Novel human plasma proteins, IHRP (acute phase protein) and PHBP (serine protease), which bind to glycosaminoglycans.
A novel human plasma protein was found in the eluate from the dextran sulfate column, which was used for the treatment of the patients with hypercholesteremia to reduce plasma low density lipoprotein. The results of sequence analysis revealed that this protein was a homologue of heavy chains of inter-alpha-trypsin inhibitor (ITI) family, and it was termed IHRP (ITI family heavy chain related protein). IHRP was identified as an acute-phase protein in animals, and slightly increased concentrations in human plasmas were observed in the patients with inflammatory disorders. IHRP bound to actin and inhibited its polymerization, and IHRP suppressed the phagocytosis and chemotaxis of polymorphonuclear cells. These results suggest that IHRP may function as an anti-inflammatory protein. Plasma hyaluronan binding protein (PHBP) is a novel serine protease which was also found in human plasma. It is consisted of three epidermal growth factor domains, one kringle domain and one serine protease domain from its amino terminus. The amino acid sequence of PHBP is homologous to that of hepatocyte growth factor activator. Purified 75-kDa single chain pro-form of PHBP was auto-activated (auto-cleaved) to 50-kDa heavy chain and 25-kDa light chain, both of them are bridged by a disulfied bond. PHBP digested alpha-chain and beta-chain of fibrinogen to prevent coagulation and cleaved single chain urokinase type plasminogen activator (scuPA) to the active hetero dimer form (tcuPA). The auto-activation of PHBP was accelerated in the presence of dextran sulfate or phosphatidylethanolamine as well as factor XII of the coagulation system. C1 inhibitor of the complement system was identified as the main inhibitor of PHBP in human plasma. Partial hepatectomy and administration of carbon tetrachloride or galactosamine caused the conversion of pro-PHBP to the active form in mouse but administrations of turpentine and mercury chloride did not, suggesting the hepatic injury specific activation of PHBP. These results indicate that PHBP participates not only in the fibrinolytic system but also in the degradation cascade of extracellular matrix (ECM), i.e., PHBP activates scuPA to tcuPA, tcuPA activates matrix metalloproteases (MMPs) and activated MMPs degrade ECM for the tissue remodeling after hepatic injury.


Sex identification of elk (Cervus elaphus canadensis), moose (Alces alces), and white-tailed deer (Odocoileus virginianus) using the polymerase chain reaction.
We have developed a PCR-based protocol to determine the gender of tissue samples originating from elk (Cervus elaphus canadensis), moose (Alces alces) and white-tailed deer (Odocoileus virginianus). The technique simultaneously amplifies a conserved region of the sex-determining gene on the Y-chromosome (Sry) and a region of the Fragile X mental retardation gene (Fmr-1). The multiplex nature of this protocol allows the determination of gender using the Sry marker with the Fmr-1 marker providing an internal control. This technique is applicable to the enforcement of the validation tag system for game species. Data are provided from a wildlife investigation in Ontario.


Dependence of Trichomonas vaginalis upon polyamine backconversion.
Trichomonas vaginalis grown for 16 h in the presence of [(14)C]spermine formed a high intracellular pool of [(14)C]spermidine and a small but detectable pool of [(14)C]putrescine. When [(3)H]putrescine was added to the growth medium, a large intracellular pool of [(3)H]putrescine was found, but it was not further metabolized, confirming previous studies suggesting the absence of a forward-directed polyamine synthetic pathway in T. vaginalis. Spermidine:spermineN:(1)-acetyltransferase (SSAT) and polyamine oxidase enzyme activities were detected which collectively converted spermine to spermidine. Polyamine oxidase was localized in the hydrogenosome-enriched fraction, whereas SSAT was found predominantly in the cytosolic fraction. In the presence of saturating substrate, the trichomonad SSAT had an activity of 0. 39+/-0.09 nmol min(-1) (mg protein)(-1) (the mean of five analyses) and an apparent K:(m) for spermine of 1.7 microM. The enzyme was competitively inhibited by di(ethyl)norspermine with a K:(i) of 28 microM. Growth studies indicated that 50 microM di(ethyl)norspermine caused a 68% and 84% reduction in the intracellular concentrations of spermidine and spermine, respectively. The trichomonad polyamine oxidase required FAD as a cofactor and had an apparent K:(m) of 6.0 microM for N(1)-acetylspermine. The potential of bis(alkyl) polyamine analogues as antitrichomonad agents is discussed.


Two cases of pineal germinoma with granulomatous inflammation.
We report two cases of pineal germinoma with remarkable chronic granulomatous inflammation. In the first case, the pineal mass was totally removed via an occipital transtentorial approach as symptoms were due to direct mass effect. In the second case, endoscopic third ventriculostomy and tissue biopsy was performed to alleviate worsening hydrocephalus. Pathological examination of specimens of both cases showed chronic granulomatous inflammation associated with a few germ cell tumor nests, which demonstrated positive staining for placental alkaline phosphatase. Both patients received post-operative craniospinal irradiation with no subsequent neurological deficits. Follow-up magnetic resonance imaging (MRI) of the second case showed an asymptomatic, shrunken residual tumor mass. MRI of the first case showed no residual or recurrent disease. Thus, a pineal mass with unusual features on MRI and chronic granulomatous inflammation on histopathology, should raise the suspicion of germinoma. In cases with symptomatic mass effect, open resection can be considered. In cases with lesser mass effect, conventional therapeutic modalities without resection can achieve a good outcome, as for other germinomas.


Progress in monte carlo calculations of fermi systems: normal liquid 3He
The application of the diffusion Monte Carlo method to a strongly interacting Fermi system as normal liquid 3He is explored. We show that the fixed-node method together with the released-node technique and a systematic method to analytically improve the nodal surface constitute an efficient strategy to improve the calculation up to a desired accuracy. This methodology shows unambiguously that backflow correlations are enough to generate an equation of state of liquid 3He in excellent agreement with experimental data from equilibrium up to freezing.


Oral bioaccessibility of toxic and essential elements in raw and cooked commercial seafood species available in European markets.
The oral bioaccessibility of several essential and toxic elements was investigated in raw and cooked commercially available seafood species from European markets. Bioaccessibility varied between seafood species and elements. Methylmercury bioaccessibility varied between 10 (octopus) and 60% (monkfish). Arsenic (>64%) was the toxic element showing the highest bioaccessibility. Concerning essential elements bioaccessibility in raw seafood, selenium (73%) and iodine (71%) revealed the highest percentages. The bioaccessibility of elements in steamed products increased or decreased according to species. For example, methylmercury bioaccessibility decreased significantly after steaming in all species, while zinc bioaccessibility increased in fish (tuna and plaice) but decreased in molluscs (mussel and octopus). Together with human exposure assessment and risk characterization, this study could contribute to the establishment of new maximum permissible concentrations for toxic elements in seafood by the European food safety authorities, as well as recommended intakes for essential elements.


[Normal values of the shoulder strength in dependency on age and gender--comparison with the constant, UCLA, ASES scores and SF36 health survey].
The purpose of this study was to establish normal strength values of shoulder abduction in a male and female population aged between 6 to 90 years. These values were compared to the sex- and age-related values given by Constant for an Irish population, referred to as Constant 1991. Further strength values resulting from fixation of the measuring device at the deltoid insertion or at the wrist were compared. The assessment and comparison of shoulder function using different shoulder scores (Constant, UCLA, ASES) and the SF-36 was another aim of this study. 120 male and 120 female probands were examined. For interpretation age- and sex-related groups of 20 probands each were used (group 1: 6 - 15 years; group 2: 16 - 30 years; group 3: 31 - 45 years; group 4: 46 - 60 years; group 5: 60 - 70 years, group 6: 71 - 90 years). Subjective and objective clinical parameters were registered, shoulder abduction strength was obtained using an isometric measuring device with fixation points at the deltoid insertion and at the wrist and the respective torque values were calculated. The shoulder function was quantified using Constant, UCLA and ASES scores. With the exception of group 1, the quality of life was measured with the SF-36 health-status questionnaire. Normal values of the shoulder abduction strength and valuation according to the Constant score are given for a German reference group related to age and gender. In addition to the Constant score more values for children are given. Strength values measured at the deltoid insertion (fixation point 1, FP1) and wrist (fixation point 2, FP2) are in a linear relation. Thus FP1 = 2.5 x FP2 and FP2 = 0.4 x FP1. If torque values instead of strength are used, 25 points correspond to 50 Nm. Total score values calculated by the use of the Constant score (methods published 1991) were markedly higher in groups 3 - 6 related to the values of Constant in the Irish population; the main reason is the higher abduction strength in our population. There exists a good relation between the Constant, UCLA and ASES scores (Constant 1991). The results of the SF-36 health survey were similar to the results of Bullinger et al. 1996. The normal values of C. R. Constant of an Irish population differ in part to those of our groups due to the different strength values. Our values may be more representative for German patients. The linear regression between strength values measured at a fixation point at the deltoid insertion or the wrist facilitates the calculation of each point from the other. This allows a comparison of the results of studies with different fixation points. The additional calculation of the torque allows a comparison of different studies independently of the fixation point of the strength measuring device.


Routine surveillance imaging after end of therapy for pediatric extracranial tumors: A retrospective analysis.
Frequent surveillance imaging is routine practice for pediatric patients after cancer therapy. This retrospective study evaluated the follow-up of 301 children with extracranial tumors diagnosed between 2002 and 2012, at a tertiary pediatric cancer center in Beirut, Lebanon. Recurrence occurred in 15% of patients, at a median of 12 months after end of primary therapy. Outcome was not different comparing patients with recurrence detected via imaging surveillance versus clinically. False positive findings in 55 patients led to further interventions. These results raise important questions regarding benefit of current surveillance practices as standard care, especially in countries with limited resources.


