested neuroprotective activities of inosine; however its role in HD is yet to be elucidated. The current study aimed to demonstrate the neuroprotective effect of inosine in 3-nitropropionic acid (3-NP)-induced neurotoxicity in rats while investigating possible underlying mechanisms. Rats were randomly divided into five groups; group 1 received i.p. injections of 1% DMSO, whereas groups 2, 3, 4, and 5 received 3-NP (10 mg/kg, i.p.) for 14 days, concomitantly with inosine (200 mg/kg., i.p.) in groups 3, 4, and 5, SCH58261, a selective adenosine 2A receptor (A2AR) antagonist, (0.05 mg/kg, i.p.) in group 4, and PD98059, an extracellular signal-regulated kinase (ERK) inhibitor, (0.3 mg/kg, i.p.) in group 5. Treatment with inosine mitigated 3-NP-induced motor abnormalities and body weight loss. Moreover, inosine boosted the striatal brain-derived neurotrophic factor (BDNF) level, p-tropomyosin receptor kinase B (TrKB), p-ERK, and p-cAMP response element-binding protein (CREB) expression, which subsequently suppressed oxidative stress biomarkers (malondialdehyde and nitric oxide) and pro-inflammatory cytokines (tumor necrosis factor alpha and interleukin-1β) and replenished the glutathione content. Similarly, histopathological analyses revealed decreased striatal injury score, the expression of the glial fibrillary acidic protein, and neuronal loss after inosine treatment. These effects were attenuated by the pre-administration of SCH58261 or PD98059. In conclusion, inosine attenuated 3-NP-induced HD-like symptoms in rats, at least in part, via the activation of the A2AR/BDNF/TrKB/ERK/CREB signaling pathway.


Infectious disease and the conservation of free-ranging large carnivores.
Large carnivores are of vital importance to the stability and integrity of most ecosystems, but recent declines in free-ranging populations have highlighted the potentially devastating effect of infectious diseases on their conservation. We reviewed the literature on infectious diseases of 34 large (maximum body mass of adults >20 kg) terrestrial carnivore species, 18 of which are considered to be threatened in the wild, and examined reports of antibody prevalence (seroprevalence) and cases of infection, mortality and population decline. Of 52 diseases examined, 44% were viral, 31% bacterial and the remainder were protozoal or fungal. Many infections were endemic in carnivores and/or infected multiple taxonomic families, with the majority probably occurring via inhalation or ingestion. Most disease studies consisted of serological surveys for disease antibodies, and antibody detection tended to be widespread implying that exposure to micro-organisms was common. Seroprevalence was higher in tropical than temperate areas, and marginally higher for infections known to occur in multiple carnivore groups. Confirmation of active infection via micro-organism recovery was less common for ursids than other taxonomic groups. Published descriptions of disease-induced population decline or extinction were rare, and most outbreaks were allegedly the result of direct transmission of rabies or canine distemper virus (CDV) from abundant carnivore species to less-common large carnivores. We conclude that the threat of disease epidemics in large carnivores may be serious if otherwise lethal infections are endemic in reservoir hosts and transmitted horizontally among taxa. To prevent or mitigate future population declines, research efforts should be aimed at identifying both the diseases of potential importance to large carnivores and the ecological conditions associated with their spread and severity.


Virus-induced pancreatic disease by Venezuelan encephalitis virus. Alterations in glucose tolerance and insulin release.
Viral infections have been implicated in the induction of diabetes mellitus in man and laboratory animals. Since virus-specific immunofluorescence (FA) is detectable in hamster pancreas during the acute phase of Venezuelan encephalitis (VE), experiments were designed to correlate pathologic and virologic events with metabolic studies in VE-infected hamsters. Golden Syrian hamsters were inoculated s.c. in groups of four to 12 with 100,000 plaque-forming units (PFU) of the vaccine strain (TC-83) of VE or 1,000 PFU of the virulent Trinidad strain of VE. Ultrastructurally, during Trinidad infection, mature virions were associated with the cell surfaces and within pancreatic beta cells in contrast to absence of virus-related changes in TC-83-infected hamsters. Virus-specific-FA was noted in islet cells and acinar cells of Trinidad-infected hamsters. VE growth curves demonstrated viral replication in pancreas with both strains. Although ultrastructural and FA changes were much more prominent in Trinidad-infected hamsters in contrast to TC-83-infected hamsters during the first few days of illness, the rapid lethality of the Trinidad-infected group necessitated performing all metabolic studies in TC-83-strain-infected hamsters. Accordingly, for the metabolic studies, glucose tolerance tests (GTT) using 2 mg. or 5 gm./kg. glucose i.p. were performed in groups of hamsters acutely infected two days earlier with the TC-83 vaccine strain and in 24-day and 90-day convalescent hamsters after TC-83 vaccine strain. Samples were obtained for glucose and immunoreactive insulin (IRI) determinations. Glucose intolerance occurred in hamsters in each of the infected groups given 5 gm./kg. glucose except for the 90-day convalescent TC-83 group. Severely decreased IRI responses occurred in the 24-day and 90-day convalescent TC-83 hamsters following both 2- and 5-gm./kg. glucose. Pancreatic IRI content in 24-day convalescent TC-83 hamsters was within normal limits, suggesting a defect in IRI release from the beta cells at this stage of convalescence.


Imaging regulatory T cell dynamics and CTLA4-mediated suppression of T cell priming.
Foxp3(+) regulatory T cells (Tregs) maintain immune homoeostasis through mechanisms that remain incompletely defined. Here by two-photon (2P) imaging, we examine the cellular dynamics of endogenous Tregs. Tregs are identified as two non-overlapping populations in the T-zone and follicular regions of the lymph node (LN). In the T-zone, Tregs migrate more rapidly than conventional T cells (Tconv), extend longer processes and interact with resident dendritic cells (DC) and Tconv. Tregs intercept immigrant DCs and interact with antigen-induced DC:Tconv clusters, while continuing to form contacts with activated Tconv. During antigen-specific responses, blocking CTLA4-B7 interactions reduces Treg-Tconv interaction times, increases the volume of DC:Tconv clusters and enhances subsequent Tconv proliferation in vivo. Our results demonstrate a role for altered cellular choreography of Tregs through CTLA4-based interactions to limit T-cell priming.


The Japan Medical Association's disaster preparedness: lessons from the Great East Japan Earthquake and Tsunami.
A complex disaster, the Great East Japan Earthquake of March 11, 2011, consisted of a large-scale earthquake, tsunami, and nuclear accident, resulting in more than 15 000 fatalities, injuries, and missing persons and damage over a 500-km area. The entire Japanese public was profoundly affected by "3/11." The risk of radiation exposure initially delayed the medical response, prolonging the recovery efforts. Japan's representative medical organization, the Japan Medical Association (JMA), began dispatching Japan Medical Association Teams (JMATs) to affected areas beginning March 15, 2011. About 1400 JMATs comprising nearly 5500 health workers were launched. The JMA coordinated JMAT operations and cooperated in conducting postmortem examination, transporting large quantities of medical supplies, and establishing a multiorganizational council to provide health assistance to disaster survivors. Importantly, these response efforts contributed to the complete recovery of the health care system in affected areas within 3 months, and by July 15, 2011, JMATs were withdrawn. Subsequently, JMATs II have been providing long-term continuing medical support to disaster-affected areas. However, Japan is at great risk for future natural disasters because of its Pacific Rim location. Also, its rapidly aging population, uneven distribution of and shortage of medical resources in regional communities, and an overburdened public health insurance system highlight the need for a highly prepared and effective disaster response system.


