Female Honor Killing: The Role of Low Socio-Economic Status and Rapid Modernization.
Female honor killing is a particular form of femicide, where the killing of a woman is perpetrated by a member or members of her family who do not approve of her social behavior in general and her sexual behavior in particular. The study of female honor killing tends to focus on a cultural examination of honor cultures yet lacks exploration of possible social factors that may influence such gendered killing. Possible links between female honor killing incidence and various social factors, among them poverty, low social status, and rapid modernization, were recently postulated, however empirical validation of these hypotheses has yet to be thoroughly explored. This article offers empirical observations of an explorative nature of social factors that may play a role in the frequency of female honor killing. The research's methodological design distinguishes between the various Arab subgroups in Israel along their correlated ingrained social characteristics and offers a comparative empirical analysis obtained from nation-based data on female honor killings among the various Arab subgroups (excluding the West Bank, Gaza, and East Jerusalem) during a 6-year period (2010-2015). The research is based on a secondary analysis of data extrapolated from media surveillance. A total of 58 eligible cases were found and comprised the research sample. Frequency analysis of femicide events and victims was performed for each Arab subgroup. Despite the small number of cases and the research's explorative and tentative nature, it provides preliminary empirical indications of possible links between female honor killing frequency and social factors such as low economic status and rapid modernization. The article's novel empirical indications may be of great relevance to societies currently facing the challenge of assimilating a growing number of Arab and Muslim social groups.


Risk assessment of endometrial cancer and endometrial intraepithelial neoplasia in women with abnormal bleeding and implications for clinical management algorithms.
Most endometrial cancer cases are preceded by abnormal uterine bleeding, offering a potential opportunity for early detection and cure of endometrial cancer. Although clinical guidelines exist for diagnostic workup of abnormal uterine bleeding, consensus is lacking regarding optimal management for women with abnormal bleeding to diagnose endometrial cancer. We report the baseline data from a prospective clinical cohort study of women referred for endometrial evaluation at the Mayo Clinic, designed to evaluate risk stratification in women at increased risk for endometrial cancer. Here, we introduce a risk-based approach to evaluate diagnostic tests and clinical management algorithms in a population of women with abnormal bleeding undergoing endometrial evaluation at the Mayo Clinic. A total of 1163 women aged ≥45 years were enrolled from February 2013 to May 2019. We evaluated baseline absolute risks and 95% confidence intervals of endometrial cancer and endometrial intraepithelial neoplasia according to clinical algorithms for diagnostic workup of women with postmenopausal bleeding (assessment of initial vs recurrent bleeding episode and endometrial thickness measured through transvaginal ultrasound). We also evaluated risks among women with postmenopausal bleeding according to baseline age (<60 vs 60+ years) as an alternative example. For this approach, biopsy would be conducted for all women aged 60+ years and those aged <60 years with an endometrial thickness of >4 mm. We assessed the clinical efficiency of each strategy by estimating the percentage of women who would be referred for endometrial biopsy, the percentage of cases detected and missed, and the ratio of biopsies per case detected. Among the 593 women with postmenopausal bleeding, 18 (3.0%) had endometrial intraepithelial neoplasia, and 47 (7.9%) had endometrial cancer, and among the 570 premenopausal women with abnormal bleeding, 8 (1.4%) had endometrial intraepithelial neoplasia, and 7 (1.2%) had endometrial cancer. Maximum risk was noted in women aged 60+ years (17.7%; 13.0%-22.3%), followed by those with recurrent bleeding (14.7%; 11.0%-18.3%). Among women with an initial bleeding episode for whom transvaginal ultrasound was recommended, endometrial thickness did not provide meaningful risk stratification: risks of endometrial cancer and endometrial intraepithelial neoplasia were nearly identical in women with an endometrial thickness of >4 mm (5.8%; 1.3%-10.3%) and ≤4 mm (3.6%; 0.9%-8.6%). In contrast, among those aged <60 years with an endometrial thickness of >4 mm, the risk of endometrial cancer and endometrial intraepithelial neoplasia was 8.4% (4.3%-12.5%), and in those with an endometrial thickness of ≤4 mm, the risk was 0% (0.0%-3.0%; P=.01). The most efficient strategy was to perform biopsy in all women aged 60+ years and among those aged <60 years with an endometrial thickness of >4 mm, with the lowest percentage referred to biopsy while still detecting all cases. Existing clinical recommendations for endometrial cancer detection in women with abnormal bleeding are not consistent with the underlying risk. Endometrial cancer risk factors such as age can provide important risk stratification compared with the assessment of recurrent bleeding. Future research will include a formal assessment of clinical and epidemiologic risk prediction models in our study population as well as validation of our findings in other populations.


