Artificial Intelligence-Assisted Evaluation of the Spatial Relationship between Brain Arteriovenous Malformations and the Corticospinal Tract to Predict Postsurgical Motor Defects.
Preoperative evaluation of brain AVMs is crucial for the selection of surgical candidates. Our goal was to use artificial intelligence to predict postsurgical motor defects in patients with brain AVMs involving motor-related areas. Eighty-three patients who underwent microsurgical resection of brain AVMs involving motor-related areas were retrospectively reviewed. Four artificial intelligence-based indicators were calculated with artificial intelligence on TOF-MRA and DTI, including FN5mm/50mm (the proportion of fiber numbers within 5-50mm from the lesion border), FN10mm/50mm (the same but within 10-50mm), FP5mm/50mm (the proportion of fiber voxel points within 5-50mm from the lesion border), and FP10mm/50mm (the same but within 10-50mm). The association between the variables and long-term postsurgical motor defects was analyzed using univariate and multivariate analyses. Least absolute shrinkage and selection operator regression with the Pearson correlation coefficient was used to select the optimal features to develop the machine learning model to predict postsurgical motor defects. The area under the curve was calculated to evaluate the predictive performance. In patients with and without postsurgical motor defects, the mean FN5mm/50mm, FN10mm/50mm, FP5mm/50mm, and FP10mm/50mm were 0.24 (SD, 0.24) and 0.03 (SD, 0.06), 0.37 (SD, 0.27) and 0.06 (SD, 0.08), 0.06 (SD, 0.10) and 0.01 (SD, 0.02), and 0.10 (SD, 0.12) and 0.02 (SD, 0.05), respectively. Univariate and multivariate logistic analyses identified FN10mm/50mm as an independent risk factor for long-term postsurgical motor defects (P = .002). FN10mm/50mm achieved a mean area under the curve of 0.86 (SD, 0.08). The mean area under the curve of the machine learning model consisting of FN10mm/50mm, diffuseness, and the Spetzler-Martin score was 0.88 (SD, 0.07). The artificial intelligence-based indicator, FN10mm/50mm, can reflect the lesion-fiber spatial relationship and act as a dominant predictor for postsurgical motor defects in patients with brain AVMs involving motor-related areas.


National epidemiology of mycoses survey (NEMIS): variations in rates of bloodstream infections due to Candida species in seven surgical intensive care units and six neonatal intensive care units.
Candida species are the fourth most frequent cause of nosocomial bloodstream infections, and 25%-50% occur in critical care units. During an 18-month prospective study period, all patients admitted for > or = 72 hours to the surgical (SICUs) or neonatal intensive care units (NICUs) at each of the participant institutions were followed daily. Among 4,276 patients admitted to the seven SICUs in six centers, there were 42 nosocomial bloodstream infections due to Candida species (9.8/1,000 admissions; 0.99/1,000 patient-days). Of 2,847 babies admitted to the six NICUs, 35 acquired a nosocomial bloodstream infection due to Candida species (12.3/1,000 admissions; 0.64/1,000 patient-days). The following were the most commonly isolated Candida species causing bloodstream infections in the SICU: Candida albicans, 48%; Candida glabrata, 24%; Candida tropicalis, 19%; Candida parapsilosis, 7%; Candida species not otherwise specified, 2%. In the NICU the distribution was as follows: C. albicans, 63%; C. glabrata, 6%; C. parapsilosis, 29%; other, 3%. Of the patients, 30%-50% developed incidental stool colonization, 23% of SICU patients developed incidental urine colonization, and one-third of SICU health care workers' hands were positive for Candida species.


[Malnutrition of home-based hospital patients].
We pretend to know the nutritional state in all patients that are being treated in the the Home Care Services Hospital Based (HCSHB) units, be which is their entrance causes and we also pretend to know the prevalence of undernutrition. To know the prevalence of nutritional treatments in the HCSHB units, their relationship with the nutritional state, the pathology and the patient's origin inside the sanitary environment. A Multicentric study, in which the HCSHB units of three hospitals of the Valencia Community have intervened. 40 patients that remained in that moment entered by different causes in the HCSHB units. Sex, age. Origin service, pathology, Subjective Global Valuation (SGV), IMC, nutritional support, type of nutritional support, albumin, Cholesterol, lymphocytes. The half age has been of 77,45 years (SD 11 years) with 67,5% of males. The patients, in all the cases, came from hospital Services, being the pathology responsible for the entrance mainly the oncological 32,5%, surgical 7,5%, neurological 7,5% and 52,5% others. According to GSV 52.5% present a good nutritional status, 37.5% had a suspect of under nourishment and 10% had a clear under nourishment. The IBM for the 12.5% of the patients is < or = 20 and the IBM for the 42.5% < or = 22. The 35% were receiving nutritional support, supplements the 78% and oral enteral nutrition the 14% of the patients. We have found a lineal relation between the IBM and the levels of albumin that the patients presented, also with the figures of cholesterol and it has not been found any relationship with the lymphocytes number.


Comorbidity in childhood in northern Ghana: magnitude, associated factors, and impact on mortality.
It has been observed that in developing countries terminal illness in children under 5 yr of age is frequently characterized by comorbidity. This study seeks to quantify the co-occurrence of illness at the community level and investigates whether this co-occurrence increases the risk of mortality. We develop an appropriate measure of co-occurrence and investigate whether the comorbidity occurs by chance or whether it is due to shared risk factors. The data used for the analysis was taken from a study carried out from 1989 to 1991 in northern Ghana on children aged 2-59 months (n = 1879). Coding for diarrhoea, pneumonia, and measles was carried out using the classification system of the WHO/UNICEF strategy for the Integrated Management of Childhood Illness; malaria was confirmed by laboratory analysis. A bivariate probit analysis was conducted to quantify comorbidity. We used an additive regression model, implemented using the Generalized Estimating Equation approach, to examine the impact on mortality. There is evidence of co-occurrence of diarrhoeal diseases and pneumonia, with greater comorbidity with increasing severity of disease. There is no evidence that the co-occurrence of diarrhoea with severe dehydration and severe pneumonia is characterized by a synergistic effect on mortality risk. Our study has shown that it is possible to have significant co-occurrence of illness at the community level. The bivariate probit procedure was easily adopted and considered appropriate for the analysis of comorbidity. The lack of suitable datasets for a more thorough analysis of comorbidity, and for the evaluation of synergistic effects on mortality, is a major limitation.


Simultaneous release of diclofenac sodium and papaverine hydrochloride from tablets and pellets using the flow-through cell apparatus described by dimensionless equations.
The release of diclofenac sodium and papaverine hydrochloride from tablets and pellets using the flow-through cell apparatus was studied. The influence of excipients and of a size of the solid dosage forms on the amount of the released substances at the intervals of time using the different rates of flow of the dissolution medium was investigated. Physical parameters corresponding to the dissolution process as the mass transfer coefficient, the thickness of the boundary diffusion layer and the concentration of the saturated solution at this layer were calculated. The results of release were described by dimensionless equations.


Proteasome Activity Is Affected by Fluctuations in Insulin-Degrading Enzyme Distribution.
Insulin-Degrading-Enzyme (IDE) is a Zn2+-dependent peptidase highly conserved throughout evolution and ubiquitously distributed in mammalian tissues wherein it displays a prevalent cytosolic localization. We have recently demonstrated a novel Heat Shock Protein-like behaviour of IDE and its association with the 26S proteasome. In the present study, we examine the mechanistic and molecular features of IDE-26S proteasome interaction in a cell experimental model, extending the investigation also to the effect of IDE on the enzymatic activities of the 26S proteasome. Further, kinetic investigations indicate that the 26S proteasome activity undergoes a functional modulation by IDE through an extra-catalytic mechanism. The IDE-26S proteasome interaction was analyzed during the Heat Shock Response and we report novel findings on IDE intracellular distribution that might be of critical relevance for cell metabolism.


Inhibitory effects of cinnamic acid on melanin biosynthesis in skin.
Cinnamic acid is a wildly distributed phenylpropanoid component naturally occurring in plants, and is mainly found in Cinnamomum cassia BLUME and Panax ginseng. Cinnamic acid was recently reported to exert a tyrosinase inhibitory effect. However, research on melanocytes and animal bodies was not reported until now. In this study, we examined the effects of cinnamic acid on melanin biosynthesis within the melanocytes and brown guinea pigs. Melan-a cells were used to examine the effects of cinnamic acid in the melanocytes. Treatment with 100 ppm of cinnamic acid resulted in a significant reduction of melanin production in the melan-a cells at 29.0%. This compound also exhibited a potent inhibitory effect on tyrosinase activity and reduced tyrosinase expression in the melan-a cells. Moreover, cinnamic acid exhibited depigmenting activity on the UV-B-induced hyperpigmentation of brown guinea pig skin. Our results suggest that cinnamic acid might act as a skin whitening agent via inhibition of tyrosinase activity and expression within melanocytes.


MicroRNA signatures differentiate melanoma subtypes.
Melanoma is an aggressive cancer that is highly resistance to therapies once metastasized. We studied microRNA (miRNA) expression in clinical melanoma subtypes and evaluated different miRNA signatures in the background of gain of function somatic and inherited mutations associated with melanoma. Total RNA from 42 patient derived primary melanoma cell lines and three independent normal primary melanocyte cell cultures was evaluated by miRNA array. MiRNA expression was then analyzed comparing subtypes and additional clinicopathologic criteria including somatic mutations. The prevalence and association of an inherited variant in a miRNA binding site in the 3'UTR of the KRAS oncogene, referred to as the KRAS-variant, was also evaluated. We show that seven miRNAs, miR-142-3p, miR-486, miR-214, miR-218, miR-362, miR-650 and miR-31, were significantly correlated with acral as compared to non-acral melanomas (p < 0.04). In addition, we discovered that the KRAS-variant was enriched in non-acral melanoma (25%), and that miR-137 under expression was significantly associated with melanomas with the KRAS-variant. Our findings indicate that miRNAs are differentially expressed in melanoma subtypes and that their misregulation can be impacted by inherited gene variants, supporting the hypothesis that miRNA misregulation reflects biological differences in melanoma.