Diagnostic value of anti-cyclic citrullinated Peptide antibody in patients with rheumatoid arthritis.
To explore the diagnostic value of anti-cyclic citrullinated peptide antibody (anti-CCP) detected by ELISA in patients with rheumatoid arthritis (RA). The synthesized cyclic citrullinated peptide was used as substrate for ELISA. Anti-CCP antibody was detected by ELISA in 191 patients with RA, 132 with rheumatic diseases other than RA, and 98 with nonrheumatic diseases. The antiperinuclear factor (APF), anti-keratin antibody (AKA), rheumatoid factor (RF), and HLA-DR4 gene complex were also tested in each RA patient. The results of these tests were compared with anti-CCP antibody to examine the correlation between them. Ninety (47.1%) patients with RA, 4 (3.0%) with other rheumatic diseases, and 2 (2.0%) with nonrheumatic diseases were found to be anti-CCP antibody positive by ELISA. The sensitivity of anti-CCP antibody was 47.1%, with a high specificity (97.4%) in RA. Anti-CCP antibody correlated with APF, AKA, RF, and HLA-DR4 gene complex. A new modified anti-CCP antibody test had a moderate sensitivity (47.1%) but a high specificity (97.4%) in patients with RA and was found as a valuable supplement to diagnosis of RA. Anti-CCP correlated with APF, AKA, RF, and HLA-DR4 gene complex, but did not completely overlap with them. Anti-CCP antibody could be regarded as a new diagnostic marker for RA.


patRoon: open source software platform for environmental mass spectrometry based non-target screening.
Mass spectrometry based non-target analysis is increasingly adopted in environmental sciences to screen and identify numerous chemicals simultaneously in highly complex samples. However, current data processing software either lack functionality for environmental sciences, solve only part of the workflow, are not openly available and/or are restricted in input data formats. In this paper we present patRoon, a new R based open-source software platform, which provides comprehensive, fully tailored and straightforward non-target analysis workflows. This platform makes the use, evaluation and mixing of well-tested algorithms seamless by harmonizing various common (primarily open) software tools under a consistent interface. In addition, patRoon offers various functionality and strategies to simplify and perform automated processing of complex (environmental) data effectively. patRoon implements several effective optimization strategies to significantly reduce computational times. The ability of patRoon to perform time-efficient and automated non-target data annotation of environmental samples is demonstrated with a simple and reproducible workflow using open-access data of spiked samples from a drinking water treatment plant study. In addition, the ability to easily use, combine and evaluate different algorithms was demonstrated for three commonly used feature finding algorithms. This article, combined with already published works, demonstrate that patRoon helps make comprehensive (environmental) non-target analysis readily accessible to a wider community of researchers.


Ethical considerations for telemedical delivery of fertility care: an Ethics Committee opinion.
Telemedicine has the potential to both increase access to and decrease the cost of care. However, it also alters the nature of the physician-patient relationship and the interaction of patients with the healthcare system, which may limit access to care in some circumstances. Regardless of the modality of care delivery, the basic tenets of medical ethics and the obligations of physicians to their patients still hold.


Temperature modulates immune gene expression in mosquitoes during arbovirus infection.
The principal vector of dengue, Zika and chikungunya viruses is the mosquito Aedes aegypti, with its ability to transmit pathogens influenced by ambient temperature. We use chikungunya virus (CHIKV) to understand how the mosquito transcriptome responds to arbovirus infection at different ambient temperatures. We exposed CHIKV-infected mosquitoes to 18, 28 and 32°C, and found that higher temperature correlated with higher virus levels, particularly at 3 days post infection, but lower temperature resulted in reduced virus levels. RNAseq analysis indicated significantly altered gene expression levels in CHIKV infection. The highest number of significantly differentially expressed genes was observed at 28°C, with a more muted effect at the other temperatures. At the higher temperature, the expression of many classical immune genes, including Dicer-2, was not substantially altered in response to CHIKV. The upregulation of Toll, IMD and JAK-STAT pathways was only observed at 28°C. Functional annotations suggested that genes in immune response and metabolic pathways related to energy supply and DNA replication were involved in temperature-dependent changes. Time post infection also led to substantially different gene expression profiles, and this varied with temperature. In conclusion, temperature significantly modulates mosquito gene expression in response to infection, potentially leading to impairment of immune defences at higher temperatures.


On cosine-modulated wavelet orthonormal bases.
Multiplicity M, K-regular, orthonormal wavelet bases (that have implications in transform coding applications) have previously been constructed by several authors. The paper describes and parameterizes the cosine-modulated class of multiplicity M wavelet tight frames (WTFs). In these WTFs, the scaling function uniquely determines the wavelets. This is in contrast to the general multiplicity M case, where one has to, for any given application, design the scaling function and the wavelets. Several design techniques for the design of K regular cosine-modulated WTFs are described and their relative merits discussed. Wavelets in K-regular WTFs may or may not be smooth, Since coding applications use WTFs with short length scaling and wavelet vectors (since long filters produce ringing artifacts, which is undesirable in, say, image coding), many smooth designs of K regular WTFs of short lengths are presented. In some cases, analytical formulas for the scaling and wavelet vectors are also given. In many applications, smoothness of the wavelets is more important than K regularity. The authors define smoothness of filter banks and WTFs using the concept of total variation and give several useful designs based on this smoothness criterion. Optimal design of cosine-modulated WTFs for signal representation is also described. All WTFs constructed in the paper are orthonormal bases.


Mesh or no mesh: a hamletic dilemma to prevent Renal Allograft Compartment Syndrome (RACS).
Tension-free muscle closure is essential in kidney transplantation, both in adult and pediatric patients. Tight muscle closure may lead to renal allograft compartment syndrome either due to compression of the renal parenchyma or due to kinking of the renal vessels. It may also cause kinking of the transplant kidney ureter, wound dehiscence and incisional hernia. Many techniques have been proposed in an attempt to achieve tension-free closure. There is a wrong belief among surgeons that using prosthetic mesh may increase the incidence of infective complications in these immunosuppressed patients. Also, there is fear that one is not able to monitor the renal graft by ultrasound and perform biopsy in the presence of a mesh. Other alternative techniques to mesh closure include subcutaneous placement and intraperitonealization of the kidney transplant. These techniques however, are valuable when mesh closure is unfavorable or contraindicated as in case of a potential source of infection, like a stoma. Abdominal wall fasciotomy can be adjunctive to the various techniques of muscle closure. Abdominal mesh closure, Post transplant incisional hernia, Renal transplantation, Renal Allograft Compartment syndrome (RACS).


Fluorinated photoreduced graphene oxide with semi-ionic C-F bonds: An effective carbon based photocatalyst for the removal of volatile organic compounds.
There is much interest in developing metal-free halogenated graphene such as fluorinated graphene for various catalytic applications. In this work, a fluorine-doped graphene oxide photocatalyst was investigated for photocatalytic oxidation (PCO) of a volatile organic compound (VOC), namely gaseous methanol. The fluorination process of graphene oxide (GO) was carried out via a novel and facile solution-based photoirradiation method. The fluorine atoms were doped on the surface of the GO in a semi-ionic C-F bond configuration. This presence of the semi-ionic C-F bonds induced a dramatic 7-fold increment of the hole charge carrier density of the photocatalyst. The fluorinated GO photocatalyst exhibited excellent photodegradation up to 93.5% or 0.493 h-1 according pseudo-first order kinetics for methanol. In addition, 91.7% of methanol was mineralized into harmless carbon dioxide (CO2) under UV-A irradiation. Furthermore, the photocatalyst demonstrated good stability in five cycles of methanol PCO. Besides methanol, other VOCs such as acetone and formaldehyde were also photodegraded. This work reveals the potential of fluorination in producing effective graphene-based photocatalyst for VOC removal.


Native Hawaiian and Pacific Islander Elders: What Gerontologists Should Know.
Native Hawaiian and other Pacific Islanders (NHOPI) experience significant health disparities compared with other racial groups in the United States. Lower life expectancy has resulted in small proportions of elders in the population distribution of NHOPI, yet the number of NHOPI elders is growing. This article presents data on NHOPI elders and discusses possible reasons for continuing health disparities, including historical trauma, discrimination, changing lifestyle, and cultural values. We outline promising interventions with NHOPI and make suggestions for future research.


Role of Smac in cephalostatin-induced cell death.
Cephalostatin 1 is a natural compound isolated from a marine worm that induces apoptosis in tumor cells via an apoptosome-independent but caspase-9-dependent pathway and through an endoplasmic reticulum stress response that is accompanied by caspase-4 activation. Here, we show that cephalostatin evokes mitochondrial Smac (second mitochondria-derived activator of caspases) but not cytochrome c release in various carcinoma cell lines. We also show that Smac is critically involved in caspase-9 activation as evidenced by gene silencing experiments. Remarkably, caspase-2 appears to be a major target for cephalostatin-induced cytosolic Smac. Using biochemical and genetic inhibition experiments, we demonstrate that caspase-2 participates in the apoptotic machinery induced by cephalostatin. Cephalostatin-activated caspase-2 appears to act as initiator caspase and is not involved in the activation of caspase-9. Importantly, experiments immunoprecipitating PIDD (p53-induced protein with a DD), RAIDD (RIP-associated ICH-1/CED-3-homologous protein with DD) and caspase-2 identify cephalostatin as an experimental drug that induces the formation of the PIDDosome. The bis-steroid cephalostatin proves to be both a helpful tool to investigate apoptotic signaling and a promising chemotherapeutic agent.


Antiangiogenesis signals by endostatin.
Endostatin is a potent endogenous angiogenesis inhibitor that induces regression of tumors in mice. Neither an extracellular receptor for endostatin nor intracellular signals that result in the regression of tumor vascular beds have been identified. We demonstrate that endostatin, but not angiostatin, at comparable concentrations to those used in in vivo animal trials, rapidly down-regulates many genes in exponentially growing endothelial cells. These include immediate early response genes, cell cycle-related genes, and genes regulating apoptosis inhibitors, mitogen-activated protein kinases, focal adhesion kinase, G-protein-coupled receptors mediating endothelial growth, a mitogenic factor, adhesion molecules, and cell structure components. Suppression of both apoptosis inhibitors and cell proliferation genes may have a limited contribution to the antiangiogenesis process because endostatin induces neither apoptosis nor growth inhibition, unless studied under reduced serum conditions. In contrast, the antimigratory effect of endostatin was rapid and potent even under serum-supplemented conditions. Endostatin caused gene suppression and migration arrest exclusively in endothelial cells, most profoundly in microvascular endothelial cells. The c-myc null fibroblasts obtained by targeted homologous recombination showed an attenuated migration rate compared with isogenic parental cells, whereas the introduction of the c-myc gene into endothelial cells abrogated the antimigratory effect of endostatin. Inhibition of E-box-driven transcription by overexpressing max or mad suppressed endothelial migration. Thus, rapid down-regulation of genes by endostatin neither restores proliferating endothelial cells to their resting states nor induces apoptosis; rather, it potently inhibits endothelial cell migration partly via suppression of c-myc expression.