1,25(OH)2D3 Protects Liver Fibrosis Through Decreasing the Generation of TH17 Cells.
BACKGROUND The aim of this study was to study the effects of 1-alpha,25-dihydroxy-cholecalcifero (1,25(OH)2D3) on liver fibrosis and the generation of Th17 cells in vivo and in vitro. MATERIAL AND METHODS Thirty C57 mice were randomly divided into control, model, and treatment groups. Hepatic fibrosis was induced by subcutaneous injection of CCl4. Liver fibrosis condition was evaluated through pathological inspection and blood biochemical examination of liver function. Immunohistochemical assays were used to detect the expression of α-SMA, TGF-β, and collagen I to observe hepatic stellate cell activation level. Flow cytometry, ELISA, and RT-PCR were performed to explore the association between 1,25(OH)2D3 and Th17 cell differentiation. RESULTS Collagen I, TGF-β, and α-SMA were decreased after 1,25(OH)2D3 treatment. Consistently, RORγt mRNA and the rate of Th17 cells was significantly reduced after 1,25(OH)2D3 treatment. In vitro, the proportion of Th17 cells was also obviously reduced in the 1,25(OH)2D3 group, and mRNA levels of IL-17A, IL-22, RORγt, and RORa were significantly decrease in the 1,25(OH)2D3 group compared to the control group. CONCLUSIONS Treatment with 1,25(OH)2D3 can alleviate the damage caused by liver fibrosis. Experiments in vivo and in vitro showed that 1,25(OH)2D3 treatment deceased the rates of Th1 and Th17 cells and increased the rate of Th2 cells. The level of IL-17A, IL-22 and IFN-γ were decreased, while the level of IL-4 was increased by the treatment of 1,25(OH)2D3.


Dopant enhanced etching of TiSe2 by scanning tunneling microscopy.
The surfaces of pure and Mn doped TiSe(2) were etched using a scanning tunneling microscope. Both types of samples were found to etch easily when scanning was performed in ambient conditions. This process was enhanced at step edges or other surface defects. In pure samples, material was removed in a layer-by-layer fashion with a strong dependence on the scanning direction of the tip. Doped samples etched far more rapidly, to the point that stable scanning conditions were difficult to establish. Doped samples also showed a greater number of pits and other defects on their surface. A relatively small percentage of dopants was necessary to strongly impact the surface topography and stability. These results show that impurities can play a dominant role when using scanning tunneling microscopy to create surface nanostructures.


Enriching consumer health vocabulary through mining a social Q&A site: A similarity-based approach.
The widely known vocabulary gap between health consumers and healthcare professionals hinders information seeking and health dialogue of consumers on end-user health applications. The Open Access and Collaborative Consumer Health Vocabulary (OAC CHV), which contains health-related terms used by lay consumers, has been created to bridge such a gap. Specifically, the OAC CHV facilitates consumers' health information retrieval by enabling consumer-facing health applications to translate between professional language and consumer friendly language. To keep up with the constantly evolving medical knowledge and language use, new terms need to be identified and added to the OAC CHV. User-generated content on social media, including social question and answer (social Q&A) sites, afford us an enormous opportunity in mining consumer health terms. Existing methods of identifying new consumer terms from text typically use ad-hoc lexical syntactic patterns and human review. Our study extends an existing method by extracting n-grams from a social Q&A textual corpus and representing them with a rich set of contextual and syntactic features. Using K-means clustering, our method, simiTerm, was able to identify terms that are both contextually and syntactically similar to the existing OAC CHV terms. We tested our method on social Q&A corpora on two disease domains: diabetes and cancer. Our method outperformed three baseline ranking methods. A post-hoc qualitative evaluation by human experts further validated that our method can effectively identify meaningful new consumer terms on social Q&A.