Down-regulation of SFRP1 as a putative tumor suppressor gene can contribute to human hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. SFRP1 (the secreted frizzled-related protein 1), a putative tumor suppressor gene mapped onto chromosome 8p12-p11.1, the frequent loss of heterozygosity (LOH) region in human HCC, encodes a Wingless-type (Wnt) signaling antagonist and is frequently inactivated by promoter methylation in many human cancers. However, whether the down-regulation of SFRP1 can contribute to hepatocarcinogenesis still remains unclear. We investigated the expression of SFRP1 through real time RT-PCR and immunohistochemistry staining. The cell growth and colony formation were observed as the overexpression and knockdown of SFRP1. The DNA methylation status within SFRP1 promoter was analyzed through methylation-specific PCR or bisulphate-treated DNA sequencing assays. Loss of heterozygosity was here detected with microsatellite markers. SFRP1 was significantly down-regulated in 76.1% (35/46) HCC specimens at mRNA level and in 30% (30/100) HCCs indicated by immunohistochemistry staining, as compared to adjacent non-cancerous livers. The overexpression of SFRP1 can significantly inhibit the cell growth and colony formation of YY-8103, SMMC7721, and Hep3B cells. The RNA interference against the constitutional SFRP1 in the offspring SMMC7721 cells, which were stably transfected by ectopic SFRP1, can markedly promote cell growth of these cells. LOH of both microsatellite markers D8S532 and D8SAC016868 flanking the gene locus was found in 13% (6 of 46 HCCs) and 6.5% (3 of 46 HCCs) of the informative cases, respectively, where 5 of 8 HCC specimens with LOH showed the down-regulation of SFRP1. DNA hypermethylation within SFRP1 promoter was identified in two of three HCC specimens without SFRP1 expression. Moreover, the DNA methylation of SFRP1 promoter was significantly reduced, along with the re-expression of the gene, in those HCC cell lines, Bel7404, QGY7701, and MHCC-H, as treated by DAC. Our data suggested that the down-regulation of SFRP1 as a candidate tumor suppressor gene, triggered by the epigenetic and/or genetic events, could contribute to the oncogenesis of HCC.


Predicting wildlife reservoirs and global vulnerability to zoonotic Flaviviruses.
Flaviviruses continue to cause globally relevant epidemics and have emerged or re-emerged in regions that were previously unaffected. Factors determining emergence of flaviviruses and continuing circulation in sylvatic cycles are incompletely understood. Here we identify potential sylvatic reservoirs of flaviviruses and characterize the macro-ecological traits common to known wildlife hosts to predict the risk of sylvatic flavivirus transmission among wildlife and identify regions that could be vulnerable to outbreaks. We evaluate variability in wildlife hosts for zoonotic flaviviruses and find that flaviviruses group together in distinct clusters with similar hosts. Models incorporating ecological and climatic variables as well as life history traits shared by flaviviruses predict new host species with similar host characteristics. The combination of vector distribution data with models for flavivirus hosts allows for prediction of global vulnerability to flaviviruses and provides potential targets for disease surveillance in animals and humans.


Comparison of the effects of controlled-rate cryopreservation and vitrification on 2-cell mouse embryos and their subsequent development.
Effects of two cryopreservation procedures (conventional slow controlled-rate freezing using a programmable freezer and vitrification by direct plunging into liquid nitrogen) were compared on 2-cell embryos and their subsequent development to blastocysts, fresh or cryopreserved 2-cell mouse embryos were developed into blastocysts in vitro. The percentage of vitrified embryos which developed into blastocysts was significantly lower than that of fresh and slow controlled-rate frozen embryos. Although blastocysts from each cryopreservation procedure appeared morphologically normal and neither number of cells in the blastocysts nor in-vitro trophoblast spreading differed significantly, there were significant differences in their functional viability. First, the glucose incorporation activity in terms of [(3)H]2-deoxyglucose (2-DG) uptake in vitrified and thawed 2-cell embryos significantly decreased compared with fresh or slow controlled-rate frozen and thawed 2-cell embryos. Second, 2-DG uptake by blastocysts developed in vitro from fresh 2-cell embryos and from slow controlled-rate frozen or vitrified 2-cell embryos was 105 +/- 75, 43.0 +/- 28.3 and 22.0 +/- 11.4 fmol/embryo/h respectively. Third, the implantation rate of blastocysts developed in vitro from vitrified 2-cell embryos (10.2%) was significantly lower than that from fresh 2-cell embryos (30.8%) or slow controlled-rate frozen 2-cell embryos (22.1%). Since these data suggest that cryopreservation may have ulterior consequences on the functional development of embryos and that vitrification may exert a more harmful effect than slow controlled-rate freezing, more attention should be paid to its safety before vitrification is used routinely in a clinical programme.


Asymmetric Synthesis of N-Alkyl Amino Acids through a Biocatalytic Dynamic Kinetic Resolution of PEGylated N-Alkyl Amino Esters.
The first examples of a practical procedure for a lipase-catalyzed dynamic kinetic resolution of PEGylated N-alkyl amino esters is reported. This method allows for the preparation of a broad range of aromatic and aliphatic enantiomerically enriched N-alkyl unnatural amino acids in up to 98% yield and 99% ee. We have found that PEGylated esters have a significant solubility advantage and improved reactivity over traditional hydrophobic lipase substrates, thereby allowing for efficient and scalable dynamic kinetic resolution (DKR) under aqueous conditions.


Contributions of Cathepsin A and Carboxylesterase 1 to the Hydrolysis of Tenofovir Alafenamide in the Human Liver, and the Effect of CES1 Genetic Variation on Tenofovir Alafenamide Hydrolysis.
The prodrug tenofovir alafenamide (TAF) is a first-line antiviral agent for the treatment of chronic hepatitis B infection. TAF activation involves multiple steps, and the first step is an ester hydrolysis reaction catalyzed by hydrolases. This study was to determine the contributions of carboxylesterase 1 (CES1) and cathepsin A (CatA) to TAF hydrolysis in the human liver. Our in vitro incubation studies showed that both CatA and CES1 catalyzed TAF hydrolysis in a pH-dependent manner. At their physiologic pH environment, the activity of CatA (pH 5.2) was approximately 1,000-fold higher than that of CES1 (pH 7.2). Given that the hepatic protein expression of CatA was approximately 200-fold lower than that of CES1, the contribution of CatA to TAF hydrolysis in the human liver was estimated to be much greater than that of CES1, which is contrary to the previous perception that CES1 is the primary hepatic enzyme hydrolyzing TAF. The findings were further supported by a TAF incubation study with the CatA inhibitor telaprevir and the CES1 inhibitor bis-(p-nitrophenyl) phosphate. Moreover, an in vitro study revealed that the CES1 variant G143E (rs71647871) is a loss-of-function variant for CES1-mediated TAF hydrolysis. In summary, our results suggest that CatA may play a more important role in the hepatic activation of TAF than CES1. Additionally, TAF activation in the liver could be affected by CES1 genetic variation, but the magnitude of impact appears to be limited due to the major contribution of CatA to hepatic TAF activation. SIGNIFICANCE STATEMENT: Contrary to the general perception that carboxylesterase 1 (CES1) is the major enzyme responsible for tenofovir alafenamide (TAF) hydrolysis in the human liver, the present study demonstrated that cathepsin A may play a more significant role in TAF hepatic hydrolysis. Furthermore, the CES1 variant G143E (rs71647871) was found to be a loss-of-function variant for CES1-mediated TAF hydrolysis.


Therapeutic Drug Monitoring in Perianal Fistulizing Crohn's Disease.
Perianal fistulas are a common complication of Crohn's disease (CD) that has, historically, been challenging to manage. Despite the strong available evidence that anti-tumor necrosis factor (anti-TNF) agents are useful in the treatment of perianal fistulizing Crohn's disease (PFCD), a significant number of these patients do not respond to therapy. The use of therapeutic drug monitoring (TDM) in patients with CD receiving biologic agents has evolved and is currently positioned as an important tool to optimize and guide biologic treatment. Considering the treatment of PFCD can represent a challenge; identifying novel tools to improve the efficacy of current treatments is an important unmet need. Given its emerging role in other phenotypes of Crohn's disease, the use of TDM could also offer an opportunity to enhance the effectiveness of available therapies and improve outcomes in the subset of patients with PFCD receiving biologics. Overall, there is mounting evidence that higher anti-TNF drug levels are associated with better rates of "fistula healing". However, studies have been limited by their use of subjective outcomes and observational designs. Ultimately, further interventional, randomized controlled trials looking into the relationship between drug exposure and fistula outcomes are needed.


Probing the Impact of Local Structural Dynamics of Conformational Epitopes on Antibody Recognition.
Antibody-antigen interactions are governed by recognition of specific residues and structural complementarity between the antigen epitope and antibody paratope. While X-ray crystallography has provided detailed insights into static conformations of antibody-antigen complexes, factors such as conformational flexibility and dynamics, which are not readily apparent in the structures, can also have an impact on the binding event. Here we investigate the contribution of dynamics in the HIV-1 gp120 glycoprotein to antibody recognition of conserved conformational epitopes, including the CD4- and coreceptor-binding sites, and an inner domain site that is targeted by ADCC-active antibodies. Hydrogen/deuterium-exchange mass spectrometry (HDX-MS) was used to measure local structural dynamics across a panel of variable loop truncation mutants of HIV-1 gp120, including full-length gp120, ΔV3, ΔV1/V2, and extended core, which includes ΔV1/V2 and V3 loop truncations. CD4-bound full-length gp120 was also examined as a reference state. HDX-MS revealed a clear trend toward an increased level of order of the conserved subunit core resulting from loop truncation. Combined with biolayer interferometry and enzyme-linked immunosorbent assay measurements of antibody-antigen binding, we demonstrate that an increased level of ordering of the subunit core was associated with better recognition by an array of antibodies targeting complex conformational epitopes. These results provide detailed insight into the influence of structural dynamics on antibody-antigen interactions and suggest the importance of characterizing the structural stability of vaccine candidates to improve antibody recognition of complex epitopes.


Neurofibromas in NF1: Schwann cell origin and role of tumor environment.
Neurofibromatosis type 1 (NF1) is one of the most prevalent dominantly inherited genetic diseases of the nervous system. NF1 encodes a tumor suppressor whose functional loss results in the development of benign neurofibromas that can progress to malignancy. Neurofibromas are complex tumors composed of axonal processes, Schwann cells, fibroblasts, perineurial cells, and mast cells. Through use of a conditional (cre/lox) allele, we show that loss of NF1 in the Schwann cell lineage is sufficient to generate tumors. In addition, complete NF1-mediated tumorigenicity requires both a loss of NF1 in cells destined to become neoplastic as well as heterozygosity in non-neoplastic cells. The requirement for a permissive haploinsufficient environment to allow tumorigenesis may have therapeutic implications for NF1 and other familial cancers.


