Clozapine, ziprasidone and aripiprazole but not haloperidol protect against kainic acid-induced lesion of the striatum in mice, in vivo: role of 5-HT1A receptor activation.
Excessive activation of non-NMDA receptors, AMPA and kainate, contributes to neuronal degeneration in acute and progressive pathologies, possibly including schizophrenia. Because 5-HT(1A) receptor agonists have neuroprotective properties (e.g., against NMDA-induced neurotoxicity), we compared the effects of the antipsychotics, clozapine, ziprasidone and aripiprazole, that are partial agonists at 5-HT(1A) receptor, with those of haloperidol, which is devoid of 5-HT(1A) agonist properties, on kainic acid (KA)-induced striatal lesion volumes, in C57Bl/6N mice. The involvement of 5-HT(1A) receptors was determined by antagonist studies with WAY100635, and data were compared with those obtained using the potent and high efficacy 5-HT(1A) receptor agonist, F13714. Intra-striatal KA lesioning and measurement of lesion volumes using cresyl violet staining were carried out at 48 h after surgery. F13714, antipsychotics or vehicle were administered ip twice, 30 min before and 3 1/2 h after KA injection. WAY100635 (0.63 mg/kg) or vehicle were given sc 30 min before each drug injection. Clozapine (2 x 10 mg/kg), ziprasidone (2 x 20 mg/kg) and aripiprazole (2 x 10 mg/kg) decreased lesion volume by 61%, 59% and 73%, respectively. WAY100635 antagonized the effect of ziprasidone and of aripiprazole but only slightly attenuated that of clozapine. In contrast, haloperidol (2 x 0.16 mg/kg) did not affect KA-induced lesion volume. F13714 dose-dependently decreased lesion volume. The 61% decrease of lesion volume obtained with F13714 (2 x 0.63 mg/kg) was antagonized by WAY100635. WAY100635 alone did not affect lesion volume. These results show that 5-HT(1A) receptor activation protects against KA-induced striatal lesions and indicate that some atypical antipsychotic agents with 5-HT(1A) agonist properties may protect against excitotoxic injury, in vivo.


Aspirin acts in esophageal cancer: a brief review.
Improved survival in esophageal cancer patients with regular aspirin use have been reported. However, with conflicting experimental results existed, an explicit definition on the role of aspirin as an adjuvant chemotherapy of esophageal cancer remains unestablished. We have summarized the current epidemiologic trials evidence over antitumor effect of aspirin in esophageal cancer in the past decades, and most of the clinical data supports that long-term regular aspirin use could reduce the mortality and improve the survival in patients with esophageal cancer. Although most of the clinical trials of aspirin on esophageal cancer are designed focusing on the prediagnosed chemo-preventive role, other than the post-diagnosed therapeutic role, it has been suggested by some studies that aspirin use as an adjuvant treatment after the standard surgery in esophageal cancer may benefit more. In the meanwhile, post diagnosed aspirin use may lead to lower risk of hemorrhage and other side effects of NSAIDs. Potential involved molecular pathways in the antitumor activities of aspirin are under studied worldwide for years and the possible mechanisms so far are reviewed in this article as cyclooxygenase (COX)-dependent pathways and COX-independent pathways, involving anti-inflammatory activity, apoptosis, platelet deactivation, PIK3CA mutation specificity and heparanase-related microenvironment changes of tumor cells. NOSH-aspirin has been developed as a succedaneum of aspirin with a wider application ranges by reducing the risk of hemorrhage in aspirin users. Further clinical and basic studies are suggested focusing on whether regular aspirin use as an adjuvant treatment prolongs survival and prevents recurrence in patients with esophageal cancer.


Analysis of T cell subsets present in the peripheral blood and synovial fluid of reactive arthritis patients.
Reactive arthritis (ReA), a HLA-B27 associated arthropathy, develops in susceptible people after infection with certain bacteria. T cells have been implicated in the pathogenesis of the arthritis but which of the different subsets is involved is still debated. This study has further elucidated the role of the CD4+ and CD8+ T cells by examining the expression of various surface markers associated with activation. Three colour flow cytometry was used to examine the phenotype of the T cells within the synovial fluid (SF) and peripheral blood (PB) of ReA patients. ReA SF, compared with paired PB, contained a higher percentage of CD69+, CD25+, and HLA-DR+ CD3+ T cells. The majority of SF T cells also expressed the putative memory marker CD45RO. Within the T cell subsets, CD25 was expressed primarily on the CD4+ T cells; however more CD8+ T cells were HLA-DR+. The results show that both CD4+ and CD8+ T cell populations demonstrate evidence of recent activation. Whether these cells are involved in inducing inflammation, regulating the inflammation, or have become active as a result of migration through the endothelium, remains to be determined by functional studies.


Giant prolactinoma: case report and review of literature.
"Invasive giant prolactinoma" is a large prolactinoma (>4 cm in dimension) presenting with serum prolactin levels of >1000 ng/dL and mass related clinical symptoms. Here we report a patient with a giant prolactinoma presented with central hypogonadism, suppressed adrenal and thyroid function, supra sellar extension, visual field impairment and high prolactin level.The patient was treated with cabergoline, levothyroxin and prednisolone. After 18 months, tumor size markedly reduced, associated with adrenal function and visual field improvement, but central hypogonadism and secondary hypothyroidism persisted.Previous studies showed normalization of thyrotropin secretion after treatment but it remained low in our patient even after 18 months follow up.


Osteopontin-mediated enhanced hyaluronan binding induces multidrug resistance in mesothelioma cells.
Malignant pleural mesothelioma (MPM) is resistant to chemotherapy and thus shows a dismal prognosis. Osteopontin (OPN), a secreted noncollagenous and phosphoprotein, is suggested to be involved in the pathogenesis of MPM. However, the precise role of OPN, especially in the multidrug resistance of MPM, remains to be elucidated. We therefore established stable transfectants (ACC-MESO-1/OPN), which constitutively express OPN, to determine its role in the chemoresistance observed in MPM. The introduction of the OPN gene provides MPM cells with upregulated multidrug resistance through the mechanism of enhanced hyaluronate (HA) binding. The expression of CD44 variant isoforms, which inhibit HA binding, significantly decreased in ACC-MESO-1/OPN cells in comparison to control transfectants. Interestingly, the inhibition of the HA-CD44 interaction abrogated multidrug resistance in the ACC-MESO-1/OPN, thus suggesting the involvement of the surviving signal emanating from the HA-CD44 interaction. An enhanced level of the p-Akt in ACC-MESO-1/OPN cells was observed, and was diminished by CD44 siRNA. Inhibition of the Akt phosphorylation increased in number of the cells underwent apoptosis induced by NVB, VP-16 and GEM. Collectively, these results indicate that OPN is strongly involved in multidrug resistance by enhancing the CD44 binding to HA.


Race, everyday discrimination, and cognitive function in later life.
Discrimination is pernicious in many ways, but there are inconsistent findings regarding whether it is harmful to cognitive function in later life. To address the inconsistency, we use two closely related concepts of everyday discrimination to predict cognitive trajectories in a diverse sample. Using data from the Health and Retirement Study (HRS), we examine whether the frequency of discrimination, measured at baseline with six questions, is related to poorer cognitive function and change in function over time (2008-2016). Age at baseline ranged from 53 to 100. Growth curve models of initial cognitive function and change in function were estimated. Everyday global discrimination was associated with poorer initial cognition and slower declines over time, and these relationships were not moderated by race and ethnicity. By contrast, the relationship between everyday racial discrimination and cognition was moderated by race: more frequent everyday racial discrimination was associated with better initial cognitive function among Black adults but not among Hispanic and White adults. Discrimination is a multifaceted concept, and specific types of discrimination manifest lower or higher cognitive function during later life for White, Black, and Hispanic adults.


Can NMDA Spikes Dictate Computations of Local Networks and Behavior?
Intelligence is the ability to learn appropriate responses to stimuli and the capacity to master new skills. Synaptic integration at the dendritic level is thought to be essential for this ability through linear and non-linear processing, by allowing neurons to be tuned to relevant information and to maximize adaptive behavior. Showing that dendrites are able to generate local computations that influence how animals perceive the world, form a new memory or learn a new skill was a break-through in neuroscience, since in the past they were seen as passive elements of the neurons, just funneling information to the soma. Here, we provide an overview of the role of dendritic integration in improving the neuronal network and behavioral performance. We focus on how NMDA spikes are generated and their role in neuronal computation for optimal behavioral output based on recent in vivo studies on rodents.


Paper based SERS aptasensor towards dual-modal detection of interferon gamma.
Interferon gamma (IFN-γ), can serve as an active diagnostic biomarker of a broad spectrum of diseases such as auto inflammatory disease, viral and bacterial, parasites infections, and tumor control. The low physiological concentration of IFN-γ at pg‧mL-1 level for most diseases such as tuberculosis and lung cancer demand highly sensitive and selective detection methods. To achieve the goal, a novel paper-based SERS aptasensor towards rapid, dual-modal (visual and ultrasensitive) detection of IFN-γ is presented for the first time. A lateral flow platform with low-cost and user-friendly format in this study is adopted. The detection relies on the competition of the specific aptamer sequence of IFN-γ between its complementary DNA in the test line and IFN-γ in the sample solution. The presence of IFN-γ can be easily observed in the test line by naked eye and detected at pg‧mL-1 level by a portable Raman spectrometer. Linear detection range of 10-2000 pg‧mL-1 could be obtained with detection limit of 8.7 pg‧mL-1. In addition, as low as 10 pg/mL of IFN-γ in human serum could be detected, which is comparable with the results from ELISA.Clinical Relevance- This study establishes a simple, rapid, and low-cost assay for dual-modal detection of IFN-γ, which is in urgent demand in clinics especially vitally important in resource-limited areas.


[Cancer research program performed by surgeons invade the biology field - from dormancy to metastasis].
Cancer research program was analyzed. This research was identified using the "master of science in surgery" performed by the majority of surgical resident and fellow. It was analyzed as three axes studying: (i) how to improve the technical practice; (ii) the contribution of surgical skills in basic research, in particular via orthotopic animal models as microenvironment; and (iii) the research in basic biology, testing hypotheses and strategies not confined to surgery but totally multidisciplinary. This research is active with more than half of the fellowships grant in urology sponsored via the French Urologist Association, for projects studying cancer and more than a third of subjects pertaining to the master oncology.