Challenges and Solutions in the Recombinant Expression of Membrane Proteins.
Membrane proteins are important components of the proteome and play key roles in many biological processes, such as signal transduction, material transport, cell recognition, etc. Membrane proteins are involved in several fields, and more and more researchers want to understand them. However, the structural properties of membrane proteins make their recombinant expression yield low. This adversely affects the study of the structure and function of membrane proteins. Therefore, it is crucial to have a comprehensive and up-to-date understanding of membrane protein recombinant expression. Based on the current stage of research on membrane proteins, the article describes the current challenges faced by membrane protein recombinant expression and the solutions that can be applied to lay the foundation for a better study of membrane proteins in the future.


The dynamic evolution of focal-onset epilepsies--combining theoretical and clinical observations.
Focal-onset seizures have traditionally been conceptualised as having a highly circumscribed onset in an 'abnormal' brain region, with evolution of the seizure requiring recruitment of adjacent or connected 'normal' brain regions. Complementing this concept of the spatial evolution of seizures, the purpose of our present paper is to explore the evidence for the dynamic evolution of focal epilepsy using bifurcation analysis of a neural mass model, and subsequently relating these bifurcations to specific features of clinical data recordings in the time domain. Our study was motivated by recent research in idiopathic generalised epilepsies which has suggested that the temporal evolution of seizures may arise out of gradual changes in underlying physiological mechanisms. We found that spikes in the considered model arose out of so-called 'false' bifurcations, a finding consistent with other neural models with two timescales of inhibitory processes. We compared these results with previous studies of the model before extending them to characterise other more complex model behaviours. We then explored the relationship between model dynamics and clinical recordings from patients with focal epilepsies. Here we used an algorithm to subdivide each recording into time windows for which the data is approximately stationary. We then used our bifurcation findings to map out the evolution of seizures based on features of the clinical data from each of the epochs identified by our algorithm. We finally explored the similarity of the seizure evolution within patients, using random surrogates to test for statistical significance.


Cerebral Blood Flow Response to Simulated Hypovolemia in Essential Hypertension: A Magnetic Resonance Imaging Study.
Hypertension is associated with raised cerebral vascular resistance and cerebrovascular remodeling. It is currently unclear whether the cerebral circulation can maintain cerebral blood flow (CBF) during reductions in cardiac output (CO) in hypertensive patients thereby avoiding hypoperfusion of the brain. We hypothesized that hypertension would impair the ability to effectively regulate CBF during simulated hypovolemia. In the present study, 39 participants (13 normotensive, 13 controlled, and 13 uncontrolled hypertensives; mean age±SD, 55±10 years) underwent lower body negative pressure (LBNP) at -20, -40, and -50 mmHg to decrease central blood volume. Phase-contrast MR angiography was used to measure flow in the basilar and internal carotid arteries, as well as the ascending aorta. CBF and CO decreased during LBNP (P<0.0001). Heart rate increased during LBNP, reaching significance at -50 mmHg (P<0.0001). There was no change in mean arterial pressure during LBNP (P=0.3). All participants showed similar reductions in CBF (P=0.3, between groups) and CO (P=0.7, between groups) during LBNP. There was no difference in resting CBF between the groups (P=0.36). In summary, during reductions in CO induced by hypovolemic stress, mean arterial pressure is maintained but CBF declines indicating that CBF is dependent on CO in middle-aged normotensive and hypertensive volunteers. Hypertension is not associated with impairments in the CBF response to reduced CO.