Adequate Utilization of Emergency Services in Germany: Is There a Differential by Migration Background?
Background: The role of emergency services (ES) is to provide round-the-clock acute care. In recent years, inadequate use of ES has been internationally thematised because of overcrowding and the associated cost. Evidence shows that migrant populations tend to use more ES than non-migrant but it remains to show if there is a differential in inadequacy. Method: Quantitative data from consecutive patients visiting three ES in Berlin (hospital-based outpatient clinics for internal medicine or gynecology) from July 2017 to July 2018 were obtained. Utilization was defined as adequate if the patient was admitted to hospital and/or if all of the three following criteria were fulfilled: reported to have been sent by medical staff; reported strong pain; and reported a high urgency (both ≥7, scale from 0 to 10). Differences between migrants (1st generation), their offspring (2nd generation), and non-migrants were evaluated using logistic regression. Results: Of the 2,327 patients included, 901 had a migration background. Adjusting for gender, age, gynecological hospital-based outpatient clinic, and the number of chronic diseases, 1st generation migrant patients (n = 633) had significantly lower odds than non-migrants to have an adequate utilization of services [OR 0.78, 95% confidence interval (0.62, 0.99), p-value 0.046]. For 2nd generation patients (n = 268), no statistically significant difference was found [OR 0.80, 95% confidence interval (0.56, 1.15), p-value 0.231]. Only adjusting for gynecological hospital-based outpatient clinic did weaken the association between migration status on adequacy but interactions between type of hospital-based outpatient clinic and migration were not significant. Discussion: First generation migrants show lower odds of adequate ES use compared to non-migrants. Only visiting a gynecological hospital-based outpatient clinic as opposed to internal medicine could partly explain the lower odds of adequate use among immigrants. This indicates a need for structural changes in the healthcare system: The threshold of access to general practices needs to be lowered, considering the needs of diverse subgroups of migrant patients.


Growth and in situ characterization of 2D materials by chemical vapour deposition on liquid metal catalysts: a review.
2D materials (2DMs) have now been established as unique and attractive alternatives to replace current technological materials in a number of applications. Chemical vapour deposition (CVD), is undoubtedly the most renowned technique for thin film synthesis and meets all requirements for automated large-scale production of 2DMs. Currently most CVD methods employ solid metal catalysts (SMCat) for the growth of 2DMs however their use has been found to induce structural defects such as wrinkles, fissures, and grain boundaries among others. On the other hand, liquid metal catalysts (LMCat), constitute a possible alternative for the production of defect-free 2DMs albeit with a small temperature penalty. This review is a comprehensive report of past attempts to employ LMCat for the production of 2DMs with emphasis on graphene growth. Special attention is paid to the underlying mechanisms that govern crystal growth and/or grain consolidation and film coverage. Finally, the advent of online metrology which is particularly effective for monitoring the chemical processes under LMCat conditions is also reviewed and certain directions for future development are drawn.


Pharmacokinetics and pharmacodynamics of the reverse transcriptase inhibitor tenofovir and prophylactic efficacy against HIV-1 infection.
Antiviral pre-exposure prophylaxis (PrEP) through daily drug administration can protect healthy individuals from HIV-1 infection. While PrEP was recently approved by the FDA, the potential long-term consequences of PrEP implementation remain entirely unclear. The aim of this study is to predict the efficacy of different prophylactic strategies with the pro-drug tenofovir-disoproxil-fumarate (TDF) and to assess the sensitivity towards timing- and mode of TDF administration (daily- vs. single dose), adherence and the number of transmitted viruses. We developed a pharmacokinetic model for TDF and its active anabolite tenofovir-diphosphate (TFV-DP) and validated it with data from 4 different trials, including 4 distinct dosing regimes. Pharmacokinetics were coupled to an HIV model and viral decay following TDF mono-therapy was predicted, consistent with available data. Subsequently, a stochastic approach was used to estimate the % infections prevented by (i) daily TDF-based PrEP, (ii) one week TDF started either shortly before, or -after viral exposure and (iii) a single dose oral TDF before viral challenge (sd-PrEP). Analytical solutions were derived to assess the relation between intracellular TFV-DP concentrations and prophylactic efficacy. The predicted efficacy of TDF was limited by a slow accumulation of active compound (TFV-DP) and variable TFV-DP half-life and decreased with increasing numbers of transmitted viruses. Once daily TDF-based PrEP yielded [Formula: see text]80% protection, if at least 40% of pills were taken. Sd-PrEP with 300 mg or 600 mg TDF could prevent [Formula: see text]50% infections, when given at least before virus exposure. The efficacy dropped to [Formula: see text]10%, when given 1 h before 24 h exposure. Efficacy could not be increased with increasing dosage or prolonged administration. Post-exposure prophylaxis poorly prevented infection. The use of drugs that accumulate more rapidly, or local application of tenofovir gel may overcome the need for drug administration long before virus exposure.


Air-generated electron contamination of 4 and 10 MV photon beams: a comparison of theory and experiment.
The contribution to the surface dose of contaminant electrons produced in air is studied for the photon beams of the Clinac 4 and Clinac 18 by measuring the change in per cent surface ionisation when a portion of the air path is replaced by helium. Measurements are made both with and without a magnetic field to sweep away electrons produced in the jaws. The measured changes are compared with the predictions of the theory of Nilsson and Brahme and also with the theory of Howarth et al, modified for the photon spectrum.


Pharmacogenetic Development of Personalized Medicine: Multiple Sclerosis Treatment as a Model.
The goal of pharmacogenetics is to identify "genetic fingerprints" that may predict a patient's response to pharmaceutical treatment. The use of pharmacogenetics replaces the trial-and-error strategy, which governs much of our clinical decision-making regarding treatment allocation in current medical practice, with individually tailored therapy. We review a pharmacogenetic research model, which implements high-throughput single nucleotide polymorphism technology to establish the correlation between drug-responsiveness and genetic polymorphisms of Copaxone(R)-treated multiple sclerosis patients. Implementation of similar pharmacogenetic approaches may promote the development of personalized medicine in multiple sclerosis as well as in other diseases. (c) 2002 Prous Science. All rights reserved.