[Changes in serum lipids, plasma fibrinogen and other haemostatic parameters induced by ciprofibrate action in hyperlipidemic patients with and without coronary artery disease].
The effects of drugs with hypolipidemic properties in the prevention of the atherothrombotic vascular disease, go further than reducing serum lipids, suggesting that there are other nonlipid-related mechanisms involved; the maintenance of appropriate haemostatic balance being one of them. The objective of this investigation was a drug intervention with ciprofibrat in hyperlipidemic people with high level of plasmatic fibrinogen with the purpose of knowing the effects of the drug over these risk factors and other haemostatic parameters. Forty people, both sexes, 20 of them apparently healthy and the other 20 with clinical and angiographic evidence of coronary artery disease, were randomized to receive 100 mg of ciprofibrat or placebo during an average of 56 weeks. All of them had a clinical exam, EKG and stress test. Laboratory exams included lipid profile, plasma fibrinogen (Fg), VII factor, vonWillebrand factor, protein C (PC) and the tissue plasminogen activator with samples taken every 8 weeks. The Ciprofibrat group showed significant changes of lipids: cholesterol -23%, triglycerides -31%, high-density lipoprotein (HDLc) +24% and very low-density lipoprotein -23%, except low-density lipoprotein -24%. The haemostatic parameters in 40 weeks showed that Fg decreased 21% (p = 0.001), decreasing to 9% at the end of the follow-up. In the placebo group the HDLc showed a 10% increase (p = 0.02), PC reduced to 20% (p = 0.01) and Fg kept blood levels close to basal line, descending 10% at the end of the follow-up. In this study, the use of ciprofibrat in patients with high risk of developing atherothrombotic events, showed efficiency and security in handling hyperlipidemia, such as keeping and appropriate haemostatic balance.


[Video thoracoscopy and video-assisted thoracic surgery. An analysis of 303 consecutive cases].
To present our experience in video thoracoscopy and video-assisted thoracic surgery from November of 1991 until November of 1997. 303 endoscopic thoracic surgery procedures (210 males and 93 females with a mean age of 42.2 years) with the following indications: 151 spontaneous pneumothorax, 51 pulmonary biopsies, 50 pulmonary nodules, 15 mediastinal tumors, 13 pleuroparietal tumors, 8 pericardial windows and 15 thoracic sympathectomies. Mean postoperative stay was of 5.5 days. The thoracotomy conversion was necessary in 32 cases (10.9%). The morbimortality has been: one parietal recidive of a tumor in the way of one of the trocars and one death of a patient to who was accomplished a pulmonary biopsy by diffuse pneumopathy. The video thoracoscopy and thoracic surgery are effective and sure technical options for diagnosis and treatment of various thoracic affections.


Overtreating Alzheimer's Disease.
The management of frailty in older persons is not easy, implying interventions beyond the simple prescription of medications. Biological complexity, multimorbidity, polypharmacy, and social issues often hamper the possibility to directly translate the evidence coming from research into clinical practice. Frailty indeed represents the most relevant cause of the "evidence-based medicine issue" influencing clinical decisions in geriatric care. Today, patients with Alzheimer's disease (AD) are much older and frailer than some decades ago. They also tend to have more drugs prescribed. In parallel, research on AD has evolved over the years, hypothesizing that anticipating the interventions to the earliest stages of the disease may provide beneficial effects (to date, still lacking). In this article, we argue that, by focusing exclusively on "the disease" and pushing to anticipate its detection (sometimes even before the appareance of its clinical manifestations) may overshadow the person's values and priorities. Research should be developed for better integrating the concept of aging and frailty in the design of clinical trials in order to provide results that can be implemented in real life. On the other hand, clinicians should be less prone to the easy (but unsupported by evidence) pharmacological prescription.


FTY720-induced lymphocyte homing modulates post-transplant preservation/reperfusion injury.
A novel immunomodulator, FTY720, modulates lymphocyte migration to injured tissues via enhanced lymphocyte sequestration to secondary lymphoid organs. We tested whether or not single-dose FTY720 (0.5 mg/kg) pretreatment rescues renal grafts from post-transplant preservation/reperfusion injury. Rat renal grafts were cold-preserved in University of Wisconsin (UW) solution for 4 hours and then transplanted into syngeneic or allogeneic recipients that received a single dose of FTY720 24 hours before transplantation. Flow cytometry analysis of peripheral blood and lymph nodes was performed to confirm the biologic effect of FTY720. Grafts were harvested after 24 hours. Renal sections were examined histologically and stained for intracellular adhesion molecule-1 (ICAM-1), vascular cellular adhesion molecule-1 (VCAM-1), platelet endothelial cellular adhesion molecule-1 (PECAM-1), major histocompatibility complex (MHC) class II, and inflammatory cells. Interleukin-1 (IL-1) production was determined in renal protein extracts. FTY720 pretreatment significantly increased CD3+ T-cell sequestration to lymph nodes in the face of peripheral lymphopenia. Isografts and allografts from the FTY720-treated groups did not develop increased creatinine (0.55 +/- 0.12 in isografts and 0.62 +/- 0.08 mg/dL in allografts), compared with vehicle controls (2.28 +/- 0.20 in isografts and 2.24 +/- 0.18 mg/dL in allografts). Kidneys from FTY720-treated groups also showed lower acute tubular damage scores. Furthermore, FTY720 decreased neutrophil influx, although circulating neutrophils were unchanged. FTY720 also prevented postischemic IL-1 intragraft production not affecting infiltration with recipient ED-1+ macrophages and MHC class II-positive cells. Expression of ICAM-1, VCAM-1, and PECAM did not differ among groups. FTY720 ameliorated morphologic and functional consequences of post-transplant reperfusion injury. Thus, FTY720-induced peripheral T-cell absence may influence intragraft IL-1 production and neutrophil infiltration, despite proadhesive endothelial properties. FTY720 may broaden the utility in renal transplantation as a pretreatment strategy against preservation/reperfusion injury.


Thermostable adenosine 5'-monophosphate phosphorylase from Thermococcus kodakarensis forms catalytically active inclusion bodies.
Catalytically active inclusion bodies (CatIBs) produced in Escherichia coli are an interesting but currently underexplored strategy for enzyme immobilization. They can be purified easily and used directly as stable and reusable heterogenous catalysts. However, very few examples of CatIBs that are naturally formed during heterologous expression have been reported so far. Previous studies have revealed that the adenosine 5'-monophosphate phosphorylase of Thermococcus kodakarensis (TkAMPpase) forms large soluble multimers with high thermal stability. Herein, we show that heat treatment of soluble protein from crude extract induces aggregation of active protein which phosphorolyse all natural 5'-mononucleotides. Additionally, inclusion bodies formed during the expression in E. coli were found to be similarly active with 2-6 folds higher specific activity compared to these heat-induced aggregates. Interestingly, differences in the substrate preference were observed. These results show that the recombinant thermostable TkAMPpase is one of rare examples of naturally formed CatIBs.


Hepatoprotective effect of carob against acute ethanol-induced oxidative stress in rat.
The present study was undertaken to determine whether subacute treatment with aqueous extract of carob (Ceratonia siliqua L.) pods (AECPs) protects against ethanol (EtOH)-induced oxidative stress in rat liver. Animals were divided into four groups: control, carob, EtOH and EtOH + carob. Wistar rats were intraperitoneally pretreated with AECP (600 mg/kg body weight (bw)) during 7 days and intoxicated for 6 h by acute oral administration of EtOH (6 g/kg bw) 24 h after the last injection. We found that acute administration of EtOH leads to hepatotoxicity as monitored by the increase in the levels of hepatic marker aspartate aminotransferase and alanine aminotransferase as well as hepatic tissue injury. EtOH also increased the formation of malondialdehyde in the liver, indicating an increase in lipid peroxidation and depletion of antioxidant enzyme activities as superoxide dismutase, catalase and glutathione peroxidase. Subacute carob pretreatment prevented all the alterations induced by EtOH and returned their levels to near normal. Importantly, we showed that acute alcohol increased hepatic and plasmatic hydrogen peroxide and free iron levels. The carob pretreatment reversed EtOH effects to near control levels. These data suggest that carob could have a beneficial effect in inhibiting the oxidative damage induced by acute EtOH administration and that its mode of action may involve an opposite effect on plasma and tissue-free iron accumulation. Indeed, carob can be offered as a food additive to protect against EtOH-induced oxidative damage.


Ceftriaxone - a new broad-spectrum semisynthetic cephalosporin. In vitro activity against gram-negative bacilli sensitive and resistant to gentamicin.
Ceftriaxone (Rocephin 13-9904) was tested against 409 isolates of gram-negative bacilli. No difference was found in the susceptibility of the 262 gentamicin-sensitive or 147 gentamicin-resistant isolates to ceftriaxone. Comparison with other third-generation cephalosporins showed that ceftriaxone was as active as or more active than lamoxactam, cefoperazone, cefotaxime and ceftazidime against Escherichia coli, Proteus mirabilis, Proteus sp., Klebsiella. Ceftriaxone was not as active as ceftazidime against Pseudomonas aeruginosa, but was more active than lamoxactam, cefoperazone and cefotaxime.


Modulating Anxiety and Functional Capacity with Anodal tDCS Over the Left Dorsolateral Prefrontal Cortex in Primary Dysmenorrhea.
Primary dysmenorrhea is a common and often debilitating condition affecting 40-90% of menstruating women. This condition reduces functionality, quality of life, and social activities. Transcranial direct current stimulation (tDCS) has been used in many chronic pain syndromes, with evidence of improved pain, functionality, and mood in women with primary dysmenorrhea. The objective of this study was to determine whether tDCS could offer clinical benefits on pain, anxiety, affectivity, and functionality in women with primary dysmenorrhea. This parallel, sham, randomized, double-blind trial was conducted with 26 women randomized into sham tDCS and active tDCS. Anodal tDCS was applied for 5 consecutive days over F3 corresponding to the left dorsolateral prefrontal cortex (DLPFC) and the cathode electrode over Fp2 for 20 min with an intensity of 2 mA. A numeric rating scale (NRS) was used to assess pain, anxiety, positive and negative affect, and submaximal aerobic performance during two consecutive menstrual cycles. No significant interaction was found between intervention and time on the NRS [F(2,44) = 1.358, p = 0.26], and a significant main effect of time [F(2,44) = 4.446, p = 0.01] was found. The active group showed a significant reduction in anxiety (p = 0.03) with a mean difference of 5.12 (95% CI 0.79 to 11.05). No significant differences in positive and negative affect were found (p = 0.95 and p = 0.15, respectively). Submaximal aerobic performance was significantly greater in the active group [F(2,21) = 5.591, p = 0.02], with a mean difference of 70.87 (95% CI 8.53 to 133.21). Anodal tDCS over the DLPFC seems to be an effective therapeutic approach for improving anxiety and functionality in women with primary dysmenorrhea.