The fidelity of misinsertion and mispair extension throughout DNA synthesis exhibited by mutants of the reverse transcriptase of human immunodeficiency virus type 2 resistant to nucleoside analogs.
The AIDS-causing retroviruses, human immunodeficiency virus types 1 and type 2 (HIV-1 and HIV-2, respectively) undergo extensive genetic variations, which effect their pathogenesis and resistance to drug therapy. It was postulated that this genetic hypervariability results from high rates of viral replication in conjugation with a relatively low fidelity of DNA synthesis [typical to the reverse transcriptases (RT) of these retroviruses]. As part of studying structure/function relationship in HIV RT, mutational analyses were conducted to identify amino acid residues which are involved in affecting the fidelity of DNA synthesis. The formation of 3'-mispaired DNA due to nucleotide misinsertions, and the subsequent elongation of this mismatched DNA were shown to be major determinants in affecting those substitutions during DNA synthesis (exhibited in vitro by HIV RT). It was interesting to find a correlation between sensitivity to nucleoside analogs (due to the ability to incorporate or reject an incoming analog) and the fidelity of DNA synthesis (which depends on the capacity to incorporate and extend a wrong nucleotide). Such a connection has already been found for several drug-resistant mutants of HIV-1 RT, with an increased fidelity of DNA synthesis relative to the wild-type RT. In the present study we have examined the fidelity of DNA synthesis using the same parameters of misinsertion and mispair extension for five novel drug-resistant mutants of HIV-2 RT; i.e. the single mutants [Val74]RT, [Gly89]RT and [Tyr215]RT and the double mutants [Val74,Tyr215]RT and [Gly89, Tyr215]RT. This comparative study suggests that unlike the Val74 mutant of HIV-1 RT, which was shown earlier to display a substantially enhanced fidelity, the comparable mutant of HIV-2 RT has fidelity similar to that of the wild-type RT. Depending on the assay employed and the DNA sequences extended, most other mutants of HIV-2 RT display moderate effects on the enzyme, leading to mild increases in fidelity of DNA synthesis. This implies a more complex and less distinctive correlation between drug-resistance, misinsertion and mispair extension in HIV-2 RT in contrast to HIV-1 RT, providing evidence for potential biochemical differences between these two related RT.


Role of the fungal cell wall in the granulomatous response of mice to the agents of chromomycosis.
Mice were given, intraperitoneally, inocula of a cell-wall preparation and fractions thereof from Fonsecaea pedrosoi, F. compactum, Cladosporium carrioni and Phialophora verrucosum. Large doses of cell-wall preparation, with or without trypsin treatment, produced a pronounced loss of body weight, a granulomatous reaction and, sometimes, death. After extraction of the cell wall preparation with 1N NaOH, three fractions were obtained: an alkali-insoluble fraction 1; an alkali-soluble acid-insoluble fraction 2; and an alkali- and acid-soluble fraction 3. Intravenous administration showed that only fraction 1 induced a granulomatous reaction and death in mice.


Psychometric Properties of the Worry Behaviors Inventory: Replication and Extension in a Large Clinical and Community Sample.
The use of maladaptive behaviors by individuals with generalized anxiety disorder (GAD) is theoretically important and clinically meaningful. However, little is known about the specificity of avoidant behaviors to GAD and how these behaviors can be reliably assessed. This study replicated and extended the psychometric evaluation of the Worry Behaviors Inventory (WBI), a brief self-report measure of avoidant behaviors associated with GAD. The WBI was administered to a hospital-based sample of adults seeking treatment for symptoms of anxiety and/or depression (n = 639) and to a community sample (n = 55). Participants completed measures of symptom severity (GAD, depression, panic disorder, health anxiety, and personality disorder), and measures of checking, reassurance-seeking and behavioral inhibition. Analyses evaluated the factor structure, convergent, divergent, incremental, and discriminant validity, as well the temporal stability and treatment sensitivity of the WBI. The two-factor structure found in the preliminary psychometric evaluation of the WBI was replicated. The WBI was sensitive to changes across treatment and correlated well with measures of GAD symptom severity and maladaptive behaviors. The WBI was more strongly related to GAD symptom severity than other disorders. The WBI discriminated between clinical and community samples. The WBI provides clinicians and researchers with a brief, clinically meaningful index of problematic behaviors that may guide treatment decisions and contribute to our understanding of maintaining factors in GAD.


Lipid clearance from fatty streak lesions by foam cell migration.
Dietary-induced hypercholesterolemia in swine produces fatty streak lesions in the aortic arch within 15 wks. These lesions, though becoming more extensive in area, do not progress beyond the fatty streak stage up to 30 wks on the diet. The stabilization of these lesions may be attributed, in part, to the extensive migration of foam cells from the lesion into the aortic lumen. Morphological evidence indicates a lumenal movement of these cells. Previous studies (1) indicate that foam cells in these lesions are monocyte-derived. The combined evidence suggests the existence of a monocyte lipid clearance mechanism which may represent an initial response of the blood-vascular system to atherogenesis.