A virtual reality platform to evaluate the effects of supernumerary limbs' appearance.
Supernumerary robot limbs (SL) can expand the ability of users by increasing the number of degrees of freedom that they control. While several SLs have been designed and tested on human participants, the effect of the limb's appearance on the user's acceptance, embodiment and device usage is not yet understood. We developed a virtual reality platform with a three-arm avatar that enabled us to systematically investigate the effect of the supernumerary limb's appearance on their perception and motion control performance. A pilot study with 14 participants exhibited similar performance, workload and preference in human-like or robot-like appearance with a trend of preference for the robotic appearance.


Histopathological Study to Evaluate the Effect of Aqueous Extract of Portunuspelagicus and Mebendazole on Hydatid Cysts in Mice.
Hydatid disease is a parasitic infestation by a tapeworm of the genus Echinococcus sp., which has a global distribution. The current study was conducted to evaluate the effectiveness of the crustacean aqueous extract of Portunuspelagicus for 2 weeks of treatment compared to mebendazole on hydatid cyst in laboratory mice male Balb / C strain. Mice were infected intraperitoneally with 2000 protoscolices. After 12 weeks of infection, each mouse was treated with mebendazole (50mg/kg) and the hot aqueous extract of p. pelagicus (8, 16 g/kg). Samples of infected organs (liver, spleen, and lungs) were examined under a microscope to evaluate the morphological and histopathological changes of hydatid cysts and tissues. The study confirmed macroscopically that there were a number of hydatid cysts of different sizes in the liver, spleen, and lungs, splenomegaly, and congestion of the lungs of the positive control group. The histological changes in the organs of the group treated with the crustacean extract were represented by the vacuolation of hepatocytes in the centrilobular area of the liver. At the same time, the lungs show intensive peri-bronchiolar inflammation, pulmonary vascular congestion, and in the spleen, the deposition of amyloid-like material in the white pulp, extramedullary hematopoiesis, While the histopathological changes in the organs of mice treated with mebendazole, were represented by the presence in the mild liver vacuolation of the centrilobular area. In contrast, the lungs show mild pulmonary vascular congestion and emphysema, and the spleen shows normal white pulp, the normal red pulp of mice. The aqueous extract Portunuspelagicus and mebendazole are effective in controlling the contamination in the intermediate hosts.


Identification and localization of Tospovirus genus-wide conserved residues in 3D models of the nucleocapsid and the silencing suppressor proteins.
Tospoviruses (genus Tospovirus, family Peribunyaviridae, order Bunyavirales) cause significant losses to a wide range of agronomic and horticultural crops worldwide. Identification and characterization of specific sequences and motifs that are critical for virus infection and pathogenicity could provide useful insights and targets for engineering virus resistance that is potentially both broad spectrum and durable. Tomato spotted wilt virus (TSWV), the most prolific member of the group, was used to better understand the structure-function relationships of the nucleocapsid gene (N), and the silencing suppressor gene (NSs), coded by the TSWV small RNA. Using a global collection of orthotospoviral sequences, several amino acids that were conserved across the genus and the potential location of these conserved amino acid motifs in these proteins was determined. We used state of the art 3D modeling algorithms, MULTICOM-CLUSTER, MULTICOM-CONSTRUCT, MULTICOM-NOVEL, I-TASSER, ROSETTA and CONFOLD to predict the secondary and tertiary structures of the N and the NSs proteins. We identified nine amino acid residues in the N protein among 31 known tospoviral species, and ten amino acid residues in NSs protein among 27 tospoviral species that were conserved across the genus. For the N protein, all three algorithms gave nearly identical tertiary models. While the conserved residues were distributed throughout the protein on a linear scale, at the tertiary level, three residues were consistently located in the coil in all the models. For NSs protein models, there was no agreement among the three algorithms. However, with respect to the localization of the conserved motifs, G18 was consistently located in coil, while H115 was localized in the coil in three models. This is the first report of predicting the 3D structure of any tospoviral NSs protein and revealed a consistent location for two of the ten conserved residues. The modelers used gave accurate prediction for N protein allowing the localization of the conserved residues. Results form the basis for further work on the structure-function relationships of tospoviral proteins and could be useful in developing novel virus control strategies targeting the conserved residues.


The digital motor output: a conceptual framework for a meaningful clinical performance metric for a motor neuroprosthesis.
In recent years, the majority of the population has become increasingly reliant on continuous and independent control of smart devices to conduct activities of daily living. Upper extremity movement is typically required to generate the motor outputs that control these interfaces, such as rapidly and accurately navigating and clicking a mouse, or activating a touch screen. For people living with tetraplegia, these abilities are lost, significantly compromising their ability to interact with their environment. Implantable brain computer interfaces (BCIs) hold promise for restoring lost neurologic function, including motor neuroprostheses (MNPs). An implantable MNP can directly infer motor intent by detecting brain signals and transmitting the motor signal out of the brain to generate a motor output and subsequently control computer actions. This physiological function is typically performed by the motor neurons in the human body. To evaluate the use of these implanted technologies, there is a need for an objective measurement of the effectiveness of MNPs in restoring motor outputs. Here, we propose the concept of digital motor outputs (DMOs) to address this: a motor output decoded directly from a neural recording during an attempted limb or orofacial movement is transformed into a command that controls an electronic device. Digital motor outputs are diverse and can be categorized as discrete or continuous representations of motor control, and the clinical utility of the control of a single, discrete DMO has been reported in multiple studies. This sets the stage for the DMO to emerge as a quantitative measure of MNP performance.


Update in Management of Severe Hypoxemic Respiratory Failure.
Mortality related to severe-moderate and severe ARDS remains high. We searched the literature to update this topic. We defined severe hypoxemic respiratory failure as Pao2/Fio2 < 150 mm Hg (ie, severe-moderate and severe ARDS). For these patients, we support setting the ventilator to a tidal volume of 4 to 8 mL/kg predicted body weight (PBW), with plateau pressure (Pplat) ≤ 30 cm H2O, and initial positive end-expiratory pressure (PEEP) of 10 to 12 cm H2O. To promote alveolar recruitment, we propose increasing PEEP in increments of 2 to 3 cm provided that Pplat remains ≤ 30 cm H2O and driving pressure does not increase. A fluid-restricted strategy is recommended, and nonrespiratory causes of hypoxemia should be considered. For patients who remain hypoxemic after PEEP optimization, neuromuscular blockade and prone positioning should be considered. Profound refractory hypoxemia (Pao2/Fio2 < 80 mm Hg) after PEEP titration is an indication to consider extracorporeal life support. This may necessitate early transfer to a center with expertise in these techniques. Inhaled vasodilators and nontraditional ventilator modes may improve oxygenation, but evidence for improved outcomes is weak.


Isolation of an intrinsic precursor to molecular chemisorption
Over the past 70 years, numerous gas-surface adsorption studies have indicated the existence of a weakly bound, mobile intermediate that is a precursor to chemical bond formation. The direct observation and characterization of such a species are presented. Precursor and chemisorbed benzene on a silicon surface were clearly distinguished with the use of a tunable-temperature scanning tunneling microscope. Precursor decay to chemisorption was observed, allowing the salient features of the potential energy surface to be determined.