Tumor Immune Microenvironment and Chemosensitivity Signature for Predicting Response to Chemotherapy in Gastric Cancer.
Current gastric cancer staging alone cannot predict prognosis and adjuvant chemotherapy benefits in stage II and III gastric cancer. Tumor immune microenvironment biomarkers and tumor-cell chemosensitivity might add predictive value to staging. This study aimed to construct a predictive signature integrating tumor immune microenvironment and chemosensitivity-related features to improve the prediction of survival and adjuvant chemotherapy benefits in patients with stage II to III gastric cancer. We used IHC to assess 26 features related to tumor, stroma, and chemosensitivity in tumors from 223 patients and evaluated the association of the features with disease-free survival (DFS) and overall survival (OS). Support vector machine (SVM)-based methods were used to develop the predictive signature, which we call the SVM signature. Validation of the signature was performed in two independent cohorts of 445 patients. The diagnostic signature integrated seven features: CD3+ cells at the invasive margin (CD3 IM), CD8+ cells at the IM (CD8 IM), CD45RO+ cells in the center of tumors (CD45RO CT), CD66b+ cells at the IM (CD66b IM), CD34+ cells, periostin, and cyclooxygenase-2. Patients fell into low- and high-SVM groups with significant differences in 5-year DFS and OS in the training and validation cohorts (all P < 0.001). The signature was an independent prognosis indicator in multivariate analysis in each cohort. The signature had better prognostic value than various clinicopathologic risk factors and single features. High-SVM patients exhibited a favorable response to adjuvant chemotherapy. Thus, this SVM signature predicted survival and has the potential for identifying patients with stage II and III gastric cancer who could benefit from adjuvant chemotherapy.


Placental 5-methylcytosine and 5-hydroxymethylcytosine patterns associate with size at birth.
Altered placental function as a consequence of aberrant imprinted gene expression may be one mechanism mediating the association between low birth weight and increased cardiometabolic disease risk. Imprinted gene expression is regulated by epigenetic mechanisms, particularly DNA methylation (5mC) at differentially methylated regions (DMRs). While 5-hydroxymethylcytosine (5hmC) is also present at DMRs, many techniques do not distinguish between 5mC and 5hmC. Using human placental samples, we show that the expression of the imprinted gene CDKN1C associates with birth weight. Using specific techniques to map 5mC and 5hmC at DMRs controlling the expression of CDKN1C and the imprinted gene IGF2, we show that 5mC enrichment at KvDMR and DMR0, and 5hmC enrichment within the H19 gene body, associate positively with birth weight. Importantly, the presence of 5hmC at imprinted DMRs may complicate the interpretation of DNA methylation studies in placenta; future studies should consider using techniques that distinguish between, and permit quantification of, both modifications.


Resveratrol protects against high glucose-induced steroidogenesis and apoptosis in murine granulosa cells.
Resveratrol (Res) is a polyphenolic compound that exhibits a diverse array of biological effects. Herein, we detected the ability of Res on murine granulosa cells (GCs) against impaired steroidogenesis and apoptotic death in response to high glucose levels. Ovarian GCs were harvested from C57BL/6 mice and cultured in steroidogenic media supplemented with follicle-stimulating hormone (FSH, 30 ng/mL), Res (50 μmol/L), and low or high glucose concentrations (5 mM or 30 mM). After culture for 24 h, cell supernatants were harvested and the levels of progesterone and estradiol therein were measured. Also, caspase-3 activity and the expression of genes associated with apoptosis and steroidogenesis were assessed. High-glucose treatment suppressed steroidogenesis in this assay system, resulting in the impaired expression of steroidogenesis-related genes including Cyp11a1, Cyp19a1, 3βHSD, and StAR and a concomitant decrease in progesterone and estradiol production. Cells exposed to high glucose also exhibited apoptotic phenotypes characterized by Bax upregulation, Bcl-2 downregulation, and increased caspase-3 activity levels. However, Res treatment was sufficient to reverse this high glucose level-induced apoptotic and steroidogenic phenotypes with improving progesterone and estradiol production, and these maybe related the effects of Res on Cyp11a1, Cyp19a1, 3βHSD, and StAR expressions. These data suggested that Res is well suited to overcoming the negative effects of hyperglycemia of GC functionality.


[Psychiatric evaluation of immigrants ].
The psychiatric evaluation of immigrants presents a particular challenge in the medical assessment process. Knowledge of cultural aspects of the aetiology, epidemiology and manifestation as well as the treatment of mental disorders is not only an important facet in daily psychiatric work with immigrants, it is also important for the assessment process itself.


Early Management of Acute Ischaemic Stroke: A Clinical Perspective.
Stroke is a leading cause of disability and mortality globally. In the first few hours after ischaemic stroke, the severity and irreversibility of brain injury increase as time passes. The primary goal of the emergent management of acute ischaemic stroke is stabilization and reperfusion of the ischaemic penumbra if eligibility criteria are met and contraindications are ruled out. The primary reperfusion strategies are administration of intravenous tissue plasminogen activator (IV tPA) and endovascular thrombectomy (EVT). Close monitoring is warranted prior to, during, and after these reperfusion procedures to detect early neurologic deterioration that may signify complications from treatment.


Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes.
Ezrin, radixin, and moesin (ERM) regulate cortical morphogenesis and cell adhesion by connecting membrane adhesion receptors to the actin-based cytoskeleton. We have studied the interaction of moesin and ezrin with the vascular cell adhesion molecule (VCAM)-1 during leukocyte adhesion and transendothelial migration (TEM). VCAM-1 interacted directly with moesin and ezrin in vitro, and all of these molecules colocalized at the apical surface of endothelium. Dynamic assessment of this interaction in living cells showed that both VCAM-1 and moesin were involved in lymphoblast adhesion and spreading on the endothelium, whereas only moesin participated in TEM, following the same distribution pattern as ICAM-1. During leukocyte adhesion in static or under flow conditions, VCAM-1, ICAM-1, and activated moesin and ezrin clustered in an endothelial actin-rich docking structure that anchored and partially embraced the leukocyte containing other cytoskeletal components such as alpha-actinin, vinculin, and VASP. Phosphoinositides and the Rho/p160 ROCK pathway, which participate in the activation of ERM proteins, were involved in the generation and maintenance of the anchoring structure. These results provide the first characterization of an endothelial docking structure that plays a key role in the firm adhesion of leukocytes to the endothelium during inflammation.


[A new case of a rare anomaly of the biliary tract].
We present a 36 year-old female with jaundice, who underwent surgical exploration with the diagnosis of probable biliary fasciolosis vs. Mirizzi´s syndrome. At surgery we found a short common duct leading to the body of gallbladder followed by a long cystic duct draining into the duodenum. Patient underwent hepaticojejunostomy with a Roux Y. The suspicious images of fasciola corresponded to inflammatory nodes in the hepatic hilium. A literature review was conducted and we found very few cases with this rare anomaly, some of them were managed with preservation of a portion of the gallbladder. We discuss the possible implications of this treatment and present an alternative management.


Morphological, molecular, and functional changes in the chicken small intestine of the late-term embryo.
The rapid development of the gastrointestinal tract posthatch has been described; however, little information exists concerning the development of the small intestine in the prehatch period. The present study examined the morphological, cellular, and molecular changes occurring in the small intestine toward the end of the incubation period by examining the expression of intestinal genes that code for brush border digestive enzymes and transporters, their biochemical activities, and the morphological changes in the mucosal layer. The results indicated that during the last 3 d of incubation the weight of the intestine, as a proportion of embryo weight, increased from approximately 1% on d 17 of embryonic age to 3.5% at hatch. At this time the villi could be divided into two main developmental stages, differing in their length and shape, with the larger villi often being pear-shaped and the smaller villi being narrower and having a rocket-like shape. However, on d 19 a further stage of villus development was observed. Activities of maltase, aminopeptidase, sodium-glucose transporter (SGLT)-1, and ATPase began to increase on d 19 and further increased on the day of hatch. The expression of mRNA for these brush-border membrane (BBM) enzymes and transporters was detected from d 15. Determining quantities relative to beta-actin indicated that expression of all parameters examined was low on d 15 and 17, increased 9- to 25-fold on d 19, and all decreased again on the day of hatch. Relative expression of mRNA of the different enzymes and transporters were correlated as were their activities (r = 0.75 to 0.96); however, expression was not correlated with enzymatic activities. The role of these parameters in the ontogeny of absorption is discussed. Thus, major changes in the expression and localization of the functional brush-border proteins prepare the framework for ingestion of carbohydrate- and protein-rich exogenous feed posthatch.


Indo-1 derivatives for local calcium sensing.
The role of calcium in signal transduction relies on the precise spatial and temporal control of its concentration. The existing means to detect fluctuations in Ca2+ concentrations with adequate temporal and spatial resolution are limited. We introduce here a method to measure Ca2+ concentrations in defined locations in living cells that is based on linking the Ca2+-sensitive dye Indo-1 to SNAP-tag fusion proteins. Fluorescence spectroscopy of SNAP-Indo-1 conjugates in vitro showed that the conjugates retained the Ca2+-sensing ability of Indo-1. In a proof-of-principle experiment, local Ca2+ sensing was demonstrated in single cells dissociated from muscle of adult mice expressing a nucleus-localized SNAP-tag fusion. Ca2+ concentrations inside nuclei of resting cells were measured by shifted excitation and emission ratioing of confocal microscopic images of fluorescence. After permeabilizing the plasma membrane, changes in the bathing solution induced corresponding changes in nuclear [Ca2+] that were readily detected and used for a preliminary calibration of the technique. This work thus demonstrates the synthesis and application of SNAP-tag-based Ca2+ indicators that combine the spatial specificity of genetically encoded calcium indicators with the advantageous spectroscopic properties of synthetic indicators.


Regulation of cAMP-stimulated ion current by intracellular pH, Ca2+, and calmodulin blockers.
1. Iontophoretic injection of adenosine 3',5'-cyclic monophosphate (cAMP) into identified neurons elicited a slow transient Na+ current whose amplitude and duration were sensitive to altered intracellular pH (pHi), calmodulin blocking drugs, depolarization, and manipulations of internal and external Ca2+. 2. Intracellular acidification between resting pHi to several tenths of a pH unit increased the amplitude of the cAMP-stimulated current and prolonged its duration. 3. Intracellular alkalinization of similar magnitude also increased the amplitude and duration of the current response. The effects of alkalinization were somewhat labile. In cells alkalinized by NH4+-containing salines, washout of NH4+ with normal saline caused acidification and further enhanced the cAMP current response. The immediacy of the increase and the dual acid/basic sensitivity of the response suggest an accommodative process whereby the responsiveness of the cell to cAMP adapts to a maintained pHi. 4. The calmodulin blockers trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide increased the amplitude and duration of the current response. Phorbol ester activators of Ca2+/phospholipid-dependent kinase had no effect on the current. 5. Periods of depolarization preceding tests significantly reduced current response amplitude. This effect was dependent on saline Ca2+ and was blocked by Co2+. 6. Intracellular injection of the Ca2+ chelator ethylene glycol-bis(beta-aminoethyl ether)N,N,N',N',-tetraacetic acid also augmented the amplitude and duration of the current response. 7. The above effects are consistent with a possible common site of action on cAMP degradation. This interpretation is consistent with previous evidence for pH-sensitive and Ca2+/calmodulin-dependent cAMP phosphodiesterase activity in Pleurobranchaea nervous tissue.