[Use of drugs for CNSLD (asthma and COPD) in Dutch residential homes and nursing homes].
Of the 1019 residents of eight dutch homes for the elderly and 699 patients of five nursing homes, respectively 6.0 and 8.1% were administered drugs for chronic non-specific lung disease (CNSLD), which is a term covering asthma as well as copd. The treatment consisted of, usually inhaled, beta-agonists and/or anti-cholinergics in 82%, inhaled as well as oral corticosteroids in 60%, and xanthine-derivates and N-acetylcysteïne, both of which were taken orally, in 28 and 21% of the patients respectively. It was found that almost half (47%) of the patients using inhaled drugs, which 90% of them did either with or without help, made at least three mistakes during inhalation. Considering that CSNLD is probably underdiagnosed, especially when it occurs as a cause of co-morbidity and will have an unfavourable influence on the general state of health by reducing lung function, the suboptimal application of inhaled drugs should be a cause of concern for those who treat elderly patients with asthma and or copd.


Limitations of the Millon Behavioral Medicine Diagnostic (MBMD) with bariatric surgical candidates.
In this paper, we critique the Millon Behavioral Medicine Diagnostic's (MBMD) psychometric characteristics for use with bariatric surgery patients. The reliability data presented by the test authors in their manual were examined. The results found 16 of 32 scales of have internal consistency reliability coefficients that do not meet minimal standards for use with bariatric populations. Of the remaining 16 scales, 13 do not have any compelling evidence that they are reliable. We suggest that if a test is not psychometrically reliable then its validity is called into question. Based on these data, 16 of the MBMD's 32 scales have inadequate reliability and 13 are lacking evidence of reliability. We urge clinicians to carefully consider these findings and the implications for their work with bariatric surgery patients.


Long-term follow-up of residual disease in acute lymphoblastic leukemia patients in complete remission using clonogeneic IgH probes and the polymerase chain reaction.
We sequentially studied bone marrow (BM) samples of 25 patients in complete remission of an acute lymphoblastic leukemia (ALL) using a simplified polymerase chain reaction (PCR) strategy (direct use of the PCR product as a clonogenic probe recognizing rearranged Ig heavy chain sequences) as a first approach. BM aspirates were serially investigated after obtention of a complete response. When sensitivity was less than 1:10(4), the PCR fragment was sequenced and a specific oligonucleotide was synthetized and used as a probe (five cases). Cases in which minimal residual disease (MRD) became undetectable were cross-controlled using either TCR delta rearrangement or a specific translocation to circumvent the problem of false-negative results arising from clonal evolution. The median follow-up was 30 months (3 to 51 months). Within the first 3 months of complete remission, MRD was detectable in 22 of 23 investigated patients and remained so in 19 of 21 patients examined at 6 months, regardless of the long-term clinical outcome. In patients remaining in complete remission at 30 months or more, two patterns of MRD emerged during the follow-up. Either it continuously decreased to ultimately become undetectable (five patients) or remained detectable (five patients) with an increase after discontinuation of treatment in two. In the eight patients who relapsed, MRD persisted throughout the clinical course, and eventually increased 3 to 12 months before relapse was clinically detectable. In one case, clonal evolution of the VDJ heavy chain region was observed and recurrence of MRD shown by the use of TCR delta rearrangement as a control. We conclude that the use of this simplified methodology is a valuable tool for the follow-up of MRD in a majority of ALL patients, though in a few cases, sequencing needs to be performed to achieve a relevant sensitivity. The possibility of clonal evolution requires a cross-control of any sample becoming negative whatever the initial rearrangement used to generate a probe. In patients on therapy, sequential search for MRD seems to be a good tool for predicting the long-term outcome. In addition, patients remaining positive at the time treatment is discontinued or with a high tumor burden after a few months therapy may be at a higher risk of subsequent relapse, although a longer follow-up is needed to answer this question.


Ternary nylon-3 copolymers as host-defense peptide mimics: beyond hydrophobic and cationic subunits.
Host-defense peptides (HDPs) are produced by eukaryotes to defend against bacterial infection, and diverse synthetic polymers have recently been explored as mimics of these natural peptides. HDPs are rich in both hydrophobic and cationic amino acid residues, and most HDP-mimetic polymers have therefore contained binary combinations of hydrophobic and cationic subunits. However, HDP-mimetic polymers rarely duplicate the hydrophobic surface and cationic charge density found among HDPs ( Hu , K. ; et al. Macromolecules 2013 , 46 , 1908 ); the charge and hydrophobicity are generally higher among the polymers. Statistical analysis of HDP sequences ( Wang , G. ; et al. Nucleic Acids Res. 2009 , 37 , D933 ) has revealed that serine (polar but uncharged) is a very common HDP constituent and that glycine is more prevalent among HDPs than among proteins in general. These observations prompted us to prepare and evaluate ternary nylon-3 copolymers that contain a modestly polar but uncharged subunit, either serine-like or glycine-like, along with a hydrophobic subunit and a cationic subunit. Starting from binary hydrophobic-cationic copolymers that were previously shown to be highly active against bacteria but also highly hemolytic, we found that replacing a small proportion of the hydrophobic subunit with either of the polar, uncharged subunits can diminish the hemolytic activity with minimal impact on the antibacterial activity. These results indicate that the incorporation of polar, uncharged subunits may be generally useful for optimizing the biological activity profiles of antimicrobial polymers. In the context of HDP evolution, our findings suggest that there is a selective advantage to retaining polar, uncharged residues in natural antimicrobial peptides.


Core Cariology Curriculum Framework in Spanish for Latin American dental schools: development and consensus.
The aim of this study was to develop and achieve consensus on a cariology teaching framework for dental schools in Latin American Spanish-speaking countries. The Delphi process, with a ≥8 0% pre-defined participants' agreement, included three phases and a Coordinating Group. During the Preparation phase three panels of experts were selected and invited to participate: a) Regional academic/professional Dental Associations (Associations-Panel): n = 12; b) Regional Dental Schools (Dental-Schools-Panel): existing dental schools (n = 263) from the 19 Spanish-speaking regional countries; c) International academic/professional associations Peer Experts (Peer-Panel): n = 4. Based on consensus documents from Europe, Colombia, the Caribbean, USA, Chile and Spain, and updated scientific evidence, the Coordinating Group developed a baseline framework proposal of domains, main competencies (MC) and specific competencies (SC). The Consultation-Agreement and Consensus phases included three rounds of questionnaires with a step-wise sharing of the MC updated version of the consensus framework with the Dental-Schools-Panel and including SC with the Associations-Panel. Diverse communication strategies were used ( e.g ., independent google-form questionnaires and workshops). Consensus was reached after an on-site Associations-Panel workshop and secret voting, followed by an online meeting with the Peers-Panel. A total of 127 academic/professional institutions participated (Associations-Panel: 11, 91.6%; Dental-Schools-Panel: 112, 42.6%, all countries; Peers-Panel: 4, 100%). The baseline Cariology teaching framework of 5 domains, 10 MC and 92 SC underwent modifications after agreements for a final consensus framework consisting of 5 domains, 10 MC and 85 SC. A Core Cariology curriculum framework in Spanish for Latin American Dental Schools was successfully developed and agreed upon with regional dental academic and professional institutions.


Roles of adherent myogenic cells and dynamic culture in engineered muscle function and maintenance of satellite cells.
Highly functional engineered skeletal muscle constructs could serve as physiological models of muscle function and regeneration and have utility in therapeutic replacement of damaged or diseased muscle tissue. In this study, we examined the roles of different myogenic cell fractions and culturing conditions in the generation of highly functional engineered muscle. Fibrin-based muscle bundles were fabricated using either freshly-isolated myogenic cells or their adherent fraction pre-cultured for 36 h. Muscle bundles made of these cells were cultured in both static and dynamic conditions and systematically characterized with respect to early myogenic events and contractile function. Following 2 weeks of culture, we observed both individual and synergistic benefits of using the adherent cell fraction and dynamic culture on muscle formation and function. In particular, optimal culture conditions resulted in significant increase in the total cross-sectional muscle area (- 3-fold), myofiber size (- 1.6-fold), myonuclei density (- 1.2-fold), and force generation (- 9-fold) compared to traditional use of freshly-isolated cells and static culture. Curiously, we observed that only a simultaneous use of the adherent cell fraction and dynamic culture resulted in accelerated formation of differentiated myofibers which were critical for providing a niche-like environment for maintenance of a satellite cell pool early during culture. Our study identifies key parameters for engineering large-size, highly functional skeletal muscle tissues with improved ability for retention of functional satellite cells.


Versatile methods for the fabrication of polyvinylidene fluoride microstructures.
Polyvinylidene fluoride (PVDF) microstructures are of interest for a number of BioMEMS applications both for their piezoelectric and biocompatible properties. In this work, simple soft lithography-based techniques were developed to fabricate PVDF microstructures with diverse geometries, including microarrays of pillars, lines, and wells. Four different microstructure configurations were created: freestanding, stamped discontinuous, stamped continuous and imprinted patterns. Features with lateral dimensions down to 1 μm were consistently reproduced on 2.5 cm diameter areas. Atomic force microscopy (AFM) measurements of poled PVDF microstructures confirmed a marked inverse piezoelectric behavior. The techniques presented here have a number of advantages over previously demonstrated PVDF micropatterning approaches.


Multi-scale characterisation of stream nutrient and carbon dynamics in sandy near coastal catchments of south-western Australia.
Managers tasked with repairing degraded stream ecosystems require restoration strategies that are tailored to local and regional characteristics. Emerging evidence suggests that local reach-scale approaches may be as effective, if not more so, than catchment-scale actions in highly permeable coastal landscapes, particularly if there is hydraulic connectivity to shallow groundwater and where recharge is strongly seasonal. This study assessed the relative influence of catchment-scale land use and reach-scale vegetation structure on the distribution of carbon and nutrient concentrations of streams within urban and agricultural catchments of the Perth region of south-western Australia. We used linear mixed-effects models to evaluate the extent to which phosphorus, nitrogen and carbon concentrations in different stream zones (streamwater, and fluvial and parafluvial sediments) were explained by catchment and reach-scale attributes and moderated by high versus low-flow periods, i.e., in wet versus dry months. We found that reach-scale vegetation (woody plant cover, annual plant cover) was a better predictor of nutrient concentrations than catchment-scale land use, particularly total imperviousness, a common measure of urbanisation. Flow was also important, with carbon and nutrient concentrations better described by reach- or catchment-scale attributes during the low flow period. The extent to which individual catchment and reach attributes influenced the distribution of nutrients in different stream zones was complex. However, our results suggest that planting woody vegetation can reduce nitrogen concentrations in surface water and fluvial sediments. Reducing the abundance of weedy annual species and restoring woody perennial species may further reduce phosphorus concentrations in surface water. We conclude that local riparian restoration can be a cost-effective strategy for managing excess nutrients and carbon in flat and permeable urban landscapes, particularly during low flow periods.