Secondary intramedullary spinal cord non-Hodgkin's lymphoma.
Intramedullary spinal cord metastases of solid neoplasms are associated with poor long-term survival. As the characteristics of secondary intramedullary spinal cord non-Hodgkin's lymphoma (NHL) are not well understood, we sought to describe its clinical features and outcome. We retrospectively reviewed the Mayo Clinic patient database, lymphoma database, and pathology records from 1996 to 2010 and identified patients with clinical myelopathy and neuroimaging evidence of secondary intramedullary spinal cord involvement from pathologically confirmed systemic NHL. Seven patients were included in this study. The median age was 61 years (range, 41-81). Symptom onset was subacute (≤8 weeks) in six. Four patients were wheelchair-dependent at diagnosis. Spinal cord NHL was diagnosed by cerebrospinal fluid cytology in four; Positron emission tomography hypermetabolism in two; or MRI features alone. Myelopathy developed in five patients at a median 8 months (range, 1-58) following systemic NHL diagnosis, while myelopathy was the heralding symptom of NHL in two patients. Spinal cord MRI lesions were characteristically gadolinium enhancing and expansile. Four patients had co-existing MRI brain lesions. Six patients had B-cell NHL and one patient T-cell NHL. Six of the seven were treated (high dose intravenous methotrexate in three; radiation therapy in two; and R-CHOP in one). Median survival was 11.5 months (range, 1-28) with a 33% 2-year survival compared to historical median survival estimates of spinal cord metastases due to solid tumors of 3 months. In secondary intramedullary spinal cord involvement of NHL early neurological morbidity is common, but overall survival compares favorably to previously reported survival in spinal cord metastases from solid tumors.


Transition of early-phase treatment for acute pancreatitis: An analysis of nationwide epidemiological survey.
Treatment of acute pancreatitis (AP) is one of the critical challenges to the field of gastroenterology because of its high mortality rate and high medical costs associated with the treatment of severe cases. Early-phase treatments for AP have been optimized in Japan, and clinical guidelines have been provided. However, changes in early-phase treatments and the relationship between treatment strategy and clinical outcome remain unclear. Retrospective analysis of nationwide epidemiological data shows that time for AP diagnosis has shortened, and the amount of initial fluid resuscitation has increased over time, indicating the compliance with guidelines. In contrast, prophylactic use of broad-spectrum antibiotics has emerged. Despite the potential benefits of early enteral nutrition, its use is still limited. The roles of continuous regional arterial infusion in the improvement of prognosis and the prevention of late complications are uncertain. Furthermore, early-phase treatments have had little impact on late-phase complications, such as walled-off necrosis, surgery requirements and late (> 4 w) AP-related death. Based on these observations, early-phase treatments for AP in Japan have approached the optimal level, but late-phase complications have become concerning issues. Early-phase treatments and the therapeutic strategy for late-phase complications both need to be optimized based on firm clinical evidence and cost-effectiveness.


Simulated rRNA/DNA Ratios Show Potential To Misclassify Active Populations as Dormant.
The use of rRNA/DNA ratios derived from surveys of rRNA sequences in RNA and DNA extracts is an appealing but poorly validated approach to infer the activity status of environmental microbes. To improve the interpretation of rRNA/DNA ratios, we performed simulations to investigate the effects of community structure, rRNA amplification, and sampling depth on the accuracy of rRNA/DNA ratios in classifying bacterial populations as "active" or "dormant." Community structure was an insignificant factor. In contrast, the extent of rRNA amplification that occurs as cells transition from dormant to growing had a significant effect (P < 0.0001) on classification accuracy, with misclassification errors ranging from 16 to 28%, depending on the rRNA amplification model. The error rate increased to 47% when communities included a mixture of rRNA amplification models, but most of the inflated error was false negatives (i.e., active populations misclassified as dormant). Sampling depth also affected error rates (P < 0.001). Inadequate sampling depth produced various artifacts that are characteristic of rRNA/DNA ratios generated from real communities. These data show important constraints on the use of rRNA/DNA ratios to infer activity status. Whereas classification of populations as active based on rRNA/DNA ratios appears generally valid, classification of populations as dormant is potentially far less accurate.IMPORTANCE The rRNA/DNA ratio approach is appealing because it extracts an extra layer of information from high-throughput DNA sequencing data, offering a means to determine not only the seedbank of taxa present in communities but also the subset of taxa that are metabolically active. This study provides crucial insights into the use of rRNA/DNA ratios to infer the activity status of microbial taxa in complex communities. Our study shows that the approach may not be as robust as previously supposed, particularly in complex communities composed of populations employing different growth strategies, and identifies factors that inflate the erroneous classification of active populations as dormant.


The anti-hyperuricemic effect of epigallocatechin-3-gallate (EGCG) on hyperuricemic mice.
Epigallocatechin-3-gallate (EGCG), a major constituent of green tea catechin, has been used for antioxidant. This study aimed to evaluate the antihyperuricemic activity of EGCG on hyperuricemic mice. We demonstrated that serum uric acid (UA) level was decreased significantly with dose-dependence by EGCG treated with 10, 20, and 50mg/kg. Compared with the model, data on blood urea nitrogen (BUN) supported that there was significance with high dose of EGCG (50mg/kg). Levels of serum creatinine (Cr) in each EGCG-treated group were decreased but not significant; the activities of hepatic xanthine oxidase (XOD) and adenosine deaminase (ADA) in high dose groups' EGCG were notably lower than those of model group. EGCG could downregulate the renal mRNA expression levels of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) on hyperuricemic mice. These results presented that EGCG had obvious hypouricemic and renal protective effects on hyperuricemic mice. Our data may have a potential value in clinical practice in the treatment of hyperuricemia.


Interaction of reelin with amyloid precursor protein promotes neurite outgrowth.
The processing of amyloid precursor protein (APP) to Abeta is an important event in the pathogenesis of Alzheimer's disease, but the physiological function of APP is not well understood. Our previous work has shown that APP processing and Abeta production are regulated by the extracellular matrix protein Reelin. In the present study, we examined whether Reelin interacts with APP, and the functional consequences of that interaction in vitro. Using coimmunoprecipitation, we found that Reelin interacted with APP through the central domain of Reelin (repeats 3-6) and the E1 extracellular domain of APP. Reelin increased cell surface levels of APP and decreased endocytosis of APP in hippocampal neurons in vitro. In vivo, Reelin levels were increased in brains of APP knock-out mice and decreased in APP-overexpressing mice. RNA interference knockdown of APP decreased neurite outgrowth in vitro and prevented Reelin from increasing neurite outgrowth. Knock-out of APP or Reelin decreased dendritic arborization in cortical neurons in vivo, and APP overexpression increased dendritic arborization. APP and Reelin have previously been shown to promote neurite outgrowth through interactions with integrins. We confirmed that APP interacted with alpha3beta1 integrin, and alpha3beta1 integrin altered APP trafficking and processing. Addition of an alpha3beta1 integrin antibody prevented APP and Reelin-induced neurite outgrowth. These findings demonstrate that Reelin interacts with APP, potentially having important effects on neurite development.