Homosexual desire after AIDS: an analysis of the criteria adopted by men in the search for same sex partners.
This article analyzes changes and continuities in partner search criteria by homosexual men considering the impact of the HIV-AIDS epidemic in the city of São Paulo, Brazil. Thus, it compares two different historical moments: between 1979 and 1981 (pre-epidemic) and 2015 to 2017 (post-epidemic). In the first period, the source incorporated 120 classified ads collected from the Lampião da Esquina newspaper and in the second period, the preferences and criteria used to search for partners were analyzed using geolocalized applications, based on 120 online profiles. The data show that that between 1979-1981 the search for "discreet" partners took place, while the sexual panic created in the deadliest period of the AIDS epidemic boosted the use of the Internet in search of partners less likely to be infected with HIV, the "out of the (gay) scene". Since then, the search for "discreet and out of the (gay) scene" has consolidated itself by shaping the body's ideals and conduct that shape the current São Paulo online sex market in which part of the homosexuals take part.


In-person and telephone treatment of tobacco dependence: a comparison of treatment outcomes and participant characteristics.
We compared participant characteristics and abstinence outcomes of smokers who chose in-person or telephone tobacco dependence treatment. We provided the same treatment content to 7267 smokers in Arkansas between 2005 and 2008 who self-selected treatment modality; examined demographic, clinical, environmental, and treatment utilization differences between modalities; and modeled outcomes and participants' choice of modality with logistic regression. At end of treatment, in-person participants were more likely to be abstinent than telephone participants, and smokers of higher socioeconomic status (SES) were more likely to be abstinent with telephone treatment than lower-SES smokers. Long term, modality had no effect on treatment outcomes. Higher-SES smokers and smokers exposed to more treatment content were more likely to achieve long-term abstinence, regardless of modality. Men and more recalcitrant smokers were more likely to choose in-person treatment; lower-SES, ethnic minority, and more dependent smokers were more likely to choose telephone treatment. Treatment modality attracts different groups of smokers, but has no effect on long-term abstinence. Multiple treatment modalities are needed to provide treatment to a heterogeneous population of smokers. More research is needed to understand the influences on treatment choice.


Long-term monitoring of insulin-like growth factor I in adult growth hormone deficiency: a critical appraisal.
Serum insulin-like growth factor I (IGF-I) levels predominantly reflect the hepatic effect of growth hormone (GH). Compared with serum GH levels, which reflect pulsatile GH secretion, serum IGF-I levels exhibit no major diurnal variation and thus provide a better estimate of integrated GH secretion in an individual patient. Measurement of serum IGF-I levels allows reliable identification of states of GH excess. In contrast, in a large proportion of adults with severe GH deficiency, serum IGF-I levels are within the normal range. Serum IGF-I levels increase markedly in response to GH administration and are often used as a surrogate variable for overall responsiveness to such treatment. Current data, however, suggest a poor relationship between changes in or levels of IGF-I and efficacy variables such as body composition, muscle function and well-being. The use of serum IGF-I as a guide during dose titration in the initial phase of treatment and during long-term monitoring of GH replacement therapy in adults, and its use as a safety marker or predictor of future morbidity and mortality are discussed here.


Cerebral vasculitis in chronic mucocutaneous candidiasis: autopsy case report.
An autopsy case of chronic mucocutaneous candidiasis (CMCC) is reported here, in which cerebral vasculitis developed in the final stage. A 32-year-old man who had suffered from superficial candidial infection since his childhood was diagnosed as having CMCC. During the past 7 years the patient had developed various associated disorders including insulin-dependent diabetes mellitus (IDDM), common variable immunodeficiency (CVID), candidial esophagitis, multiple digestive tract ulcers and pyothorax. In 1998, at the age of 32, he developed convulsions that were accompanied by impairment of consciousness, and which were temporarily treated with steroid pulsed-medication. Epileptic status associated with widespread cerebral infarctions occurred subsequently, however, and the patient died of sepsis 2 months later. At autopsy, multiple cerebral infarctions and arterial thrombosis were evident. These were histologically proven to be primary vasculitis which was confined solely to the brain, and this was verified by general pathological examination. Thus, some as yet unknown cerebrovascular factors might be involved in the onset of an autoimmune-related vasculitis in patients with a longstanding immunodeficiency state such as CMCC.


FK506 and sildenafil promote erectile function recovery after cavernous nerve injury through antioxidative mechanisms.
Immunophilin ligands and phosphodiesterase type 5 (PDE5) inhibitors are touted to promote erectile function recovery after cavernous nerve (CN) injury. However, the mechanisms for their effects remain unclear. To compare the erection recovery effects of the immunophilin ligand FK506 and the PDE5 inhibitor sildenafil after CN injury and determine whether they involve antioxidative and/or antiapoptotic mechanisms. Initial experiments established conditions of our CN injury model in adult male Sprague-Dawley rats. Subsequently, we evaluated treatment effects 14 days after: (i) unilateral CN injury (UNI) + saline (vehicle control); (ii) UNI + FK506 (5 mg/kg once daily, subcutaneous x 5 days); (iii) UNI + sildenafil (20 mg/kg every 8 hours, subcutaneous x 7 days); (iv) UNI + FK506/sildenafil; and (v) sham surgery. Intracavernous pressure (ICP) measurement after CN electrical stimulation to assess erectile function and Western blot analysis of expressions of glutathione peroxidase (GPX; antioxidant enzyme), nitrotyrosine (NT; oxidative stress marker), and phosphorylated and total Akt (antiapoptotic factor) in penes. In the UNI model, GPX expression was increased at Days 1 and 7, while p-Akt expression decreased at Day 1 and returned to baseline at Day 7. GPX expression was significantly higher in the UNI + FK506 group compared with the saline-treated group (P < 0.05). ICP increased in all treatment groups compared with that of the saline-treated group (P < 0.05). NT levels were increased after saline treatment (P < 0.05) but not after FK506 and sildenafil treatment, alone or in combination. GPX was localized to nerves coursing through the penis and to smooth muscle and endothelium of the dorsal vein and arteries. Both FK506 and sildenafil protect erectile function after CN injury by decreasing oxidative stress-associated tissue damage. FK506 may act through increased GPX activity. Further research is required to elucidate mechanisms associated with the beneficial effect of sildenafil.


Adult spinal deformity surgery: posterior three-column osteotomies vs anterior lordotic cages with posterior fusion. Complications, clinical and radiological results. A systematic review of the literature.
The aim of our study is to analyse mid- to long-term severe adult spinal deformity (ASD) surgery outcomes by comparing three-column osteotomies (3CO) and multiple anterior interbody fusion cages (AC). The PRISMA flowchart was used to systematically review the literature. Only articles with a minimum 24-month follow-up were examined, and 11 articles were included. The following radiological parameters were observed: pelvic incidence (PI), pelvic tilt (PT), lumbar lordosis (LL), sagittal vertical axis (SVA), Cobb angle and T1-sacrum plumbline. Clinical outcome was assessed using the visual analogue scale (VAS) and Oswestry disability index (ODI) scores. The main complications were analysed, and the two groups were compared. Except for age, the two populations were homogeneous. Both techniques had the same number of posterior instrumented levels (7.4 ± 1.7). The AC group had a mean 3 ± 1.4 interbody fusions per patient. In the PSO group, all patients had 1 3CO and 89.8% of the osteotomies were performed at L2 or L3 vertebrae. No difference was observed between the two groups in terms of clinical outcomes. Both techniques were effective in sagittal parameters restoration with a final PI-LL mismatch = 4.4°. The PSO group had a statistically higher rate of intraoperative blood loss (p = 0.036), major complications, pseudoarthrosis and dural tears (p < 0.001). Both PSO and multiple AC are effective in treating ASD. Multiple AC seems more suitable when treating older patients because of a lower intraoperative blood loss, lower rate of major complications and fewer number of revision surgeries.


Identification and Characterization of Novel Maize Mirnas Involved in Different Genetic Background.
MicroRNAs (miRNAs) are a class of small, non-coding regulatory RNAs that regulate gene expression by guiding target mRNA cleavage or translational inhibition in plants and animals. At present there is relatively little information regarding the role of miRNAs in the response to drought stress in maize. In this study, two small RNA libraries were sequenced, and a total of 11,973,711 and 14,326,010 raw sequences were generated from growing leaves of drought-tolerant and drought-sensitive maize seedlings, respectively. Further analysis identified 192 mature miRNAs, which include 124 known maize (zma) miRNAs and 68 potential novel miRNA candidates. Additionally, 167 target genes (259 transcripts) of known and novel miRNAs were predicted to be differentially expressed between two maize inbred lines. Of these, three novel miRNAs were up-regulated and two were down-regulated under drought stress. The expression of these five miRNAs and nine target genes was confirmed using quantitative reverse transcription PCR. The expression of three of the miRNAs and their putative target genes exhibited an inverse correlation, and expression analysis suggested that all five may play important roles in maize leaves. Finally, GO annotations of the target genes indicated a potential role in photosynthesis, may therefore contribute to the drought stress response. This study describes the identification and characterization of novel miRNAs that are the differentially expressed in drought-tolerant and drought-sensitive inbred maize lines. This provides the foundation for further investigation into the mechanism of miRNA function in response to drought stress in maize.


Delaware's medicolegal investigation of death. Part 1.
In 1194, the coroner system was formally established in England with the original interest in death to protect the financial interest of the crown. This coroner system was brought to the United States during the early 1600s where the first recorded autopsy was performed in Massachusetts in 1647. Significant changes were made to improve upon the coroner system. In 1877, the first medical examiner system was established in the state of Massachusetts requiring that the coroner be supplanted by a physician known as a medical examiner. Using the system established in Massachusetts as a model, New York City developed an improved medical examiner system in 1915. The improvements made by New York City, under the leadership of men such as Drs. Charles Norris and Alex Gettler, essentially laid down the foundation for medical examiner systems and forensic toxicology throughout the country. Part II of this series will begin in Maryland. Maryland soon followed in New York City's footsteps and in 1939 developed the first statewide medical examiner system in the U.S. Influenced by systems such as Maryland's and New York City's, Delaware established a medical examiner system in 1955 to work alongside of the pre-existing coroner system. It was not until about a decade later in 1964 that the system became successful under the leadership of Dr. All Z. Hamell. In 1970, after 15 years of uphill battles with supporters of the antiquated coroner system, it was abolished, resulting in a statewide medical examiner system. Today, Delaware's medical examiner system has one of the best medicolegal investigative facilities in the country, complete with its own forensic sciences laboratory under the jurisdiction of a Chief Medical Examiner. Delaware's Office of Chief Medical Examiner will try to continue its tradition to serve as a model for other states and possibly other countries to follow.