Activation of heat shock response augments fibroblast growth factor-1 expression in wounded lung epithelium.
We previously showed that coincident exposure to heat shock (HS; 42°C for 2 h) and TNF-α synergistically induces apoptosis in mouse lung epithelium. We extended this work by analyzing HS effects on human lung epithelial responses to clinically relevant injury. Cotreatment with TNF-α and HS induced little caspase-3 and poly(ADP-ribose) polymerase cleavage in human small airway epithelial cells, A549 cells, and BEAS2B cells. Scratch wound closure rates almost doubled when A549 and BEAS2B cells and air-liquid interface cultures of human bronchial epithelial cells were heat shocked immediately after wounding. Microarray, qRT-PCR, and immunoblotting showed fibroblast growth factor 1 (FGF1) to be synergistically induced by HS and wounding. Enhanced FGF1 expression in HS/wounded A549 was blocked by inhibitors of p38 MAPK (SB203580) or HS factor (HSF)-1 (KNK-437) and in HSF1 knockout BEAS2B cells. PCR demonstrated FGF1 to be expressed from the two most distal promoters in wounded/HS cells. Wound closure in HS A549 and BEAS2B cells was reduced by FGF receptor-1/3 inhibition (SU-5402) or FGF1 depletion. Exogenous FGF1 accelerated A549 wound closure in the absence but not presence of HS. In the presence of exogenous FGF1, HS slowed wound closure, suggesting that it increases FGF1 expression but impairs FGF1-stimulated wound closure. Frozen sections from normal and idiopathic pulmonary fibrosis (IPF) lung were analyzed for FGF1 and HSP70 by immunofluorescence confocal microscopy and qRT-PCR. FGF1 and HSP70 mRNA levels were 7.5- and 5.9-fold higher in IPF than normal lung, and the proteins colocalized to fibroblastic foci in IPF lung. We conclude that HS signaling may have an important impact on gene expression contributing to lung injury, healing, and fibrosis.


Kinetic modeling of 52Fe/52mMn-citrate at the blood-brain barrier by positron emission tomography.
The kinetics of iron at the blood-brain barrier of the monkey were studied in vivo using positron emission tomography (PET) and the tracer 52Fe/52mMn-citrate. 52mMn is the beta(+)-emitting daughter nuclide of 52Fe and therefore contributes to the observed signal and background in the PET images and may influence the quantification of physiological relevant iron parameters. The kinetics of pure (52m)Mn-citrate at the blood-brain barrier of the monkey were studied experimentally, and the analysis of the data with a reasonable compartment model led to equal efflux and influx parameters for Mn (1.35 +/- 0.3 x 10(-2) min(-1)). By using complexes between Mn and diethylenetriaminepentaacetic acid, the validity of the proposed model could be confirmed. To describe the observed kinetics of 52Fe/(52m)Mn-citrate, the manganese model was coupled to an iron model, which finally allowed the quantification of two iron-specific parameters: an input rate into global brain tissue of 7.15 +/- 2.6 x 10(-4) min(-1) and a time delay of roughly 24 min to account for the observed activities. The simpler linearization procedure has been proposed and could be applied to all our data sets and is able to replace the complicated nonlinear iron/manganese tracer kinetic model neglecting any influence of manganese on the analysis.


The effect of social support around pregnancy on postpartum depression among Canadian teen mothers and adult mothers in the maternity experiences survey.
Postpartum depression (PPD) is a mood disorder that affects 10-20 percent of women, and can begin any time during first year after delivery lasting for months. Social support may decrease risk of depression during pregnancy for women. However, literature shows that the amount of social support received during and after pregnancy is different for teen mothers and adult mothers. This study examined the effects of social support received during and after pregnancy on PPD among Canadian women and identified if the relationship was different for teen mothers compared to adult mothers. The study was based on secondary analysis of the Maternity Experiences Survey. A total of 6,421 women with singleton live births, aged 15 years and older were analyzed. Teen mothers were identified as 15-19 years old and adult mothers were identified as 20 years and older. The main outcome of the study was PPD, which was evaluated using the Edinburg Postnatal Depression Scale. The main independent variable was social support received during pregnancy and after birth. Logistic regression was computed to assess the relationship between social support and PPD after adjusting for confounding variables and age as an interaction term. Adjusted Odds Ratios and 95% Confidence Intervals were reported. PPD was experienced by 14.0% among teen mothers and 7.2% among adult mothers (p < .001). Overall, teen mothers reported receiving more support during pregnancy and after birth than adult mothers (p < .010). The relationship between social support and PPD did not significantly differ for teen compared to adult mothers. Both teen and adult mothers were approximately five times more likely to experience PPD if they received no support or minimal support after the birth of the baby (95% CI, 3.51-7.36). Receiving social support especially after birth is important for mothers of all ages to reduce the risk of PPD.


[Effect of verapamil and nifedipine on the fractional composition of calcium in the blood serum].
A single administration of verapamil (5 mg infused intravenously) and nifedipin (20 mg sublingually) in 31 patients with chronic cardiac failure of stage I and IIA decreased the levels of ionizing calcium (Ca2+) in the blood serum (the maximum reduction averaged 19.8% and 16.8%, respectively). The total concentration of calcium (Ca0) in the blood serum did not alter, so the degree of ionization of the serum calcium (Ca2+/Ca0) decreased. This effect was felt 5 min after verapamil administration and 15 min after nifedipin administration, generally reaching the peak in 30 min and somewhat subsiding in 60 min. The nature and time-course of changes of Ca0 and Ca2+ in the blood serum following the drug administration suggest that they are induced by a transient increase in the Ca-binding capacity of the serum buffers, i. e. they are realized on the physicochemical level. This effect shows no tendency to cumulate following a prolonged (1.3-15 months) administration of the above drugs. The coefficients of the paired correlation between the shifts in the Ca2+ content on the one hand and hemodynamic parameters on the other indicate no significant correlation between them. However, the author believes that the consistent decrease in the Ca2+ concentration in the blood serum is involved in the pharmacodynamics of verapamil and nifedipin.


The Effect of High-Altitude Acclimatisation on Ultra-Short Heart Rate Variability.
High-altitude (HA) exposure affects heart rate variability (HRV) and has been inconsistently linked to acute mountain sickness (AMS). The influence of increasing HA exposure on ultra-short HRV and its relationship to gold standard HRV measures at HA has not been examined. This was a prospective observational study of adults aged ≥ 18 years undertaking a HA trek in the Dhaulagiri region of the Himalayas. Cardiac inter-beat-intervals were obtained from a 10-s recording of supra-systolic blood pressure (Uscom BP+ device) immediately followed by 300 s single lead ECG recording (CheckMyHeart device). HRV was measured using the RMSSD (root mean square of successive differences of NN intervals) at sea level (SL) in the United Kingdom and at 3,619, 4,600, and 5,140 m at HA. Oxygen saturations (SpO2) were measured using finger-based pulse oximetry. The level of agreement between the 10 and 300 s RMSSD values were examined using a modified Bland-Altman relative-difference analysis. Overall, 89 participants aged 32.2 ± 8.8 years (range 18-56) were included of which 70.8% were men. HA exposure (SL vs. 3,619 m) was associated with an initial increase in both 10 s (45.0 [31.0-82.0]) vs. 58.0 [33.0-119.0] ms) and 300 s (45.67 [33.24-70.32] vs. 56.48 [36.98-102.0] ms) in RMSSD. Thereafter at 4,600 and 5,140 m both 10 and 300 s RMSSD values were significantly lower than SL. From a total of 317 paired HRV measures the 10 and 300 s RMSSD measures were moderately correlated (Spearman r = 0.66; 95% CI: 0.59-0.72; p < 0.0001). The median difference (bias) in RMSSD values (300 s - 10 s) was -2.3 ms with a lower and upper limit of agreement of -107.5 and 88.61 ms, respectively with no differences with altitude. Overall, 293/317 (92.4%) of all paired HRV values fell within the 95% CI limits of agreement. Neither HRV method was predictive of AMS. Increasing HA affects ultra-short HRV in a similar manner to gold-standard 300 s. Ultra-short HRV has a moderate agreement with 300 s measurements. HRV did not predict AMS.


Membranes of sorting organelles display lateral heterogeneity in receptor distribution.
This study describes the distribution of an intrinsic membrane protein, the asialoglycoprotein receptor (ASGP-R) in the trans-Golgi reticulum and compartment of uncoupling receptor and ligand (CURL) of rat liver cells. Using quantitative immunogold electron microscopy and membrane length measurements, we showed lateral nonhomogeneity of receptors in the membranes of trans-Golgi reticulum and CURL, in particular in the membranes of secretory vesicles (identified by their content of albumin and very low density lipoprotein particles) and of CURL vesicles (endosomes), including multivesicular bodies. The characteristic tubulovesicular morphology of both sorting organelles defines the transition of receptor-rich tubular membrane and the receptor-poor limiting membrane of the attached vesicles. There was a direct relationship between the size of the secretory and CURL vesicles and the density of ASGP-Rs in their membranes. Receptor density in the smallest vesicles was similar to that found in adjacent continuous tubules. The larger the vesicles, the less receptor was detectable in their membranes. We propose that the receptor molecules are excluded from the vesicle membranes by dynamic lateral redistribution. Nonrandom receptor distribution in the CURL vesicle membranes was present even at the multivesicular body stage. These observations strongly suggest the existence of barriers to ASGP-R diffusion at the junctions of tubules and vesicles. In addition, our observations suggest that ASGP-Rs are transported to the plasma membrane via a mechanism other than the normal secretory pathway.