Non-Markovian temporal networks with auto- and cross-correlated link dynamics.
Many of the biological, social and man-made networks around us are inherently dynamic, with their links switching on and off over time. The evolution of these networks is often observed to be non-Markovian, and the dynamics of their links are often correlated. Hence, to accurately model these networks, predict their evolution, and understand how information and other relevant quantities propagate over them, the inclusion of both memory and dynamical dependencies between links is key. In this article we introduce a general class of models of temporal networks based on discrete autoregressive processes for link dynamics. As a concrete and useful case study, we then concentrate on a specific model within this class, which allows to generate temporal networks with a specified underlying structural backbone, and with precise control over the dynamical dependencies between links and the strength and length of their memories. In this network model the presence of each link is influenced not only by its past activity, but also by the past activities of other links, as specified by a coupling matrix, which directly controls the causal relations, and hence the correlations, among links. We propose a maximum likelihood method for estimating the model's parameters from data, showing how the model allows a more realistic description of real-world temporal networks and also to predict their evolution. Due to the flexibility of maximum likelihood inference, we illustrate how to deal with heterogeneity and time-varying patterns, possibly including also nonstationary network dynamics. We then use our network model to investigate the role that, both the features of memory and the type of correlations in the dynamics of links have on the properties of processes occurring over a temporal network. Namely, we study the speed of a spreading process, as measured by the time it takes for diffusion to reach equilibrium. Through both numerical simulations and analytical results, we are able to separate the roles of autocorrelations and neighborhood correlations in link dynamics, showing that not only is the speed of diffusion nonmonotonically dependent on the memory length, but also that correlations among neighboring links help to speed up the spreading process, while autocorrelations slow it back down. Our results have implications in the study of opinion formation, the modeling of social networks, and the spreading of epidemics through mobile populations.


Novel Wearable HD-EMG Sensor With Shift-Robust Gesture Recognition Using Deep Learning.
In this work, we present a hardware-software solution to improve the robustness of hand gesture recognition to confounding factors in myoelectric control. The solution includes a novel, full-circumference, flexible, 64-channel high-density electromyography (HD-EMG) sensor called EMaGer. The stretchable, wearable sensor adapts to different forearm sizes while maintaining uniform electrode density around the limb. Leveraging this uniformity, we propose novel array barrel-shifting data augmentation (ABSDA) approach used with a convolutional neural network (CNN), and an anti-aliased CNN (AA-CNN), that provides shift invariance around the limb for improved classification robustness to electrode movement, forearm orientation, and inter-session variability. Signals are sampled from a 4×16 HD-EMG array of electrodes at a frequency of 1 kHz and 16-bit resolution. Using data from 12 non-amputated participants, the approach is tested in response to sensor rotation, forearm rotation, and inter-session scenarios. The proposed ABSDA-CNN method improves inter-session accuracy by 25.67% on average across users for 6 gesture classes compared to conventional CNN classification. A comparison with other devices shows that this benefit is enabled by the unique design of the EMaGer array. The AA-CNN yields improvements of up to 63.05% accuracy over non-augmented methods when tested with electrode displacements ranging from -45 ° to +45 ° around the limb. Overall, this article demonstrates the benefits of co-designing sensor systems, processing methods, and inference algorithms to leverage synergistic and interdependent properties to solve state-of-the-art problems.


Kinetics of calcium channel opening by inositol 1,4,5-trisphosphate.
The subsecond mobilization of intracellular Ca2+ by IP3 was measured with rapid mixing techniques to determine how cells achieve rapid rises in cytosolic [Ca2+] during receptor-triggered calcium spiking. In permeabilized rat basophilic leukemia cells at 11 degrees C, more than 80% of the 0.7 fmol of Ca2+/cell sequestered by the ATP-driven pump could be released by IP3. Half of the stored Ca2+ was released within 200 ms after addition of saturating (1 microM) IP3. The flux rate was half-maximal at 120 nM IP3. Ca2+ release from fully loaded stores was highly cooperative; the Hill coefficient over the 2-40 nM range was greater than 3. The delay time of channel opening was inversely proportional to [IP3], increasing from 150 ms at 100 nM IP3 to 1 s at 15 nM, indicating that the rate-limiting step in channel opening is IP3 binding. Multiple binding steps are required to account for the observed delay and nonexponential character of channel opening. A simple model is proposed in which the binding of four IP3 molecules to identical and independent sites leads to channel opening. The model agrees well with the data for KD = 18 nM, kon = 1.2 X 10(8) M-1 s-1, and koff = 2.2 s-1. The approximately 1-s exchange time of bound IP3 indicates that the channel gating sites are distinct from binding sites having approximately 100-s exchange times that were previously found with radiolabeled IP3. The approximately 1-1s response time of [Ca2+] to a rapid increase in IP3 level can account for observed rise times of calcium spikes.


Dual dimensionality reduction reveals independent encoding of motor features in a muscle synergy for insect flight control.
What are the features of movement encoded by changing motor commands? Do motor commands encode movement independently or can they be represented in a reduced set of signals (i.e. synergies)? Motor encoding poses a computational and practical challenge because many muscles typically drive movement, and simultaneous electrophysiology recordings of all motor commands are typically not available. Moreover, during a single locomotor period (a stride or wingstroke) the variation in movement may have high dimensionality, even if only a few discrete signals activate the muscles. Here, we apply the method of partial least squares (PLS) to extract the encoded features of movement based on the cross-covariance of motor signals and movement. PLS simultaneously decomposes both datasets and identifies only the variation in movement that relates to the specific muscles of interest. We use this approach to explore how the main downstroke flight muscles of an insect, the hawkmoth Manduca sexta, encode torque during yaw turns. We simultaneously record muscle activity and turning torque in tethered flying moths experiencing wide-field visual stimuli. We ask whether this pair of muscles acts as a muscle synergy (a single linear combination of activity) consistent with their hypothesized function of producing a left-right power differential. Alternatively, each muscle might individually encode variation in movement. We show that PLS feature analysis produces an efficient reduction of dimensionality in torque variation within a wingstroke. At first, the two muscles appear to behave as a synergy when we consider only their wingstroke-averaged torque. However, when we consider the PLS features, the muscles reveal independent encoding of torque. Using these features we can predictably reconstruct the variation in torque corresponding to changes in muscle activation. PLS-based feature analysis provides a general two-sided dimensionality reduction that reveals encoding in high dimensional sensory or motor transformations.