Acoustic neuroma manifesting as toothache and numbness.
Acoustic neuroma, also known as vestibular schwannoma, is a rare benign brainstem tumour involving the abnormal growth and proliferation of Schwann cells surrounding the vestibular division of the eighth cranial nerve. Although the most common symptoms are non-dentally related, there are instances where diagnosis of this potentially life-threatening condition is triggered by an emergency presentation to the dentist for the most trivial of reasons. A 56-year-old male presented to a dental clinic complaining of a toothache. Following history taking, examination and radiographs a carious lower right molar was extracted. The patient reported relief but later described post-extraction numbness on the opposite side (left) of his lower jaw that could not be explained by anatomical principles or previous dental history. Further investigations revealed an acoustic neuroma as the underlying cause. This case highlights that not all signs and symptoms that occur in the mouth are abnormalities within the mouth. In particular, this case underscores the importance of recognizing that the spontaneous onset of certain symptoms may be due to significant non-dental pathology. Any numbness over the distribution of the trigeminal nerve must be investigated. The importance of the basic sciences and referring will also be emphasized.


Oxidative stress and iron homeostasis: mechanistic and health aspects.
Iron is an essential cofactor for important biological activities and biochemical reactions, including the transport of oxygen via red blood cells and its reduction to water during respiration. While iron's bioavailability is generally limited, pathological accumulation of the metal within tissues aggravates the generation of reactive oxygen species (ROS) and elicits toxic effects, which are mainly related to oxidative stress. Here, we describe the role of iron in ROS-induced toxicity and discuss molecular mechanisms and physiological aspects of ROS- and iron-mediated signaling. In addition, we review our current understanding of the regulation of iron homeostasis at the cellular and systemic levels, and focus on the pathogenesis and management of iron overload disorders.


Neuropsychological attention deficits in tuberous sclerosis complex (TSC).
Tuberous sclerosis complex (TSC) (OMIM191100) is a genetic disorder with multi-system involvement including neurodevelopmental manifestations. There is great interest in understanding the pathogenetic mechanisms underlying these neurobehavioral and neurocognitive manifestations. However, there are still significant gaps in knowledge about the exact neuropsychiatric phenotypes observed in TSC. Here we report on the first systematic evaluation of neuropsychological attentional skills in a population-derived sample of children and adolescents with TSC. The study showed that, even when age, gender, IQ, and intra-familial clustering were controlled for, the TSC group had significantly lower scores than their unaffected siblings on a range of neuropsychological attentional tasks, and that they had significantly more neuropsychological attention deficits. Eighteen of the 20 children (90%) showed deficits on one or more attentional tasks, with dual task performance most consistently impaired (85%) and visual selective attention a relative strength. Active seizures and anti-epilepsy medication did not influence attentional profiles. Furthermore, parent rating of attention-related behaviors were not able to identify children at risk of neuropsychological deficits. The findings suggest that clinical neuropsychological evaluation of attentional skills should be performed in children and adolescents with TSC even when they have normal global intellectual abilities, no seizures, and no disruptive behaviors. Results suggest that the mechanisms underlying these deficits may include contributions from structural, seizure-related and molecular factors.


The use of imidazolium ionic liquids for the formation and stabilization of ir0 and rh0 nanoparticles: efficient catalysts for the hydrogenation of arenes.
Stable transition-metal nanoparticles of the type [M(0)](n) are easily accessible through the reduction of Ir(I) or Rh(III) compounds dissolved in "dry" 1-n-butyl-3-methylimidazolium hexafluorophosphate ionic liquid by molecular hydrogen. The formation of these [M(0)](n) nanoparticles is straightforward; they are prepared in dry ionic liquid whereas the presence of the water causes the partial decomposition of ionic liquid with the formation of phosphates, HF and transition-metal fluorides. Transmission electron microscopy (TEM) observations and X-ray diffraction analysis (XRD) show the formation of [Ir(0)](n) and [Rh(0)](n) nanoparticles with 2.0-2.5 nm in diameter. The isolated [M(0)](n) nanoparticles can be redispersed in the ionic liquid, in acetone or used in solventless conditions for the liquid-liquid biphasic, homogeneous or heterogeneous hydrogenation of arenes under mild reaction conditions (75 degrees C and 4 atm). The recovered iridium nanoparticles can be reused several times without any significant loss in catalytic activity. Unprecedented total turnover numbers (TTO) of 3509 in 32 h, for arene hydrogenation by nanoparticles catalysts, have been achieved in the reduction of benzene by the [Ir(0)](n) in solventless conditions. Contrarily, the recovered Rh(0) nanoparticles show significant agglomeration into large particles with a loss of catalytic activity. The hydrogenation of arenes containing functional groups, such as anisole, by the [Ir(0)](n) nanoparticles occurs with concomitant hydrogenolysis of the C-O bond, suggesting that these nanoparticles behave as "heterogeneous catalysts" rather than "homogeneous catalysts".


Ankle joint arthroscopy.
Today, more emphasis is being placed on ambulatory surgery and its decreased morbidity. Arthroscopic surgery is a valid approach to many disease entities and is very responsive to early ambulation. The authors present a brief history of ankle arthroscopy--the technique, indications and contraindications, difficulties, and possible complications of the procedure.


Transmission electron microscopy characterization of fluorescently labelled amyloid β 1-40 and α-synuclein aggregates.
Fluorescent tags, including small organic molecules and fluorescent proteins, enable the localization of protein molecules in biomedical research experiments. However, the use of these labels may interfere with the formation of larger-scale protein structures such as amyloid aggregates. Therefore, we investigate the effects of some commonly used fluorescent tags on the morphologies of fibrils grown from the Alzheimer's disease-associated peptide Amyloid β 1-40 (Aβ40) and the Parkinson's disease-associated protein α-synuclein (αS). Using transmission electron microscopy (TEM), we verify that N-terminal labeling of Aβ40 with AMCA, TAMRA, and Hilyte-Fluor 488 tags does not prevent the formation of protofibrils and amyloid fibrils of various widths. We also measure the two-photon action cross-section of Aβ40 labelled with Hilyte Fluor 488 and demonstrate that this tag is suitable for use with two-photon fluorescence techniques. Similarly, we find that Alexa Fluor 488 labelling of αS variant proteins near either the N or C terminus (position 9 or 130) does not interfere with the formation of amyloid and other types of αS fibrils. We also present TEM images of fibrils grown from αS C-terminally labelled with enhanced green fluorescent protein (EGFP). Near neutral pH, two types of αS-EGFP fibrils are observed via TEM, while denaturation of the EGFP tag leads to the formation of additional species. We demonstrate that several small extrinsic fluorescent tags are compatible with studies of amyloid protein aggregation. However, although fibrils can be grown from αS labelled with EGFP, the conformation of the fluorescent protein tag affects the observed aggregate morphologies. Thus, our results should assist researchers with label selection and optimization of solution conditions for aggregation studies involving fluorescence techniques.


Plant-based, no-added-fat or American Heart Association diets: impact on cardiovascular risk in obese children with hypercholesterolemia and their parents.
To perform a randomized trial to determine whether there is cardiovascular disease (CVD) risk reduction from a plant-based (PB), no-added-fat diet and the American Heart Association (AHA) diet in children. A 4-week (April 20, 2013 to May 18, 2013), prospective randomized trial was undertaken in a large, Midwestern hospital system's predominantly middle class outpatient pediatric practices. Thirty children (9-18 years of age) parent pairs with a last recorded child body mass index >95th percentile and child cholesterol >169 mg/dL were randomized to PB or AHA with weekly 2-hour classes of nutrition education. Children on PB had 9 and children on AHA had 4 statistically significant (P < .05) beneficial changes from baseline (mean decreases): body mass index z-score(PB) (-0.14), systolic blood pressure(PB) (-6.43 mm Hg), total cholesterol(PB) (-22.5 mg/dL), low-density lipoprotein(PB) (-13.14 mg/dL), high-sensitivity C-reactive protein(PB) (-2.09 mg/L), insulin(PB) (-5.42 uU/mL), myeloperoxidase(PB/AHA) (-75.34/69.23 pmol/L), mid-arm circumference(PB/AHA) (-2.02/-1.55 cm), weight(PB/AHA) (-3.05/-1.14 kg), and waist circumference(AHA) (-2.96 cm). Adults on PB and AHA had 7 and 2, respectively, statistically significant (P < .05) beneficial changes. The significant change favoring AHA was a 1% difference in children's waist circumference. Difficulty shopping for food for the PB was the only statistically significant acceptability barrier. PB and the AHA in both children and adults demonstrated potentially beneficial changes from baseline in risk factors for CVD. Future larger, long-term randomized trials with easily accessible PB foods will further define the role of the PB in preventing CVD.


Impacts of visual impairment on pragmatic impairment: A systematic review and meta-analysis.
Consideration for patients with visual impairment, from low vision to blindness, is an important part of building a barrier-free society. Some authors have elaborated that visual impairment can indeed lead to delayed development in theory of mind, thereby causing pragmatic knowledge deficiency. Verifying whether those with eye conditions have pragmatic impairment is an essential way for their clinical evaluation, intervention and rehabilitation. We primarily carry out a meta-analysis of visual impairment from low vision to blindness and pragmatic impairment in people with low vision or blindness to verify visual impairment may cause pragmatic impairment. Electronic databases Pubmed, Medline, MesH, Psychinfo, Ovid, EBSCO and CNKI and the reference sections of previous reviews. Studies were included when they built on primary data from clinical questionnaire surveys or field trials anywhere in the world, and when they reported impacts of visual impairment on social cognition, communication, skills, behavior and intelligence. In total, 25 original studies were included, in which 25735 people were evaluated. Statistically, visual impairments and pragmatic impairment exist correlation due to the significant p value(p = 0.0005 < 0.05) in group and the subgroup sorted in the light of 18 years old (p < 0.0001 and p = 0.003 < 0.05). Psychologically, because people with visual impairment can not normally get non-verbal information, they can not get a complete pragmatic knowledge system. Pragmatic knowledge deficiency leads to abnormal in executive functions and development delay from the perspective of theory of mind, inducing pragmatic impairment. Therefore, visual impairment has an impact on pragmatic impairment. The meta-analysis reveals robust evidence on the relationship of vision impairment and pragmatic impairment in children or adults. Such evidence may help to gradually improve the clinical evaluation, intervention and rehabilitation of these people.