The measurement of the left ventricle ejection fraction by a bedside FoCUS examination.
The use of point-of-care ultrasound is rapidly increasing in medical practice. This study aims to evaluate the left ventricle systolic function by the bedside focus cardiac ultrasound (FoCUS). We consecutively enrolled n.59 patients of the Emergency Medicine Unit of S. Andrea Hospital. Every patient received a bedside FoCUS examination to estimate the left ventricle (LV) ejection fraction (EF); the LV EF measurements were compared with those obtained by standard echocardiography (as gold standard). The LV EF obtained by the bedside FoCUS examination and the standard echocardiography, resulted, respectively: 50.2 ± 15.1% (by the Quinones equation), 39.5 + 12.0% (by the Lvivo app) and 53.7 + 11.1% (by the standard echocardiography). The correlations between the bedside FoCUS EF measurements versus standard echocardiography were statistically significant: r = + 0.694 p < 1.9 × 10-6 (Quinones equation, Bland-Altman analysis mean = - 2.3%) and r = + 0.571 p < 0.01 (Lvivo app, Bland-Altman analysis mean = - 13.3%). In conclusion, the present study showed a high accuracy of the bedside FoCUS EF evaluations, which may support the diagnosis of the heart failure in an emergency setting without delaying. The EF measurements by the operational method are more precise than those obtained by the unselected images of the software application.


Giant enhancement of surface second-harmonic generation using photorefractive surface waves with diffusion and drift nonlinearities.
Giant enhancement of second-harmonic generation (SHG) with 83.4%/W coversion efficiency is obtained, taking advantage of photorefractive surface waves with diffusion and drift nonlinearity. In this method, the self-bending induced by diffusion nonlinearity can be utilized at the surface and can solve the phase-mismatch problem in bulk due to beam self-bending. With drift nonlinearity, an applied external electric filed and background illumination can further constringe surface waves to the surface and consequently enhance SHG, which provides the possibility and flexibility of control.


A targeted gene silencing technique shows that Drosophila myosin VI is required for egg chamber and imaginal disc morphogenesis.
We report that Drosophila unconventional myosin VI, encoded by Myosin heavy chain at 95F (Mhc95F), is required for both imaginal disc and egg chamber morphogenesis. During oogenesis, Mhc95F is expressed in migrating follicle cells, including the border cells, which migrate between the nurse cells to lie at the anterior of the oocyte; the columnar cells that migrate over the oocyte; the centripetal cells that migrate between the oocyte and nurse cells; and the dorsal-anterior follicle cells, which migrate to secrete the chorionic appendages. Its function during development has been studied using a targeted gene silencing technique, combining the Gal4-UAS targeted expression system and the antisense RNA technique. Antibody staining shows that the expression of myosin 95F is greatly decreased in follicle cells when antisense Mhc95F RNA is expressed. Interfering with expression of Drosophila myosin VI at various developmental stages frequently results in lethality. During metamorphosis it results in adult flies with malformed legs and wings, indicating that myosin VI is essential for imaginal disc morphogenesis. During oogenesis, abnormal follicle cell shapes and aberrant follicle cell migrations are observed when antisense Mhc95F is expressed in follicle cells during stages 9 to 10, suggesting that the Drosophila myosin VI is required for follicle cell epithelial morphogenesis.


Local perianal block for anal surgery.
We refined a technique for local block of all terminal nerve branches to the anus. A total of 30 consecutive patients with proctological disorders consented to ambulatory (n=29) or hospitalised (n=1) operation with local perianal block for skin tags, Milligan- Morgan haemorrhoidectomy, stapled haemorrhoidopexy or anocutaneous fistulae. Patients were operated prone. A total of 40 ml of a 4.75 mg/ml solution of ropivacaine (Narop; Astra, Sweden) was injected in 8 directions (5 ml each) into the ischiorectal fat immediately peripheral to the external sphincter as anaesthetic columns reaching from the skin to the levator. This injection scheme targets the terminal nerve branches of the anus rather than blocking the trunk of major nerves. The relaxation of a pain-free anus was obtained in 2-3 minutes with exposure similar to a general anaesthetic. Postoperative pain was evaluated on a 0 to 10 visual analogue scale (VAS). Patients were pain-free at discharge. However, mean postoperative VAS score at 24 hours was 3.2 following Milligan-Morgan haemorrhoidectomy, 4.8 following stapled haemorrhoidopexy and skin tags or polyps excision, and 2.7 after fistula lay-open. At telephone follow-up 1-2 weeks later, the patients were satisfied with the method of anaesthesia and would willingly accept it for any further anal surgery. The perianal block is easy to apply and effective as sole method of anaesthesia for proctological operations.


Seroprevalence of antibodies to hepatitis E virus in the normal blood donor population and two aboriginal communities in Malaysia.
The prevalence of antibodies to hepatitis E virus (HEV) has been examined in many countries, but such studies have generally been limited to majority populations such as those represented in healthy blood donors or cross sections of urban populations. Due to its major route of enteric transmission, large differences in HEV prevalence might be expected between populations in the same country but with different living conditions. Using an ELISA based on GST-ORF2.1 antigen, the prevalence of IgG-class antibodies to HEV was examined in three distinct populations in Malaysia: the normal (urban) blood donor population and two aboriginal communities located at Betau, Pahang and Parit Tanjung, Perak. IgG anti-HEV was detected in 45 (44%) of 102 samples from Betau and 15 (50%) of 30 samples from Parit Tanjung, compared to only 2 (2%) of 100 normal blood donors. The distribution of sample ELISA reactivities was also consistent with ongoing sporadic infection in the aboriginal communities, while there was no significant relationship between HEV exposure and age, sex, or malaria infection. The high prevalence of antibodies to HEV in the two aboriginal communities indicates that this group of people are at high risk of exposure to HEV compared to the general blood donors, and the results suggest that studies of HEV seroprevalence within countries must take into account the possibility of widely varying infection rates between populations with marked differences in living conditions.


Stimulatory and inhibitory actions of carbachol on chloride secretory responses in human colonic cell line T84.
The muscarinic agonist carbachol (CCh) was shown to elicit both stimulatory and inhibitory actions on Cl- secretion in T84 cells. These effects were observed in cells that had been prestimulated with adenosine 3',5'-cyclic monophosphate (cAMP) agonists. The addition of CCh to cells treated with submaximal concentrations (1-10 nM) of the receptor-mediated agonist prostaglandin (PG) E2 resulted in a biphasic effect on short-circuit current (Isc) involving a transient synergistic rise followed by a slower and sustained attenuation of the PGE2-activated Isc response. In contrast at higher PGE2 concentrations (greater than 10 nM) or with nonreceptor-mediated cAMP agonists (forskolin, dibutyryl cAMP) CCh elicited a prolonged synergistic response. Both effects of CCh could be reproduced by selective activation of the Ca2+ pathway. Increasing cytosolic Ca2+ with ionophore A23187 partially mimicked the "early" stimulation of secretion, though there was evidence that a combination of A23187 and the protein kinase C activator phorbol 12,13-dibutyrate (PDB) was required for full expression of the secretory response. In contrast, treatment with PDB alone closely mimicked the CCh-induced inhibition of PGE2-stimulated Isc. The antisecretory effects of CCh were associated with a marked attenuation of cAMP production in response to receptor-mediated agonists, including PGE2 and vasoactive intestinal peptide. This effect could also be closely mimicked by PDB. Pretreatment with pertussis toxin partially inhibited the ability of CCh to inhibit cAMP production. CCh potentiated the cAMP response to the nonreceptor agonist forskolin.(ABSTRACT TRUNCATED AT 250 WORDS)


DHA-enriched phosphatidylserine ameliorates non-alcoholic fatty liver disease and intestinal dysbacteriosis in mice induced by a high-fat diet.
Docosahexaenoic acid-enriched phosphatidylserine (DHA-PS) has attracted increasing attention because of its unique health benefits. In this study, DHA-PS was biosynthesized from DHA-enriched phosphatidylcholine (DHA-PC), which was extracted from herring roe, Clupea harengus. The ameliorating effect of DHA-PS on high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) was investigated using a mouse model. The DHA-PS treatment ameliorated NAFLD and effectively decreased the serum total cholesterol, triglyceride, non-esterified fatty acid, and low-density lipoprotein cholesterol levels and considerably increased the serum high-density lipoprotein cholesterol levels. Moreover, the DHA-PS treatment reduced the levels of liver-function enzymes and pro-inflammatory cytokines and also the oxidative stress indices. Furthermore, DHA-PS increased the diversity and richness of the beneficial intestinal microorganisms, suggesting its potential as a dietary supplement and functional food to combat HFD-induced NAFLD.


Biochemical characterization of Arabidopsis wild-type and mutant phytochrome B holoproteins.
Although phytochrome B (phyB) plays a particularly important role throughout the life cycle of a plant, it has not been studied in detail at the molecular level due to its low abundance. Here, we report on the expression, assembly with chromophore, and purification of epitope-tagged Arabidopsis phyB. In addition, we have reconstructed two missense mutations, phyB-4 and phyB-101, isolated in long hypocotyl screens. We show that mutant proteins phyB-4 and phyB-101 exhibit altered spectrophotometric and biochemical properties relative to the wild-type protein. In particular, we demonstrate that phyB-101 Pfr exhibits rapid nonphotochemical (dark) reversion to Pr that results in a lower photoequilibrium level of the active Pfr form. We conclude that this occurs in vivo as well because phyB-101 mutants are shown to lack an end-of-day-far-red hypocotyl elongation response that requires a stable Pfr species. We propose that this Pfr instability may be the primary molecular mechanism underlying the phyB-101 mutant phenotype.


