Blood transfusion and the risk of acute kidney injury after transcatheter aortic valve implantation.
Blood transfusion is associated with acute kidney injury (AKI) after transcatheter aortic valve implantation (TAVI). We sought to elucidate in more detail the relation between blood transfusion and AKI and its effects on short- and long-term mortality. Nine hundred ninety-five patients with aortic stenosis underwent TAVI with the Medtronic CoreValve or the Edwards Valve in 7 centers. AKI was defined by the Valve Academic Research Consortium (absolute increase in serum creatinine ≥0.3 mg/dL [≥26.4 μmol/L] or ≥50% increase ≤72 hours). Logistic and Cox regression was used for predictor and survival analysis. AKI occurred in 20.7% (n=206). The number of units of blood transfusion ≤24 hours was the strongest predictor of AKI (≥5 units, OR, 4.81 [1.45-15.95], 3-4 units, OR, 3.05 [1.24-7.53], 1-2 units, OR, 1.47 [0.98-2.22]) followed by peripheral vascular disease (OR, 1.48 [1.05-2.10]), history of heart failure (OR, 1.43 [1.01-2.03]), leucocyte count ≤72 hours after TAVI (OR, 1.05 [1.02-1.09]) and European System for Cardiac Operative Risk Evaluation (EuroSCORE; OR, 1.02 [1.00-1.03]). Potential triggers of blood transfusion such as baseline anemia, bleeding-vascular complications, and perioperative blood loss were not identified as predictors. AKI and life-threatening bleeding were independent predictors of 30-day mortality (OR, 3.15 [1.56-6.38], OR, 6.65 [2.28-19.44], respectively), whereas transfusion (≥3 units), baseline anemia, and AKI predicted mortality beyond 30 days. AKI occurred in 21% of the patients after TAVI. The number of blood transfusions but not the indication of transfusion predicted AKI. AKI was a predictor of both short- and long-term mortality, whereas blood transfusion predicted long-term mortality. These findings indicate that outcome of TAVI may be improved by more restrictive use of blood transfusions.


Utility and cost-effectiveness of preoperative autologous blood donation in gynecologic and gynecologic oncology patients.
To evaluate utility and cost-effectiveness of preoperative autologous blood donation in gynecologic and gynecologic oncology patients. Pheresis unit records were retrospectively reviewed to identify all women who performed autologous blood donation. Clinical charts were abstracted. Use rate (number of units used/number of units donated) and quality-adjusted life years were calculated. Statistical analysis consisted of chi(2), Student t, and Fisher exact tests. A total of 106 women with benign (n = 63) and malignant disease (n = 43) donated 143 units (1.4 units per patient) of which 126 (88%) were discarded. Fifteen patients (14%) were transfused a total of 24 units, 17 autologous (71%) and seven allogeneic (29%). Those transfused had a significantly higher estimated blood loss (700 mL versus 275 mL, P <.001), lower nadir hemoglobin (7.9 versus 9.6, P <.001), and longer hospital stay (4.9 days versus 4.0 days, P =.05). Despite similar estimated blood loss (370 mL versus 310 mL), the use rate for malignant versus benign disease was significantly greater (0.31 versus 0.07, P =.005). Radical versus nonradical surgery had a significantly higher estimated blood loss (620 mL versus 250 mL, P =.001) and use rate (0.26 versus 0.11, P =.001) as well. Estimated cost per quality-adjusted life years for autologous blood donation for each category exceeded $1,000,000. Autologous blood donation is an expensive medical practice and does not guarantee that exposure to allogeneic blood will not occur. If pursued, it should be directed towards those who have a known malignancy or those for whom radical surgery is anticipated. Other methods of blood conservation may be safer and more cost-effective.


Cytology of collagenous spherulosis of the breast: a diagnostic dilemma--report of three cases.
Collagenous spherulosis is a rare incidental finding seen in association with benign breast lesions. Cytological findings in three cases of collagenous spherulosis diagnosed on fine needle aspiration are presented. The presence of hyaline pink globules surrounded by benign myoepithelial cells in Giemsa stained smears was a diagnostic feature. Associated lesions were atypical papillary hyperplasia (2) and fibroadenoma (1). Adenoid cystic carcinoma was the close differential diagnosis on cytology. Awareness of this entity is important to avoid a false positive diagnosis of malignancy.


Membrane lipids and proteins as modulators of urothelial endocytic vesicles pathways.
The increased studies on urinary bladder umbrella cells as an important factor for maintaining the permeability barrier have suggested new pathways for the discoidal/fusiform endocytic vesicles which is one of the main features of the umbrella cells. The biological role of these vesicles was defined, for many years, as a membrane reservoir for the umbrella cell apical plasma membrane which are subject to an increased tension during the filling phase of the micturition cycle and, therefore, the vesicles are fused with the apical membrane. Upon voiding, the added membrane is reinserted via a non-clathrin or caveolin-dependant endocytosis thereby restoring the vesicle cytoplasmic pool. However, in the last decade, new evidence appeared indicating alternative pathways of the endocytic vesicles different than the cycling process of exocytosis/endocytosis. The purpose of this review is to analyze the molecular modulators, such as membrane lipids and proteins, in the permeability of endocytic vesicles, the sorting of endocytosed material to lysosomal degradation pathway and recycling of both membrane and fluid phases.


Socioeconomic status and executive function in early childhood: Exploring proximal mechanisms.
Although there is substantial evidence that socioeconomic status (SES) predicts children's executive function (EF), the mechanisms underlying this association are poorly understood. This study tested the utility of two theories proposed to link SES to children's EF: the family stress model and the family investment model. Data came from the Midwestern Infant Development Study (N = 151). To measure SES, parental education and income were assessed during pregnancy, and income was also assessed when children were 6 and 36 months old. Children's EF, operationalized as working memory/inhibitory control (WMIC) and self-control, was assessed at 36 months of age, along with potential mediators including maternal psychological distress, harsh parenting, and cognitive stimulation. Using structural equation modeling, we tested simultaneous pathways from SES to EF: (a) via maternal psychological distress to harsh parenting (family stress model) and (b) via cognitive stimulation (family investment model). Of the SES measures, lower education predicted poorer WMIC directly and indirectly via greater maternal psychological distress. Lower education also predicted poorer self-control via greater maternal psychological distress. This effect was partially suppressed by an indirect path from lower education to better self-control via greater psychological distress and increased harsh parenting. Cognitive stimulation did not act as a mediator. Income was not directly or indirectly associated with EF. These findings provide partial support for the family stress model and suggest that family functioning is an important proximal mechanism for children's EF development. This study also highlights the importance of considering SES as a multidimensional construct.


Clinical patterns and significance of non-compliance with guideline-recommended treatment of acute pulmonary embolism.
Evidence-based clinical practice guidelines define initial management of acute pulmonary embolism (PE) according to risk stratification for early death. The aims of the present study were to investigate patterns of non-compliance with guidelines for the acute PE treatment, and the associated risk of adverse events. We performed an observational, multicentre, cohort study of acute PE. Inclusion criteria were all patients with pulmonary embolism admitted to the participating centres between January 2011 and April 2017. The measure of 100% compliance was used to allocate patients in the compliant or non-compliant groups. The primary outcome was all-cause death at 6 months. Secondary outcomes included recurrent venous thromboembolism and major bleeding. In total, 1285 patients were included. Treatment was not in compliance with the guidelines in 172 patients (13.4%). Four factors were identified to be related to non-compliance with the guidelines: shock or hypotension (relative risk [RR] 5.23, 95% confidence interval [CI] 2.64-10.30; P<0.001), renal insufficiency (RR 1.80, 95% CI 1.41-2.28; P<0.001), active cancer (RR 1.35, 95% CI 1.24-1.48; P<0.001) and right ventricular dysfunction at admission (RR 1.06, 95% CI 1.01-1.11; P=0.01). The primary endpoint of all-cause death at 6 months occurred in 62 of 172 patients (36.0%) in the non-compliant group and in 131 of 1113 patients (11.8%) in the compliant group (hazard ratio 2.02, 95% CI 1.45-2.81; P<0.001). The rates of recurrent venous thromboembolism (8.7% vs 1.1%; P<0.001) and major bleeding (13.4% vs 4.9%, P=0.04) from admission to 6-month follow-up were higher in the non-compliant group. Non-compliance with guidelines was independently associated with worse outcomes, including death, recurrent venous thromboembolism and bleeding.


Effectiveness of computed tomography scanning to detect blunt bowel and mesenteric injuries requiring surgical intervention: A systematic literature review.
Computed tomography (CT) diagnostic accuracy for blunt bowel and mesenteric injuries (BBMI) is controversial. A literature review to compute aggregate CT performance and individual CT sign sensitivity, specificity, and positive predictive value (PPV) for operative BBMI. Sensitivity, specificity, and PPV were: overall CT performance 85.3%, 96.1%, 51.4%; abnormal wall enhancement 30.1%, 95.7%, 64.0%; bowel wall discontinuity 22.3%, 99.0%, 87.9%; bowel wall hematoma 22.5%, 100%, 19.5%; bowel wall thickening 35.2%, 96.5%, 32.1%; free air 32.0%, 98.7%, 57.1%; free fluid 65.6%, 85.0%, 25.5%; mesenteric air 27.6%, 99.1%, 85.3%; mesenteric extravasation 22.9%, 99.6%, 73.9%; mesenteric hematoma/fluid 33.9%, 98.7%, 52.8%; mesenteric stranding/streaking 34.3%, 91.8%, 31.6%; mesenteric vessel beading 32.1%, 97.2%, 60.4%; mesenteric vessel termination 31.6%, 97.2%, 63.5%; oral contrast extravasation 10.0%, 100%, 100%; retroperitoneal air 9.4%, 94.9%, 55.6%; and retroperitoneal fluid 44.2%, 49.4%, 38.5%. Sensitivity, specificity, and PPV vary substantially among known signs. Other clinical factors are necessary for comprehensive BBMI identification.