Binding of netropsin to several DNA constructs: evidence for at least two different 1:1 complexes formed from an -AATT-containing ds-DNA construct and a single minor groove binding ligand.
Isothermal titration calorimetry, ITC, has been used to determine the thermodynamics (DeltaG, DeltaH, and -TDeltaS) for binding netropsin to a number of DNA constructs. The DNA constructs included: six different 20-22mer hairpin forming sequences and an 8-mer DNA forming a duplex dimer. All DNA constructs had a single -AT-rich netropsin binding with one of the following sequences, (A(2)T(2))(2), (ATAT)(2), or (AAAA/TTTT). Binding energetics are less dependent on site sequence than on changes in the neighboring single stranded DNA (hairpin loop size and tail length). All of the 1:1 complexes exhibit an enthalpy change that is dependent on the fractional saturation of the binding site. Later binding ligands interact with a significantly more favorable enthalpy change (partial differential DeltaH(1-2) from 2 to 6 kcal/mol) and a significantly less favorable entropy change (partial differential (-TDeltaS(1-2))) from -4 to -9 kcal/mol). The ITC data could only be fit within expected experimental error by use of a thermodynamic model that includes two independent binding processes with a combined stoichiometry of 1 mol of ligand per 1 mol of oligonucleotide. Based on the biophysical evidence reported here, including theoretical calculations for the energetics of "trapping" or structuring of a single water molecule and molecular docking computations, it is proposed that there are two modes by which flexible ligands can bind in the minor groove of duplex DNA. The higher affinity binding mode is for netropsin to lay along the floor of the minor groove in a bent conformation and exclude all water from the groove. The slightly weaker binding mode is for the netropsin molecule to have a slightly more linear conformation and for the required curvature to be the result of a water molecule that bridges between the floor of the minor groove and two of the amidino nitrogens located at one end of the bound netropsin molecule.


Integration of whole genome sequencing and transcriptomics reveals a complex picture of the reestablishment of insecticide resistance in the major malaria vector Anopheles coluzzii.
Insecticide resistance is a major threat to gains in malaria control, which have been stalling and potentially reversing since 2015. Studies into the causal mechanisms of insecticide resistance are painting an increasingly complicated picture, underlining the need to design and implement targeted studies on this phenotype. In this study, we compare three populations of the major malaria vector An. coluzzii: a susceptible and two resistant colonies with the same genetic background. The original colonised resistant population rapidly lost resistance over a 6-month period, a subset of this population was reselected with pyrethroids, and a third population of this colony that did not lose resistance was also available. The original resistant, susceptible and re-selected colonies were subject to RNAseq and whole genome sequencing, which identified a number of changes across the transcriptome and genome linked with resistance. Firstly, an increase in the expression of genes within the oxidative phosphorylation pathway were seen in both resistant populations compared to the susceptible control; this translated phenotypically through an increased respiratory rate, indicating that elevated metabolism is linked directly with resistance. Genome sequencing highlighted several blocks clearly associated with resistance, including the 2Rb inversion. Finally, changes in the microbiome profile were seen, indicating that the microbial composition may play a role in the resistance phenotype. Taken together, this study reveals a highly complicated phenotype in which multiple transcriptomic, genomic and microbiome changes combine to result in insecticide resistance.


Global population genetic structure and demographic trajectories of the black soldier fly, Hermetia illucens.
The black soldier fly (Hermetia illucens) is the most promising insect candidate for nutrient-recycling through bioconversion of organic waste into biomass, thereby improving sustainability of protein supplies for animal feed and facilitating transition to a circular economy. Contrary to conventional livestock, genetic resources of farmed insects remain poorly characterised. We present the first comprehensive population genetic characterisation of H. illucens. Based on 15 novel microsatellite markers, we genotyped and analysed 2862 individuals from 150 wild and captive populations originating from 57 countries on seven subcontinents. We identified 16 well-distinguished genetic clusters indicating substantial global population structure. The data revealed genetic hotspots in central South America and successive northwards range expansions within the indigenous ranges of the Americas. Colonisations and naturalisations of largely unique genetic profiles occurred on all non-native continents, either preceded by demographically independent founder events from various single sources or involving admixture scenarios. A decisive primarily admixed Polynesian bridgehead population serially colonised the entire Australasian region and its secondarily admixed descendants successively mediated invasions into Africa and Europe. Conversely, captive populations from several continents traced back to a single North American origin and exhibit considerably reduced genetic diversity, although some farmed strains carry distinct genetic signatures. We highlight genetic footprints characteristic of progressing domestication due to increasing socio-economic importance of H. illucens, and ongoing introgression between domesticated strains globally traded for large-scale farming and wild populations in some regions. We document the dynamic population genetic history of a cosmopolitan dipteran of South American origin shaped by striking geographic patterns. These reflect both ancient dispersal routes, and stochastic and heterogeneous anthropogenic introductions during the last century leading to pronounced diversification of worldwide structure of H. illucens. Upon the recent advent of its agronomic commercialisation, however, current human-mediated translocations of the black soldier fly largely involve genetically highly uniform domesticated strains, which meanwhile threaten the genetic integrity of differentiated unique local resources through introgression. Our in-depth reconstruction of the contemporary and historical demographic trajectories of H. illucens emphasises benchmarking potential for applied future research on this emerging model of the prospering insect-livestock sector.


Height, body weight, and risk of prostate cancer.
Using data from the Health Professionals Follow-Up Study, we prospectively examined the relationships between height, body mass index, waist and hip circumferences, and risk of total and advanced (extraprostatic and metastatic) prostate cancer. In addition, we assessed adiposity during childhood, adolescence, and early, middle, and late adulthood using pictograms in relation to prostate cancer risk. Between 1986 and 1994, 1,369 cases of prostate cancer (excluding stage A1) were confirmed in 47,781 men. Adult body mass index and waist and hip circumferences were not appreciably related to risk of total prostate cancer or advanced prostate cancer. In contrast, preadult (age 10) obesity assessed in 33,336 men in 1988 was prospectively related to lower risk of advanced [relative risk (RR) = 0.72 with 95% confidence interval (CI) = 0.47-1.10, between high and low quintiles; P(trend) = 0.06] and metastatic prostate cancer (RR = 0.38 with 95% CI = 0.19-0.77; P(trend) = 0.004). For the advanced lesions, an association was observed with height (RR = 1.68 with 95% CI = 1.16-2.43 for men 74 inches or taller, relative to men 68 inches or shorter; P(trend) = 0.01). In an analysis limited to particularly aggressive forms of prostate cancer, i.e., cases found to be metastatic at time of diagnosis between 1988 and 1994 after a negative digital rectal examination in 1988, we found that obesity at ages 5 and 10 had a strong inverse association (RR = 0.16 with 95% CI = 0.05-0.54, between high and low quintiles at age 10) and that tallness had a strong direct association with risk of metastatic disease (RR = 2.29 with 95% CI = 1.04-5.05, for height > or = 74 inches versus < or = 68 inches). Our findings suggest that the preadult hormonal milieu, as reflected in attained height and childhood obesity, may have a strong influence on prostate carcinogenesis.


Event-related potential correlates of negation in a sentence-picture verification paradigm.
In a sentence-picture verification paradigm, participants were presented in a rapid-serial-visual-presentation paradigm with affirmative or negative sentences (e.g., "In the front of the tower there is a/no ghost") followed by a matching or mismatching picture. Response latencies and event-related potentials (ERPs) were measured during reading and verification. An enhanced negative shift in the ERPs for the subject noun (i.e., "ghost") in negative, compared to affirmative sentences, was found during reading. We relate this ERP deflection to enhanced processing demands required by the negative particle no. Although this effect suggests a direct impact of negation on language processing, results for picture processing reveal that negation is not immediately integrated into sentence meaning. When the delay of picture presentation was short (250 msec), verification latencies and ERPs evoked by the picture showed a priming effect independent of whether the sentence contained a negation. Unprimed pictures (foreground object not mentioned in the sentence) led to longer latencies and higher N400 amplitudes than primed pictures (foreground object mentioned in the sentence). Main effects of negation showed up only in a late positive-going ERP effect. In contrast, when the delay was long (1500 msec), we observed main effects of truth value and negation in addition to the priming effect already in the N400 time window, that is, negation is fully integrated into sentence meaning only at a later point in the comprehension process. When negation has not yet been integrated, verification decisions appear to be modulated by additional time-consuming reanalysis processes.


A typology of barriers and enablers of scientific evidence use in conservation practice.
Over the last decade, there has been an increased focus (and pressure) in conservation practice globally towards evidence-based or evidence-informed decision making. Despite calls for increased use of scientific evidence, it often remains aspirational for many conservation organizations. Contributing to this is the lack of guidance on how to identify and classify the array of complex reasons limiting research use. In this study, we collated a comprehensive inventory of 230 factors that facilitate or limit the use of scientific evidence in conservation management decisions, through interviews with conservation practitioners in South Africa and UK and a review of the healthcare literature. We used the inventory, combined with concepts from knowledge exchange and research use theories, to construct a taxonomy that categorizes the barriers and enablers. We compared the similarities and differences between the taxonomies from the conservation and the healthcare fields, and highlighted the common barriers and enablers found within conservation organizations in the United Kingdom and South Africa. The most commonly mentioned barriers limiting the use of scientific evidence in our case studies were associated with the day-to-day decision-making processes of practitioners, and the organizational structures, management processes and resource constraints of conservation organizations. The key characteristics that facilitated the use of science in conservation decisions were associated with an organization's structure, decision-making processes and culture, along with practitioners' attitudes and the relationships between scientists and practitioners. This taxonomy and inventory of barriers and enablers can help researchers, practitioners and other conservation actors to identify aspects within their organizations and cross-institutional networks that limit research use - acting as a guide on how to strengthen the science-practice interface.


Preoperative angiographic guidewire localization of the bleeding small bowel segment.
Angiography is helpful to detect the site of bleeding in patients with overt gastrointestinal bleeding. However, angiography sometimes cannot give bleeding location precisely to the surgeons particularly for small bowel bleedings. We described angiography-directed preoperative guidewire placement for localization of the bleeding during laparotomy. This method was used successfully in a 45-year-old women with overt small intestinal bleeding. Method was simple and effective. Catheter was kept in the artery for 45 minutes, guidewire pointed out the bleeding point as closer as 1 cm and a limited resection of bowel (15 cm) resolved the gastrointestinal bleeding. There was no complication because of surgery or interventional radiology, and the patient was discharged on day 6 uneventfully.