Promises and pitfalls in erythopoietin-mediated tissue protection: are nonerythropoietic derivatives a way forward?
The essential biological role of erythropoietin (EPO) in maintaining erythrocyte mass has been well understood for many years. Although EPO is required for the maturation of red cells, it also has strong procoagulant effects on the vascular endothelium and platelets, which limit erythrocyte losses after hemorrhage. Like other members of the type 1 cytokine superfamily, EPO has multiple biological activities. For the past 10 years, multiple investigators have shown that EPO acts as a locally produced antagonist of proinflammatory cytokines that are generated by the innate immune response in response to infection, trauma, or metabolic stress. Specifically, EPO inhibits apoptosis of cells surrounding a locus of injury, reduces the influx of inflammatory cells, and recruits tissue-specific stem cells and endothelial progenitor cells. Available evidence suggests that these multiple, nonerythropoietic effects of EPO are mediated by a tissue protective receptor (TPR) that is distinct from the homodimeric receptor responsible for erythropoiesis. Notably, activation of the TPR requires a higher concentration of EPO than is needed for maximal erythropoiesis. Unfortunately, these higher concentrations of EPO also stimulate hematopoietic and procoagulant pathways, which can cause adverse effects and, therefore, potentially limit the clinical use of EPO for tissue protection. To circumvent these problems, the EPO molecule has been successfully modified in a variety of ways to interact only with the TPR. Early clinical experience has shown that these compounds appear to be safe, and proof of concept trials are ready to begin.


Novel recombinant phenotypic assay for clonal analysis of reverse transcriptase mutations conferring drug resistance to HIV-1 variants.
A novel rapid reverse transcriptase (RT) recombinant HIV-1 drug-susceptibility assay was developed to evaluate resistance to RT inhibitors. HIV-1 RTs from five treatment-naive and 10 highly active antiretroviral therapy-experienced patients were evaluated. HIV-1 isolates recovered by culturing peripheral blood mononuclear cells from patients were used in the conventional isolate phenotype analysis. Recombinant HIV-1 strains were obtained by cloning the RT gene amplified from the supernatant of HIV-1 cultures in a plasmid carrying the HIV-1 strain HXB2 backbone, and the most represented clone for each virus isolate was then tested for antiviral drug susceptibility in parallel with HIV-1 isolates. Comparison of conventional virus isolate and the novel recombinant virus phenotypic assays showed a large concordance of results. However, some discrepant results were observed, in that higher drug-resistance levels were detected by the conventional isolate phenotypic assay in HIV-1 isolates showing the presence of a mixture of HIV-1 variants, whereas the novel recombinant phenotypic assay could more precisely detect the level of drug resistance of the single viral clones selected for the analysis. The novel recombinant phenotype assay, compared with the conventional virus isolate phenotype assay, showed widely overlapping results. The comparison of the two assays show that the conventional phenotypic assay is able to identify more efficiently the combined effect of drug-resistant viral variants, whereas the novel recombinant phenotypic assay is better able to define the level of drug resistance of the single viral variants. In addition, rapidity (2 weeks versus 4 weeks required by the reference recombinant assay and 6 weeks required by the conventional virus isolate phenotypic assay) is a major advantage of the novel assay.


[Pregnancy and postpartum control in HIV infected women].
Pregnancy and postpartum control in HIV infected women. We present data from a retrospective observational descriptive study with the objective of evaluating characteristics of HIV-infected pregnant women, analyze the level of control of pregnancy and assess adherence to treatment and loss of follow up after delivery. We analyzed reported data of 104 pregnancies, 32.7% of them under 25 years old. The diagnosis was performed as part of pregnancy control in 36.5% of women. TARV started before 24 weeks of pregnancy in 70% of them and a regimen with 2 nucleos(t)ides and 1 ritonavir potenciated protease inhibitor (PIr) was prescribed in 84.5%. Elective c-section was the most frequent mode of delivery. The viral load after 32 weeks of pregnancy was available in 82.7%, being less than 1000 cop/ml in 78 (75%), less than 200 cop/ml in 70 (67.3%) and not available in 18 (17.3%) of cases. We observed a considered high rate of adherence failure and loss of follow up after delivery. Reported data should alert programs on the need to implement strategies to promote early pregnancy control and increase adherence and retention in care, especially in the postpartum period.


Primary cerebellopontine angle melanoma: a case report and review.
Primary melanomas at the cerebellopontine (CP) angle are extremely rare and considered a diagnostic dilemma. With only 16 prior cases reported so far, there is not enough material in world literature. We report a 29-year-old male who presented with vertigo, headache and features of lower cranial nerve involvement with MRI revealing a melanotic lesion at CP angle. The patient underwent right suboccipital craniectomy and only subtotal excision of the tumor was possible. Histopathologically it turned out to be malignant melanoma. Since a thorough search for any possible primary was futile, it was considered a primary melanoma. Patient was given adjuvant radiotherapy. Ten months later, he presented with weakness and multiple spinal metastases and two months later he succumbed to his disease. We did a comprehensive review of literature about various melanocytic tumors at the CP angle. Pathologically, melanocytic tumors range from benign melanocytomas to malignant melanoma with variable prognosis. The clinical presentation depends upon whether the lesions are diffuse or discrete. Surgery is the primary modality of treatment and the amount of tumor excised is related to the prognosis. We conclude the discussion with a novel classification for melanotic tumors of CNS and the current diagnostic pathway for a melanotic lesion at the CP angle.


Maturation grade of coals as revealed by Raman spectroscopy: progress and problems.
The present study questions the sensitivity and the accuracy of Raman spectroscopy as a tool for determining the maturity of natural organic matter (NOM). It focuses on the definition of optimized experimental parameters in order to maximize the quality of the Raman signal and control the accuracy and reproducibility of measurements. A series of 11 coals has been investigated, sampling a wide maturity range (2-7% vitrinite reflectance VR). The role of experimental parameters is first investigated. An excitation wavelength of 514.5 nm gives better results than 457.9 and 632.8 nm, minimizing the fluorescence background observed in the spectra of low-rank coals. Both Raman and fluorescence spectra were investigated with time-resolved experiments in air and argon. These data show that fluorescence and Raman spectra are sensitive to acquisition time and laser power parameters, and reveal a physicochemical instability of the samples under laser irradiation, mostly due to photo-oxidation processes. These data clearly show that the experiments, especially in air, should be performed with strictly constant acquisition parameters. In addition, the results of a whole series of coal measurements performed in air under constant experimental conditions show that Raman spectroscopy is definitely sensitive to the maturity of coal samples with VR> approximately 1%. The most sensitive spectral maturity tracers are the width of the D-band (FWHM-D), the ratio of the peak intensities of the D- and G-bands (I(D)/I(G)), the normalized ratio of the band integrated intensities A(D)/[A(D)+A(G)] for the maturity range VR=3-7% and the width of the G-band (FWHM-G) for VR=1-5%. However, the accuracy and reproducibility are definitely weaker in such measurements compared to the standard VR. Future work must solve the problem of sample stability under laser irradiation, and greatly increase the number of samples to improve the statistical significance of the results.


Model of electroretinogram b-wave generation: a test of the K+ hypothesis.
Generation of the electroretinogram b-wave is simulated with a computer model representing a dark-adapted amphibian retina. The simulation tests the K+ hypothesis of b-wave generation, which holds that b-wave currents arise from localized Müller cell depolarizations generated by light-evoked increases in extracellular K+ concentration, [K+]o. The model incorporates the following components and processes quantitatively: 1) two time-dependent K+ sources representing the light-evoked [K+]o increases in the inner and outer plexiform layers, 2) a time- and [K+]o-dependent K+ sink representing the [K+]o decrease in the rod inner segment layer, 3) diffusion of released K+ through extracellular space, 4) active K+ reuptake and passive K+ drift across the Müller cell membrane, 5) spatial variations in the tortuosity factor and the volume fraction of extracellular space, 6) an extraretinal shunt resistance. Müller cells are modeled with 1) cytoplasmic resistance, 2) spatial variations in membrane permeability to K+, and 3) a membrane potential specified by the Nernst equation and transmembrane current flow. For specified K+ source and sink densities, the model computes [K+]o variations in time and retinal depth. Based on these [K+]o distributions, Müller cell potentials, current source-density profiles, and intraretinal and transretinal voltages are calculated. Imposed [K+]o distributions similar to those seen experimentally during the b-wave lead to the generation of a transient b-wave response and to a prolonged Müller response in the model system. These response time courses arise because the b-wave is dominated by the short-lived distal [K+]o increase, while the Müller response primarily reflects the long-lived proximal [K+]o increase. Current source-density distributions and intraretinal voltage profiles that are generated by the model at the peak of the b-wave closely resemble experimental results. The model generates a realistic slow PIII potential in response to prolonged [K+]o decreases in the distal retina and reproduces the K+ ejection results of Yanagida and Tomita (50) accurately. Simulations also suggest that tissue damage caused by K+-selective micropipettes in experimental preparations can lead to an underestimation of the distal [K+]o increase. The simulations demonstrate that the spatiotemporal properties of intraretinal b-wave voltages and currents and Müller cell responses can be generated according to the K+ hypothesis: by passive Müller cell depolarization driven by variations in [K+]o.


Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy.
Epilepsy affects more than 0.5% of the world's population and has a large genetic component. It is due to an electrical hyperexcitability in the central nervous system. Potassium channels are important regulators of electrical signalling, and benign familial neonatal convulsions (BFNC), an autosomal dominant epilepsy of infancy, is caused by mutations in the KCNQ2 or the KCNQ3 potassium channel genes. Here we show that KCNQ2 and KCNQ3 are distributed broadly in brain with expression patterns that largely overlap. Expression in Xenopus oocytes indicates the formation of heteromeric KCNQ2/KCNQ3 potassium channels with currents that are at least tenfold larger than those of the respective homomeric channels. KCNQ2/KCNQ3 currents can be increased by intracellular cyclic AMP, an effect that depends on an intact phosphorylation site in the KCNQ2 amino terminus. KCNQ2 and KCNQ3 mutations identified in BFNC pedigrees compromised the function of the respective subunits, but exerted no dominant-negative effect on KCNQ2/KCNQ3 heteromeric channels. We predict that a 25% loss of heteromeric KCNQ2/KCNQ3-channel function is sufficient to cause the electrical hyperexcitability in BFNC. Drugs raising intracellular cAMP may prove beneficial in this form of epilepsy.


A microfluidic device for evaluating the dynamics of the metabolism-dependent antioxidant activity of nutrients.
Various food components are known for their health-promoting effects. However, their biochemical effects are generally evaluated in vitro, and their actual in vivo effect can vary significantly, depending on their metabolic profiles. To evaluate the effect of the liver metabolism on the antioxidant activity, we have developed a two-compartment microfluidic system that integrates the dynamics of liver metabolism and the subsequent antioxidant activity of food components. In the first compartment of the device, human liver enzyme fractions were immobilized inside a poly(ethylene glycol) diacrylate (PEGDA) hydrogel to mimic the liver metabolism. The radical scavenging activity was evaluated by the change of the 2,2-diphenyl-1-picrylhydrazyl (DPPH) absorbance in the second compartment. Reaction engineering and fluid mechanics principles were used to develop a simplified analytical model and a more complex finite element model, which were used to design the chip and determine the optimal flow conditions. For real-time measurements of the reaction on a chip, we developed a custom-made photospectrometer system with an LED light source. The developed microfluidic system showed a linear and dose-dependent antioxidant activity in response to increasing concentration of flavonoid. We also compared the antioxidant activity of flavonoid after various liver metabolic reactions. This microfluidic system can serve as a novel in vitro platform for predicting the antioxidant activity of various food components in a more physiologically realistic manner, as well as for studying the mechanism of action of such food components.