Pattern of infection and selective loss of Ia positive cells in suckling and adult mice inoculated with lactic dehydrogenase virus.
Lactic dehydrogenase virus (LDV) infected cells were localised in cryostat sections of infected adult and suckling mice by fluorescent antibody staining. In almost every organ except brain and spinal cord, LDV infected cells were present in interstitial connective tissue, including dermis and submucosa of gastrointestinal and urinogenital tracts. They were also present in liver sinusoids and red pulp of spleen. The tissue distribution, shape, and fluorescence staining pattern of infected cells were similar in adult and suckling mice. The reactivity with monoclonal antibody to mouse macrophages (F4/80) and to Ia antigens indicated that infected cells were Ia antigen positive macrophages, and this was confirmed in double labelling experiments. Peak numbers of LDV infected cells were seen in every organ 12-18 hours post infection (p.i.), disappearing rapidly thereafter until at 48 hours p.i. they could no longer be detected. At the same time Ia positive cells fell to undetectable levels, although macrophages were still present in reduced numbers. At 7 days p.i. the total number of macrophages in sections had returned to normal, but the number of Ia positive cells remained at low levels. Macrophages recovered from peritoneal cavity and spleen of intraperitoneally infected mice were also studied. Ia positive cells had virtually disappeared from peritoneal cavity at 24-48 hours, and from spleen at 24-72 hours. Three weeks after infection the proportion of Ia positive cells was still low when compared with that of normal mice suggesting selective loss of these cells.


Isolation and absolute configuration of SMTP-0, a simplest congener of the SMTP family nonlysine-analog plasminogen modulators.
SMTP-0, a new simple congener of the SMTP nonlysine-analog plasminogen modulators, was isolated from a culture of Stachybotrys microspora. Based on the physico-chemical data, SMTP-0 was shown to be an enantiomer of the antimicrobial compound stachybotrin B. The absolute configuration of SMTP-0 was determined by the modified Mosher method. The stereochemistry was further confirmed using an epimer of SMTP-0. Unlike most SMTPs with an amino acid side chain linked to the nitrogen atom of the lactam moiety, SMTP-0, which lacks the N-linked side chain, showed no plasminogen modulator activity.


Interpersonal comparison of subjective probabilities: toward translating linguistic probabilities.
Interpersonal variability in understanding linguistic probabilities can adversely affect decision making. Using the fact that everyone judges canonical probability events similarly in a manner consistent with axiom systems that yield a probability measure, we developed and tested a method for comparing the meanings of probability phrases across individuals. An experiment demonstrated that despite extreme heterogeneity in participants' linguistic probability lexicons, interpersonal similarity in phrase meaning is well predicted by phrase rank order within the lexicons. Thus, equally ranked phrases have similar meanings, and individual differences in linguistic probabilities may simply be explained by the phrases people use at each rank.


Racial Disparities in Financial Security, Work and Leisure Activities, and Quality of Life Among the Direct Care Workforce.
Personal care, home health, and nursing aides provide the majority of care to chronically ill and disabled older adults. This workforce faces challenging working conditions, resulting in high turnover and workforce instability that affect the quality of care for older adults. We examine financial security, work-life balance, and quality of life of Black, Hispanic, and workers of other race/ethnicity compared to White workers. We hypothesize that Black and Hispanic workers experience greater financial insecurity, spend more time on work-related activities and have less time available for leisure activities, and have a lower quality of life compared to White workers. To test these hypotheses, we analyze the American Time Use Survey using descriptive analyses and multivariable and compositional regression. Black and Hispanic individuals were 2-3 times more likely to live in poverty than White individuals. The time use analysis indicated that Black and Hispanic workers spent more time on work-related activities and less time on nonwork-related activities, including longer work commutes and less time exercising. In analyses of aggregated paid/unpaid work and leisure, Black workers were the only group that spent significantly more time working and less time on leisure activities compared to White workers. This may explain the lower quality of life that we only observed in Black workers. Racial/ethnic disparities in well-being among direct care workers may affect the care older adults receive and contribute to widening inequities in this workforce and society. Policymakers should direct efforts toward securing funding for workers, incentivizing employer provisions, and implementing racial equity approaches.


Culturing with trehalose produces viable endothelial cells after cryopreservation.
Dimethylsulfoxide, the most commonly employed cryoprotectant for cells, has well documented cytotoxic effects in patients. Among the compounds available that may provide protection to cells and tissues during preservation with less cytotoxicity is trehalose. Some animals, such as brine shrimp and tardigrades, accumulate trehalose during periods of extreme environmental stress. In this study, experiments were performed to evaluate the effects of culturing a bovine endothelial cell line (ATCC #CCL-209) in the presence of trehalose prior to preservation by freezing. A number of factors were shown to contribute to cell retention of metabolic activity and proliferative potential including cell culture time with trehalose and the solution conditions during cryopreservation. Using an optimized protocol consisting of 24 h of cell culture with 0.2 M trehalose followed by cryopreservation with 0.2-0.4 M trehalose in sodium bicarbonate buffered Eagles minimum essential medium at pH 7.4 resulted in 87±4% post-preservation cell metabolic activity expressed as relative fluorescence based upon reduction of resazurin to resorufin. This new method provides an alternative preservation strategy to the more classical preservation methods employing dimethylsulfoxide available for cells and tissues.


HLA-DRB1* and DQB1* allele and haplotype diversity in eight tribal populations: Global affinities and genetic basis of diseases in South India.
The distribution of HLA class-II DRB1* and DQB1* alleles/ haplotypes were studied in 438 individuals of 8 Dravidian tribal groups inhabiting the Western Ghats, south India. The HLA typing was performed by PCR-SSP method. In order to identify the 5-locus Ancestral Extended Haplotypes (AEH), the alleles of HLA-A, -B and -C loci were typed for DNAs with predominant 2-locus haplotypes. The analyses have revealed allele HLA-DRB1*15 as the most predominant allele (Lowest / Highest range: Urali, 14.81 / Malasar, 48.94), followed by the alleles DRB1*10 (Katunayakan, 1.85 / Paliyan, 48.21), DRB1*14 (Paliyan 4.46 / Katunayakan, 40.74), DRB1*12 (Mannan, 1.64 / Katunayakan, 20.37) and DRB1*03 (Mannan, 1.64 / Urali, 29.63). The most frequent DQB1* alleles were DQB1*02 (Paliyan 3.57 / Urali, 23.15), DQB1*05 (Katunayakan, 27.77 / Paliyan 84.82) and DQB1*06 (Malasar, 8.51 / Kuruman, 33.51). The most predominant two-locus haplotypes observed were DRB1*15-DQB1*05, DRB1*10-DQB1*05, DRB1*15-DQB1*06 and DRB1*04-DQB1*05. The present study of HLA immunogenetics of south Indian tribes have revealed the presence of globally shared two and 5-locus haplotypes. Many of these haplotypes were implicated in a number of diseases in south India. We observed the presence of ancestral extended haplotypes (AEHs), hitherto not reported in Indian populations such as, A*68-B*35-C*02-DRB1*15:01-DQB1*05:01, A*24-B*57-C*06-DRB1*04:01-DQB1*05:01 and A*24-B*35-C*02-DRB1*15:01-DQB1*05:02. The dendrogram based phylogenetic analyses have revealed the Caucasian affinity of Urali, palaeo-Mediterranean and Indo-European affinity of Malasar tribes. The presence of globally shared susceptible and protective haplotypes reiterated the mosaic immunogenetic fabric of south Indian tribes.


Formation of 2-nitrophenol from salicylaldehyde as a suitable test for low peroxynitrite fluxes.
There has been some dispute regarding reaction products formed at physiological peroxynitrite fluxes in the nanomolar range with phenolic molecules, when used to predict the behavior of protein-bound aromatic amino acids like tyrosine. Previous data showed that at nanomolar fluxes of peroxynitrite, nitration of these phenolic compounds was outcompeted by dimerization (e.g. biphenols or dityrosine). Using 3-morpholino sydnonimine (Sin-1), we created low fluxes of peroxynitrite in our reaction set-up to demonstrate that salicylaldehyde displays unique features in the detection of physiological fluxes of peroxynitrite, yielding detectable nitration but only minor dimerization products. By means of HPLC analysis and detection at 380nm we could identify the expected nitration products 3- and 5-nitrosalicylaldehyde, but also novel nitrated products. Using mass spectrometry, we also identified 2-nitrophenol and a not fully characterized nitrated dimerization product. The formation of 2-nitrophenol could proceed either by primary generation of a phenoxy radical, followed by addition of the NO2-radical to the various resonance structures, or by addition of the peroxynitrite anion to the polarized carbonyl group with subsequent fragmentation of the adduct (as seen with carbon dioxide). Interestingly, we observed almost no 3- and 5-nitrosalicylic acid products and only minor dimerization reaction. Our results disagree with the previous general assumption that nitration of low molecular weight phenolic compounds is always outcompeted by dimerization at nanomolar peroxynitrite fluxes and highlight unique features of salicylaldehyde as a probe for physiological concentrations of peroxynitrite.


Splice-site mutations in KIF5A in the Japanese case series of amyotrophic lateral sclerosis.
Our objective was to investigate the frequency of KIF5A variants in amyotrophic lateral sclerosis (ALS) and the clinical characteristics of familial ALS (FALS) associated with variants in KIF5A. Whole-exome sequence analysis was performed for a Japanese series of 43 families with FALS and 444 patients with sporadic ALS (SALS), in whom causative variants had not been identified. We compared the frequencies of rare variants (MAF < 0.01) in KIF5A, including missense and loss of function (LoF) variants, between ALS and control subjects (n = 1163). Clinical characteristics of patients with FALS carrying pathogenic variants in KIF5A were also described. LoF variants were identified only in the probands of two families with FALS, both of which were 3' splice-site variants leading to exon skipping and an altered C-terminal domain, located in the mutational hotspot causing FALS, and were considered to be pathogenic for FALS. Rare missense variants in KIF5A were identified in five patients with SALS (1.13%) and 11 control subjects (0.95%, carrier frequency), which were not significantly different. Consequently, the pathogenic LoF variants in KIF5A accounted for 2.1% of all FALS families in this study. These patients suffered from ALS characteristically associated with the predominant involvement of upper motor neuron. In conclusion, we identified two pathogenic splice-site variants in KIF5A in the probands in two Japanese families with FALS, which altered the C-terminal region of KIF5A. Our findings broaden the phenotype spectrum of ALS associated with variants in KIF5A in the Japanese series.


The stress inoculation training management of self-mutilating behavior: a case study.
A combination of techniques, based mainly on the stress inoculation training approach, was used to treat severe self-mutilating behavior in a 32-year-old woman who for 15 years had manifested different kinds of this type of behavior. In 18 therapy sessions over 6 weeks in a psychiatric inpatient setting she achieved complete control of the self-mutilating behavior. After a year of follow-up she was completely symptom free and had made additional social and personal gains.