Non-linear stimulus-response behavior of the human stance control system is predicted by optimization of a system with sensory and motor noise.
We developed a theory of human stance control that predicted (1) how subjects re-weight their utilization of proprioceptive and graviceptive orientation information in experiments where eyes closed stance was perturbed by surface-tilt stimuli with different amplitudes, (2) the experimentally observed increase in body sway variability (i.e. the "remnant" body sway that could not be attributed to the stimulus) with increasing surface-tilt amplitude, (3) neural controller feedback gains that determine the amount of corrective torque generated in relation to sensory cues signaling body orientation, and (4) the magnitude and structure of spontaneous body sway. Responses to surface-tilt perturbations with different amplitudes were interpreted using a feedback control model to determine control parameters and changes in these parameters with stimulus amplitude. Different combinations of internal sensory and/or motor noise sources were added to the model to identify the properties of noise sources that were able to account for the experimental remnant sway characteristics. Various behavioral criteria were investigated to determine if optimization of these criteria could predict the identified model parameters and amplitude-dependent parameter changes. Robust findings were that remnant sway characteristics were best predicted by models that included both sensory and motor noise, the graviceptive noise magnitude was about ten times larger than the proprioceptive noise, and noise sources with signal-dependent properties provided better explanations of remnant sway. Overall results indicate that humans dynamically weight sensory system contributions to stance control and tune their corrective responses to minimize the energetic effects of sensory noise and external stimuli.


The information trail of the 'Freshman 15'--a systematic review of a health myth within the research and popular literature.
How does health misinformation become part of the American and Canadian vernacular? Twenty-three databases were searched for articles discussing university freshmen weight gain. Research articles were examined for methodology, number and gender of the participants and weight gain. Popular press articles were reviewed for the types of information published: expert/anecdotal, weight gain, nutrition, exercise, health and alcohol. A timeline of article publication dates was generated. Twenty peer-reviewed, 19 magazine, 146 newspaper, and 141 university newspaper articles were discovered. Appearance of media articles about the 'Freshman 15' mirrored the peer-reviewed articles, yet the information did not reliably depict the research. Research indicated a weight gain of less than five pounds (2.268 kg), while half of the popular press publications claimed a 15-pound (6.804 kg) weight gain. The misinformation was frequently accompanied by information about achieving weight control through diet, exercise, stress reduction and alcohol avoidance. Understanding of how the concept of the 'Freshman 15' developed indicates that remediation efforts are needed. Collaborative efforts between health science and academic librarians, faculty and journalists to construct new paradigms for the translation of scientific evidence into information that individuals can use for decisions about health and well-being is suggested.


Musculoskeletal manifestations in Alkaptonuria: A cross-sectional study.
This study aimed to determine the patient characteristics and clinical presentation of Alkaptonuria cases reported by the Biochemical Genetics Lab.An observational study was conducted at the Biochemical Genetics Lab. Alkaptonuria patients were diagnosed based on the homogentisic acid peak in urine and their demographics and clinical data collected from to 2013 to 2019. Clinical history related to joint diseases, ochronotic presentation, and urine darkening on standing was collected.During 7 years, 21 Alkaptonuria cases were reported from BGL; mean age 19.4 ± 24.5 years (range 0.2-66 years) and male to female ratio of 2:1. Of the total, only 9 were adults (mean age, 44 ± 12 years). Most adult patients had musculoskeletal involvement, with joint pain (n = 9) and ochronotic pigmentation (n = 6), whereas all patients presented with a history of urine darkening on standing (21/21 cases).The high prevalence of musculoskeletal involvement observed in patients with albuminuria is likely to be missed by physicians unless specifically tested for in such cases.


No major thermogenic role for (Na+ + K+)-dependent adenosine triphosphatase apparent in hepatocytes from hyperthyroid rats.
(Na+ + K+)-dependent ATPase activity, heat production and oxygen consumption were increased by 59%, 62% and 75% respectively in hepatocytes from tri-iodothyronine-treated rats. Ouabain at concentrations of 1 and 10 mM decreased oxygen uptake by 2--8% in hepatocytes from euthyroid rats and by 5--15% in hepatocytes from hyperthyroid animals. Heat output was decreased by 4--9% with the glycoside in isolated liver parenchymal cells from the control animals and by 11% in the cells from the tri-iodothyronine-treated animals. These results do not support the hypothesis that hepatic (Na+ + K+)-ATPase plays a major role in increased heat production in hepatocytes from hyperthyroid rats.


Driving under the influence of central stimulant amines: age and gender differences in concentrations of amphetamine, methamphetamine, and ecstasy in blood.
A zero-tolerance law for driving under the influence of drugs (DUID) was introduced in Sweden in 1999. This change in legislation has led to a 12-fold increase in the number of blood samples sent by the police for toxicological analysis. Here we report the age and gender of offenders, along with the concentrations of amphetamine, methamphetamine, and ecstasy (3,4-methylenedioxymeth-amphetamine) in blood samples analyzed since the institution of the new legislation. A forensic toxicology database (TOXBASE) was used to identify cases of DUID in which central stimulant amines were verified in blood during a 5-year period (2000-2004). Amphetamine was present in 15,898 of 26,556 cases of DUID (60%) either alone or together with other licit or illicit drugs. In 6,094 cases, amphetamine was the only psychoactive substance in blood at mean (median) and highest concentrations of 1.01 mg/L (0.80 mg/L) and 11.9 mg/L, respectively. The users of amphetamine were mainly men (85% vs 15% women; p < .001), and men tended to be a few years older than the women; the mean (SD) age for men was 37 (9.2) years and for women it was 35 (8.1) years (p < .001). In 644 cases, amphetamine and methamphetamine were present in blood samples at mean (median) concentrations of 0.85 mg/L (0.60 mg/L) and 0.34 mg/L (0.20 mg/L), respectively (p < .001). The mean (median) and highest concentrations of ecstasy in 493 DUID offenders were 0.23 mg/L (0.10 mg/L) and 3.5 mg/L, respectively. The mean age of ecstasy users was 26 (7.2) years, which was about 10 years younger than those using amphetamine (p < .001). The high prevalence of amphetamines in blood of apprehended drivers in Sweden verifies widespread use of these stimulants as recreational drugs. The findings from this study suggest that a zero-tolerance DUID law has not deterred offenders, which suggests that more attention should be given to the underlying substance-abuse problem instead of conventional penalties such as monetary fines and/or imprisonment.


Regioselective C-H Trifluoromethylation of Aromatic Compounds by Inclusion in Cyclodextrins.
A regioselective radical C-H trifluoromethylation of aromatic compounds was developed using cyclodextrins (CDs) as additives. The C-H trifluoromethylation proceeded with high regioselectivity to afford the product in good yield, even on the gram scale. In the presence of CDs, some substrates underwent a single trifluoromethylation selectively, whereas mixtures of single- and double-trifluoromethylated products were formed in the absence of the CD. 1H NMR experiments indicated that the regioselectivity was controlled by the inclusion of a substrate inside the CD cavity.


[ECMO in Neonates with Congenital Diaphragmatic Hernia: The Experience of a Portuguese ECMO Referral Center].
The use of extracorporeal membrane oxygenation (ECMO) is considered by many authors as one of the most important technological advances in the care of newborns with congenital diaphragmatic hernia. The main objective of this study was to report the experience of a Portuguese ECMO center in the treatment of congenital diaphragmatic hernia. Descriptive retrospective study of newborns with congenital diaphragmatic hernia requiring ECMO support in a Pediatric Intensive Care Unit from January 2012 to December 2019. Data collection using the Extracorporeal Life Support Organization registration and unit data base. Fourteen newborns were included, all with left congenital diaphragmatic hernia, in a total of 15 venoarterial ECMO cycles. The median gestational age was 38 weeks and the median birth weight was 2.950 kg. Surgical repair was performed before entry into ECMO in six, during in seven and after in one newborn. The average age at placement was 3.3 days and the median cycle duration was 16 days. Prior to ECMO, all newborns had severe hypoxemia and acidosis despite optimized ventilatory support, with nitric oxide and inotropic therapy. After 24 hours on ECMO, there was correction of acidosis, improvement of oxygenation and hemodynamic stability. All cycles presented mechanical complications, the most frequent being the presence of clots in the circuit. The most frequent physiological complications were hemorrhagic and embolic (three newborns suffered an ischemic stroke during the cycle). Five newborns (35.7%) died, all associated with complications (two strokes, two massive bleedings and one accidental decannulation). Chronic lung disease, poor weight gain and psychomotor developmental delay were the most frequent long-term morbidities. Despite technological advances in respiratory care and improved safety of the ECMO technique, the management of these newborns is complex and there are still several open questions, including the appropriate selection of patients, the best approach and time for surgical correction, and the treatment of pulmonary hypertension in the presence of persistent fetal shunts. Survival rate was higher than reported in 2017 Extracorporeal Life Support Organization report (64% versus 50%). Mechanical and hemorrhagic complications were very frequent.


Isoantiserum-augmented development of lymphocyte-mediated cytotoxicity.
Passive administration of anti-P-814 isoantiserum (IS) with P-815 mastocytoma was shown to augment the development of T-lymphocyte-mediated cytotoxicity (LMC). The LMC activity augmented by IS was specific to immunizing tumor cells, but required the simultaneous administration of P-815 tumor cells and anti-P-815 serum, suggesting that the antigen-antibody complex is involved in the development of specific cytotoxic T cells. The serum component responsible for augmented development of LMC activity appeared to be IgM in that the augmenting activity fractionated in the void volume of a G-200 Sephadex column and appears very early after immunization. Our experimental results suggest the development of specific T-cell cytotoxicity can be directly regulated by specific IgM antibodies.