Dual anti-platelet therapy after coronary artery bypass grafting: is there any benefit? A systematic review and meta-analysis.
Anti-platelet therapy is an important component of medical therapy post coronary artery bypass grafting (CABG). While aspirin administration is a Class I indication after CABG, the benefit of concomitant clopidogrel is a controversial issue. We searched OVID Medline, Cochrane, Scopus, and EMBASE for randomized control trials and observational studies comparing aspirin ± placebo to aspirin + clopidogrel after CABG. Eleven articles (five randomized control trials and six observational studies) including 25,728 patients met inclusion criteria. Early saphenous vein graft occlusion was reduced with the use of dual anti-platelet therapy (risk ratio (RR) = 0.59, 95% CI 0.43-0.82, p = 0.02). In-hospital or 30-day mortality was lower with aspirin + clopidogrel (0.8%) compared to aspirin alone (1.9%) (p < 0.0001), while risk of angina or perioperative myocardial infarction was comparable (RR = 0.60, 95% CI 0.31-1.14, p = 0.12). Patients treated with aspirin + clopidogrel demonstrated a trend towards a higher incidence of major bleeding episodes as compared to patients treated with aspirin alone (RR = 1.17, 95% CI 1.00-1.37, p = 0.05). In a pooled analysis of studies involving off-pump CABG compared to aspirin alone, dual anti-platelet therapy reduced the risk of perioperative myocardial infarction and saphenous graft occlusion by 68% (47% to 71%) and 55% (2% to 79%) respectively. Dual anti-platelet therapy after CABG improved early saphenous vein graft patency, but may increase the risk of bleeding. The use of dual anti-platelet therapy appears to be most beneficial in patients undergoing off-pump CABG. Prospective randomized studies are necessary to determine whether this beneficial effect of dual therapy is also achieved in patients undergoing on pump CABG.


The ARGA study with general practitioners: impact of medical education on asthma/rhinitis management.
To evaluate the impact of a medical education course (MEC) on the behaviour of general practitioners (GPs) to treat asthma and allergic rhinitis (AR). Data on 1820 patients (mean age 41 yrs ± 17 yrs) with asthma or AR were collected by 107 Italian GPs: 50% attended a MEC and 50% didn't (group B). The adherence for AR and asthma treatment was evaluated according to ARIA and GINA guidelines (GL). AR and asthma were diagnosed in 78% and 56% of patients; 34% had concomitant AR and asthma. Regardless of the MEC, the adherence to GL was significantly higher for AR than for asthma treatment (52 versus 19%). Group B GPs were more compliant to ARIA guidelines in the treatment of mild AR, whereas group A were more compliant in the treatment of moderate-severe AR; the adherence didn't differ between the groups for AR patients with comorbid asthma. Adherence to GINA GL for asthma treatment did not differ between GPs of groups A and B, independently from concomitant AR. Though insignificantly, group A were more compliant to GINA GL in the treatment of patients with only severe persistent asthma (63 versus 46%) as group B were for patients with severe persistent asthma and concomitant AR. GPs often tend to treat patients independently from GL. The impact of a single MEC did not improve adherence to GL in treating less severe AR and asthma patients, while there was a trend towards the opposite attitude in more severe AR patients without concomitant asthma.


[Risk assessment in twin pregnancy].
248 twin pregnancies had been examined retrospectively between 1980 and 1988. Each case of twin pregnancy was confronted with a singleton pregnancy of similar age and parity as matched-pair. Aim of the study was to examine the course of delivery as well as fetal outcome. Main reasons of prematurity have been preterm uterine contractions and rupture of fetal membranes. Rates of cesarean sections had been 41.2 per cent in twin pregnancy and 18.8 per cent in singleton ones. Apgar score had been better in singletons. Ph of umbilical artery had similar values in singleton pregnancy and first twin, but lower values in the second twin. Also nowadays twin pregnancy is a risk pregnancy with a 2.3 fold higher perinatal mortality compared with singleton pregnancy in our matched-pair-group.


CRISPR/Cas9 genome editing system confirms centriolin's role in cytokinesis.
In addition to its function as the microtubule organizing center of the cell, the centrosome has functions in many other cellular processes including primary cilia formation, DNA damage checkpoints, and cell cycle progression. But the role of individual components of the centrosome in these processes remains unclear. Previous studies used siRNA (small interfering RNA) to "knock down" protein levels of the centrosome component centriolin, resulting in failed cytokinesis. Since this approach was transient, only targeting centriolin at the mRNA level, we sought to confirm these findings by permanently disrupting the gene encoding centriolin using the CRISPR/Cas9 system of genome editing. This study provides evidence that the CRISPR/Cas9 system is capable of effectively reducing centriolin protein levels in the cell. Furthermore, this disruption leads to a failure of cytokinesis that is reminiscent of the phenotype previously reported for the siRNA-mediated disruption of centriolin. Furthermore, no additional defects in cell division were observed, consistent with results seen with previous siRNA studies. We conclude that the CRISPR/Cas9 system is an effective means of permanently removing the cellular pools of centriolin and that the disruption of centriolin at both the mRNA level and genomic level lead to similar cell division defects.


Distinct fast and slow processes contribute to the selection of preferred step frequency during human walking.
Humans spontaneously select a step frequency that minimizes the energy expenditure of walking. This selection might be embedded within the neural circuits that generate gait so that the optimum is pre-programmed for a given walking speed. Or perhaps step frequency is directly optimized, based on sensed feedback of energy expenditure. Direct optimization is expected to be slow due to the compounded effect of delays and iteration, whereas a pre-programmed mechanism presumably allows for faster step frequency selection, albeit dependent on prior experience. To test for both pre-programmed selection and direct optimization, we applied perturbations to treadmill walking to elicit transient changes in step frequency. We found that human step frequency adjustments (n = 7) occurred with two components, the first dominating the response (66 ± 10% of total amplitude change; mean ± SD) and occurring quite quickly (1.44 ± 1.14 s to complete 95% of total change). The other component was of smaller amplitude (35 ± 10% of total change) and took tens of seconds (27.56 ± 16.18 s for 95% completion). The fast process appeared to be too fast for direct optimization and more indicative of a pre-programmed response. It also persisted even with unusual closed-loop perturbations that conflicted with prior experience and rendered the response energetically suboptimal. The slow process was more consistent with the timing expected for direct optimization. Our interpretation of these results is that humans may rely heavily on pre-programmed gaits to rapidly select their preferred step frequency and then gradually fine-tune that selection with direct optimization.


The difference between induced insight by hints and induced insight by answers: an event-related potential study.
We can solve insight problems by ourselves, by hints or by answers. This study compared the temporal features of different types of insight (spontaneous insight, induced insight by hints and induced insight by answers). Fifteen college students participated in the Chinese Remote Association Task. If they did not come up with an answer, the cue word was presented. Finally, they needed to judge whether the answer was correct or not. Participants' brain electroencephalography-event-related potentials (ERPs) were recorded. Induced insight by hints elicited a more negative ERP deflection than spontaneous insight within 260-400 ms (N2). Induced insight by hints and induced insight by answers elicited a more negative late negative component (LNC) than spontaneous insight. Induced insight by hints elicited a more positive ERP deflection than induced insight by answers and spontaneous insight in the right frontal area. Spontaneous insight and induced insight by answers elicited a more positive ERP deflection than induced insight by hints in the right part of the central region. When solving insight problems, the N2 may be related to representation restructuring. The first LNC may be related to the breaking of mental set. The positive component of the right frontal area before pressing the button may be related to the formation of novel associations, and the positive component of the right part of the central region may be related to the intensity of the 'Aha!' experience.


The flavouring phytochemical 2-pentanone reduces prostaglandin production and COX-2 expression in colon cancer cells.
Many phytochemicals found in the diet may prevent colon carcinogenesis by affecting biochemical processes in the colonic mucosa. Inflammation and subsequent elevation of the enzyme cyclooxygenase-2 (COX-2) are two such factors involved in the development of colon cancer, and inhibition of these processes could be important targets for chemoprevention. We have previously shown COX-2 inhibitory activity locally in the colon; e.g. in human fecal water from a group of vegetarians. In this study we focus on 2-pentanone, a frequently occurring compound in common foods such as banana and carrot. The aim was to study the inhibitory effects on prostaglandin production and COX-2 protein expression in tumour necrosis factor-alpha stimulated colon cancer cells (HT29) by radioimmunoassay and Western blotting. 2-Pentanone inhibited both prostaglandin production and COX-2 protein expression in human colon cancer cells. A concentration of 400 mumol/l 2-pentanone inhibited the prostaglandin production by 56.9+/-12.9% which is in the same range as the reference compound NS398 (59.8+/-7.6%). The two highest concentrations of 2-pentanone were further analyzed by Western blot, and 400 micromol/l and 200 micromol/l 2-pentanone resulted in a 53.3+/-9.6% and +/-27.1% reduction of the COX-2 protein levels respectively. Further studies on flavouring compounds, for example 2-pentanone, as colon cancer chemopreventives would be very valuable, and such results may contribute to future dietary recommendations.


Distribution of thiobacillus ferrooxidans and leptospirillum ferrooxidans: implications for generation of acid mine drainage
Although Thiobacillus ferrooxidans and Leptospirillum ferrooxidans are widely considered to be the microorganisms that control the rate of generation of acid mine drainage, little is known about their natural distribution and abundance. Fluorescence in situ hybridization studies showed that at Iron Mountain, California, T. ferrooxidans occurs in peripheral slime-based communities (at pH over 1.3 and temperature under 30 degreesC) but not in important subsurface acid-forming environments (pH 0.3 to 0.7, temperature 30 degrees to 50 degreesC). Leptospirillum ferrooxidans is abundant in slimes and as a planktonic organism in environments with lower pH. Thiobacillus ferrooxidans affects the precipitation of ferric iron solids but plays a limited role in acid generation, and neither species controls direct catalysis at low pH at this site.