Wastewater and marine bioindicators surveillance to anticipate COVID-19 prevalence and to explore SARS-CoV-2 diversity by next generation sequencing: One-year study.
This study presents the results of SARS-CoV-2 surveillance in sewage water of 11 municipalities and marine bioindicators in Galicia (NW of Spain) from May 2020 to May 2021. An integrated pipeline was developed including sampling, pre-treatment and biomarker quantification, RNA detection, SARS-CoV-2 sequencing, mechanistic mathematical modeling and forecasting. The viral load in the inlet stream to the wastewater treatment plants (WWTP) was used to detect new outbreaks of COVID-19, and the data of viral load in the wastewater in combination with data provided by the health system was used to predict the evolution of the pandemic in the municipalities under study within a time horizon of 7 days. Moreover, the study shows that the viral load was eliminated from the treated sewage water in the WWTP, mainly in the biological reactors and the disinfection system. As a result, we detected a minor impact of the virus in the marine environment through the analysis of seawater, marine sediments and, wild and aquacultured mussels in the final discharge point of the WWTP.


A mechanism linking extra centrosomes to chromosomal instability.
Chromosomal instability (CIN) is a hallmark of many tumours and correlates with the presence of extra centrosomes. However, a direct mechanistic link between extra centrosomes and CIN has not been established. It has been proposed that extra centrosomes generate CIN by promoting multipolar anaphase, a highly abnormal division that produces three or more aneuploid daughter cells. Here we use long-term live-cell imaging to demonstrate that cells with multiple centrosomes rarely undergo multipolar cell divisions, and the progeny of these divisions are typically inviable. Thus, multipolar divisions cannot explain observed rates of CIN. In contrast, we observe that CIN cells with extra centrosomes routinely undergo bipolar cell divisions, but display a significantly increased frequency of lagging chromosomes during anaphase. To define the mechanism underlying this mitotic defect, we generated cells that differ only in their centrosome number. We demonstrate that extra centrosomes alone are sufficient to promote chromosome missegregation during bipolar cell division. These segregation errors are a consequence of cells passing through a transient 'multipolar spindle intermediate' in which merotelic kinetochore-microtubule attachment errors accumulate before centrosome clustering and anaphase. These findings provide a direct mechanistic link between extra centrosomes and CIN, two common characteristics of solid tumours. We propose that this mechanism may be a common underlying cause of CIN in human cancer.


[Functional tests for the assessment of the healthy people state using heart rate variabilIty].
An overview of current approaches to interpreting the results of spectral analysis of heart rate variability and blood pressure is demonstrated. The analysis of own obtained results were done using the method of assessment of heart rate variability and blood pressure in a variety of functional tests (mental load, moderate exercise, cold test, the restriction of pulmonary ventilation, controlled breathing at a frequency of 6 cycles per minute) in healthy adults. It was shown that all tests induced pronounced changes in the spectral indices of heart rate variability as well as the blood pressure, which were interpreted as changes in the state of autonomous regulation of subject's cardiovascular system. The direction and the degree of changes depend on the form of action.


Benzoylurea pesticides used as veterinary medicines in aquaculture: Risks and developmental effects on nontarget crustaceans.
Diflubenzuron and teflubenzuron are benzoylureas that are used in aquaculture to control sea lice. Flubenzurons have low toxicity to many marine species such as fish and algae but by their nature are likely to have significant adverse effects on nontarget species such as crustaceans and amphipods. Although the exact mechanism of toxicity is not known, these compounds are thought to inhibit the production of the enzyme chitin synthase during molting of immature stages of arthropods. These chitin synthesis inhibitors are effective against the larval and pre-adult life stages of sea lice. Due to their low solubility and results of recent monitoring studies conducted in Norway, the sediment compartment is considered the most likely reservoir for these compounds and possible remobilization from the sediment to benthic crustaceans could be of importance. For this reason, the epibenthic copepod Tisbe battagliai was selected for investigations into the acute and developmental effects of these compounds. For comparative purposes, azamethiphos was investigated to identify differences in sensitivity and act as a negative control for developmental effects at environmentally relevant concentrations. Standard acute studies with adult copepods showed little or no acute toxicity at milligrams per liter levels with the flubenzurons, whereas a naupliar developmental test demonstrated that environmentally relevant concentrations (e.g., nanograms per liter) caused a complete cessation of molting and finally death in the exposed copepods.


Fatty acid synthase expression and its association with clinico-histopathological features in triple-negative breast cancer.
Triple-Negative Breast Cancer (TNBC) has poor prognosis and no approved targeted therapy. We previously showed that the enzyme fatty acid synthase (FASN) was largely expressed in a small TNBC patients' cohort and its inhibition synergized with cetuximab in TNBC preclinical mouse models. Here, we evaluated FASN and EGFR expression in a cohort of TNBC patients and we study their prognostic role and their association with clinico-histopathological features, intrinsic TNBC subtypes and survival. FASN, EGFR, CK5/6 and vimentin expression were retrospective evaluated by Immunohistochemistry in 100 primary TNBC tumors. FASN expression was classified into high and low FASN groups. EGFR, CK5/6 and vimentin expression were used in TNBC intrinsic subtypes classification. FASN was expressed in most of the TNBC patients but did not correlate with overall survival or disease-free survival in this cohort. High FASN group was significantly associated with positive node status. FASN expression was significantly higher in Basal-Like patients than in Mesenchymal-Like ones. EGFR expression was positive in 50% of the tumors, and those patients showed poorer DFS. Altogether, our findings provide a rationale for further investigation the prognostic role of FASN and EGFR expression in a larger cohort of TNBC patients.


Clinical Observation on the Improvement of Serum Sex Hormone and Ovarian Function in Premature Ovarian Failure Patients with Deficiency-Cold Syndrome by Combining Wenjing Decoction with Tiaobu Chongren Acupuncture and Moxibustion.
To explore the effect of Wenjing Decoction and Tiaobu Chongren acupuncture and moxibustion therapy on serum sex hormones and ovarian function recovery in premature ovarian failure (POF) patients with deficiency-cold syndrome. From February 2018 to October 2019, 119 POI patients with deficiency-cold syndrome who met the selection criteria were randomly divided into the control group (n = 59) and the observation group (n = 60). The control group was treated with hormone replacement therapy, and the observation group was treated with Wenjing Decoction and Tiaobu Chongren acupuncture and moxibustion therapy on the basis of the control group. Both groups were treated continuously for 3 months. After treatment, the clinical efficacy of the two groups was compared, the Chinese medicine syndrome score, serum estradiol (E 2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-mullerian hormone (AMH) and bilateral antral follicle count (AFC), mean ovarian volume, and endometrial thickness of the two groups before and after treatment were compared. The effective rate of the observation group (93.10%) was higher than that of the control group (77.59%) (P < 0.05). After treatment, the index scores of traditional Chinese medicine syndromes in two groups were lower than before (P < 0.05), and the observation group was lower than the control group (P < 0.05). The serum E 2 and AMH levels in the two groups increased, while FSH and LH levels decreased compared with before treatment, and the observation group improved significantly compared with the control group (P < 0.05). The bilateral AFC, mean ovarian volume, and endometrial thickness of the two groups increased compared with before treatment, and the observation group was higher than the control group (P < 0.05). On the basis of hormone replacement therapy, the combination of Wenjing Decoction and Tiaobu Chongren acupuncture and moxibustion therapy is effective in treating POF patients with deficiency-cold syndrome, which can effectively regulate their serum sex hormone levels and promote the recovery of ovarian function.