Sound attenuation of polymerizing actin reflects supramolecular structures: viscoelastic properties of actin gels modified by cytochalasin D, profilin and alpha-actinin.
Polymerization and depolymerization of cytoskeletal elements maintaining cytoplasmic stiffness are key factors in the control of cell crawling. Rheometry is a significant tool in determining the mechanical properties of the single elements in vitro. Viscoelasticity of gels formed by these polymers strongly depends on both the length and the associations of the filaments (e.g. entanglements, annealings and side-by-side associations). Ultrasound attenuation is related to viscosity, sound velocity and supramolecular structures in the sample. In combination with a small glass fibre (2 mm x 50 microm), serving as a viscosity sensor, an acoustic microscope was used to measure the elasticity and acoustic attenuation of actin solutions. Changes in acoustic attenuation of polymerizing actin by far exceed the values expected from calculations based on changes in viscosity and sound velocity. During the lag-phase of actin polymerization, attenuation slightly decreases, depending on actin concentration. After the half-maximum viscosity is accomplished and elasticity turns into steady state, attenuation distinctly rises. Changes in ultrasound attenuation depend on actin concentration, and they are modulated by the addition of alpha-actinin, cytochalasin D and profilin. Thus absorption and scattering of sound on the polymerization of actin is related to the packing density of the actin net, entanglements and the length of the actin filaments. Shortening of actin filaments by cytochalasin D was also confirmed by electron micrographs and falling-ball viscosimetry. In addition to viscosity and elasticity, the attenuation of sound proved to be a valuable parameter in characterizing actin polymerization and the supramolecular associations of F-actin.


[Development of the hormonal reaction to stress in the ontogenesis of the baboon Papio hamadryas].
The hormonal reaction of adrenal and gonadal glands of baboons at various ages was studied under 2 hr immobilization stress condition. Concentrations of cortisol, 11-deoxycortisol, 17-hydroxypregnenolone, dehydroepiandrosterone and testosterone were determined by radioimmunoassay in the monkey blood plasma at different times during the stress reaction. A more pronounced reaction of adrenal cortex was shown in 1 year old baboons. The peak of cortisol level in immature monkeys under stress conditions was registered much earlier than in adult monkeys.


ESPEN expert statements and practical guidance for nutritional management of individuals with SARS-CoV-2 infection.
The COVID-19 pandemics is posing unprecedented challenges and threats to patients and healthcare systems worldwide. Acute respiratory complications that require intensive care unit (ICU) management are a major cause of morbidity and mortality in COVID-19 patients. Patients with worst outcomes and higher mortality are reported to include immunocompromised subjects, namely older adults and polymorbid individuals and malnourished people in general. ICU stay, polymorbidity and older age are all commonly associated with high risk for malnutrition, representing per se a relevant risk factor for higher morbidity and mortality in chronic and acute disease. Also importantly, prolonged ICU stays are reported to be required for COVID-19 patients stabilization, and longer ICU stay may per se directly worsen or cause malnutrition, with severe loss of skeletal muscle mass and function which may lead to disability, poor quality of life and additional morbidity. Prevention, diagnosis and treatment of malnutrition should therefore be routinely included in the management of COVID-19 patients. In the current document, the European Society for Clinical Nutrition and Metabolism (ESPEN) aims at providing concise guidance for nutritional management of COVID-19 patients by proposing 10 practical recommendations. The practical guidance is focused to those in the ICU setting or in the presence of older age and polymorbidity, which are independently associated with malnutrition and its negative impact on patient survival.


Structural and Function Correlation of Cone Packing Utilizing Adaptive Optics and Microperimetry.
To assess the functional aspects of cone mosaic and correlate cone packing with retinal sensitivity utilizing microperimetry in emmetropes at different eccentricities. Twenty-four healthy volunteers underwent microperimetry (MAIA Centervue, Italy) and assessment of photoreceptors using adaptive optics retinal camera, rtx1 (Imagine Eyes, Orsay, France), at 2 and 3 degrees from the foveal centre in 4 quadrants: superior, inferior, temporal, and nasal. Data was analyzed using SPSS version 17 (IBM). Spearman's correlation tests were used to establish correlation between mean cone packing density and retinal sensitivity at different quadrants. Thirteen females and 11 males (age range 20-40 years) were included. The cone density was found to be significantly different among all quadrants (temporal = 25786.68/mm(2) ± 4367.07/mm(2), superior = 23009.35/mm(2) ± 5415.81/mm(2), nasal = 22838.09/mm(2) ± 4166.22/mm(2), and inferior = 21097.53/mm(2) ± 4235.84/mm(2)). A statistical significance (P < 0.008) was found between orthogonal meridians, that is, temporal, nasal (48624.77/mm(2))> superior, inferior (44106.88/mm(2)). A drop in retinal sensitivity was observed as the eccentricity increased (P < 0.05). It was also found that as cone packing density decreased retinal sensitivity also decreased (P < 0.05) in all quadrants. This was observed at both 2 and 3 degrees. It is of crucial importance to establish normative variations in cone structure-function correlation. This may help in detection of subtle pathology and its early intervention.


M proteins of group C streptococci isolated from patients with acute pharyngitis.
We studied 15 strains of group C (Streptococcus equi subsp. equisimilis) [corrected] isolated from the throats of college students with acute pharyngitis and 5 strains isolated from patients with noninfectious problems. Nineteen of the 20 strains resisted phagocytic killing during incubation in normal human blood, suggesting that they might express M proteins. Genomic DNA from all 20 strains hybridized with a probe corresponding to the carboxyterminal one-third of the group A M-protein gene emm24, a region that is highly conserved among M proteins of group A and group G streptococci. The DNA sequences of the N-terminal (variable) regions of the M-protein-encoding genes from two disease-associated group C isolates and one control isolate were determined. The predicted amino acid sequences of the two pharyngitis strains were identical and were 88% homologous to the amino acid sequence of a group G M-protein gene. The predicted terminal amino acid sequence of the control strain does not correspond to any such sequences in the GenBank database. All three strains studied possess the conserved region domain common to class I group A M-protein types epidemiologically associated with rheumatic fever. These studies demonstrate the presence of M proteins in strains of S. equi subsp. equisimilis [corrected] isolated in cases of endemically occurring acute pharyngitis. Certain of these proteins are similar to those of group G streptococci, while others may represent new M types. The similarity in structure and function between M proteins of nonrheumatogenic serogroups and those of rheumatogenic group A streptococci suggests that factors other than or in addition to M protein per se are likely involved in the pathogenesis of rheumatic fever.


High-fat diet delays and fasting advances the circadian expression of adiponectin signaling components in mouse liver.
The circadian clock controls energy homeostasis by regulating circadian expression and/or activity of enzymes involved in metabolism. Disruption of circadian rhythms may lead to obesity and metabolic disorders. We tested whether the biological clock controls adiponectin signaling pathway in the liver and whether fasting and/or high-fat (HF) diet affects this control. Mice were fed low-fat or HF diet and fasted on the last day. The circadian expression of clock genes and components of adiponectin metabolic pathway in the liver was tested at the RNA, protein, or enzyme activity level. In addition, serum levels of glucose, adiponectin, and insulin were measured. Under low-fat diet, adiponectin signaling pathway components exhibited circadian rhythmicity. However, fasting and HF diet altered this circadian expression; fasting resulted in a phase advance, and HF diet caused a phase delay. In addition, adenosine monophosphate-activated protein kinase levels were high during fasting and low during HF diet. Changes in the phase and daily rhythm of clock genes and components of adiponectin signaling pathway as a result of HF diet may lead to obesity and may explain the disruption of other clock-controlled output systems, such as blood pressure and sleep/wake cycle, usually associated with metabolic disorders.


The Affordable Care Act improved health insurance coverage and cardiovascular-related screening rates for cancer survivors seen in community health centers.
This study assessed the impact of Affordable Care Act (ACA) Medicaid expansion on health insurance rates and receipt of cardiovascular-related preventive screenings (body mass index, glycated hemoglobin [HbA1c], low-density lipoproteins, and blood pressure) for cancer survivors seen in community health centers (CHCs). This study identified cancer survivors aged 19 to 64 years with at least 3 CHC visits in 13 states from the Accelerating Data Value Across a National Community Health Center Network (ADVANCE). Via inverse probability of treatment weighting multilevel multinomial modeling, insurance rates before and after the ACA were estimated by whether a patient lived in a state that expanded Medicaid, and changes between a pre-ACA time period and 2 post-ACA time periods were assessed. The weighted estimated sample size included 409 cancer survivors in nonexpansion states and 2650 in expansion states. In expansion states, the proportion of uninsured cancer survivors decreased significantly from 20.3% in 2012-2013 to 4.5%in 2016-2017, and the proportion of those with Medicaid coverage increased significantly from 38.8% to 55.6%. In nonexpansion states, there was a small decrease in uninsurance rates (from 33.6% in 2012-2013 to 22.5% in 2016-2017). Cardiovascular-related preventive screening rates increased over time in both expansion and nonexpansion states: HbA1c rates nearly doubled from the pre-ACA period (2012-2013) to the post-ACA period (2016-2017) in expansion states (from 7.2% to 12.8%) and nonexpansion states (from 9.3% to 16.8%). This study found a substantial decline in uninsured visits among cancer survivors in Medicaid expansion states. Yet, 1 in 5 cancer survivors living in a state that did not expand Medicaid remained uninsured. Several ACA provisions likely worked together to increase cardiovascular-related preventive screening rates for cancer survivors seen in CHCs.


Prediction of clinical toxicity in locally advanced head and neck cancer patients by radio-induced apoptosis in peripheral blood lymphocytes (PBLs).
Head and neck cancer is treated mainly by surgery and radiotherapy. Normal tissue toxicity due to x-ray exposure is a limiting factor for treatment success. Many efforts have been employed to develop predictive tests applied to clinical practice. Determination of lymphocyte radio-sensitivity by radio-induced apoptosis arises as a possible method to predict tissue toxicity due to radiotherapy. The aim of the present study was to analyze radio-induced apoptosis of peripheral blood lymphocytes in head and neck cancer patients and to explore their role in predicting radiation induced toxicity. Seventy nine consecutive patients suffering from head and neck cancer, diagnosed and treated in our institution, were included in the study. Toxicity was evaluated using the Radiation Therapy Oncology Group scale. Peripheral blood lymphocytes were isolated and irradiated at 0, 1, 2 and 8 Gy during 24 hours. Apoptosis was measured by flow cytometry using annexin V/propidium iodide. Lymphocytes were marked with CD45 APC-conjugated monoclonal antibody. Radiation-induced apoptosis increased in order to radiation dose and fitted to a semi logarithmic model defined by two constants: alpha and beta. Alpha, as the origin of the curve in the Y axis determining the percentage of spontaneous cell death, and beta, as the slope of the curve determining the percentage of cell death induced at a determined radiation dose, were obtained. beta value was statistically associated to normal tissue toxicity in terms of severe xerostomia, as higher levels of apoptosis were observed in patients with low toxicity (p = 0.035; Exp(B) 0.224, I.C.95% (0.060-0.904)). These data agree with our previous results and suggest that it is possible to estimate the radiosensitivity of peripheral blood lymphocytes from patients determining the radiation induced apoptosis with annexin V/propidium iodide staining. beta values observed define an individual radiosensitivity profile that could predict late toxicity due to radiotherapy in locally advanced head and neck cancer patients. Anyhow, prospective studies with different cancer types and higher number of patients are needed to validate these results.