Treatment patterns for schizophrenia in psychiatric hospitals.
This paper analyzes the patterns of clinical treatments prescribed to patients diagnosed with schizophrenia who were admitted to state and county mental hospitals, private for-profit psychiatric hospitals, and private nonprofit psychiatric hospitals in July 1980. Treatment patterns were specified by examining the distribution of treatment types provided to patients over a 3-month period through standard tabular arrays and matrix analysis that holds constant the number of treatment types received by the patients. Data for this study are based on nationwide patient sample surveys and facility enumerations conducted in 1980 by the Survey and Reports Branch, National Institute of Mental Health. Clear differences and similarities emerged among the three types of hospitals in terms of the number and type of treatments provided to patients with schizophrenia. In general, patients with schizophrenia admitted to private psychiatric hospitals received a more comprehensive care regimen (generally inclusive of individual therapy) than similarly diagnosed patients admitted to state and county mental hospitals; private nonprofit psychiatric hospitals had marginally discernible treatment patterns from private for-profit psychiatric hospitals, especially with respect to assignment of group and self-care skill training.


Characterization and functional analysis of the 5' flanking region of Sparus aurata myostatin-1 gene.
Myostatin (MSTN) is a member of the transforming growth factor-beta superfamily that functions as a negative regulator of skeletal muscle development and growth in mammals. Although several MSTN promoters were described in fish, no functional analysis was reported so far. Here, the 5' flanking region (1372 bp) of the MSTN-1 gene of the marine fish Sparus aurata (saMSTN-1) was cloned, sequenced and characterized. It contains two consensus sequences for TATA box (TATAA), a CAAT box, ten putative E-boxes known as binding sites to myogenic basic helix-loop-helix transcription factors (TFs) and two putative binding sites to TF Myocyte enhancing factor-2 (MEF2). In addition, it has several putative binding sites to TF Pit-1a and several response elements to nuclear receptors (GRE, ERE, PRE, ARE, TRE, RARE and PPARRE) and cAMP-response elements. Transcriptional activity of five genomic fragments (truncated at their upstream region) of 372, 941, 972, 1113 and 1355 bp was studied in vitro, using transient transfection in A204 cells. All constructs directed luciferase activity, with the highest activity obtained by the 1113 bp fragment. These experiments show that all five genomic fragments are functional MSTN promoters and differences in promoter activity might be due to presence of enhancers and/or repressor sequences, regulating MSTN promoter activity.


Development of a simple high-performance capillary electrophoretic method with on-line mode in capillary derivatization for the determination of spermidine.
A new high-performance capillary electrophoretic (HPCE) method with an on-line mode in-capillary derivatization (ICD) procedure for determinations of some amines using 20 mmol/L sodium dodecyl sulfate (SDS) - 2 mmol/L o-phthalaldehyde (OPA) - 2 mmol/L N-acetylcysteine (NAC) - 20 mmol/L phosphate-borate buffer [9] has previously been shown. Although this technique offers direct fluorescence detection of free amines without any derivatization procedures before or after HPCE separation, the presence of spermidine (Spd) is difficult to detect due to low fluorescence intensity. The purpose of this study is to improve the detection sensitivity of Spd by reoptimizing this method with regard to the run buffer; the reoptimized method was applied to the determination of Spd in human plasma. To enhance the fluorescence intensity of the Spd signal, it is effective to use the run buffer in the presence of both beta-cyclodextrin (beta-CD: 8.8 mmol/L) and NAC at high concentration (16 mmol/L). By contrast, the intensity was remarkably decreased when SDS was used in the presence of beta-CD. After ultrafiltrating (UF) spiked human plasma with Spd, UF plasma was directly analyzed using the reoptimized method. Spd peak was detected and separated from the other peaks of blank plasma. The present method gave good linearity (r = 0.999), reproducibility (3.85% coefficient of variation at 5 micromol/L level; n = 10) and specificity. The detection limit and lower limit of quantitation is for 0.2 micromol/L and 1 micromol/L, respectively.


Psoas attenuation and cross-sectional area improve performance of traditional sarcopenia measurements in predicting one-year mortality among elderly patients undergoing emergency abdominal surgery: a pilot study of five computed tomography techniques.
Risk stratification is challenging in the growing population of geriatric patients requiring emergency surgery. Sarcopenia, which assesses muscle bulk, is a surrogate for frailty and predicts 1-year mortality, but does not incorporate potentially valuable additional information about muscle quality. To describe five different CT methods of measuring sarcopenia and muscle quality and to determine which method has the greatest sensitivity for predicting 1-year mortality following emergency abdominal surgery in elderly patients. This retrospective study includes 297 patients 70 years and older who underwent "urgent" or "emergent" laparotomy or laparoscopy for acute abdominal disease between 2006 and 2011 at a single quaternary academic medical center. All patients received a CT abdomen and pelvis with intravenous contrast within 1 month of surgery. Five different methods were applied to the psoas muscles on CT: method 1 (total psoas index TPI, which is total psoas area TPA normalized by height), method 2 ("pseudoarea" = anterior-posterior × transverse dimensions), method 3 (average HU), method 4 (TPA × HU), and method 5 ("pseudoarea" × HU). For all five CT measures, mortality was greatest for the lowest quartile by univariate and adjusted Cox proportional hazard analyses at all time points up to 1-year. The C-statistic was highest for Method 4, using a composite index of TPA and Hounsfield Units, indicating the greatest predictive ability to estimate mortality at all time points. Muscle quality and muscle size can be used in tandem to refine risk assessment of older patients undergoing emergency abdominal surgery. Routine calculation of the composite score of psoas cross-sectional area and HU in the emergency room setting may provide surgeons and patients valuable insight on the risk of 1-year mortality to guide preoperative decision-making and counseling. Muscle quality and size, both strong independent predictors of surgical outcomes in older patients undergoing emergency abdominal surgery, may be used in tandem to refine risk assessment. A composite score of psoas muscle cross-sectional area and Hounsfield units on CT may provide insight on 1-year mortality in this patient population.


The epidemic dynamics of hepatitis C virus subtypes 4a and 4d in Saudi Arabia.
The relatedness between viral variants sampled at different locations through time can provide information pertinent to public health that cannot readily be obtained through standard surveillance methods. Here, we use virus genetic data to identify the transmission dynamics that drive the hepatitis C virus subtypes 4a (HCV4a) and 4d (HCV4d) epidemics in Saudi Arabia. We use a comprehensive dataset of newly generated and publicly available sequence data to infer the HCV4a and HCV4d evolutionary histories in a Bayesian statistical framework. We also introduce a novel analytical method for an objective assessment of the migration intensity between locations. We find that international host mobility patterns dominate over within country spread in shaping the Saudi Arabia HCV4a epidemic, while this may be different for the HCV4d epidemic. This indicates that the subtypes 4a and 4d burden can be most effectively reduced by combining the prioritized screening and treatment of Egyptian immigrants with domestic prevention campaigns. Our results highlight that the joint investigation of evolutionary and epidemiological processes can provide valuable public health information, even in the absence of extensive metadata information.


Fate and Growth Kinetics of Salmonella and Listeria monocytogenes on Mangoes During Storage.
Imported mangoes have been linked to outbreaks of salmonellosis in the USA. The purpose of this research was to evaluate the persistence and growth kinetics of Salmonella and Listeria monocytogenes on the intact surface of whole 'Ataulfo', 'Kent', and 'Tommy Atkins' mangoes stored at three different temperatures. L. monocytogenes was also evaluated on fresh-cut 'Tommy Atkins' mangoes stored at 4, 12, 20 ± 2°C. Whole mangoes were spot inoculated with rifampicin-resistant pathogen cocktails (6 log CFU/mango) onto the midsection of whole fruit (n = 6). Fruit was stored at 12, 20, or 30 ± 2°C and sampled for up to 28 days. The specific growth rates derived from DMFit models as a function of time were used to develop secondary models. On 'Kent' mangoes, Salmonella had a population increase from 0.3 to 1.1 log CFU/mango with a linear growth rate of ∼0.004, 0.01, and 0.06 log CFU/mango/h at 12, 20, and 30°C, respectively. At 20 and 30°C, Salmonella growth rates were significantly higher than 12°C (P < 0.05). No clear Salmonella growth trend was observed; populations decreased up to 1.6 log CFU/mango on 'Tommy Atkins' and 'Ataulfo' at 12°C. Populations of L. monocytogenes on whole and fresh-cut mangoes declined regardless of temperature and storage period. Food safety during storage should be the top priority for fresh-cut tropical fruit processors.


Isolation of macrocyclic and non-macrocyclic trichothecenes (stachybotrys and fusarium toxins) from the Environment of 200 III Sport Horses.
Satratoxins H and G, verrucarin J, and roridin E were isolated from the bedding straw of 200 sport horses exhibiting typical symptoms of stachybotryo-toxicosis. At the same time, the oat feed consumed by the horses contained non-macrocyclicFusarium trichothecenes: T-2 toxin and diacetoxyscirpenol.


Risk factors for negative blood cultures in adult medical inpatients--a retrospective analysis.
The identification of clinical factors associated with negative blood cultures could help to avoid unnecessary blood cultures. C-reactive protein (CRP) is a well-established inflammation marker commonly used in the management of medical inpatients. We studied the association of clinical factors, CRP levels and changes of CRP documented prior to blood culture draws with the absence of bacteremia for hospitalized medical patients. In the retrospective analysis of 710 blood cultures obtained from 310 medical inpatients of non-intensive-care wards during one year (admission blood cultures obtained in the emergency room were excluded), the following retrospectively available factors were the only independent predictors of blood cultures negative for obligate pathogens: a good clinical condition represented by the lowest of three general nursing categories (OR 4.2, 95% CI 1.8 - 9.5), a CRP rise > 50 mg/L documented before the blood culture draw (OR 2.0 95% CI 1.8-9.5) and any antibiotic treatment in the previous seven days (OR 2.0, 95% CI 1.1-3.5). Including the general clinical condition, antibiotic pre-treatment and a substantial rise of CRP into the decision, whether or not to obtain blood cultures from medical inpatients with a suspected infection, could improve the diagnostic yield.


Occurrence of spontaneous malignant lymphoma in the course of idiopathic myelofibrosis.
The spontaneous development of malignant non-Hodgkin lymphoma in a patient with idiopathic myelofibrosis is described. The tumor appeared 3 years after clinical diagnosis of the latter. Implications of the association between myeloproliferative and lymphoproliferative disorders at a pathogenetic level are briefly discussed.


Fluvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, scavenges free radicals and inhibits lipid peroxidation in rat liver microsomes.
We investigated the effect of fluvastatin sodium (fluvastatin) and pravastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, on the formation of thiobarbituric acid reactive substances both in vivo and in vitro in rat liver microsomes and on active oxygen species. Oral administration of fluvastatin at low doses (3.13 and 6.25 mg/kg) inhibited the formation of thiobarbituric acid reactive substances in rat liver microsomes, but high doses (12.5 and 25 mg/kg) did not change the formation of thiobarbituric acid reactive substances. Fluvastatin at any dose used had no effect on the content of cytochrome P-450 and the activity of NADPH-cytochrome P-450 reductase. In in vitro experiments, concentrations of fluvastatin ranging from 1 x 10(-6) - 1 x 10(-4) M markedly inhibited NADPH-dependent lipid peroxidation in liver microsomes, but pravastatin weakly inhibited lipid peroxidation. The order of magnitude of inhibition of each drug on in vitro lipid peroxidation was butylated hydroxytoluene > probucol > or = fluvastatin > pravastatin. Moreover, fluvastatin chemically scavenged active oxygen species such as hydroxyl radicals and superoxide anion generated by the Fenton reaction and by the xanthine-xanthine oxidase system, respectively, but pravastatin showed no scavenging of superoxide anion. These results indicate that the suppression of in vivo and in vitro lipid peroxidation in liver microsomes may be, at least in part, due to the scavenging by fluvastatin of free radicals.


The antibiotics supplemented bone cement improved the masquelet's induced membrane in a rat femur critical size defect model.
Masquelet technique is a two-stage surgical procedure used in the treatment of critical-size bone defects (CSD). Adding antibiotics to polymethylmethacrylate (PMMA) is still questionable to create higher quality induced membrane (IM). The aim of the study was to evaluate the effects of three antibiotic-supplemented cement, fusidic acid, teicoplanin, and gentamicin, on osteogenesis and IM progression applied to rat femur CSD model by comparing histopathological, biochemical, and immunohistochemical findings. Twenty-eight male rats were divided into four groups control, gentamicin (G), teicoplanin (T), and fusidic acid (FA). A 10 mm CSD was created in rat femurs. In the postoperative 4th week, intracardiac blood samples were collected for biochemical analysis of bone alkaline phosphatase (BALP), osteocalcin (OC), and tumor necrosis factor-alpha (TNF-α) levels. IMs obtained in secondary operation were fixed and prepared for histopathological scoring of membrane progression and immunohistochemical evaluation of rat-specific Transforming Growth Factor-Beta (TGF-β), Runt-related Transcription Factor 2 (Runx2), and Vascular Endothelial Growth Factor (VEGF) expressions. Levels of BALP and OC in serum didn't change among groups significantly while serum TNF-α levels significantly decreased in all antibiotic groups compared to the control group (P = 0.017). Histological scores of groups FA and T were significantly higher than those of groups Control and G (P = 0.0007). IMs of groups T and FA showed good progression while those of groups Control and G were also moderately progressed. A significant increase in TGF-β expression was observed in group G and FA (P = 0.001) while a significant increase in the expression of VEGF was observed in groups G and T compared to the control group (P = 0.036). The bone cement impregnated with thermostable and safe antibiotics, gentamicin, fusidic acid, and teicoplanin can increase osteogenesis and support IM progression by increasing the expressions of TGF-β and VEGF. Anabolic effects of induced membranes used in the treatment of critical-size bone defects can be enhanced by antibiotic-supplemented PMMAs applied by altering the original technique.


Should Robot-Assisted Surgery Tolerate or Even Accommodate Less Surgical Dexterity?
Since their adoption during the 1990s, minimally invasive surgical techniques have demonstrated postoperative surgical recovery benefits for patients. As robotic surgery platforms continue to be developed and utilized in surgical specialty areas, dexterity and visual field limitations of laparoscopy are coming under close clinical and ethical scrutiny. This article compares robotic and laparoscopic modalities, with special attention to dexterity, surgeon performance, ergonomics, and patient outcomes. This article also examines robotic platforms' advantages for surgeons' technical capacity and career longevity.


HSP47 as a collagen-specific molecular chaperone: function and expression in normal mouse development.
A large family of molecular chaperones can be divided into two major groups: general chaperone and substrate-specific chaperone. HSP47 is a collagen-specific molecular chaperone residing in the endoplasmic reticulum (ER). Recent studies revealed that HSP47 is essential molecular chaperone for mouse development and is essential for collagen molecular maturation in the ER. In the absence of HSP47, collagen microfibril formation and basement membrane formation are impaired in mouse embryos because the failure in the molecular maturation of types I and IV collagens, respectively. The tissue-specific expression of HSP47 is always correlated with that of various types of collagens and closely related with the collagen-related diseases including fibrosis in various organs. The importance of HSP47 in the therapeutic strategy for fibrotic diseases as well as for a marker of collagen-related autoimmune diseases will also be discussed.


Animal Models and Antifungal Agents in Paracoccidioidomycosis: An Overview.
Paracoccidioides brasiliensis is the etiologic agent of paracoccidioidomycosis, the most prevalent systemic mycosis in Latin America. The morbidity and mortality associated with paracoccidioidomycosis necessitate our understanding of fungal pathogenesis and discovering of new agents to treat this infection. Animal models have contributed much to the knowledge of fungal infections and their corresponding therapeutic treatments. This is true for animal models of the primary fungal pathogens such as P. brasiliensis. This review describes the development, details and utility of animal models of paracoccidioidomycosis for studying and developing the current antifungal agents used for therapy of this fungal disease and novel agents with antifungal properties against P. brasiliensis.


Extracts and molecules from medicinal plants against herpes simplex viruses.
Herpes simplex viruses (HSV-1 and -2) are important pathogens for humans, especially in the case of highly susceptible adults. Moreover, HSV-2 has been reported to be a high risk factor for HIV infection. Therefore, the discovery of novel anti-HSV drugs deserves great efforts. In this paper, we review anti-HSV substances from natural sources, including both extracts and pure compounds from herbal medicines, reported in studies from several laboratories. The role of traditional medicine for the development of anti-HSV compounds is also discussed. Interestingly, it was found that traditional medicines, like Ayurvedic, traditional Chinese (TCM), Chakma medicines, are good and potential sources for promising anti-HSV drugs. A second objective of this review is to discuss several anti-HSV compounds with respect to their structure-activity relationship (SAR). A large number of small molecules, like phenolics, polyphenols, terpenes (e.g., mono-, di-, tri-), flavonoids, sugar-containing compounds, were found to be promising anti-herpetic agents. Our major conclusion is that natural products from medicinal plant extracts are very important source of anti-HSV agents.


The Effect of Molecular Subtype and Residual Disease on Locoregional Recurrence in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy and Postmastectomy Radiation.
The relative contribution of biologic subtype to locoregional recurrence (LRR) in patients treated with neoadjuvant chemotherapy (NAC), mastectomy, and postmastectomy radiotherapy (PMRT) is not clearly defined. 233 patients with stages 2 and 3 breast cancer who received NAC, mastectomy, and PMRT between 2000 and 2009 were included: 53 % (n = 123) had HR+ (ER or PR+/HER2-), 23 % (n = 53) had HER2+ (HER2+/HR+ or HR-), and 24 % (n = 57) had triple-negative (TN) disease (HR-/HER2-). The 5-year LRR rates were estimated by Kaplan-Meier methods. Cox regression analysis was performed to evaluate covariates associated with LRR. The median follow-up period was 62 months. A pathologic complete response (pCR) was seen in 14 % of the patients. The 5-year LRR rate was 8 % for the entire cohort. The LRR rate was 0 % for the patients with a pCR versus 9 % for the patients without a pCR (p = 0.05). TN disease [Hazard ratio (HR) 4.4; p = 0.003] and pathologic node positivity (HR 9.8; p = 0.03) were associated with LRR. Patients with TN disease had a higher LRR rate than patients with HER2+ or HR+ disease (20 vs. 6 and 4 %; p = 0.005). Among patients without a pCR, TN subtype was associated with increased LRR risk (26 versus 7 % HER+ and 4 % HR+; p < 0.001). Patients with TN breast cancer had the highest LRR rate after NAC, mastectomy and PMRT. Whereas no LRR was observed among TN patients with a pCR, TN patients with residual disease had a significantly higher LRR risk. Patients with HR+ and HER2+ breast cancer had favorable LRR rates regardless of NAC response, likely due to receipt of adjuvant systemic targeted therapies.


Easy access to constrained peptidomimetics and 2,2-disubstituted azetidines by the unexpected reactivity profile of α-lithiated N-Boc-azetidines.
The reactivity profile of lithiated N-Boc-2-arylazetidines has been investigated filling a gap in the chemistry of this class of four-membered heterocycles. Two unexpected and unprecedented results have been observed: an "ortho-effect" accounting for the regioselective functionalization of the azetidine ring, and self-condensation leading to new and interesting azetidine-based peptidomimetics.


Two forms of Vibrio cholerae O1 El Tor hemolysin derived from identical precursor protein.
Vibrio cholerae O1 grown in heart infusion broth produces two forms of El Tor hemolysin (ETH) monomers of 65 and 50 kDa. These monomers form several different sizes of mixed oligomers ranging from 180 to 280 kDa in the liposomal membranes. We found that the N-terminal amino acid sequences, NH2-Trp-Pro-Ala-Pro-Ala-Asn-Ser-Glu, of both the 65- and 50-kDa toxins were identical. We assumed, therefore, that the 65- and 50-kDa toxins were derivatives of the identical precursor protein and the 50-kDa protein was a truncated derivative of 65-kDa ETH. To substantiate this assumption, we treated the 260-kDa oligomer with trypsin and obtained a 190-kDa oligomer. This 190-kDa oligomer consisted of only the 50-kDa subunits. Both 260- and 190-kDa oligomers formed ion channels indistinguishable from each other in planar lipid bilayers. These results suggest that the essential part of the ETH in forming the membrane-damaging aggregate is a 50-kDa protein.