Why fat taxes won't make us thin.
Increasing prevalence of overweight and obesity has led policy-makers to consider health-related taxes to limit the consumption of unhealthy foods and beverages. Such taxes are currently already in place in countries in Europe (e.g. Hungary, France and Finland) and in various states in the USA. Although these taxes are possibly efficient in reducing by a small amount the consumption of targeted products if the tax is fully transmitted to the consumer, there is too little available evidence on what will be consumed instead and whether these food substitutions undermine the hoped-for health benefits of the tax. We also know very little on how the food supply side will respond and what overall impact this will have. Without a proper appreciation of the potential indirect impacts we do not know the overall impact of taxes foods on unhealthy foods and beverages and further that there is a very real possibility that they may not be beneficial for health after all.


Cell growth inhibition upon deletion of four toxin-antitoxin loci from the megaplasmids of Sinorhizobium meliloti.
Toxin and antitoxin (TA) gene pairs are addiction systems that are present in many microbial genomes. Sinorhizobium meliloti is an N2-fixing bacterial symbiont of alfalfa and other leguminous plants, and its genome consists of three large replicons, a circular chromosome (3.7 Mb) and the megaplasmids pSymA (1.4 Mb) and pSymB (1.7 Mb). S. meliloti carries 211 predicted type II TA genes, each encoding a toxin or an antitoxin. We constructed defined deletion strains that collectively removed the entire pSymA and pSymB megaplasmids except for their oriV regions. Of approximately 100 TA genes on pSymA and pSymB, we identified four whose loss was associated with cell death or stasis unless copies of the genes were supplied in trans. Orthologs of three of these loci have been characterized in other organisms (relB/E [sma0471/sma0473], Fic [DOC] [sma2105], and VapC [PIN] [orf2230/sma2231]), and this report contains the first experimental proof that RES/Xre (smb21127/smb21128) loci can function as a TA system. Transcriptome sequencing (RNA-seq) analysis did not reveal transcriptional differences between the TA systems to account for why deletion of the four "active" systems resulted in cell toxicity. These data suggest that severe cell growth phenotypes result from the loss of a few TA systems and that loss of most TA systems may result in more subtle phenotypes. These four TA systems do not appear to play a direct role in the S. meliloti-alfalfa symbiosis, as strains lacking these TA systems had a symbiotic N2 fixation phenotype that was indistinguishable from the wild type.


A dendritically amplified fluorescent signal probe on SiO2 microspheres for the ultrasensitive detection of mercury ions.
In this work, a new kind of dendritically amplified fluorescent signal probe on SiO2 microspheres was controllably fabricated by the terminal deoxynucleotidyl transferase (TdT)-catalyzed incorporation of nucleotides combined with bio-barcode (BBC) amplification for the ultrasensitive detection of Hg2+. A thymine T-Hg2+-T hairpin structure was first formed and further initiated the strand displacement amplification (SDA) reaction, generating a mimic target (MT). MT hybridized with a capture probe 1 (C1) on SiO2 microspheres, and the 3'-hydroxyl (OH) termini of MT initiated TdT-based DNA extension, producing abundant poly-guanine sequences (G1). Then, G1 hybridized with a capture probe 2 (C2) with abundant cytosine (C) species to assemble multiple C2/reporter probe-AuNPs onto the SiO2 microspheres. The reporter DNA further initiated TdT-based extension with a poly-T sequence (T1) to link large numbers of signal probes, which generated a very high fluorescence signal for the ultrasensitive detection of target Hg2+. This TdT-based signal amplification method coupled with SDA exhibits extraordinary sensitivity for Hg2+ assay with a limit down to 1.0 aM. The proposed highly sensitive fluorescence strategy holds great potential for detecting targets in environmental and biological fields.


Activation of PPARgamma coactivator-1 through transcription factor docking.
Transcriptional coactivators have been viewed as constitutively active components, using transcription factors mainly to localize their functions. Here, it is shown that PPARgamma coactivator-1 (PGC-1) promotes transcription through the assembly of a complex that includes the histone acetyltransferases steroid receptor coactivator-1 (SRC-1) and CREB binding protein (CBP)/p300. PGC-1 has a low inherent transcriptional activity when it is not bound to a transcription factor. The docking of PGC-1 to peroxisome proliferator-activated receptor gamma (PPARgamma) stimulates an apparent conformational change in PGC-1 that permits binding of SRC-1 and CBP/p300, resulting in a large increase in transcriptional activity. Thus, transcription factor docking switches on the activity of a coactivator protein.


Tafazzin deficiency impairs mitochondrial metabolism and function of lipopolysaccharide activated B lymphocytes in mice.
B lymphocytes are responsible for humoral immunity and play a key role in the immune response. Optimal mitochondrial function is required to support B cell activity during activation. We examined how deficiency of tafazzin, a cardiolipin remodeling enzyme required for mitochondrial function, alters the metabolic activity of B cells and their response to activation by lipopolysaccharide in mice. B cells were isolated from 3-month-old wild type or tafazzin knockdown mice and incubated for up to 72 h with lipopolysaccharide and cell proliferation, expression of cell surface markers, secretion of antibodies and chemokines, proteasome and immunoproteasome activities, and metabolic function determined. In addition, proteomic analysis was performed to identify altered levels of proteins involved in survival, immunogenic, proteasomal and mitochondrial processes. Compared to wild type lipopolysaccharide activated B cells, lipopolysaccharide activated tafazzin knockdown B cells exhibited significantly reduced proliferation, lowered expression of cluster of differentiation 86 and cluster of differentiation 69 surface markers, reduced secretion of immunoglobulin M antibody, reduced secretion of keratinocytes-derived chemokine and macrophage-inflammatory protein-2, reduced proteasome and immunoproteasome activities, and reduced mitochondrial respiration and glycolysis. Proteomic analysis revealed significant alterations in key protein targets that regulate cell survival, immunogenicity, proteasomal processing and mitochondrial function consistent with the findings of the above functional studies. The results indicate that the cardiolipin transacylase enzyme tafazzin plays a key role in regulating mouse B cell function and metabolic activity during activation through modulation of mitochondrial function.


An anatomico-radiological study of the grooves for occipital sinus in the posterior cranial fossa.
The occipital sinus (OS) lies in the attached margin of the faix cerebelli in the internal occipital crest of the occipital bone. The OS extends from the foramen magnum to the confluence of sinuses. Standard textbooks and research reports do not describe in detail any variation in the groove for the occipital sinus. In the present study, we examined a total of 50 human dried skulls for the groove of OS and its possible variations. We also performed an osteological study supplemented with digital X ray and CT scan. Out of 50 skull specimens, a single case with two grooves for OS was observed (2%). The two grooves for OS traversed as two limbs from the foramen magnum to join the other at the internal occipital protuberance. An accessory faint groove was also found at the lateral aspect of the left limb. Interestingly, in the same specimen, the superior sagittal sinus instead of continuing as right transverse sinus, continued as left transverse sinus. The X ray and CT scan of the anomalous bone specimen were compared to those of the normal bone specimen. To the best of our knowledge, this is the first anatomico-radiological study of multiple OS groove with associated anomalies. Surgeons should be aware of the variations of the OS in order to check any inadvertent injury during skull surgeries. Presence of such variations may also result in erroneous interpretation of radiological findings (Tab. 1, Fig. 7, Ref. 17).