Biological pacemaker engineered by nonviral gene transfer in a mouse model of complete atrioventricular block.
We hypothesized that a nonviral gene delivery of the hyperpolarization-activated HCN2 channel combined with the beta(2)-adrenergic receptor (ADRB2) would generate a functional pacemaker in a mouse model of complete atrioventricular block (CAVB) induced by radiofrequency ablation of the His bundle. Plasmids encoding HCN2 and ADRB2 mixed with tetronic 304, a poloxamine block copolymer, were injected in the left ventricular free wall (HCN2-ADRB2 mice). Sham mice received a noncoding plasmid. CAVB was induced 5 days later. Ventricular escape rhythms in HCN2-ADRB2 mice were significantly faster than in sham mice at day 15 after ablation and later. In HCN2-ADRB2 mice, QRS complexes were larger than in sham mice and characterized by abnormal axes. Immunostaining of GFP-HCN2 fusion protein showed an expression of HCN2 channel in left ventricular myocardium for at least 45 days after injection. In the mouse, CAVB induces progressive hypertrophy and heart failure leading to 50% mortality after 110 days. HCN2-ADRB2 mice survived 3 weeks longer than sham mice. Finally, beta-adrenergic input increased ventricular escape rhythms significantly more in HCN2-ADRB2 mice than in sham mice. In conclusion, nonviral gene transfer can produce a functional cardiac biological pacemaker regulated by sympathetic input, which improves life expectancy in a mouse model of CAVB.


Growth in Suicide Rates Among Children During the Illicit Opioid Crisis.
This article documents child suicide rates from 1980 to 2020 in the United States using the National Vital Statistics System Multiple Cause of Death database. After generally declining for decades, suicide rates among children aged 10-17 accelerated from 2011 to 2018 in an unprecedented rise in both duration and magnitude. I consider the role of the illicit opioid crisis in driving this mental health crisis. In August 2010, an abuse-deterrent version of OxyContin was introduced and the original formulation was removed from the market, leading to a shift to illicit opioids and stimulating growth in illicit opioid markets. Areas more exposed to reformulation-as measured by pre-reformulation rates of OxyContin misuse in the National Survey on Drug Use and Health-were more affected by the transition to illicit opioids and experienced sharper growth in child suicide rates. The evidence suggests that children's illicit opioid use did not increase, implying that the illicit opioid crisis engendered higher suicide propensities by increasing suicidal risk factors for children, such as increasing rates of child neglect and altering household living arrangements. In complementary analyses, I document how living conditions declined for children during this time period.


Pulmonary hypertension subtypes associated with hereditary haemorrhagic telangiectasia: Haemodynamic profiles and survival probability.
Different pulmonary hypertension (PH) mechanisms are associated with hereditary haemorrhagic telangiectasia (HHT). We conducted a retrospective study of all suspected cases of PH (echocardiographically estimated systolic pulmonary artery pressure [sPAP] ≥ 40 mmHg) in patients with definite HHT recorded in the French National Reference Centre for HHT database. When right heart catheterization (RHC) was performed, PH cases were confirmed and classified among the PH groups according to the European guidelines. Among 2,598 patients in the database, 110 (4.2%) had suspected PH. Forty-seven of these 110 patients had RHC: 38/47 (81%) had a confirmed diagnosis of PH. The majority of these had isolated post-capillary PH (n = 20). We identified for the first time other haemodynamic profiles: pre-capillary pulmonary arterial hypertension (PAH) cases (n = 3) with slightly raised pulmonary vascular resistances (PVR), and combined post- and pre-capillary PH cases (n = 4). Compared to controls, survival probability was lower in patients with PAH. This study revealed the diversity of PH mechanisms in HHT. The description of combined post- and pre-capillary PH with/or without high cardiac output (CO) suggests either a continuum between the pre- and post-capillary haemodynamic profiles or a different course in response to high CO.


The proliferative inhibition and apoptotic mechanism of Saikosaponin D in human non-small cell lung cancer A549 cells.
Saikosaponin D is a saponin extract derived from several species of Bupleurum (Umbelliferae), which is used for the treatment of various liver diseases in traditional Chinese medicine. In this study, we report that Saikosaponin D inhibits the cell growth of human lung cancer cell line A549 and provide a molecular understanding of this effect. The results showed that Saikosaponin D inhibited the proliferation of A549 by inducing apoptosis and blocking cell cycle progression in the G1 phase. ELISA assay showed that Saikosaponin D significantly increased the expression of p53 and p21/WAF1 protein, contributing to cell cycle arrest. An enhancement in Fas/APO-1 and its two form ligands, membrane-bound Fas ligand (mFasL) and soluble Fas ligand (sFasL), as well as Bax protein, was responsible for the apoptotic effect induced by Saikosaponin D. Taken together, our study suggests that the induction of p53 and activity of the Fas/FasL apoptotic system may participate in the antiproliferative activity of Saikosaponin D in A549 cells.


Signature of a conical intersection in the dissociative photoionization of formaldehyde.
The valence-shell photoionization of formaldehyde is investigated by means of combining Photo-Electron Photo-Ion COincidence (PEPICO) experiments and ab initio calculations. The formation of three ion fragments: HCO+, CO+ and H, via dissociative photoionization following excitation at 17 eV is discussed. The experimental results consisting of electron-ion kinetic energy correlation diagrams for the corresponding coincident events, i.e. (HCO+, e-), (CO+, e-) and (H, e-), as well as the fragment abundance as a function of the binding energy, are complemented by high level electronic structure calculations including potential energy curves and on-the-fly trajectories. The results are consistent with a main relaxation process via internal conversion into rovibrationally excited levels of the H2CO+ ground state, followed by statistical dissociation, preferentially into HCO+. The analysis of the experimental results reveals nevertheless the signature of a conical intersection controlling the dynamics and favoring dissociation into the molecular channel, CO+ + H2. In addition, the minor formation of the H ion is suggested to occur through a roaming pathway on the cation excited state.


Micromechanics of diffuse axonal injury: influence of axonal orientation and anisotropy.
Multiple length scales are involved in the development of traumatic brain injury, where the global mechanics of the head level are responsible for local physiological impairment of brain cells. In this study, a relation between the mechanical state at the tissue level and the cellular level is established. A model has been developed that is based on pathological observations of local axonal injury. The model contains axons surrounding an obstacle (e.g., a blood vessel or a brain soma). The axons, which are described by an anisotropic fiber-reinforced material model, have several physically different orientations. The results of the simulations reveal axonal strains being higher than the applied maximum principal tissue strain. For anisotropic brain tissue with a relatively stiff inclusion, the relative logarithmic strain increase is above 60%. Furthermore, it is concluded that individual axons oriented away from the main axonal direction at a specific site can be subjected to even higher axonal strains in a stress-driven process, e.g., invoked by inertial forces in the brain. These axons can have a logarithmic strain of about 2.5 times the maximum logarithmic strain of the axons in the main axonal direction over the complete range of loading directions. The results indicate that cellular level heterogeneities have an important influence on the axonal strain, leading to an orientation and location-dependent sensitivity of the tissue to mechanical loads. Therefore, these effects should be accounted for in injury assessments relying on finite element head models.


ANMCO POSITION PAPER: The reorganization of cardiology in times of the SARS-CoV-2 pandemic.
The COVID-19 pandemic represents an unprecedented event that has brought deep changes in hospital facilities with reshaping of the health system organization, revealing inadequacies of current hospital and local health systems. When the COVID-19 emergency will end, further evaluation of the national health system, new organization of acute wards, and a further evolution of the entire health system will be needed to improve care during the chronic phase of disease. Therefore, new standards for healthcare personnel, more efficient organization of hospital facilities for patients with acute illnesses, improvement of technological approaches, and better integration between hospital and territorial services should be pursued. With experience derived from the COVID-19 pandemic,new models, paradigms, interventional approaches, values and priorities should be suggested and implemented.


Epigenomic promoter alterations predict for benefit from immune checkpoint inhibition in metastatic gastric cancer.
Utilization of alternative transcription start sites through alterations in epigenetic promoter regions causes reduced expression of immunogenic N-terminal peptides, which may facilitate immune evasion in early gastric cancer. We hypothesized that tumors with high alternate promoter utilization would be resistant to immune checkpoint inhibition in metastatic gastric cancer. Two cohorts of patients with metastatic gastric cancer treated with immunotherapy were analyzed. The first cohort (N = 24) included patients treated with either nivolumab or pembrolizumab. Alternate promoter utilization was measured using the NanoString® (NanoString Technologies, Seattle, WA, USA) platform on archival tissue samples. The second cohort was a phase II clinical trial of patients uniformly treated with pembrolizumab (N = 37). Fresh tumor biopsies were obtained, and transcriptomic analysis was carried out on RNAseq data. Alternate promoter utilization was correlated to T-cell cytolytic activity, objective response rate and survival. In the first cohort 8 of 24 (33%) tumors were identified to have high alternate promoter utilization (APhigh), and this was used to define the APhigh tertile of the second cohort (13 APhigh of 37). APhigh tumors exhibited decreased markers of T-cell cytolytic activity and lower response rates (8% versus 42%, P = 0.03). Median progression-free survival was lower in the APhigh group (55 versus 180 days, P = 0.0076). In multivariate analysis, alternative promoter utilization was an independent predictor of immunotherapy survival [hazard ratio 0.29, 95% confidence interval 0.099-0.85, P = 0.024). Analyzing tumoral evolution through paired pre-treatment and post-treatment biopsies, we observed consistent shifts in alternative promoter utilization rate associated with clinical response. A substantial proportion of metastatic gastric cancers utilize alternate promoters as a mechanism of immune evasion, and these tumors may be resistant to anti-PD1 immune checkpoint inhibition. Alternate promoter utilization is thus a potential mechanism of resistance to immune checkpoint inhibition, and a novel predictive biomarker for immunotherapy. ClinicalTrials.gov Identifier: NCT#02589496.