Parathyroid hormone (PTH) decreases sodium-phosphate cotransporter type IIa (NpT2a) mRNA stability.
The acute inhibitory effects of parathyroid hormone (PTH) on proximal tubule Na(+)-K(+)-ATPase (Na-K) and sodium-dependent phosphate (NaPi) transport have been extensively studied, while little is known about the chronic effects of PTH. Patients with primary hyperparathyroidism, a condition characterized by chronic elevations in PTH, exhibit persistent hypophosphatemia but not significant evidence of salt wasting. We postulate that chronic PTH stimulation results in differential desensitization of PTH responses. To address this hypothesis, we compared the effects of chronic PTH stimulation on Na-P(i) cotransporter (Npt2a) expression and Na-K activity and expression in Sprague Dawley rats, transgenic mice featuring parathyroid-specific cyclin D1 overexpression (PTH-D1), and proximal tubule cell culture models. We demonstrated a progressive decrease in brush-border membrane (BBM) expression of Npt2a from rats treated with PTH for 6 h or 4 days, while Na-K expression and activity in the basolateral membranes (BLM) exhibited an initial decrease followed by recovery to control levels by 4 days. Npt2a protein expression in PTH-D1 mice was decreased relative to control animals, whereas levels of Na-K, NHERF-1, and PTH receptor remained unchanged. In PTH-D1 mice, NpT2a mRNA expression was reduced by 50% relative to control mice. In opossum kidney proximal tubule cells, PTH decreased Npt2a mRNA levels. Both actinomycin D and cycloheximide treatment prevented the PTH-mediated decrease in Npt2a mRNA, suggesting that the PTH response requires transcription and translation. These findings suggest that responses to chronic PTH exposure are selectively regulated at a posttranscriptional level. The persistence of the phosphaturic response to PTH occurs through posttranscriptional mechanisms.


Effects of cyclic changes in pH and salinity on metals release from sediments.
The effects of dynamic changes in pH and salinity on metal speciation and release are investigated with sediments posed in a simulated estuarine environment. The release of Zn, Cd, Mn, and Fe was studied using sediment from the Anacostia River (Washington, DC, USA) spiked with freshly precipitated amorphous cadmium sulfide to increase Cd content. The sediment was exposed to salt water (high pH, ionic strength) and freshwater (neutral pH, minimal ionic strength) continuously and alternately (to mimic tidal changes) in small microcosms over 100 d. At the conclusion of the experiments, the vertical profiles of acid volatile sulfide (AVS) and simultaneously extracted metals (SEM) as well as porewater metals and anion concentrations were characterized. Acid volatile sulfide oxidation at the sediment surface led to a commensurate increase in dissolved metal species and metal release that was strongly dependent on the changes in the overlying water characteristics. Total Cd release was substantially higher during exposure to salt water, although, as a result of complexation, predicted dissolved Cd(2+) concentration in the overlying water was higher during exposure to freshwater. Total Zn release was little changed during exposure to salt water and freshwater, although the predicted dissolved Zn(2+) concentration was much higher during freshwater exposures. No significant iron was released because of the rapid oxidation of ferrous iron (Fe(2+)) in aerobic surficial sediments and overlying water. The present study suggests that cyclic changes in pH and salinity in the overlying water can dramatically influence metal release from estuarine sediments.


Endogenous hormone levels affect the regeneration ability of callus derived from different organs in barley.
Hordeum vulgare (barley) is an important agricultural crop worldwide. A simple and efficient transformation system is needed to analyze the functions of barley genes and generate lines with improved agronomic traits. Currently, Golden Promise and Igri are the most amenable barley cultivars for stable transformation. Here we evaluated the regeneration ratios and endogenous hormone levels of calli derived from various malting barley cultivars, including Golden Promise, Haruna Nijo, and Morex. We harvested samples not only from immature embryos, but also from different explants of juvenile plants, cotyledons, coleoptiles, and roots. The callus properties differed among genotypes and explant types. Calli derived from the immature embryos of Golden Promise, which showed the highest ratio of regeneration of green shoots, had the highest contents of indoleacetic acid, trans-zeatin, and cis-zeatin. By contrast, calli derived from the cotyledons of Morex and the immature embryos of Haruna Nijo had elevated levels of salicylic acid and abscisic acid, respectively. We thus propose that the former phytohormones are positively associated with the regeneration ability of callus but the later phytohormones are negatively associated.