High-dose methylprednisolone in nonintubated patients with severe COVID-19 pneumonia.
Recent trials with dexamethasone and hydrocortisone have demonstrated benefit in patients with coronavirus disease 2019 (COVID-19). Data on methylprednisolone are limited. Retrospective cohort of consecutive adults with severe COVID-19 pneumonia on high-flow oxygen (FiO2 ≥ 50%) admitted to an academic centre in New York, from 1 March to 15 April 2020. We used inverse probability of treatment weights to estimate the effect of methylprednisolone on clinical outcomes and intensive care resource utilization. Of 447 patients, 153 (34.2%) received methylprednisolone and 294 (65.8%) received no corticosteroids. At 28 days, 102 patients (22.8%) had died and 115 (25.7%) received mechanical ventilation. In weighted analyses, risk for death or mechanical ventilation was 37% lower with methylprednisolone (hazard ratio 0.63; 95% CI 0.47-0.86; P = .003), driven by less frequent mechanical ventilation (subhazard ratio 0.56; 95% CI 0.40-0.79; P = .001); mortality did not differ between groups. The methylprednisolone group had 2.8 more ventilator-free days (95% CI 0.5-5.1; P = .017) and 2.6 more intensive care-free days (95% CI 0.2-4.9; P = .033) during the first 28 days. Complication rates were not higher with methylprednisolone. In nonintubated patients with severe COVID-19 pneumonia, methylprednisolone was associated with reduced need for mechanical ventilation and less-intensive care resource utilization without excess complications.


Astrocyte-derived transgene GDNF promotes complete and long-term survival of adult facial motoneurons following avulsion and differentially regulates the expression of transcription factors of AP-1 and ATF/CREB families.
Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor for motoneurons (MNs). We have previously demonstrated that overexpression of GDNF in astrocytes of GFAP-GDNF mice promotes long-term survival of neonatal MNs after facial nerve axotomy. In the present study, we investigated whether astrocyte-derived GDNF could also have a neuroprotective effect on adult MNs following facial nerve avulsion. We also examined avulsion- and GDNF-induced changes in the expression pattern of several members of the AP-1 and ATF/CREB families of transcription factors, which are involved in the fate determination of neurons following injury. We demonstrated that GDNF promotes complete rescue of avulsed MNs for at least 4 months post-injury. Transgene GDNF significantly upregulates c-Jun expression in naive MNs, further upregulates injury-induced c-Jun expression in facial MNs, and results in its activation in most surviving MNs. No significant changes were found in c-Fos expression. We found that GDNF has an opposing effect on ATF2 and ATF3 expression. It dramatically downregulates increased levels of ATF3 in response to injury, whereas the expression of ATF2, which is normally reduced after injury, is completely preserved in GFAP-GDNF mice. Our data suggest that maintenance of high levels of ATF2 in injured MNs could be crucial in modulating c-Jun function, and c-Jun/ATF2 signaling could be involved in GDNF-mediated survival of mature MNs.


Investigating the physical activity, health, wellbeing, social and environmental effects of a new urban greenway: a natural experiment (the PARC study).
Evidence for the health benefits of urban green space tends to stem from small, short-term quasi-experimental or cross-sectional observational research, whilst evidence from intervention studies is sparse. The development of an urban greenway (9 km running along 3 rivers) in Northern Ireland provided the opportunity to conduct a natural experiment. This study investigated the public health impact of the urban greenway on a range of physical activity, health, wellbeing, social, and perceptions of the environment outcomes. A repeated cross-sectional household survey of adult residents (aged ≥16 years) who lived ≤1-mile radius of the greenway (intervention sample) and > 1-mile radius of the greenway (control sample) was conducted pre (2010/2011) and 6-months post implementation (2016/2017). We assessed changes in outcomes pre- and post-intervention follow-up including physical activity behaviour (primary outcome measure: Global Physical Activity Questionnaire), quality of life, mental wellbeing, social capital and perceptions of the built environment. Linear regression was used to calculate the mean difference between post-intervention and baseline measures adjusting for age, season, education, car ownership and deprivation. Multi-level models were fitted using a random intercept at the super output area (smallest geographical unit) to account for clustering within areas. The analyses were stratified by distance from the greenway and deprivation. We assessed change in the social patterning of outcomes over time using an ordered logit to make model-based outcome predictions across strata. The mean ages of intervention samples were 50.3 (SD 18.9) years at baseline (n = 1037) and 51.7 (SD 19.1) years at follow-up (n = 968). Post-intervention, 65% (adjusted OR 0.60, 95% CI 0.35 to 1.00) of residents who lived closest to the greenway (i.e., ≤400 m) and 60% (adjusted OR, 0.64 95% CI 0.41 to 0.99) who lived furthest from the greenway (i.e.,≥1200 m) met the physical activity guidelines - 68% of the intervention sample met the physical activity guidelines before the intervention. Residents in the most deprived quintiles had a similar reduction in physical activity behaviour as residents in less deprived quintiles. Quality of life at follow-up compared to baseline declined and this decline was significantly less than in the control area (adjusted differences in mean EQ5D: -11.0 (95% CI - 14.5 to - 7.4); - 30.5 (95% CI - 37.9 to - 23.2). Significant change in mental wellbeing was not observed despite improvements in some indicators of social capital. Positive perceptions of the local environment in relation to its attractiveness, traffic and safety increased. Our findings illustrate the major challenge of evaluating complex urban interventions and the difficulty of capturing and measuring the network of potential variables that influence or hinder meaningful outcomes. The results indicate at this stage no intervention effect for improvements in population-level physical activity behaviour or mental wellbeing. However, they show some modest improvements for secondary outcomes including positive perceptions of the environment and social capital constructs. The public health impact of urban greenways may take a longer period of time to be realised and there is a need to improve evaluation methodology that captures the complex systems nature of urban regeneration.


Clinical Epidemiology of Microinvasive Cervical Carcinoma in an Italian Population Targeted by a Screening Programme.
(1) Background: This population-based study aimed at identifying the factors associated with the likelihood of detection of stage IA cervical carcinoma-versus the detection of stage IB through IV cervical carcinoma-and the patterns of surgical treatment. (2) Methods: Between 1995-2016, 3750 patients living in the Emilia-Romagna Region (northern Italy) were registered with cervical carcinoma, including 2942 eligible patients (median age, 53). Multivariate analysis was performed using binary logistic regression models. (3) Results: The likelihood of stage IA cervical carcinoma (n = 876, 29.8%) did not change over time, decreased with increasing patient age, and was lower for patients with adenocarcinoma and grade 3-4 disease. Three hundred and fifty (40.0%) patients had a conservative treatment, 317 (36.2%) had hysterectomy, 197 (22.5%) had hysterectomy with lymph node dissection (LND), and 12 (1.4%) had a conservative treatment with LND. The proportion of hysterectomy decreased from 70.6% in 1995-1999 to 46.9% in 2011-2016. The likelihood of hysterectomy increased above the age of 40. Among screening-aged (25-64 years) patients, the likelihood of hysterectomy did not differ between screen-detected and non-screen-detected ones. Hysterectomy was increasingly combined with LND. High tumour grade was the strongest determinant of LND during hysterectomy. (4) Conclusions: This study provided a multifaceted overview of stage IA cervical carcinoma over the last decades.


Risk stratification for recurrent heart failure in patients post-myocardial infarction with electrocardiographic and echocardiographic left atrial abnormality.
Left atrial enlargement is predictive of cardiovascular events. The predictive power, however, of the combination of electrocardiographic (LAE-ECG) and echocardiographic left atrial enlargement (LAE-Echo) has not been extensively evaluated. We prospectively identified patients admitted with non-ST-segment elevation myocardial infarction (NSTEMI) who developed new-onset heart failure during admission. Baseline electrocardiograms obtained < or =12 months before admission were evaluated for LAE-ECG, such as prolonged P-wave duration or positive P-wave terminal force in lead V1, and in-hospital echocardiographic reports obtained < or =1 month after admission were assessed for linear, anteroposterior LAE-Echo. Follow-up was directed toward pertinent cardiovascular events and death. Of the 462 patients with NSTEMI, 108 developed new-onset heart failure (23%); 71 patients had LAE-Echo. Follow-up was 23.2 months (mean 22.1 months). Although in-hospital (early) cardiovascular complications (other than heart failure) were not significantly higher in patients with LAE-Echo, these patients demonstrated more postdischarge (late) cardiovascular complications, predominantly recurrent heart failure. In addition, those with a combination of LAE-Echo and LAE-ECG demonstrated significantly higher recurrence of heart failure (hazard ratio 1.52, 95% confidence interval 1.12 to 4.35; p = 0.02 for interatrial conduction delay, and hazard ratio 1.07, 95% confidence interval 1.01 to 3.27 for P-wave terminal force in lead V1; p = 0.03) and increased mortality compared with those with LAE-Echo alone. In conclusion, our data suggest that a combination of electrical and mechanical left atrial dysfunction is significantly more predictive of increased cardiovascular events and mortality compared with left atrial mechanical dysfunction alone.


Intramedullary nailing for open fractures of the femoral shaft: evaluation of contributing factors on deep infection and nonunion using multivariate analysis.
The purpose of this study was to use multivariate analysis to evaluate contributing factors affecting deep infection and nonunion of open femoral fractures treated with locked intramedullary nailing (IMN). We examined 89 open femoral fractures (88 patients) treated with immediate or delayed locked IMN in static fashion at the Kitasato University Hospital from 1988 to 2001. Multiple regression models were derived to determine predictors of deep infection and nonunion. The following predictive variables of deep infection were selected for analysis: age, sex, Gustilo type (I+II or III), fracture grade by AO type (A or B+C), fracture site (proximal site+distal site or middle site), timing or method of IMN, reamed or unreamed nailing (R versus UR), debridement time (< or =6 h or >6 h), existence of polytrauma (ISS<18 or ISS> or =18), and existence of floating knee injury (+ or -). The predictive variables of nonunion selected for analysis were the same as those for deep infection, with the addition of deep infection (+ or -). Five fractures (5.6%) developed deep infections: one Gustilo type II and four type III. Multivariate analysis revealed that only Gustilo type significantly correlated with occurrence of deep infection (p<0.05). Nonunion occurred in 12 fractures (14.1%). Multivariate analysis revealed that only fracture grade by AO type significantly correlated with occurrence of nonunion (p<0.02).