Crisis resolution and home treatment: stakeholders' views on critical ingredients and implementation in England.
Crisis resolution teams (CRTs) can provide effective home-based treatment for acute mental health crises, although critical ingredients of the model have not been clearly identified, and implementation has been inconsistent. In order to inform development of a more highly specified CRT model that meets service users' needs, this study used qualitative methods to investigate stakeholders' experiences and views of CRTs, and what is important in good quality home-based crisis care. Semi-structured interviews and focus groups were conducted with service users (n = 41), carers (n = 20) and practitioners (CRT staff, managers and referrers; n = 147, 26 focus groups, 9 interviews) in 10 mental health catchment areas in England, and with international CRT developers (n = 11). Data were analysed using thematic analysis. Three domains salient to views about optimal care were identified. 1. The organisation of CRT care: Providing a rapid initial responses, and frequent home visits from the same staff were seen as central to good care, particularly by service users and carers. Being accessible, reliable, and having some flexibility were also valued. Negative experiences of some referral pathways, and particularly lack of staff continuity were identified as problematic. 2. The content of CRT work: Emotional support was at the centre of service users' experiences. All stakeholder groups thought CRTs should involve the whole family, and offer a range of interventions. However, carers often feel excluded, and medication is often prioritised over other forms of support. 3. The role of CRTs within the care system: Gate-keeping admissions is seen as a key role for CRTs within the acute care system. Service users and carers report that recovery is quicker compared to in-patient care. Lack of knowledge and misunderstandings about CRTs among referrers are common. Overall, levels of stakeholder agreement about the critical ingredients of good crisis care were high, although aspects of this were not always seen as achievable. Stakeholders' views about optimal CRT care suggest that staff continuity, carer involvement, and emotional and practical support should be prioritised in service improvements and more clearly specified CRT models.


Pain in amaXhosa women living with HIV/AIDS: a cross-sectional study of ambulant outpatients.
Pain is one of the most commonly reported symptoms in people living with HIV/AIDS, whether or not they are receiving anti-retroviral therapy. A recent systematic review identified a paucity of studies exploring pain in women in low and middle income countries. The prevalence and characteristics of pain in women living with HIV/AIDS may differ from that of men as many chronic pain conditions are more prevalent in women. The aims of this study were to establish pain prevalence, characteristics and management in amaXhosa women living with HIV/AIDS. In addition, we aimed to identify whether there were associations between pain in this population and the psychosocial factors of employment, education, self-efficacy, depression, post-traumatic stress disorder, health related quality of life and childhood trauma. A cross-sectional study of 229 women who had undergone HIV testing and were registered patients at a community health centre was conducted. Data were collected by interview with a demographic questionnaire, the Brief Pain Inventory-Xhosa, Childhood Trauma Questionnaire-Xhosa, Harvard Trauma Questionnaire-Xhosa for PTSD, Self-Efficacy for Managing Chronic Disease 6-Item Scale-Xhosa; the EQ-5D health related quality of life instrument, and the Beck Depression Inventory. 170 of the women had pain, a prevalence rate of 74.24% (95%CI 68.2 - 79.47%). The women reported significant pain with pain severity of 5.06 ± 1.57 and pain interference of 6.39 ± 1.96 out of 10. Only two women were receiving adequate pain management according to the pain management index. Participants reported a mean of 2.42 ± 1.21 different anatomical sites of pain. There were more unemployed participants in the group with pain and they had significantly fewer years of schooling. Those with pain had lower self-efficacy; health related quality of life and increased depression and PTSD symptom severity. This study highlights that pain is a common problem for amaXhosa women living with HIV/AIDS. These data emphasise the need to prioritise pain assessment and management in amaXhosa women living with HIV/AIDS. Routinely assessing for the presence of pain in women with HIV/AIDS has the potential to improve pain management and minimise the impact of pain on function.


Phosphoinositide-regulated retrograde transport of ricin: crosstalk between hVps34 and sorting nexins.
The plant toxin ricin is transported from the plasma membrane via early endosomes and the Golgi apparatus to the endoplasmic reticulum. From this compartment, it enters the cytosol and inhibits protein synthesis. Lipid phosphorylation is an important regulator of vesicular transport, and in the present study we have investigated the role of the phosphatidylinositol (PI) 3-kinase hVps34 in retrograde transport of ricin. Our data demonstrate that transport of ricin from endosomes to the Golgi apparatus in human embryonic kidney cells (HEK 293) is dependent on PI(3)P. By using PI 3-kinase inhibitors, by sequestering the hVps34 product PI(3)P and by expressing mutants of hVps34 or small interfering RNA targeted against its messenger RNA, we show that hVps34 and its product PI(3)P are involved in transport of ricin from endosome to Golgi apparatus. Furthermore, we identify two effector proteins in the hVps34-dependent pathway, namely sorting nexin (SNX) 2 and SNX4. Knockdown of SNX2 or SNX4 inhibits ricin transport to the Golgi apparatus to the same extent as when hVps34 is perturbed. Furthermore, inhibition or knockdown of hVps34 redistributes these proteins. Interestingly, knocking down both SNX2 and SNX4 results in a better inhibition than knocking down only one of them, suggesting that they may act on separate pathways.


Physico-chemical and biologic properties of the Ascaris allergen.
Ascaris species and their soluble extracts are exceptionally active in inducing atopic sensitization in a very high proportion of exposed individuals and stimulate high levels of reaginic (IgE) antibodies in many experimental animal models. A component responsible for both stimulating reaginic antibodies and eliciting skin reactions in previously sensitized animals was isolated and purified from the crude extract by associating Sephadex gel filtration and polyvinyl chloride block electrophoresis. The allergen (Asc-1) had a molecular weight of 17,000-18,000, had an isoelectric point of 5.0-5.2, contained 8.5% carbohydrate and dissociated in polyacrylamide gel electrophoresis in SDS as a subunit with a molecular weight of 8.400. A single injection of 10 mug protein Asc-1 could stimulate reagin production in rats. Experimental A.suum infections in rats determine reaginic antibody titers ranging from 1:160 after a single infection to 1:4000 after a second infection. The reagins could be detected using Asc-1 as challenge, indicating that the allergen obtained from the crude extract was present in all stages of the parasite life cycle and was directly involved in stimulating reagin production during the migratory phase of the infection. Immunization of rats with Asc-1 in complete Freund's adjuvant completely suppressed the reagin response expected to follow after either one or two infections. Asc-1 did not act as an adjuvant for reagin production nor did an A.suum infection potentiate the reagin response to irrelevant antigens.


Comparison of chemically induced and spontaneous murine thymic lymphomas in RF and AKR mice: differential expression of c-myc and c-myb.
Expression of 11 cellular oncogenes was determined in normal vs. lymphomatous thymic tissues of RF and AKR mice; only c-myc and c-myb transcripts were detected in an age-inappropriate pattern in thymomas. Normal thymocytes from young RF mice contained RNA transcripts of both genes, but the transcripts were no longer detected at 9 or more weeks of age. More than 90% of RF thymomas, occurring at 20-28 weeks of age after skin painting with 3-methylcholanthrene at 12 weeks, contained c-myc transcripts, and 70% of the tumors contained c-myb transcripts. Seven cell lines derived from these 3-methylcholanthrene thymomas expressed both cellular genes, as did 2 rare spontaneous thymomas of 12-month-old RF mice. No indication of rearrangement or amplification of either gene was seen in any of the RF tumors or cell lines. In AKR mice, transcripts of the 2 genes persisted longer in the normal thymus than in RF mice, but they were no longer detected at 26 weeks of age. Of 3 thymomas in 6-month-old 3-methylcholanthrene-treated AKR mice, all expressed c-myb and 2 expressed c-myc. Among 11 spontaneous AKR thymomas, however, only 2 showed detectable levels of both genes, and 2 more expressed c-myc or c-myb but not both.


A Glutamine-Rich Carrier Efficiently Delivers Anti-CD47 siRNA Driven by a "Glutamine Trap" To Inhibit Lung Cancer Cell Growth.
It is not efficient enough using the current approaches for tumor-selective drug delivery based on the EPR effect and ligand-receptor interactions, and they have largely failed to translate into the clinic. Therefore, it is urgent to explore an enhanced strategy for effective delivery of anticancer agents. Clinically, many cancers require large amounts of glutamine for their continued growth and survival, resulting in circulating glutamine extraction by the tumor being much greater than that for any organs, behaving as a "glutamine trap". In the present study, we sought to elucidate whether the glutamine-trap effect could be exploited to deliver therapeutic agents to selectively kill cancer cells. Here, a macromolecular glutamine analogue, glutamine-functionalized branched polyethylenimine (GPI), was constructed as the carrier to deliver anti-CD47 siRNA for the blockage of CD47 "don't eat me" signals on cancer cells. The GPI/siRNA glutamine-rich polyplexes exhibited remarkably high levels of cellular uptake by glutamine-dependent lung cancer cells, wild-type A549 cells (A549WT), and its cisplatin-resistant cells (A549DDP), specifically under glutamine-depleted conditions. It was noted that the glutamine transporter ASCT2 was highly expressed both on A549WT and A549DDP but with almost no expression in normal human lung fibroblasts cells. Inhibition of ASCT2 significantly prevented the internalization of GPI polyplexes. These findings raised the intriguing possibility that the glutamine-rich GPI polyplexes utilize the ASCT2 pathway to selectively facilitate their cellular uptake by cancer cells. GPI further delivered anti-CD47 siRNA efficiently both in vitro and in vivo to downregulate the intratumoral mRNA and protein expression levels of CD47. CD47 functions as a "don't eat me" signal and binds to the immunoreceptor SIRPα inducing evasion of phagocytic clearance. GPI/anti-CD47 siRNA polyplexes achieved significant antitumor activities both on A549WT and A549DDP tumor-bearing nude mice. Notably, it had no adverse effect on CD47-expressing red blood cells and platelets, likely because of selective delivery. Therefore, the glutamine-rich carrier GPI driven by the glutamine-trap effect provides a promising new strategy for designing anticancer drug delivery systems.