Accuracy of self-reported cancer treatment data in young breast cancer survivors.
Patient-reports of cancer treatments are sometimes used in oncology research and clinically when medical records are unavailable. We aimed to evaluate the accuracy of patient recall in this setting. Participants were recruited through an email request from the Dr. Susan Love Research Foundation Army of Women seeking women diagnosed with breast cancer under age 50 and within the past ten years, self-reporting to have been treated with chemotherapy. After informed consent, participants received a web-based survey that inquired about use of and type of chemotherapy and endocrine therapy received. Medical records were reviewed, and discrepancies were defined as patient-report of a different class of drug than documented in the medical record, failing to report a documented class of drug, or responding "don't know." Of 171 eligible participants, completed questionnaires and medical records were available for 102 (60%). Median age at diagnosis was 41 years (range 25-49), and median time from diagnosis was 65.5 months (range 7-131). Ninety-two percent had completed college. Receipt of chemotherapy was documented in the medical records of 100% of these women who self-reported a personal history of chemotherapy, and there was also 98% concordance regarding receipt of endocrine therapy (yes vs. no). However, discrepancies were identified in 29% of patients regarding chemotherapy types. Time since diagnosis did not increase the likelihood of discrepancies. Highly educated young women diagnosed with breast cancer more than five years prior accurately report whether or not they received broad systemic treatment categories. However, self-reports regarding specific drugs should be confirmed by medical record review.


The influence of persistent organic pollutants in the traditional Inuit diet on markers of inflammation.
Concentrations of persistent organic pollutants (POPs) are high in Inuit living predominately on the traditional marine diet. Adverse effects of POPs include disruption of the immune system and cardiovascular diseases that are frequent in Greenland Inuit. We aimed to assess the association between exposure to POPs from the marine diet and inflammation, taking into account other factors such as vitamin D. We invited Inuit and non-Inuit living in settlements or the town in rural East Greenland or in the capital city Nuuk. Participants completed a food frequency questionnaire and donated a blood sample for measurement of the two markers of inflammation YKL-40 and hsCRP, 25-hydroxy-vitamin D, eleven organochlorine pesticides (OCPs), fourteen polychlorinated biphenyls (PCBs), one polybrominated biphenyl, and nine polybrominated diphenyl ethers (PBDEs) adjusted to the serum lipid content. Participants were 50 through 69 years old, living in settlements, town or city (n = 151/173/211; 95% participation rate). ΣOCP, ΣPCB and ΣPBDE serum levels were higher in Inuit than in non-Inuit (p<0.001/ p<0.001/ p<0.001), in older individuals (p<0.001/p<0.001/p = 0.002) and in participants with the highest intake of Greenlandic food items (p<0.001/p<0.001/p<0.001). Both YKL-40 and hsCRP serum levels were higher in Inuit compared to non-Inuit (p<0.001/p = 0.001), and increased with age (p<0.001/p = 0.001) and with the intake of Greenlandic food items (p<0.001/p = 0.002). Multivariate analysis conformed to a marked influence on both YKL-40 and hsCRP by ΣOCP (p<0.001/p<0.001) and ΣPCBs (p<0.001/p = 0.001) after adjusting for age, BMI, vitamin D, alcohol and smoking. POP levels were associated with the intake of the traditional Inuit diet and with markers of inflammation. This supports a pro-inflammatory role of POPs to promote chronic diseases common to populations in Greenland. These data inform guidelines on 'the Arctic dilemma' and encourage follow-up on the ageing Arctic populations.


Brenner tumor in pregnancy: clinical approach and pathological findings.
The Brenner tumor is an uncommon ovarian tumor in pregnancy with only three previous cases in the English published reports. A 35-year-old woman delivered abdominally because of distress symptoms and a Brenner tumor was resected incidentally. Histological examination revealed a tumor composed of epithelial nests and areas of stromal luteinization. The patient was treated conservatively. Brenner tumor should be considered in the differential diagnosis of adnexal masses during pregnancy. These tumors are mainly benign and show typical luteinization associated with the hormonal milieu in pregnancy.


Adrenergic sensitivity of cultured murine trisomy 16 cells.
Murine trisomy 16 (Ts16) has been proposed as a model to study Down's syndrome (DS), because mouse chromosome 16 carries several genes homologous to loci on the human chromosome 21. A characteristic of DS is an increased sensitivity to adrenergic ligands. We have tested the sensitivity of murine Ts16 fibroblasts and embryonic cells to epinephrine and isoproterenol. A 2-4-fold reduction in the accumulated cyclic AMP (cAMP) was observed in response to these beta 1-adrenergic ligands. Since these cells also accumulated a 2-4-fold reduced amount of cAMP in response to prostaglandin E1, the data suggest that a change in the adenylcyclase of these cells exists which is not seen in cells derived from DS individuals. Therefore, murine Ts16 cells do not appear to constitute an appropriate model to study the altered adrenergic function of DS.


Glycoprotein IIb/IIIa inhibitors.
The GPIIb/IIIa inhibitors are potent anti-platelet agents with proven benefits in the treatment of patients with acute coronary syndromes and/or undergoing PCI. Assessment of the balance of risk and benefit needs to be undertaken in each individual case Consideration needs to be given to the economic impact of using these expensive drugs. There is much research activity in this rapidly evolving field and clinical experience is continually growing.


Association of Baseline Pelvic Floor Muscle Activities With Sexual and Urinary Functions In Female Stress Urinary Incontinence.
The presence of reactive and strong pelvic floor muscle (PFM) activities is supposed to be associated with better urinary and sexual functions in female stress urinary incontinence (SUI). This study was to explore the association of baseline PFM activities, both volitional and reflex, with urinary and sexual functions in women with SUI but who had no experience of PFM training programs before. Secondary analysis of a prospectively maintained database identified 125 sexually active women with SUI who had met the eligibility criteria. All patients had undergone intravaginal digital examination and pelvic ultrasound to detect volitional and reflex PFM activities, respectively, and responded to questionnaire surveys, including short forms of the urogenital distress inventory, incontinence impact questionnaire-7, and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire. On pelvic ultrasound, an inward clitoral motion and an anorectal lift preceding or during coughing were regarded as the presence of reflex activities of the PFM. The relationship of volitional and reflex PFM activities with pelvic floor dysfunction relating questionnaires and urethral function on urodynamic studies was analyzed. Of the 125 women studied, 30 (24.0%) had volitional PFM contraction strength less than grade 2, 74 (59.2%) grade 2 to 3, and 21 (16.8%) greater than grade 3 based on the modified Oxford grading scale. During or preceding coughing, an inward clitoral motion was not observed on ultrasound in 9 (7.2%) women and an anorectal lift was not observed in 8 (6.4%) women. The strength of volitional PFM contraction and the presence or absence of anorectal lift reflex was not associated with urethral and sexual function. In contrast, the absence of reflex inward clitoral motion was significantly associated with lower maximum urethral closure pressure (P = .042) and higher scores of urogenital distress inventory-6 (P = .006) and incontinence impact questionnaire-7 (P = .029). Higher volitional PFM contraction strength was not associated with better sexual and urinary functions; however, loss of one reflex PFM activity was associated with poorer urinary function. To our knowledge, this is the first study that evaluates the association of baseline PFM activities with sexual and urinary functions in female SUI. Nevertheless, the cross-sectional design of this study cannot well support the cause-effect relationship CONCLUSION: Besides PFM physiotherapy for enhancing sexual and urinary functions in female SUI, additional treatment strategies such as neuromodulation should take into consideration for those who had absent reflex PFM activities. Yang E, Yang SH, Huang WC, et al. Association of Baseline Pelvic Floor Muscle Activities With Sexual and Urinary Functions In Female Stress Urinary Incontinence. J Sex Med 2021;18:1698-1704.


A comparative study on the efficacy of artesunate plus sulphadoxine/pyrimethamine versus artemether-lumefantrine in eastern Sudan.
A combination of artesunate (AS) plus sulphadoxine/pyrimethamine (SP) as first-line and artemether-lumefantrine (AL) as second-line treatment are currently recommended against uncomplicated P. falciparum infection in Sudan. However, there is limited information on the efficacy of ACTs in the country and only one report of PCR-corrected results for AS/SP only. The WHO protocol for the assessment of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria was employed. Artesunate plus sulphadoxine/pyrimethamine (AS/SP) was compared to artemether-lumefantrine (AL) in a 28-day follow up. Samples that were classified as early treatment failure (ETF), late treatment failure (LCF) or late parasitological failure (LPF) were genotyped for msp-1 and msp-2 genes to differentiate recrudescence from reinfection. A total of 178 patients were screened and 160 met the enrollment criteria and were recruited to the study of which 157 (98.1%) completed the follow up and had an analysed treatment outcome. On the AS/SP arm, three (0.038%) patients were lost during the follow-up, two on day 1 and one on day 7, and 77 (96.3) completed the study, while all 80 (100%) patients completed the follow up in the AL arm. In the per protocol analysis for AS/SP the treatment outcome for patients who completed the follow-up were as follows: adequate clinical and parasitological response (ACPR); 84.4% ETF; 1.3%, LCF; 3.9%, (LPF); 10.4%. For the AL arm the out come was as follows, ACPR; 90%, ETF; 0%, LCF; 6.3% and LPF; 3.8%. However, when PCR-corrected, 6.5% (5/77) of patients treated with AS/SP maintained parasites from their primary infection, while (7/80) in the AL group maintained their initial parasite genotype. Therefore, PCR-corrected efficacy was 93.5% in the AS/SP treated group and for AL it was 91.3%. Both AS/SP and AL are highly effective for the treatment of uncomplicated falciparum malaria in eastern Sudan. However, AS/SP appears to have a slightly higher efficacy than AL, this may be due to patient compliance with the repeated dose rather than drug efficacy.


COL5A1 haploinsufficiency is a common molecular mechanism underlying the classical form of EDS.
We have identified haploinsufficiency of the COL5A1 gene that encodes the proalpha1(V) chain of type V collagen in the classical form of the Ehlers-Danlos syndrome (EDS), a heritable connective-tissue disorder that severely alters the collagen-fibrillar structure of the dermis, joints, eyes, and blood vessels. Eight of 28 probands with classical EDS who were heterozygous for expressed polymorphisms in COL5A1 showed complete or nearly complete loss of expression of one COL5A1 allele. Reduced levels of proalpha1(V) mRNA relative to the levels of another type V collagen mRNA, proalpha2(V), were also observed in the cultured fibroblasts from EDS probands. Products of the two COL5A1 alleles were approximately equal after the addition of cycloheximide to the fibroblast cultures. After harvesting of mRNAs from cycloheximide-treated cultured fibroblasts, heteroduplex analysis of overlapping reverse transcriptase-PCR segments spanning the complete proalpha1(V) cDNA showed anomalies in four of the eight probands that led to identification of causative mutations, and, in the remaining four probands, targeting of CGA-->TGA mutations in genomic DNA revealed a premature stop at codon in one of them. We estimate that approximately one-third of individuals with classical EDS have mutations of COL5A1 that result in haploinsufficiency. These findings indicate that the normal formation of the heterotypic collagen fibrils that contain types I, III, and V collagen requires the expression of both COL5A1 alleles.