TNF-α and TGF-β counter-regulate PD-L1 expression on monocytes in systemic lupus erythematosus.
Monocytes in patients with systemic lupus erythematosus (SLE) are hyperstimulatory for T lymphocytes. We previously found that the normal program for expression of a negative costimulatory molecule programmed death ligand-1 (PD-L1) is defective in SLE patients with active disease. Here, we investigated the mechanism for PD-L1 dysregulation on lupus monocytes. We found that PD-L1 expression on cultured SLE monocytes correlated with TNF-α expression. Exogenous TNF-α restored PD-L1 expression on lupus monocytes. Conversely, TGF-β inversely correlated with PD-L1 in SLE and suppressed expression of PD-L1 on healthy monocytes. Therefore, PD-L1 expression in monocytes is regulated by opposing actions of TNF-α and TGF-β. As PD-L1 functions to fine tune lymphocyte activation, dysregulation of cytokines resulting in reduced expression could lead to loss of peripheral T cell tolerance.


Role of endoscopic ultrasonography in preoperative staging of gastric carcinoma.
Preoperative staging of tumour extent in upper gastrointestinal malignancy greatly facilitates planning of therapy. The present study was undertaken to see whether preoperative endoscopic ultrasonography (EUS) accurately predicts the tumour stage in gastric carcinoma. Endoscopic ultrasonography was performed preoperatively on 112 patients with gastric cancer. All 112 patients underwent surgery. The results of EUS were compared with postoperative histological staging. Endoscopic ultrasonography was correct in determining the primary tumour (T) and regional lymph node (N) staging in 83.0% and 64.2% of patients, respectively. EUS was correct in determining the absence of lymph node metastasis in 87.5% but was not reliable in determining metastasis in one to six regional lymph nodes (N1) and metastasis in seven to 15 regional lymph nodes (N2) stages; (61.5% and 33.3%, respectively). Of 26 patients with N1 stage, 10 had false negative results, whereas 11 patients in stage N2 were diagnosed endoscopically as stage N1. The sensitivity and specificity were 67.2% and 89%, respectively. The actual resection rate (75%) was almost identical to the rate predicted preoperatively by EUS (78%). Endoscopic ultrasonography staging is the most accurate method for discriminating between potentially resectable (tumour invading lamina propria or submucosa (T1) to tumour that penetrates the serosa (visceral peritoneum) without invading adjacent structures (T3)) and potentially non-resectable (tumour invading adjacent structures (T4)) cases of upper gastrointestinal cancer.


Improved gas chromatography with electron-capture detection using a reaction pre-column for the determination of blood cyanide: a higher content in the left ventricle of fire victims.
We developed a head-space method for the determination of blood cyanide by gas chromatography with electron-capture detection. In this technique, a reaction pre-column, packed with chloramine-T, was used for the conversion of hydrogen cyanide into cyanogen chloride. Since the reaction pre-column eliminated the necessity for trapping hydrogen cyanide from the biological samples, blood cyanide was quickly analysed by acidification only. The reaction pre-column was durable for at least several months. The calibration curve gave good linearity when dichloromethane was used as the internal standard, and the lower detection limit taken from this plot was ca. 0.05 micrograms/ml. The relative standard deviation of spiked blood samples was in the range 0.6-3.9%. We determined blood cyanide levels at autopsy in victims who had died from fire using this method. A significantly higher cyanide content was detected in the left ventricular blood than in the right. There was a positive correlation between blood cyanide and carboxylhaemoglobin contents. This simple and sensitive technique could be very useful for the determination of cyanide in various samples.


Effects of acetazolamide on medullary extracellular pH and PCO2 and on ventilation in peripherally chemodenervated cats.
The responses of ventilation and of medullary extracellular fluid (ECF) pH and PCO2, to an intravenous (i.v.) infusion of 50 mg/kg acetazolamide (an inhibitor of carbonic anhydrase), were measured in cats anaesthetized with chloralose and urethane, in which both bilateral vagotomy and carotid nerve section had been performed. After 2 h, it was observed that: acetazolamide caused an acidosis in medullary ECF which was still developing after 2 h, reflected by a progressive fall in pH (mean = 0.215 pH units in 2 h), while ECF PCO2 showed an insignificant rise of about 1 kPa; acetazolamide caused a considerable rise in ventilation, which largely developed in the first 15 min after drug infusion; the direction of the ECF acid-base responses in the first 15 min varied, whereas that of the ventilatory response did not. Furthermore, the time course of the former developed quite differently from the latter. It was therefore concluded that the observed changes in medullary ECF pH and PCO2 can not explain the large and fast ventilatory response of acetazolamide.


Pliable DNA conformation of response elements bound to transcription factor p63.
We show that changes in the nucleotide sequence alter the DNA conformation in the crystal structures of p63 DNA-binding domain (p63DBD) bound to its response element. The conformation of a 22-bp canonical response element containing an AT spacer between the two half-sites is unaltered compared with that containing a TA spacer, exhibiting superhelical trajectory. In contrast, a GC spacers abolishes the DNA superhelical trajectory and exhibits less bent DNA, suggesting that increased GC content accompanies increased double helix rigidity. A 19-bp DNA, representing an AT-rich response element with overlapping half-sites, maintains superhelical trajectory and reveals two interacting p63DBD dimers crossing one another at 120°. p63DBD binding assays to response elements of increasing length complement the structural studies. We propose that DNA deformation may affect promoter activity, that the ability of p63DBD to bind to superhelical DNA suggests that it is capable of binding to nucleosomes, and that overlapping response elements may provide a mechanism to distinguish between p63 and p53 promoters.


Genomic analysis of freshwater cyanophage Pf-WMP3 Infecting cyanobacterium Phormidium foveolarum: the conserved elements for a phage.
Cyanophages are ecologically abundant, genetically diverse in aquatic environments, and affect the population and evolutionary trajectories of their hosts. After reporting the cyanophage Pf-WMP4 genome (Liu et al. in Virology 366:28-39, 2007), we hereby present a related cyanophage, Pf-WMP3, which also infects the freshwater cyanobacterium Phormidium foveolarum. The Pf-WMP3 genome contains 43,249 bp with 234 bp direct terminal repeats. The overall genome organization and core genes of the two phages are comparable to those of the T7 supergroup phages. Compared with Pf-WMP4, cyanophage Pf-WMP3 has diverged extensively at the DNA level; however, they are closely related at the protein level and genome architecture. The left arm genes for the two phages, which mainly encode the DNA replication machinery, are not conserved in the gene order. Whereas the right arm genes of the two phages coding for structural proteins show high similarity in amino acid sequences and modular architecture, indicating that they have retained similar development strategies. The differences in similarity levels between the left and right arm genes suggest that the structural genes are the most conserved elements for a phage.


Hyperfractionated, accelerated radiotherapy and concurrent chemotherapy in locally advanced bladder cancer.
A prospective study was performed on 11 patients with locally advanced transitional cell carcinoma of the bladder to evaluate the toxicity of an integrated treatment with cis-platinum (70 mg/m2 body surface), doxorubicin (10 mg/m2 body surface) and 8 meV photons. Local and systemic toxicity caused by this treatment schedule was minor. Late sequelae consisted of reduced bladder capacity in 2 patients and proctitis in 1 patient. Complete clinical clearance of the local tumor could be achieved in 9 of 11 patients after a mean follow-up of 8.1 months.


Development, implementation and perceived benefits of student pharmacist learning experiences in transitions of care.
Experiential education designed around transitions of care (TOC) offers student pharmacists a variety of educational activities to build their skills and confidence related to direct patient care, communication, and practice management. The purpose of this paper is to describe the development, implementation, and student perceptions of introductory pharmacy practice experiences (IPPEs) and advanced pharmacy practice experiences (APPEs) that emphasize TOC. Sixty students (22 IPPE and 38 APPE) completed the learning experience with the oversight of two faculty members in two, separate, large community hospitals providing pharmacy led TOC services. Each educational activity was mapped to the Pharmacists' Patient Care Process, which includes guided electronic medical record review, patient case discussions, and direct patient care (i.e. medication history collection, patient education). Other aspects of the learning experience include the use of layered learning, intention/reflection dialogues, and topic discussions. Evaluation of the learning experience occurred through review of student performance data and feedback. Student performance data demonstrated an increase in the mean score between midpoint and final evaluation of all TOC specific competencies. Students expressed a positive learning experience as demonstrated by an approximately 3.8 overall rating of the learning experience on a 4-point scale for both IPPEs and APPEs. Analysis of open comments from students demonstrated the most beneficial aspects of the learning experience as interprofessional communication, patient communication, and a variety of patient care opportunities.


Neuroimaging study in subjects at high risk of psychosis revealed by the Rorschach test and first-episode schizophrenia.
There is increasing evidence of neuroanatomical pathology in schizophrenia, but it is unclear whether changes exist prior to disease onset. This study aimed to examine whether changes exist prior to disease onset, especially in the temporal lobes. T1-weighted and diffusion tensor magnetic resonance imaging were performed on 9 first-episode schizophrenia patients, 10 patients who were at high risk of schizophrenia and 10 healthy controls. Voxel-based analysis using the normalised images of cortical volume data was examined, and the fractional anisotropy value at three component fibres of the temporal lobes, inferior longitudinal fasciculus, superior longitudinal fasciculus (SLF) and cingulum hippocampal part was compared among the three groups. There were statistically significant volume differences at the bilateral temporal lobe between the healthy subjects and high-risk group. Between the schizophrenic group and healthy subjects, statistically significant volume differences were detected at the bilateral temporal lobes and anterior cingulate cortex. The fractional anisotropy values of the SLF in the schizophrenic and high-risk groups were significantly lower than in the healthy subjects. Our findings indicate that some brain alterations may progress in patients at psychosis pre-onset, possibly because of disrupted developmental mechanisms, and these pathological changes may be predictive of functional outcome.


In vitro glycated low-density lipoprotein interaction with human monocyte-derived macrophages.
Human low-density lipoprotein (LDL) was glycated in vitro (5 days, glucose 50 mmol/l), labelled with 125I, and its binding and uptake by human monocyte-derived macrophages studied. Glycation produced lower binding and lower uptake. Competition experiments using unlabelled LDL (control, glycated, and acetyl-LDL) showed that most glycated LDL was taken up by the apolipoprotein-B100: E receptor pathway. Results suggest that less of the glycated LDL may enter the cells via scavenger receptors, and very minute amount via non-saturable receptor-independent pathways.