Long-term vaccination strategies to mitigate the impact of SARS-CoV-2 transmission: A modelling study.
Vaccines have reduced severe disease and death from Coronavirus Disease 2019 (COVID-19). However, with evidence of waning efficacy coupled with continued evolution of the virus, health programmes need to evaluate the requirement for regular booster doses, considering their impact and cost-effectiveness in the face of ongoing transmission and substantial infection-induced immunity. We developed a combined immunological-transmission model parameterised with data on transmissibility, severity, and vaccine effectiveness. We simulated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmission and vaccine rollout in characteristic global settings with different population age-structures, contact patterns, health system capacities, prior transmission, and vaccine uptake. We quantified the impact of future vaccine booster dose strategies with both ancestral and variant-adapted vaccine products, while considering the potential future emergence of new variants with modified transmission, immune escape, and severity properties. We found that regular boosting of the oldest age group (75+) is an efficient strategy, although large numbers of hospitalisations and deaths could be averted by extending vaccination to younger age groups. In countries with low vaccine coverage and high infection-derived immunity, boosting older at-risk groups was more effective than continuing primary vaccination into younger ages in our model. Our study is limited by uncertainty in key parameters, including the long-term durability of vaccine and infection-induced immunity as well as uncertainty in the future evolution of the virus. Our modelling suggests that regular boosting of the high-risk population remains an important tool to reduce morbidity and mortality from current and future SARS-CoV-2 variants. Our results suggest that focusing vaccination in the highest-risk cohorts will be the most efficient (and hence cost-effective) strategy to reduce morbidity and mortality.


Choriocarcinoma of the colon.
Primary choriocarcinoma of the colon is exceedingly rare. Only two cases have been previously reported, both located in the sigmoid colon. A case of choriocarcinoma arising in association with adenocarcinoma of the ascending colon (cecum) in a 35-year-old woman is described. Immunoperoxidase staining showed beta-human chorionic gonadotrophin to be present in the choriocarcinomatous portion of the primary tumor and in the metastases. Theories concerning the histogenesis of this rare neoplasma are briefly reviewed.


Keloids: pathogenesis, clinical features, and management.
Cutaneous wound healing is a complex response to skin injury. Deregulation of this process can lead to excessive scar formation, as seen in keloids. Keloids are common skin lesions that are difficult to treat and are associated with high recurrence rates despite the large number of available treatment options. With increased knowledge of the disease process and further scientific advancements, future approaches will hopefully improve keloid treatment. In this article, we review the epidemiology, genetic basis, etiology, clinical features, pathogenesis, and management of keloids.


Urine 4-heptanone: a beta-oxidation product of 2-ethylhexanoic acid from plasticisers.
4-Heptanone is a common volatile constituent of human urine and is of unknown origin. We hypothesised that it arises from in vivo beta-oxidation of 2-ethylhexanoic acid (EHA) from plasticisers, similar to formation of 3-heptanone from valproic acid. We investigated urine from individuals with normal and increased plasticiser exposure. Using GC/MS, solvent-extracted organic acids were analysed as trimethylsilyl (TMS) derivatives and heptanone with headspace solid-phase microextraction. We identified 3-oxo-2-ethylhexanoic acid, the beta-oxidation product of EHA, as an enol in all samples. This is the first report of its TMS mass spectrum. We also found 2-ethyl-1,6-hexanedioic acid and 5-hydroxyEHA, omega- and omega-1-oxidation products of EHA, respectively, and 2-ethylhexanoylglucuronide, but only in trace amounts in some plasticiser samples. These compounds have not been reported in human urine, nor has the TMS mass spectrum of 5-hydroxyEHA. The median concentrations of 3-oxoethylhexanoic acid and total 4-heptanone of seven plasticiser samples were around 30--175-fold higher than normal samples. 4-Heptanone was barely detectable and 3-oxoethylhexanoic acid was not increased in an eighth plasticiser sample, from a baby with deficiency of 2-methylbranched-chain acyl-CoA dehydrogenase. beta-Oxidation is a major catabolic pathway of EHA in man, and might be involved in the metabolism of other branched-chain drugs and environmental pollutants.


Detection of proteins antigenically related to Bothrops asper myotoxin in crotaline snake venoms.
The presence of components antigenically related to Bothrops asper myotoxin was investigated by Western blotting and immunoelectrophoretic techniques. B. asper myotoxin is a non-glycosylated monomeric phospholipase A with a molecular weight by SDS-PAGE of 16,000 and isoelectric point of pH 9.8-10.0. Results showed that proteins in the venoms of B. nummifer, B. godmani, B. schlegelii, B. picadoi, and Agkistrodon bilineatus were recognized by monospecific antibodies to B. asper myotoxin raised in rabbit and sheep. Western blotting indicated that cross-reacting proteins have a molecular weight of 16,000, with the exception of that of B. picadoi, which is of 24,000 mol. wt. However, immunoelectrophoresis indicated that these components are highly heterogeneous in charge, ranging from basic to acidic proteins. The cross-reacting component(s) present in newborn B. asper venom has a different charge from that of the 'adult-type'. Venoms from newborn specimens showed an additional cross-reacting band of 18,000 mol. wt. Myotoxin is an abundant component in adult B. asper venom. Myotoxin-antimyotoxin complexes had different electrophoretic mobilities in rocket immunoelectrophoresis depending upon the species in which monospecific immune sera were produced.


Risk factors for noncommunicable chronic diseases in women in China: surveillance efforts.
To investigate risk factors for chronic noncommunicable diseases (NCDs) and their determinants in Chinese women. Data from the 2010 China Chronic Disease and Risk Factor Surveillance survey, comprising a nationally representative sample of women, were obtained to determine the prevalence of eight risk factors for chronic NCDs: current smoking, harmful use of alcohol, insufficient intake of fruit and vegetables, physical inactivity, overweight and obesity, raised blood pressure, raised fasting blood glucose and raised total serum cholesterol. The mean number of risk factors per woman was estimated. Their independent demographic and socioeconomic covariates were also examined with ordinal logistic regression. THE FOLLOWING PREVALENCES WERE FOUND: insufficient intake of fruit and vegetables, 51.7%; overweight and obesity, 32.3%; raised blood pressure, 29.7%; physical inactivity, 18.3%; raised total serum cholesterol, 18.1%; raised blood glucose, 7.0%; current smoking, 2.4%; and harmful use of alcohol, 1.3%. The mean number of risk factors per woman was 1.61; 48.0% of the women had at least two risk factors. Women who were older, poorer, from rural areas or from eastern or central China had more risk factors, but only being more than 35 years old, poorly educated and a resident of eastern or central China independently increased the likelihood of having multiple risk factors. Risk factors for chronic NCDs are common among Chinese women aged 18 or older. Interventions to reduce these factors are needed and should target women who are older, who live in eastern or central China or who are poorly educated.


Personas for the translational workforce.
Twelve evidence-based profiles of roles across the translational workforce and two patients were made available through clinical and translational science (CTS) Personas, a project of the Clinical and Translational Science Awards (CTSA) Program National Center for Data to Health (CD2H). The persona profiles were designed and researched to demonstrate the key responsibilities, motivators, goals, software use, pain points, and professional development needs of those working across the spectrum of translation, from basic science to clinical research to public health. The project's goal was to provide reliable documents that could be used to inform CTSA software development projects, educational resources, and communication initiatives. This paper presents the initiative to create personas for the translational workforce, including the methodology, engagement strategy, and lessons learned. Challenges faced and successes achieved by the project may serve as a roadmap for others searching for best practices in the creation of Persona profiles.


A Phase Ib Study to Evaluate the MEK Inhibitor Cobimetinib in Combination with the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors.
Despite strong preclinical rationale, combined cobimetinib-mediated MEK inhibition and GDC-0994-mediated ERK inhibition was not tolerable on two 28-day dosing schedules in which GDC-0994 was given for 21 days continuously and cobimetinib administered over 21 days either continuously or intermittently. Adverse events were as expected for mitogen-activated protein kinase pathway inhibition, but overlapping and cumulative toxicities could not be managed on either dosing schedule. Pharmacokinetic parameters of cobimetinib and GDC-0994 given in combination were similar to those previously observed in monotherapy studies, so that there was no evidence of drug-drug interaction. Cycle 1 metabolic responses were observed by 18F-fluorodeoxyglucose-positron emission tomography but were not predictive of outcome measured by RECIST 1.1. Simultaneous targeting of multiple nodes in the mitogen-activated protein kinase (MAPK) pathway offers the prospect of enhanced activity in RAS-RAF-mutant tumors. This phase Ib trial evaluated the combination of cobimetinib (MEK inhibitor) and GDC-0994 (ERK inhibitor) in patients with locally advanced or metastatic solid tumors. Cobimetinib and GDC-0994 were administered orally on two separate dosing schedules. Arm A consisted of concurrent cobimetinib and GDC-0994 once daily for 21 days of a 28-day cycle; Arm B consisted of intermittent dosing of cobimetinib on a 28-day cycle concurrent with GDC-0994 daily for 21 days of a 28-day cycle. In total, 24 patients were enrolled. For Arm A, owing to cumulative grade 1-2 toxicity, the dose of cobimetinib was decreased. For Arm B, dose increases of GDC-0994 and cobimetinib were intolerable with grade 3 dose-limiting toxicities of myocardial infarction and rash. Pharmacokinetic data did not show evidence of a drug-drug interaction. Overall, seven patients had a best overall response of stable disease (SD) and one patient with pancreatic adenocarcinoma had an unconfirmed partial response. The safety profile of MEK and ERK inhibition demonstrated classic MAPK inhibitor-related adverse events (AEs). However, overlapping AEs and cumulative toxicity could not be adequately managed on either dosing schedule, restricting the ability to further develop this combination.


"Pure" large cell neuroendocrine carcinoma of the gallbladder. Report of a case and review of the literature.
Primary Neuroendocrine Tumours (NETs) of the gallbladder are rare. Among all NETs of the gallbladder, large cell neuroendocrine carcinoma (LCNEC) is exceedingly rare. In most of the cases LCNECs are combined with other histological components. We reviewed clinical presentation and management of all patients with "pure" LCNEC from published literature since the first case was published in 2000, as well as one patient from our experience. Only 7 cases of "pure" LCNEC has been described in the last 15 years, our case is the eighth. The diagnosis of gallbladder NETs is rarely made preoperatively since the presentation generally consists of non-specific symptoms including upper abdominal pain, discomfort, jaundice, weight loss. The majority of patients are identified incidentally at the time of cholecystectomy for cholelithiasis. It is not possible to differentiate preoperatively between gallbladder adenocarcinoma and gallbladder neuroendocrine carcinoma (NEC) with imaging techniques. The only curative therapeutic modality for LCNECs is a complete en bloc surgical resection, including regional lymph node clearances and hepatic lobectomy, but only in patients without multiple metastasis. LCNECs benefit from an aggressive surgical resection in combination with chemotherapy, if resectability is possible. If the tumour is non-resectable, the primary management is therefore medical and not surgical. All patients with LCNEC presented a poor prognosis with a median survival of 10 months after the initial diagnosis. Only in five patients (62.5%) a wide surgical excision was performed, while in the other cases the tumour was non-resectable or multiple liver metastases were present at diagnosis.