Fluorescence in situ hybridization and immunohistochemistry as diagnostic methods for ALK positive non-small cell lung cancer patients.
Anaplastic Lymphoma Kinase (ALK) positivity represents a novel molecular target in a subset of Non-Small Cell Lung Cancers (NSCLC). We explore Fluorescence in situ Hybridization (FISH) and Immunohistochemistry (IHC) as diagnostic methods for ALK positive patients and to describe its prevalence and outcomes in a population of NSCLC patients. NSCLC patients previously screened for Epidermal Growth Factor Receptor (EGFR) at our institution were selected. ALK positive patients were identified by FISH and the value of IHC (D5F3) was explored. ninety-nine patients were identified. Median age was 61.5 years (range 35-83), all were caucasians, eighty percent were adenocarcinomas, fifty-one percent were male and thirty-eight percent were current smokers. Seven (7.1%) patients were ALK positive by FISH, thirteen (13.1%) were EGFR mutant, and 65 (65.6%) were negative/Wild Type (WT) for both ALK and EGFR. ALK positivity and EGFR mutations were mutually exclusive. ALK positive patients tend to be younger than EGFR mutated or wt patients. ALK positive patients were predominantly never smokers (71.4%) and adenocarcinoma (71.4%). ALK positive and EGFR mutant patients have a better outcome than negative/WT. All patients with ALK FISH negative tumours were negative for ALK IHC. Out of 6 patients positive for ALK FISH with more tissue available, 5 were positive for ALK IHC and 1 negative. ALK positive patients represent 7.1% of a population of selected NSCLC. ALK positive patients have different clinical features and a better outcome than EGFR WT and ALK negative patients. IHC is a promising method for detecting ALK positive NSCLC patients.


Effect of low-intensity warfarin anticoagulation on level of activity of the hemostatic system in patients with atrial fibrillation. BAATAF Investigators.
The Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF) demonstrated that low-intensity warfarin anticoagulation can, with safety, sharply reduce the rate of stroke in patients with nonvalvular atrial fibrillation. The beneficial effect of warfarin was presumably related to a decrease in clot formation in the cardiac atria and subsequent embolization. To assess the effect of warfarin therapy on in vivo clotting in patients in the BAATAF, we measured the plasma level of prothrombin activation fragment F1+2. One sample was obtained from 125 patients from the BAATAF; 62 were taking warfarin and 63 were not taking warfarin (control group). The warfarin group had a 71% lower mean F1+2 level than the control group (mean F1+2 of 1.57 nmol/L in the control group compared with a mean of 0.46 nmol/L in the warfarin group; P < .001). F1+2 levels were higher in older subjects but were consistently lower in the warfarin group at all ages. Fifty-two percent of patients in the control group were taking chronic aspirin therapy at the time their F1+2 level was measured. Control patients taking aspirin had F1+2 levels very similar to control patients not taking aspirin (mean of 1.52 nmol/L for control patients on aspirin compared with 1.64 nmol/L for control patients off aspirin; P > .1). We conclude that prothrombin activation was significantly suppressed in vivo by warfarin but not aspirin among patients in the BAATAF. These findings correlate with the marked reduction in ischemic stroke noted among patients in the warfarin treatment group observed in the BAATAF.


Temporal dependence of cysteine protease activation following excitotoxic hippocampal injury.
Excitotoxic insults can lead to intracellular signaling cascades that contribute to cell death, in part by activation of proteases, phospholipases, and endonucleases. Cysteine proteases, such as calpains, are calcium (Ca(2+))-activated enzymes which degrade cytoskeletal proteins, including microtubule-associated proteins, tubulin, and spectrin, among others. The current study used the organotypic hippocampal slice culture model to examine whether pharmacologic inhibition of cysteine protease activity inhibits N-methyl-D-aspartate- (NMDA-) induced excitotoxic (20 μM NMDA) cell death and changes in synaptophysin immunoreactivity. Significant NMDA-induced cytotoxicity (as measured by propidium iodide [PI] uptake) was found in the CA1 region of the hippocampus at all timepoints examined (24, 72, 120 h), an effect significantly attenuated by co-exposure to the selective NMDA receptor antagonist DL-2-Amino-5-phosphonopentanoic acid (APV), but not MDL-28170, a potent cysteine protease inhibitor. Results indicated sparing of NMDA-induced loss of the synaptic vesicular protein synaptophysin in all regions of the hippocampus by MDL-28170, though only at early timepoints after injury. These results suggest Ca(2+)-dependent recruitment of cysteine proteases within 24h of excitotoxic insult, but activation of alternative cellular degrading mechanisms after 24h. Further, these data suggest that synaptophysin may be a substrate for calpains and related proteases.


Bite of the venomous lizard, the Gila monster.
The bite of the Gila monster may cause significant symptoms, including constitutional symptoms, pain, edema, mild hypotension, and less frequently, shock (as in the case reported here). Envenomations may be life-threatening but generally are easily managed by symptomatic and supportive measures and appear to be less toxic than envenomations by other poisonous reptiles. Prudent handling of captive animals could probably prevent the majority of these already uncommon bites.


A sequential Monte Carlo framework for haplotype inference in CNV/SNP genotype data.
Copy number variations (CNVs) are abundant in the human genome. They have been associated with complex traits in genome-wide association studies (GWAS) and expected to continue playing an important role in identifying the etiology of disease phenotypes. As a result of current high throughput whole-genome single-nucleotide polymorphism (SNP) arrays, we currently have datasets that simultaneously have integer copy numbers in CNV regions as well as SNP genotypes. At the same time, haplotypes that have been shown to offer advantages over genotypes in identifying disease traits even though available for SNP genotypes are largely not available for CNV/SNP data due to insufficient computational tools. We introduce a new framework for inferring haplotypes in CNV/SNP data using a sequential Monte Carlo sampling scheme 'Tree-Based Deterministic Sampling CNV' (TDSCNV). We compare our method with polyHap(v2.0), the only currently available software able to perform inference in CNV/SNP genotypes, on datasets of varying number of markers. We have found that both algorithms show similar accuracy but TDSCNV is an order of magnitude faster while scaling linearly with the number of markers and number of individuals and thus could be the method of choice for haplotype inference in such datasets. Our method is implemented in the TDSCNV package which is available for download at http://www.ee.columbia.edu/~anastas/tdscnv.


Possibility of testing the light dark matter hypothesis with the alpha magnetic spectrometer.
The spectrum and morphology of gamma rays from the Galactic center and the spectrum of synchrotron emission observed from the Milky Way's radio filaments have each been interpreted as possible signals of ∼ 7-10 GeV dark matter particles annihilating in the inner Galaxy. In dark matter models capable of producing these signals, the annihilations should also generate significant fluxes of ∼ 7-10 GeV positrons which can lead to a distinctive bumplike feature in a local cosmic ray positron spectrum. In this Letter, we show that while such a feature would be difficult to detect with PAMELA, it would likely be identifiable by the currently operating Alpha Magnetic Spectrometer experiment. As no known astrophysical (i.e., nondark matter) sources or mechanisms are likely to produce such a sharp feature, the observation of a positron bump at around 7-10 GeV would significantly strengthen the case for a dark matter interpretation of the reported gamma-ray and radio anomalies.


Cell shape changes during larval body plan development in Clytia hemisphaerica.
The cnidarian "planula" larva shows radial symmetry around a polarized, oral-aboral, body axis and comprises two epithelia cell layers, ectodermal and endodermal. This simple body plan is set up during gastrulation, a process which proceeds by a variety of modes amongst the diverse cnidarian species. In the hydrozoan laboratory model Clytia hemisphaerica, gastrulation involves a process termed unipolar cell ingression, in which the endoderm derives from mass ingression of individual cells via a process of epithelial-mesenchymal transition (EMT) around the future oral pole of an epithelial embryo. This contrasts markedly from the gastrulation mode in the anthozoan cnidarian Nematostella vectensis, in which endoderm formation primarily relies on cell sheet invagination. To understand the cellular basis of gastrulation in Clytia we have characterized in detail successive cell morphology changes during planula formation by Scanning and Transmission Electron Microscopy combined with confocal imaging. These changes successively accompany epithelialization of the blastoderm, EMT occurring in the oral domain through the bottle cell formation and ingression, cohesive migration and intercalation of ingressed cells with mesenchymal morphology, and their epithelialization to form the endoderm. From our data, we have reconstructed the cascade of morphogenetic events leading to the formation of planula larva. We also matched the domains of cell morphology changes to the expression of selected regulatory and marker genes expressed during gastrulation. We propose that cell ingression in Clytia not only provides the endoderm, but generates internal forces that shape the embryo in the course of gastrulation. These observations help build a more complete understanding of the cellular basis of morphogenesis and of the evolutionary plasticity of cnidarian gastrulation modes.


Effective target size for the induction of bystander effects in medium transfer experiments.
Although radiation-induced bystander effects are frequently observed biological phenomena, the mechanism for these effects has not been fully determined. The target-hit theory and related concepts from microdosimetry provide a convenient formalism to help identify the nature of the targets responsible for initiating the emission of diffusible factors in medium transfer experiments. We used the microdosimetric models proposed by Stewart et al. (Radiat. Res. 165, 460-469, 2006) to analyze the results of published medium transfer experiments for gamma-ray doses in the range of 0.04 mGy to 5 Gy. The analysis suggests that the effective size of the target responsible for initiating signal emission in HPV-G human keratinocyte donor cells is approximately 2 microm.


Design and implementation of AMBAR: an innovative evidence-based training program for childbirth and newborn care.
To present the development of a training model called AMBAR (Atención a la mujer embarazada y al recién nacido [Care for pregnant women and newborns]), which was designed to improve the quality of attention of health personnel responsible for obstetric care. AMBAR was designed based on the results of a qualitative study exploring public health providers' needs and experiences. It was implemented in three health networks, and a total of 339 health personnel participated. The educational design of the course was appealing to the trained personnel, and the inclusion of simulations in all modules encouraged interest, participation, as well as the integration of new knowledge and skills into practice. AMBAR can promote better practices and increase the quality of birth care. With the proper support and willingness of staff and management, AMBAR can be implemented in all health services, both public and private.