Wood litter consumption by three species of Nasutitermes termites in an area of the Atlantic Coastal Forest in northeastern Brazil.
Termites constitute a considerable fraction of the animal biomass in tropical forest, but little quantitative data are available that indicates their importance in the processes of wood decomposition. This study evaluated the participation of Nasutitermes corniger (Motschulsky) (Isoptera: Termitidae), N. ephratae (Holmgren), and N. macrocephalus (Silvestri) in the consumption of the wood litter in a remnant area of Atlantic Coastal Forest in northeastern Brazil. The populations of this species were quantified in nests and in decomposing tree trunks, while the rate of wood consumption was determined in the laboratory using wood test-blocks of Clitoria fairchildiana Howard (Fabales: Fabaceae), Cecropia sp. (Urticales: Cecropiaceae), and Protium heptaphyllum (Aublet) Marchand (Sapindales: Burseraceae). The abundance of the three species of termites varied from 40.8 to 462.2 individuals/m(2). The average dry wood consumption for the three species was 9.4 mg/g of termites (fresh weight)/day, with N. macrocephalus demonstrating the greatest consumption (12.1 mg/g of termite (fresh weight)/day). Wood consumption by the three species of Nasutitermes was estimated to be 66.9 kg of dry wood /ha/year, corresponding to approximately 2.9% of the annual production of wood-litter in the study area. This consumption, together with that of the other 18 exclusively wood-feeders termite species known to occur in the area, indicates the important participation of termites in removing wood-litter within the Atlantic Coastal Forest domain.


[Linear dimensions of the lamina of the tectum mesencephali during human ontogenesis].
The dynamics of the establishment of linear dimensions of the lamina of tectum mesencephali in ontogenesis was studied in 145 preparations of human brain. The investigation was performed with by the M. M. Sauliak-Savitskaja apparatus (1953). The obtained data were processed by the method of mathematical analysis. The relief of the superior colliculi was found to be formed earlier than that of the inferior colliculi. The linear dimensions of both colliculi are practically equal to those of adult men during the third year of life. No correlative relationship between the sex of the objects under study and the linear dimensions of the lamina of tectum mesencephali was found as well as between thr right and left parts of the lamina tecti. The linear dimensions of it in all age groups are very variable.


Severity of ICU-acquired pneumonia according to infectious microorganisms.
To assess the severity of intensive care unit (ICU)-acquired pneumonia (ICUAP) according to the bacteria involved, classified into seven groups: third-generation cephalosporin-resistant non-fermenting Gram-negative bacilli (resistant C3NF); sensitive C3NF; methicillin-resistant Staphylococcus aureus; methicillin-sensitive Staphylococcus aureus; extended-spectrum beta-lactamase-producing Enterobacteriaceae; Enterobacteriaceae not producing extended-spectrum beta-lactamase; Haemophilus influenzae and Streptococcus pneumoniae. Over a 4-year period, sequential organ failure assessment (SOFA) score was prospectively measured daily in 453 adult patients with ICUAP. ICUAP severity was evaluated by the severity of sepsis and by the occurrence of new organ dysfunctions or failures (OD/F) during ICUAP. Septic shock occurred in 21% of all cases of ICUAP. The occurrence of new OD/F during ICUAP was similar regardless of the identified microorganism. These new OD/F represented less than 11% of SOFAmax, defined as the sum of all OD/F occurring at any time during the ICU stay. There was a significant association between SOFApreICUAP, defined as the sum of all the OD/F occurring before ICUAP, and ICUAP severity. In the multivariate analysis, the type of bacteria was not a risk factor (RF) for occurrence of septic shock and mortality. Age and SOFApreICUAP were RF for the sepsis severity. The ICUAP severity was an RF for ICU mortality. ICUAP was responsible for a minor proportion of OD/F occurring during the ICU stay. Severity of ICUAP was related to clinical status prior to ICUAP, but not to the type of bacteria. ICU mortality depended on the severity of ICUAP.