Differential distribution and function of hyperpolarization-activated channels in sensory neurons and mechanosensitive fibers.
Sensory neurons express hyperpolarization-activated currents (I(H)) that differ in magnitude and kinetics within the populations. We investigated the structural basis for these differences and explored the functional role of the I(H) channels in sensory neurons isolated from rat nodose ganglia. Immunohistochemical studies demonstrated a differential distribution of hyperpolarization-activated cyclic nucleotide-gated (HCN) protein (HCN1, HCN2, HCN4) in sensory neurons and peripheral terminals. HCN2 and HCN4 immunoreactivity was present in all nodose neurons. In contrast, only 20% of the total population expressed HCN1 immunoreactivity. HCN1 did not colocalize with IB4 (a marker for C-type neurons), and only 15% of HCN1-positive neurons colocalized with immunoreactivity for the vanilloid receptor VR1, another protein associated primarily with C-type neurons. Therefore, most HCN1-containing neurons were A-type neurons. In further support, HCN1 was present in the mechanosensitive terminals of myelinated but not unmyelinated sensory fibers, whereas HCN2 and HCN4 were present in receptor terminals of both myelinated and unmyelinated fibers. In voltage-clamp studies, cell permeant cAMP analogs shifted the activation curve for I(H) to depolarized potentials in C-type neurons but not A-type neurons. In current-clamp recording, CsCl, which inhibits only I(H) in nodose neurons, hyperpolarized the resting membrane potential from -63 +/- 1 to -73 +/- 2 mV and nearly doubled the input resistance from 1.3 to 2.2 GOmega. In addition, action potentials were initiated at lower depolarizing current injections in the presence of CsCl. At the sensory receptor terminal, CsCl decreased the threshold pressure for initiation of mechanoreceptor discharge. Therefore, elimination of the I(H) increases excitability of both the soma and the peripheral sensory terminals.


Hyperglycemic Hyperosmolar State During Induction Chemotherapy for Acute Lymphoblastic Leukemia.
We present the case of a 16-year-old boy who presented with fatigue, polyuria, and polydipsia while on chemotherapy for his relapsed acute lymphoblastic leukemia (ALL). Blood gas examination confirmed the diagnosis of hyperosmolar hyperglycemic state. The etiology for his hyperglycemia was most likely a result of oral glucocorticoid therapy combined with asparaginase therapy-both are a cornerstone of induction chemotherapy for ALL. The patient was aggressively rehydrated with saline, and medications were administered to correct his hyperkalemia. He was then slowly brought to euglycemia with a continuous infusion of insulin. Although hyperosmolar hyperglycemic state is rare during the treatment of ALL, frontline providers should be aware of this diagnosis because of the significant risk of hypovolemic shock and death if correction of hyperglycemia occurs prior to complete fluid resuscitation.


Digoxin in patients with permanent atrial fibrillation: data from the RACE II study.
The Atrial Fibrillation Follow-up Investigation of Rhythm Management trial showed that digoxin was associated with increased mortality in patients with atrial fibrillation. To assess the association of digoxin with cardiovascular (CV) morbidity and mortality in patients with permanent atrial fibrillation enrolled in the Dutch Rate Control Efficacy in Permanent AF: A Comparison Between Lenient Versus Strict Rate Control II trial as well as to assess the role of digoxin to achieve heart rate targets. The primary outcome was a composite of CV morbidity and mortality. Secondary outcomes included CV hospitalization and all-cause mortality or heart failure (HF) hospitalization. Of the 614 patients, 608 (99%) completed the dose-adjustment phase. Outcome events were analyzed from the end of the dose-adjustment phase until the end of follow-up. The median follow-up period was 2.9 years (interquartile range 2.7-3.0 years). In total, 284 patients (46.7%) used digoxin after the dose-adjustment phase (median dosage 0.250 mg; interquartile range 0.0625-0.750 mg). These patients were more often women, previously admitted for HF, had an increased left ventricular end-systolic diameter, and more often randomized to strict rate control. By using Cox proportional hazards regression analysis, the use of digoxin was not associated with an increased risk for the primary and secondary outcomes. For the primary outcome, the 3-year estimated cumulative incidence was 12.9% vs 13.4% in the digoxin group vs the no-digoxin group (unadjusted hazard ratio [HR] 0.97; 95% confidence interval [CI] 0.62-1.52). Incidence was 19.4% vs. 19.5% for CV hospitalization (unadjusted HR 1.00; 95% CI 0.69-1.45) and 6.6% vs. 9.9% for all-cause mortality or HF hospitalization (unadjusted HR 0.62; 95% CI 0.34-1.13) in the digoxin group vs the no-digoxin group. The use of digoxin was not associated with increased morbidity and mortality.


Treatment of schistosomiasis-associated pulmonary hypertension.
Schistosomiasis mansoni is the third most prevalent endemic parasitic disease in the world. It is estimated that over 200 million people are infected with parasites belonging to one of the Schistosoma species. Of those, 270,000 people (4.6%) suffer from pulmonary arterial hypertension, which is associated with the hepatosplenic form of the disease. This high prevalence makes schistosomiasis-associated pulmonary hypertension the leading cause of pulmonary hypertension worldwide. However, no specific treatment for the pulmonary vascular component of the disease has yet been devised. We report the case of a patient with schistosomiasis-associated pulmonary hypertension who was treated satisfactorily with a phosphodiesterase-5 inhibitor (sildenafil).


Role of Crystallization in the Morphology of Polymer:Non-fullerene Acceptor Bulk Heterojunctions.
Many high efficiency organic photovoltaics use fullerene-based acceptors despite their high production cost, weak optical absorption in the visible range, and limited synthetic variability of electronic and optical properties. To circumvent this deficiency, non-fullerene small-molecule acceptors have been developed that have good synthetic flexibility, allowing for precise tuning of optoelectronic properties, leading to enhanced absorption of the solar spectrum and increased open-circuit voltages (VOC). We examined the detailed morphology of bulk heterojunctions of poly(3-hexylthiophene) and the small-molecule acceptor HPI-BT to reveal structural changes that lead to improvements in the fill factor of solar cells upon thermal annealing. The kinetics of the phase transformation process of HPI-BT during thermal annealing were investigated through in situ grazing incidence wide-angle X-ray scattering studies, atomic force microscopy, and transmission electron microscopy. The HPI-BT acceptor crystallizes during film formation to form micron-sized domains embedded within the film center and a donor rich capping layer at the cathode interface reducing efficient charge extraction. Thermal annealing changes the surface composition and improves charge extraction. This study reveals the need for complementary methods to investigate the morphology of BHJs.