Specific serological markers in the diagnosis of fulminant hepatic failure associated with halothane anaesthesia.
The aetiology of massive liver-cell necrosis which developed in 16 patients following halothane anaesthesia was investigated by means of new serological techniques. In eight patients a specific halothane-related antibody was found, indicating that these patients were sensitized to halothane-altered liver-cell membrane components. In four patients, hepatitis A viral infection was responsible and among the remainder one was receiving anti-tuberculous drugs and one had received a blood transfusion, thus raising the possibility of a non-A non-B viral infection. There were no biochemical or histological differences between patients in the three groups.


The distal lienorenal shunt: perioperative experience with 30 patients.
During the past 51/2 years, thirty consecutive and unselected patients who bled from oesophageal varices underwent distal lienorenal shunt surgery. Eight deaths occurred in the immediate postoperative period. Three of nine emergency patients died because of continued bleeding and, of the five elective patients who died, four were largely the result of technical problems encountered at surgery. In the immediate postoperative period variceal bleeding recurred in five of eight emergency patients despite shunt patency. This did not occur in the elective group. Shunt blockage was relatively common compared to that following conventional porta-systemic shunt surgery; being documented in five of the 24 patients in whom patency was assessed. No clinical, biochemical or histological criteria were identified as predictors of outcome. In particular, the presence of preoperative ascites gave no indication of postoperative problems. However, if ascites developed in the immediate postoperative period, it was a major management problem in 50% of patients. In conclusion, the distal lienorenal shunt has a high perioperative mortality, is commonly complicated by shunt thrombosis and, in the emergency situation, often fails to control bleeding. The technical difficulties encountered at surgery appear largely responsible for the early morbidity and mortality.


Value-Added Clinical Systems Learning Roles for Medical Students That Transform Education and Health: A Guide for Building Partnerships Between Medical Schools and Health Systems.
To ensure physician readiness for practice and leadership in changing health systems, an emerging three-pillar framework for undergraduate medical education integrates the biomedical and clinical sciences with health systems science, which includes population health, health care policy, and interprofessional teamwork. However, the partnerships between medical schools and health systems that are commonplace today use health systems as a substrate for learning. Educators need to transform the relationship between medical schools and health systems. One opportunity is the design of authentic workplace roles for medical students to add relevance to medical education and patient care. Based on the experiences at two U.S. medical schools, the authors describe principles and strategies for meaningful medical school-health system partnerships to engage students in value-added clinical systems learning roles. In 2013, the schools began large-scale efforts to develop novel required longitudinal, authentic health systems science curricula in classrooms and workplaces for all first-year students. In designing the new medical school-health system partnerships, the authors combined two models in an intersecting manner-Kotter's change management and Kern's curriculum development steps. Mapped to this framework, they recommend strategies for building mutually beneficial medical school-health system partnerships, including developing a shared vision and strategy and identifying learning goals and objectives; empowering broad-based action and overcoming barriers in implementation; and generating short-term wins in implementation. Applying this framework can lead to value-added clinical systems learning roles for students, meaningful medical school-health system partnerships, and a generation of future physicians prepared to lead health systems change.


Language style matching predicts relationship initiation and stability.
Previous relationship research has largely ignored the importance of similarity in how people talk with one another. Using natural language samples, we investigated whether similarity in dyads' use of function words, called language style matching (LSM), predicts outcomes for romantic relationships. In Study 1, greater LSM in transcripts of 40 speed dates predicted increased likelihood of mutual romantic interest (odds ratio = 3.05). Overall, 33.3% of pairs with LSM above the median mutually desired future contact, compared with 9.1% of pairs with LSM at or below the median. In Study 2, LSM in 86 couples' instant messages positively predicted relationship stability at a 3-month follow-up (odds ratio = 1.95). Specifically, 76.7% of couples with LSM greater than the median were still dating at the follow-up, compared with 53.5% of couples with LSM at or below the median. LSM appears to reflect implicit interpersonal processes central to romantic relationships.


Treatment of Congenital Thrombotic Thrombocytopenia Purpura: A New Paradigm.
Congenital thrombotic thrombocytopenia purpura (cTTP) is a very rare disorder worldwide. Standard treatment of recognized cases has been to administer fresh frozen plasma as the source of ADAMTS13, to replenish the absent ADAMTS13 enzyme. An alternative source, a plasma-derived factor VIII concentrate used for hemophilia A, and found to contain this enzyme, was reported to be effective in 1 patient in the United States. We now report details on a US cohort of 8 cTTP patients who have been successfully treated for varying periods with a marketed antihemophilic factor concentrate Koate-DVI. This biological product has been used successfully on demand in varying doses to treat acute exacerbations, as well as prophylactically (3 to 6 U ADAMTS13 every 3 to 21 d). Self-infused at home, in lieu of fresh frozen plasma therapy in the hospital setting, this product has effectively prevented episodes of thrombocytopenia, microangiopathic hemolytic anemia, and the concomitant organ damage in these patients. This specific virus inactivated product can be used to prevent further manifestations of this congenital enzyme deficiency.


Plasma viscosity, functional fibrinogen, and platelet reactivity in vascular surgery patients.
Platelet reactivity changes with shear stress, which in turn depends on whole blood and plasma viscosity (PV). Platelets interact with fibrinogen during thrombus formation, and fibrinogen is a determinant of PV. The respective role of PV and fibrinogen on platelet function is still unclear. 30 patients undergoing vascular surgery were admitted to this study. In each patient we measured PV using a cone-on-plate viscosimeter, functional fibrinogen using thromboelastometry, and platelet reactivity to thrombin receptor activating peptide (TRAP) stimulation using multi-electrode aggregometry. Routine coagulation parameter were measured. At the univariate analysis, platelet reactivity was positively associated with mean platelet volume (R2 = 0.15, P = 0.033) and PV (R2 = 0.35, P = 0.0006), and negatively associated with serum bilirubin (R2 = 0.20, P = 0.013) and international normalized ratio (INR) (R2 = 0.19, P = 0.017). At the multivariable analysis, only PV (P = 0.001) and INR (P = 0.019) remained independent predictors of platelet reactivity. PV is directly and independently associated with platelet reactivity, whereas functional fibrinogen is not. Aspirin treatment is inadequate to correct thrombin-induced platelet aggregation. In presence of hyperviscosity, patients at high cardiovascular risk, may benefit from more aggressive anti-platelet treatments.


Extracellular calcium antagonizes forskolin-induced aquaporin 2 trafficking in collecting duct cells.
Urinary concentrating defects and polyuria are the most important renal manifestations of hypercalcemia and the resulting hypercalciuria. In this study, we tested the hypothesis that hypercalciuria-associated polyuria in kidney collecting duct occurs through an impairment of the vasopressin-dependent aquaporin 2 (AQP2) water channel targeting to the apical membrane possibly involving calcium-sensing receptor (CaR) signaling. AQP2-transfected collecting duct CD8 cells were used as experimental model. Quantitation of cell surface AQP2 immunoreactivity was performed using an antibody recognizing the extracellular AQP2 C loop. Intracellular cyclic adenosine monophosphate (cAMP) accumulation was measured in CD8 cells using a cAMP enzyme immunoassay kit. To study the translocation of protein kinase C (PKC), membranes or cytosol fractions from CD8 cells were subjected to Western blotting using anti-PKC isozymes antibodies. The amount of F-actin was determined by spectrofluorometric techniques. Intracellular calcium measurements were performed by spectrofluorometric analysis with Fura-2/AM. We demonstrated that extracellular calcium (Ca2+ o) (5 mmol/L) strongly inhibited forskolin-stimulated increase in AQP2 expression in the apical plasma membrane. At least three intracellular pathways activated by extracellular calcium were found to contribute to this effect. Firstly, the increase in cAMP levels in response to forskolin stimulation was drastically reduced in cells pretreated with Ca2+ o compared to untreated cells. Second, Ca2+ o activated PKC, known to counteract vasopressin response. Third, quantification of F-actin demonstrated that Ca2+ o caused a nearly twofold increase in F-actin content compared with basal conditions. All these effects were mimicked by a nonmembrane permeable agonist of the extracellular CaR, Gd3+. Together, these data demonstrate that extracellular calcium, possibly acting through the endogenous CaR, antagonizes forskolin-induced AQP2 translocation to the apical plasma membrane in CD8 cells. In hypercalciuria, this mechanism might blunt water reabsorption and prevent further calcium concentration, thus protecting against a potential risk of urinary calcium-containing stone formation.


Expression of root-related transcription factors associated with flooding tolerance of soybean (Glycine max).
Much research has been conducted on the changes in gene expression of the model plant Arabidopsis to low-oxygen stress. Flooding results in a low oxygen environment in the root zone. However, there is ample evidence that tolerance to soil flooding is more than tolerance to low oxygen alone. In this study, we investigated the physiological response and differential expression of root-related transcription factors (TFs) associated with the tolerance of soybean plants to soil flooding. Differential responses of PI408105A and S99-2281 plants to ten days of soil flooding were evaluated at physiological, morphological and anatomical levels. Gene expression underlying the tolerance response was investigated using qRT-PCR of root-related TFs, known anaerobic genes, and housekeeping genes. Biomass of flood-sensitive S99-2281 roots remained unchanged during the entire 10 days of flooding. Flood-tolerant PI408105A plants exhibited recovery of root growth after 3 days of flooding. Flooding induced the development of aerenchyma and adventitious roots more rapidly in the flood-tolerant than the flood-sensitive genotype. Roots of tolerant plants also contained more ATP than roots of sensitive plants at the 7th and 10th days of flooding. Quantitative transcript analysis identified 132 genes differentially expressed between the two genotypes at one or more time points of flooding. Expression of genes related to the ethylene biosynthesis pathway and formation of adventitious roots was induced earlier and to higher levels in roots of the flood-tolerant genotype. Three potential flood-tolerance TFs which were differentially expressed between the two genotypes during the entire 10-day flooding duration were identified. This study confirmed the expression of anaerobic genes in response to soil flooding. Additionally, the differential expression of TFs associated with soil flooding tolerance was not qualitative but quantitative and temporal. Functional analyses of these genes will be necessary to reveal their potential to enhance flooding tolerance of soybean cultivars.