Burkholderia cepacia as a cause of ecthyma gangrenosum-like lesion.
Ecthyma gangrenosum (EG) is considered to be a pathognomonic sign of Pseudomonas aeruginosa septicemia and is predominantly seen in immunosuppressed patients. Although P. aeruginosa is the most recognized pathogen of EG, numerous other organisms have been reported to cause clinically identical lesions. We report a case of an EG-like eruption caused by Burkholderia cepacia, in an intensive care unit patient with multiple myeloma.


Estrogen binding protein activity in Morris hepatoma 7777 compared with normal rat liver.
Estrogen binding protein activities were determined in the cytosol from adult male Buffalo rat liver and Morris hepatoma 7777. Estrogen receptors were prepared using the protamine sulfate precipitation technique of Chamness. The ability of various unlabeled steroids competing with [3H]estradiol was examined to establish the binding specificity. Estradiol binding in Morris hepatoma 7777 cytosol was greatly decreased compared with that present in hepatic cytosol prepared from normal rat liver. The receptor concentration expressed as femtomoles per milligram of cytoplasmic protein was 31.1 +/- 2.9 SD for normal rat liver and 0.41 +/- 0.88 SD for the hepatoma. Gel filtration chromatography revealed the presence of an estrogen binder in hepatoma cytosol which was not present in either normal liver or in the protamine sulfate precipitates of hepatoma cytosol. The molecular weight, binding specificity, and precipitation of this protein by specific antiserum suggests that it is alpha-fetoprotein.


Do maternal characteristics influence maternal-fetal medicine physicians' willingness to intervene when managing periviable deliveries?
Determine the relative influence of patient characteristics on Maternal-Fetal Medicine (MFM) physicians' willingness to intervene when managing 23-week preterm premature rupture of membranes. Surveyed 750 randomly sampled US members of the Society of Maternal-Fetal Medicine. Physicians rated their willingness to offer induction, order steroids and perform cesarean across eight vignettes; then completed a questionnaire querying expectations about neonatal outcomes and demographics. Three hundred and twenty-five (43%) MFMs responded. Patient characteristics only influenced ⩽11% of participants' willingness ratings. Overall, provider characteristics and institutional norms were associated with willingness to perform antenatal interventions, for example, practice region was associated with willingness to offer induction (P<0.001), order steroids (P=0.008) and perform cesarean for distress (P=0.011); while institutional cesarean cutoffs were associated with willingness to order steroids and perform cesarean for labor and distress (all P<0.001). Physician-level factors and institutional norms, more so than patient characteristics, may drive periviable care and outcomes.


Is the go/no-go lexical decision task an alternative to the yes/no lexical decision task?
In the go/no-go lexical decision task (LDT), participants are instructed to respond as quickly as they can when a word is presented and not to respond if a nonword is presented. By minimizing part of the response selection process in the experimental task, the impact of response decision time on the obtained lexical decision time is probably reduced relative to the standard yes/no LDT (Gordon, 1983). Experiments 1 and 2 show that the go/no-go LDT is sensitive to the effects of word frequency and associative priming--the magnitude of these effects is similar with the two tasks. More important, the go/no-go LDT has a number of advantages with respect to the "standard" yes/no LDT: It offers faster response times, more accurate responding, and fewer processing demands than does the yes/no task. Accordingly, the go/no-go task appears to be an excellent alternative to the standard yes/no task.


The retinal projections to the ventral and dorsal divisions of the medial terminal nucleus and mesencephalic reticular formation in the Japanese monkey (Macaca fuscata): a reinvestigation with cholera toxin B subunit as an anterograde tracer.
After a monocular injection of the cholera toxin B subunit (CTB) into the vitreous chamber of the eye, retinal projections to the medial terminal nucleus (MTN) of the accessory optic system (AOS) were studied in the Japanese monkey. The anterogradely transported tracer was visualized with the peroxidase antibody technique by using an anti-cholera toxin antibody. One small accumulation of the CTB-immunopositive retinofugal terminals was located in a small area just medial to the medial edge of the cerebral peduncle and anterior to the attachment of the oculomotor nerve, suggesting the existence of a ventral division of the MTN of the AOS. Caudally, one very small bundle of the retinofugal fibers extending dorsally from this accumulation was seen running along the medial edge of the cerebral peduncle and substantia nigra to the small region corresponding to the dorsal division of the MTN. A few small bundles of CTB-immunopositive retinal fibers were observed to leave the superior fasciculus of the AOS at various points. These fibers coursed medially through the cerebral peduncle and substantia nigra to reach some restricted areas of the mesencephalic reticular formation between the medial lemniscus and the substantia nigra.


Veno-venous bypass without systemic anticoagulation for transplantation of the human liver.
A technique of veno-venous bypass without heparin has been developed for use during the anhepatic phase of transplantation of the liver. With this method, the ability to compress the temporarily obstructed vena caval and portal venous systems has made hepatic transplantation an easier procedure.


Association of factor expression levels with annual bleeding rate in people with haemophilia B.
Gene therapy clinical trials measure steady-state clotting factor expression levels (FELs) to evaluate the modulation of the bleeding phenotype, aiming to offer consistent protection against breakthrough bleeding events. The link between FELs and bleeding risk in people with haemophilia B (PwHB) is not well understood. We evaluated the association between FEL and ABR in PwHB. This cross-sectional study extended the CHESS burden of illness studies in Europe and the United States. Recruitment of additional adult males with haemophilia B supplemented the existing CHESS sample size of PwHB and FELs. PwHB receiving prophylaxis were excluded, as fluctuating FELs may have confounded the analysis. Demographic and clinical characteristics were reported descriptively. Any recorded baseline FEL was reported by the haemophilia-treating physicians according to the medical records. Generalised linear models with log link explored the association between changes in FEL and ABR. The study included 407 PwHB and no inhibitors receiving on-demand treatment. Mean age was 36.7 years; 56% from the EU, 44% from the United States. Mean baseline FEL was 9.95 IU/dl (SD, 10.47); mean ABR was 2.4 bleeds/year (SD, 2.64). After adjusting for covariates, the model showed that for every 1% increase in FEL the average ABR decreased by .08 (p < .001). Predicted number of bleeding events according to FEL showed a significant non-linear relationship between FEL and ABR (p < .05). This analysis showed a significant relationship between FEL and ABR, where increases in FEL were associated with decreases in ABR among men with HB in Europe and the US.


[Papillomatosis of the mitral valve as an unusual cause of myocardial ischemia. Description of a case and review of the literature].
Papilloma is a rare primary heart tumour; only 75 cases have been reported and most were casual findings at autopsy. We describe another case of this tumour in a 9 years girl. The neoformation had produced a picture of angina pectoris, followed by death due to an occluded left coronary orifice. To our knowledge, this is the first report of this type of tumour with electrocardiographic documentation.


Current state and effectiveness of abdominal ultrasonography in complete medical screening.
The current state and effectiveness of abdominal ultrasonography (US) were investigated by reviewing statistical data for US of the kidney as part of complete medical screenings conducted at our institution between April 1994 and March 2004. Among 4339 individuals with US findings, computed tomography (CT) was performed on 129 individuals at our institution. Among these individuals, US findings and CT diagnoses were compared and analyzed. US findings indicated renal tumors in 73 of the 129 subjects, and the breakdown of CT diagnoses for these 73 individuals was as follows: no lesion, n = 45 (61.6%); simple renal cyst, n = 13 (17.8%); complicated renal cyst, n = 5 (6.8%); suspected malignant tumor, n = 5 (6.8%); renal angiomyolipoma, n = 2 (2.7%); pelvic dilatation, n = 1 (1.4%); granuloma, n = 1 (1.4%); teratoma, n = 1 (1.4%). Magnetic resonance imaging (MRI) was performed on 4 of the 5 subjects with suspected malignant tumor, and surgery was performed in all 4 cases with suspected kidney cancer. Kidney cancer was histopathologically confirmed in 2 patients, resulting in a detection rate of 0.046% for kidney cancer by US as part of a complete medical screening. In the 2 patients with kidney cancer, differentiating cystic renal cell cancer from a renal cyst was not possible based on US findings alone in 1 patient, and no thorough examinations were performed in the 3 years leading up to surgery. These results suggest that additional US and thorough examinations are necessary if a lesion cannot be confirmed as a simple renal cyst on initial US. Furthermore, to improve the skill levels of healthcare professionals who perform and interpret US, a feedback system should be established where data related to complete medical screenings are available to the personnel involved.


Attention to central and peripheral visual space in a movement detection task: an event-related potential and behavioral study. I. Normal hearing adults.
The effects of focussed attention to peripherally and centrally located visual stimuli were compared via an analysis of event-related brain potentials (ERPs) while subjects detected the direction of motion of a white square in a specified location. While attention to both peripheral and foveal stimuli produced enhancements of the early ERP components, the distribution over the scalp of the attention-related changes varied according to stimulus location. The attention-related increase in the amplitude of the N1 wave (157 ms) to the peripheral stimuli was greater over the parietal region of the hemisphere contralateral to the attended visual field. By contrast, the largest effects of foveally directed attention occurred over the occipital regions where the increase was bilaterally symmetrical. Additionally, the effects of attention on the ERPs were significantly larger for moving than for stationary stimuli, and this effect was greater for peripheral than for central attention. A long-latency positive displacement component (300-600 ms) was larger over the right than the left hemisphere during attention to the lateral visual fields, but was symmetrical in amplitude when central stimuli were attended. These results suggest that different pathways are modulated when attention is deployed to different regions of the visual fields. Further, they suggest that the special role of the right hemisphere in spatial attention may be limited to analysis of information in the visual periphery.


Terminologia Anatomica versus unofficial descriptions and nomenclature of the fasciae and ligaments of the female pelvis: a dissection-based comparative study.
The aims of this study were: (1) to define and classify those connective structures of the female pelvis that are of potential clinical interest, (2) to evaluate the adequacy of the Terminologia Anatomica (official nomenclature) and (3) to establish a correspondence between the official nomenclature and the most commonly used terms. The results of 30 macroscopic and laparoscopic dissections of fresh cadavers with and without vessel injection of colored latex solutions were compared with the descriptions and definitions in the Terminologia Anatomica and the most frequently cited English and non-English literature from 1890 to 2003. We identified 3 groups of fasciae, parietal pelvic fascia, visceral pelvic fascia, and extraserosal pelvic fascia, which could be divided into diverse clinically relevant anatomical structures characterized by different locations, spatial orientation, and consistency. These structures differed considerably with regard to number and nomenclature from those described in the Terminologia Anatomica and part of the literature. Our results suggest that the official terminology applied to the connective structures of the female pelvis could be profitably revised and expanded. We offer a complete description of these structures and suggest a classification that may be useful for teaching and clinical purposes.