PSYCHOLOGICAL FACTORS IN 155 PATIENTS WITH FUNCTIONAL UTERINE BLEEDING.
One hundred and fifty-five women with functional uterine bleeding were studied to evaluate the importance of concomitant psychological disorders. Psychological illnesses were diagnosed in 128 patients (82.6%), most of which arose from problems directly related to sexual or reproductive functions. The remaining 27 patients (17.4%) were different in that they were psychologically stable and all but two were at puberty or approaching the menopause.Histological studies of endometrial samples from 135 of these patients indicated little evidence of abnormal sex hormone activity; 77 (57%) showed normal secretory phase endometrium and 32 (23.7%), proliferative phase endometrium. The remaining 26 (19.2%) showed evidence of some endocrine dysfunction, 15 such specimens being obtained from psychologically stable patients.It is probable that psychological disturbances are the principal cause of functional uterine bleeding during the prime reproductive years. The psychological component of the illness is the most important and determines the ultimate prognosis.


MnSOD and catalase transgenes demonstrate that protection of islets from oxidative stress does not alter cytokine toxicity.
Reactive oxygen species (ROS) and nitric oxide (NO) are proposed mediators of cytokine-induced beta-cell destruction in type 1 diabetes. We produced transgenic mice with increased beta-cell expression of manganese superoxide dismutase (MnSOD) and catalase. Expression of these antioxidants increased beta-cell ROS scavenging and improved beta-cell survival after treatment with different sources of ROS. MnSOD or catalase conferred protection against streptozotocin (STZ)-induced beta-cell injury. Coexpression of MnSOD and catalase provided synergistic protection against peroxynitrite and STZ. To determine the potential effect of these antioxidants on cytokine-induced toxicity, we exposed isolated islets to a cytokine mixture, including interleukin-1beta and interferon-gamma. Cytokine toxicity was measured as reduced metabolic activity after 6 days and reduced insulin secretion after 1 day. Cytokines increased ROS production, and both antioxidants were effective in reducing cytokine-induced ROS. However, MnSOD and/or catalase provided no protection against cytokine-induced injury. To understand this, the nuclear factor-kappaB (NF-kappaB) signaling cascade was investigated. Antioxidants reduced NF-kappaB activation by ROS, but none of the antioxidants altered activation by cytokines, as measured by inhibitor of kappaB phosphorylation, NF-kappaB translocation, inducible NO synthase activation, and NO production. Our data agree with previous reports that antioxidants benefit beta-cell survival against ROS damage, but they are not consistent with reports that antioxidants reduce cytokine toxicity. ROS appear to have no role in cytokine toxicity in primary beta-cells.


Representation of Women and Minorities in Clinical Trials for New Molecular Entities and Original Therapeutic Biologics Approved by FDA CDER from 2013 to 2015.
The U.S. Food and Drug Administration (FDA) has made efforts to encourage adequate assessment of women, racial/ethnic minorities, and geriatric participants in clinical trials through regulations and guidance documents. This study surveyed the demographics of clinical trial participants and the presence of efficacy and safety analyses by sex for new drugs approved between 2013 and 2015 by the FDA Center for Drug Evaluation and Research. New drug marketing applications submitted to FDA were surveyed for demographic data (sex, race, ethnicity, and age) and the presence of sex-based analyses for efficacy and safety. The Ratio of the Proportion of women in clinical trials for the indicated disease population relative to the estimated Proportion of women in the disease population (PPR) was calculated for new drug indications. Of the 102 new drugs in this cohort (defined as new molecular entity drugs and original therapeutic biologics), sex was reported for >99.9% of trial participants, and women accounted for 40.4% of these participants. An estimated 77.2% of participants were White, 6.4% were Black/African American, and 29.1% were aged ≥65 years. Sex-based analyses for both efficacy and safety were conducted for 93.1% of applications. PPR was calculated for 82 new drugs for a total of 60 indications, of which 50 indications (83.3%) had a PPR ≥0.80. Sex data are now collected for almost all study participants, and this study shows appropriate sex participation for most new drugs when estimated disease prevalence by sex (PPR) is considered. Therapeutic area and disease indication are important considerations when assessing the sex of participants because variation occurs depending on the disease under study. Some racial minorities, especially Blacks/African Americans, are still not well represented in most drug development programs and remain an area where improvement is needed.


Detection of trait donors and QTL boundaries for early blight resistance using local ancestry inference in a library of genomic sequences for tomato.
By conducting hierarchical clustering along a sliding window, we generated haplotypes across hundreds of re-sequenced genomes in a few hours. We leveraged our method to define cryptic introgressions underlying disease resistance in tomato (Solanum lycopersicum L.) and to discover resistant germplasm in the tomato seed bank. The genomes of 9 accessions with early blight (Alternaria linariae) disease resistance were newly sequenced and analyzed together with published sequences for 770 tomato and wild species accessions, most of which are available in germplasm collections. Identification of common ancestral haplotypes among resistant germplasm enabled rapid fine mapping of recently discovered quantitative trait loci (QTL) conferring resistance and the identification of possible causal variants. The source of the early blight QTL EB-9 was traced to a vintage tomato named 'Devon Surprise'. Another QTL, EB-5, as well as resistance to bacterial spot disease (Xanthomonas spp.), was traced to Hawaii 7998. A genomic survey of all accessions forecasted EB-9-derived resistance in several heirloom tomatoes, accessions of S. lycopersicum var. cerasiforme, and S. pimpinellifolium PI 37009. Our haplotype-based predictions were validated by screening the accessions against the causal pathogen. There was little evidence of EB-5 prevalence in surveyed contemporary germplasm, presenting an opportunity to bolster tomato disease resistance by adding this rare locus. Our work demonstrates practical insights that can be derived from the efficient processing of large genome-scale datasets, including rapid functional prediction of disease resistance QTL in diverse genetic backgrounds. Finally, our work finds more efficient ways to leverage public genetic resources for crop improvement.


White Matter Integrity Underlies the Physical-Cognitive Correlations in Subjective Cognitive Decline.
Objective: Although previous studies postulated that physical and cognitive decline codeveloped in preclinical dementia, the interconnected relationship among subjective cognitive complaints (SCCs), objective cognitive performance, and physical activity remained hazy. We investigated the mediating roles of physical activity between subjective and objective cognition. Diffusion tensor imaging (DTI) was utilized to test our hypothesis that brain white matter microstructural changes underlie the physical-cognitive decline in subjective cognitive decline (SCD). Methods: We enrolled cognitively normal older adults aged > 50 years in the Community Medicine Research Center of Keelung Chang Gung Memorial Hospital during 2017-2020. Regression models analyzed mediation effects of physical activity between subjective and objective cognition. The self-reported AD8 questionnaire assessed SCCs. The SCD group, defined by AD8 score ≥ 2, further underwent diffusion MRI scans. Those who agreed to record actigraphy also wore the SOMNOwatch™ for 72 h. Spearman's correlation coefficients evaluated the associations of diffusion indices with physical activity and cognitive performance. Results: In 95 cognitively normal older adults, the AD8 score and the Montreal Cognitive Assessment (MoCA) score were mediated partially by the metabolic equivalent of the International Physical Activity Questionnaire-Short Form (IPAQ-SF MET) and fully by the sarcopenia score SARC-F. That is, the relation between SCCs and poorer cognitive performance was mediated by physical inactivity. The DTI analysis of 31 SCD participants found that the MoCA score correlated with mean diffusivity at bilateral inferior cerebellar peduncles and the pyramids segment of right corticospinal tract [p < 0.05, false discovery rate (FDR) corrected]. The IPAQ-SF MET was associated with fractional anisotropy (FA) at the right posterior corona radiata (PCR) (p < 0.05, FDR corrected). In 15 SCD participants who completed actigraphy recording, the patterns of physical activity in terms of intradaily variability and interdaily stability highly correlated with FA of bilateral PCR and left superior corona radiata (p < 0.05, FDR corrected). Conclusions: This study addressed the role of physical activity in preclinical dementia. Physical inactivity mediated the relation between higher SCCs and poorer cognitive performance. The degeneration of specific white matter tracts underlay the co-development process of physical-cognitive decline in SCD.


Dihydropyridine binding sites regulate calcium influx through specific voltage-sensitive calcium channels in cerebellar granule cells.
In primary cultures of cerebellar granule cells, [3H]nitrendipine binds with high affinity to a single site (KD 1 nM and Bmax 20 fmol/mg protein). The 1,4-dihydropyridine (DHP) class of compounds such as nitrendipine, nifedipine, and BAY K 8644 displace [3H]nitrendipine binding at nanomolar concentrations. Verapamil partially inhibits whereas diltiazem slightly increases the [3H]nitrendipine binding. In these cells, the calcium influx that is induced by depolarization is very rapid and is blocked by micromolar concentrations of inorganic calcium blockers such as cadmium, cobalt, and manganese. The calcium influx resulting from cell depolarization is potentiated by BAY K 8644 and partially inhibited (approximately 40%) by nitrendipine and nifedipine. Other non-DHP voltage-sensitive calcium channel (VSCC) antagonists, such as verapamil and diltiazem, completely blocked the depolarization-induced calcium influx. This suggested that nitrendipine and nifedipine block only a certain population of VSCCs. In contrast, verapamil and diltiazem do not appear to be selective and block all of VSCCs. Perhaps some VSCCs can be allosterically modulated by the binding site for the DHPs, whereas verapamil and diltiazem may block completely the function of all VSCCs by occupying a site that differs from the DHP binding site.


Adaptive learning can result in a failure to profit from good conditions: implications for understanding depression.
Depression is a major medical problem diagnosed in an increasing proportion of people and for which commonly prescribed psychoactive drugs are frequently ineffective. Development of treatment options may be facilitated by an evolutionary perspective; several adaptive reasons for proneness to depression have been proposed. A common feature of many explanations is that depressive behaviour is a way to avoid costly effort where benefits are small and/or unlikely. However, this viewpoint fails to explain why low mood persists when the situation improves. We investigate whether a behavioural rule that is adapted to a stochastically changing world can cause inactivity which appears similar to the effect of depression, in that it persists after the situation has improved. We develop an adaptive learning model in which an individual has repeated choices of whether to invest costly effort that may result in a net benefit. Investing effort also provides information about the current conditions and rates of change of the conditions. An individual following the optimal behavioural strategy may sometimes remain inactive when conditions are favourable (i.e. when it would be better to invest effort) when it is poorly informed about the current environmental state. Initially benign conditions can predispose an individual to inactivity after a relatively brief period of negative experiences. Our approach suggests that the antecedent factors causing depressed behaviour could go much further back in an individual s history than is currently appreciated. The insights from our approach have implications for the ongoing debate about best treatment options for patients with depressive symptoms.