Origin and evolution of eukaryotic apoptosis: the bacterial connection.
The availability of numerous complete genome sequences of prokaryotes and several eukaryotic genome sequences provides for new insights into the origin of unique functional systems of the eukaryotes. Several key enzymes of the apoptotic machinery, including the paracaspase and metacaspase families of the caspase-like protease superfamily, apoptotic ATPases and NACHT family NTPases, and mitochondrial HtrA-like proteases, have diverse homologs in bacteria, but not in archaea. Phylogenetic analysis strongly suggests a mitochondrial origin for metacaspases and the HtrA-like proteases, whereas acquisition from Actinomycetes appears to be the most likely scenario for AP-ATPases. The homologs of apoptotic proteins are particularly abundant and diverse in bacteria that undergo complex development, such as Actinomycetes, Cyanobacteria and alpha-proteobacteria, the latter being progenitors of the mitochondria. In these bacteria, the apoptosis-related domains typically form multidomain proteins, which are known or inferred to participate in signal transduction and regulation of gene expression. Some of these bacterial multidomain proteins contain fusions between apoptosis-related domains, such as AP-ATPase fused with a metacaspase or a TIR domain. Thus, bacterial homologs of eukaryotic apoptotic machinery components might functionally and physically interact with each other as parts of signaling pathways that remain to be investigated. An emerging scenario of the origin of the eukaryotic apoptotic system involves acquisition of several central apoptotic effectors as a consequence of mitochondrial endosymbiosis and probably also as a result of subsequent, additional horizontal gene transfer events, which was followed by recruitment of newly emerging eukaryotic domains as adaptors.


Serum ghrelin concentrations are increased in children with growth hormone insensitivity and decrease during long-term insulinlike growth factor-I treatment.
Ghrelin increases food intake, body weight, and growth hormone (GH) secretion. Serum concentrations of ghrelin are low in obese hyperinsulinemic persons, are reduced by infusion of insulin into normal-weight subjects, and are increased in underweight hypoinsulinemic patients with anorexia nervosa. Laron syndrome is an autosomal recessive disorder of GH insensitivity that results in decreased insulinlike growth factor-I (IGF-I) synthesis and growth failure. These patients have elevated GH levels, excess adipose tissue, and are insulin resistant. Because IGF-I has insulinlike actions and patients with GH insensitivity syndrome (GHIS) exhibit excess adiposity, we sought to determine whether ghrelin levels were elevated in these patients and potentially regulated by IGF-I replacement. Thirteen children with GHIS and 20 normal control children matched for age, sex, and body mass index underwent complete physical examination and a fasting blood draw at baseline. The GHIS subjects then underwent follow-up fasting blood draws during therapy with human recombinant IGF-I (80-120 mug/kg, given subcutaneously twice daily). Fasting glucose, insulin, and IGF-I concentrations were measured at the time of collection. Fasting total ghrelin levels were measured on stored serum samples. The GHIS subjects had 2-fold higher fasting ghrelin levels (2926 +/- 1869 pg/mL) compared with the normal control children (1492 +/- 493 pg/mL; P = 0.009), and mean ghrelin values were reduced 56% during 6.4 +/- 0.2 years of IGF-I replacement (P < 0.05). Growth hormone resistance and low IGF-I levels are associated with elevated ghrelin levels, which may potentiate GH secretion and adiposity in these children. Suppression of ghrelin during IGF-I treatment suggests a novel mechanism potentially regulating ghrelin levels.


Accumulation of c-fos mRNA in rat hippocampus during acquisition of a brightness discrimination.
Training rats to attain a foot-shock-motivated brightness discrimination in a Y-maze results in an early and transient increase of hippocampal c-fos mRNA levels. Maximal accumulation was observed immediately after training, returning to basal levels during the following 2 h. A similar increase was obtained when rats were subjected to a pseudotraining with an equal number of runs, but with random pairing of the choice of bright and dark alleys with foot shock. It is suggested that induction of hippocampal c-fos mRNA expression is a necessary, but not sufficient, prerequisite for the formation of long-term memory trace. This early gene expression seems rather to correspond to an initial stage induced by complex stimulus presentation of both the training and the pseudotraining procedure. The subsequent late synthesis or processing of target proteins finally contributing to the formation of a permanent trace requires the action of further convergent signals to principal cells, probably mediating reward or emotional influences.


Common variants in SLC1A2 and schizophrenia: Association and cognitive function in patients with schizophrenia and healthy individuals.
SLC1A2 is reported to be responsible for the majority of glutamate uptake, which has a crucial role in neural development and synaptic plasticity, and a disturbance in glutamatergic transmission has been suggested to be involved in the pathophysiology of schizophrenia (SCZ) and cognition. To evaluate the relationship of common variants within SLC1A2 with SCZ and cognition in Han Chinese, 28 tag SNPs were genotyped in the discovery stage, which included 1117 cases and 2289 controls; significantly associated markers were genotyped in the replication stage with 2128 cases and 3865 controls. The rs4354668 SNP was identified to be significantly associated with SCZ in both datasets, and a similar pattern was also observed in the two-stage study on conducting imputation and haplotype association analyses. In addition, significant associations between the rs4354668 SNP and cognition were observed when processing the perseverative error of the Wisconsin Card Sorting Test in patients and controls. Our results provide supportive evidence for an effect of SLC1A2 on the etiology of SCZ, suggesting that genetic variation (rs4354668 and its haplotypes) in SLC1A2 may be involved in impaired executive function, which adds to the current body of knowledge regarding the risk of SCZ and the impairment of cognitive performance.


A comparison of culture, direct fluorescent antibody test, and a quantitative indirect immunoperoxidase assay for detection of Chlamydia trachomatis in pregnant women.
An indirect immunoperoxidase assay that quantitates antichlamydial immunoglobulin G (IgG) and IgA antibodies in serum was compared with endocervical culture and direct fluorescent antibody (MicroTrak) for detection of Chlamydia trachomatis in asymptomatic pregnant women. Of the 64 women tested by the three methods, 22 (34%) had antichlamydial IgG and IgA in their serum. The culture was positive in nine patients (14%) and the MicroTrak was positive in eight (12.5%). All positive cultures were immunoperoxidase-positive. One positive MicroTrak was immunoperoxidase- and culture-negative. Thirteen patients had IgG and IgA antichlamydial antibodies with no organisms detected in the endocervix by culture or by direct fluorescent antibody screen.


Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial.
Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAFV600E-mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAFV600E-mutated biliary tract cancer. This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAFV600E-mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAFV600E-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov, NCT02034110. These results are based on an interim analysis; the study is active but not recruiting. Between March 12, 2014, and July 18, 2018, 43 patients with BRAFV600E-mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6-15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36-67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31-62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported. Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAFV600E-mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAFV600E mutations should be considered in patients with biliary tract cancer. GlaxoSmithKline and Novartis.


The characteristics and metabolism of a genetically hypercholesterolemic strain of rats (RICO).
A genetically hypercholesterolemic strain of rats was selectively bred, starting from an ordinary albino mutant of Rattus norvegicus. The new strain was given the designation RICO, standing for rats with increased cholesterol. In these animals, hypercholesterolemia is established, in both sexes, one day after weaning, and it increases progressively thereafter. It is due to elevated concentrations of LDL- and HDL-cholesterol. As in the ordinary rat, the HDL fraction makes up the main part of the serum cholesterol in the RICO rat. Metabolic studies revealed that in the RICO strain the overall rate of hepatic cholesterol synthesis is accelerated, as a result of higher than normal activity of 3-hydroxy-3-methylglutaryl-CoA reductase. The activity of cholesterol-7 alpha-hydroxylase is decreased in RICO rats, indicating a lower than normal rate of cholesterol catabolism. No difference was found between RICO and ordinary rats with respect to fecal excretion of bile acids and cholesterol.


No association between female circumcision and prolonged labour: a case control study of immigrant women giving birth in Sweden.
Several authors' associate female genital circumcision with obstructed and prolonged labour, but the World Health Organization recently stated that no scientific evidence confirms such a relationship. The object of this study was to compare the duration of the second stage of labour between circumcised and non-circumcised women in a high-income community in Europe. Sixty-eight circumcised nulliparous women originally from the Horn of Africa were compared to a group of 2486 non-circumcised nulliparous who gave birth at a university hospital setting in Sweden, 1990-1996. Defibulation was routinely performed during labour. Circumcised women were found to have had second stage labour, which was significantly statistically shorter (35/53 min, respectively, p < or = 0.001) and a lower risk of prolonged labour than the non-circumcised group. Prolonged labour does not seem to be associated to female genital circumcision in affluent societies with high standards of obstetric care.


Inverted Takotsubo cardiomyopathy masking acute myocardial infarction.
We report a case of inverted Takotsubo cardiomyopathy masking acute myocardial infarction. In this case, echocardiography on admission showed left ventricular mid and basal akinesis and apical hyperkinesis compatible with an inverted Takotsubo contractile pattern. In the subacute phase, however, he was suspected of having acute myocardial infarction by serial changes of cardiac enzymes. After 8 days of admission, echocardiography showed normalization of the left ventricular contraction, except the inferior wall which was compatible with inferior myocardial infarction. Subsequent myocardial scintigraphy confirmed the diagnosis. It is important to recognize that inverted Takotsubo cardiomyopathy may mask acute myocardial infarction when they occur simultaneously.


Dopamine D2 receptor dimers in human and rat brain.
In order to determine whether dimers of dopamine D2 receptors can occur in mammalian brain, rat and human brain striatal membranes were photolabelled with two radioactive photoaffinity compounds selective for dopamine D2 receptors, [125I]azidophenethylspiperone and [125I]-4-azido-5-iodonemonapride. It was found that [125I]azidophenethylspiperone only labelled the D2 monomer, while [125I]-4-azido-5-iodonemonapride labelled both D2 monomers and dimers, despite the fact that very high concentrations (6 nM) of both radiocompounds were used. In addition, human cloned D2 receptors were probed with a D2-specific antibody, revealing multiple bands indicating the existence of trimers, tetramers and pentamers of D2 receptors. The different D2-binding patterns of the spiperone and benzamide congeners may explain the different densities of dopamine D2 receptors found with these two radioligands in human brain positron tomography in health and disease.