Molecular cloning and characterization of genes required for ribose transport and utilization in Escherichia coli K-12.
We isolated spontaneous and transposon insertion mutants of Escherichia coli K-12 that were specifically defective in utilization or in high-affinity transport of D-ribose (or in both). Cotransduction studies located all of the mutations near ilv, at the same position as previously identified mutations causing defects in ribokinase ( rbsK ) or ribose transport ( rbsP ). Plasmids that complemented the rbs mutations were isolated from the collection of ColE1 hybrid plasmids constructed by Clarke and Carbon. Analysis of those plasmids as well as of fragments cloned into pBR322 and pACYC184 allowed definition of the rbs region. Products of rbs genes were identified by examination of the proteins produced in minicells containing various rbs plasmids. We identified four rbs genes: rbsB , which codes for the 29-kilodalton ribose-binding protein; rbsK , which codes for the 34-kilodalton ribokinase ; rbsA , which codes for a 50-kilodalton protein required for high-affinity transport; and rbsC , which codes for a 27-kilodalton protein likely to be a transport system component. Our studies showed that these genes are transcribed from a common promoter in the order rbsA rbsC rbsB rbsK . It appears that the high-affinity transport system for ribose consists of the three components, ribose-binding protein, the 50-kilodalton RbsA protein, and the 27-kilodalton RbsC protein, although a fourth, unidentified component could exist. Mutants defective in this transport system, but normal for ribokinase , are able to grow normally on high concentrations of the sugar, indicating that there is at least a second, low-affinity transport system for ribose in E. coli K-12.


The heterogeneity of tumor-infiltrating CD8+ T cells in metastatic melanoma distorts their quantification: how to manage heterogeneity?
CD8 T-cell infiltration of metastatic melanoma may be a useful biomarker for prediction of prognosis and response to therapy. The heterogeneous distribution of CD8 T cells within a single tumor, and across different tumors within a single patient, may complicate quantification of infiltration. However, the impact of heterogeneity has not been quantified sufficiently. To address this, we have assessed intratumoral heterogeneity of CD8 T-cell counts, as well as intertumoral heterogeneity for synchronous and metachronous metastases. In a tissue microarray containing 189 melanoma metastases from 147 patients, the density of CD8 T cells per sample was determined by immunohistochemistry. The mean density and coefficient of variation were calculated for each tumor and the rates of discordant values were determined. CD8 counts varied widely among different core samples of the same tumors (average coefficient of variation=0.77, 95% confidence interval: 0.70-0.85), with discordance occurring in 40% of tumors. CD8 densities were similar among pairs of simultaneous tumors; however, significant changes in CD8 densities were observed among 35 pairs of metachronous tumors. CD8 T-cell density is not well represented by a single 1 mm diameter sample. Differences in CD8 T-cell counts, observed in clinical trials, from pretreatment to post-treatment specimens may be explained by the spatial and temporal heterogeneity of CD8 distribution, especially if the assessed samples are small (i.e. 1 mm). A sufficiently large biopsy of one of several synchronous tumors may be representative of CD8 T-cell infiltration of a patient's disease.


Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study.
Vitamin D insufficiency and low calcium intake contribute to increase parathyroid function and bone fragility in elderly people. Calcium and vitamin D supplements can reverse secondary hyperparathyroidism thus preventing hip fractures, as proved by Decalyos I. Decalyos II is a 2-year, multicenter, randomized, double-masked, placebo-controlled confirmatory study. The intention-to-treat population consisted of 583 ambulatory institutionalized women (mean age 85.2 years, SD = 7.1) randomized to the calcium-vitamin D3 fixed combination group (n = 199); the calcium plus vitamin D3 separate combination group (n = 190) and the placebo group (n = 194). Fixed and separate combination groups received the same daily amount of calcium (1200 mg) and vitamin D3 (800 IU), which had similar pharmacodynamic effects. Both types of calcium-vitamin D3 regimens increased serum 25-hydroxyvitamin D and decreased serum intact parathyroid hormone to a similar extent, with levels returning within the normal range after 6 months. In a subgroup of 114 patients, femoral neck bone mineral density (BMD) decreased in the placebo group (mean = -2.36% per year, SD = 4.92), while remaining unchanged in women treated with calcium-vitamin D3 (mean = 0.29% per year, SD = 8.63). The difference between the two groups was 2.65% (95% CI = -0.44, 5.75%) with a trend in favor of the active treatment group. No significant difference between groups was found for changes in distal radius BMD and quantitative ultrasonic parameters at the os calcis. The relative risk (RR) of HF in the placebo group compared with the active treatment group was 1.69 (95% CI = 0.96, 3.0), which is similar to that found in Decalyos I (RR = 1.7; 95% CI = 1.0, 2.8). Thus, these data are in agreement with those of Decalyos I and indicate that calcium and vitamin D3 in combination reverse senile secondary hyperparathyroidism and reduce both hip bone loss and the risk of hip fracture in elderly institutionalized women.


Fetomaternal opioid levels and parturition.
The present study evaluates the plasma level changes in beta-lipotropin and beta-endorphin in nine women at term throughout spontaneous labor, in ten pregnant women undergoing elective cesarean section in the absence of uterine contractions, and in ten women submitted to emergency cesarean section because of fetal distress occurring during labor. A basal plasma sample was taken before labor in the 39th week of pregnancy. Two subsequent samples were then obtained before and after parturition, together with umbilical cord samples at birth. beta-lipotropin and beta-endorphin were measured by radioimmunoassay after silicic acid plasma extraction and gel filtration. In cases of spontaneous labor, there was a progressive increase in opioid concentrations as labor progressed, the maximal values being observed after delivery. Cord values were similar to those observed in the mother, without showing any relationship to them. Pregnant women undergoing cesarean section in the absence of labor show constant beta-lipotropin and beta-endorphin concentrations both before and after fetal extraction, both values being significantly lower than those found at delivery after spontaneous labor. beta-Endorphin neonatal levels were significantly higher than in the respective mothers and were in the same range as those of infants born through vaginal delivery. In the third group (cesarean section performed at the first stage of labor), presurgical opioid levels were higher than in women at the same stage of spontaneous labor, whereas postextraction values showed a wide range, with mean values similar to those observed after spontaneous delivery.(ABSTRACT TRUNCATED AT 250 WORDS)


Analysis of the Resistance Mechanism of a Benzoxaborole Inhibitor Reveals Insight into the Leucyl-tRNA Synthetase Editing Mechanism.
A new class of antimicrobial benzoxaborole compounds was identified as a potent inhibitor of leucyl-tRNA synthetase (LeuRS) and therefore of protein synthesis. In a novel mechanism, AN2690 (5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole) blocks fungal cytoplasmic LeuRS by covalently trapping tRNA(Leu) in the editing site of the enzyme's CP1 domain. However, some resistant mutation sites are located outside of the CP1 hydrolytic editing active site. Thus, their mode of action that undermines drug inhibition was not understood. A combination of X-ray crystallography, molecular dynamics, metadynamics, biochemical experiments, and mutational analysis of a distal benzoxaborole-resistant mutant uncovered a eukaryote-specific tyrosine "switch" that is critical to tRNA-dependent post-transfer editing. The tyrosine "switch" has three states that shift between interactions with a lysine and the 3'-hydroxyl of the tRNA terminus, to inhibit or promote post-transfer editing. The oxaborole's mechanism of action capitalizes upon one of these editing active site states. This tunable editing mechanism in eukaryotic and archaeal LeuRSs is proposed to facilitate precise quality control of aminoacylation fidelity. These mechanistic distinctions could also be capitalized upon for development of the benzoxaboroles as a broad spectrum antibacterial.


Survey of bed bugs in infested premises in Malaysia and Singapore.
A total of 54 bed bug-infested sites (hotels, public accommodations, and residential premises) in Malaysia and Singapore was surveyed between July, 2005 and December, 2008. Only one species of bed bug was found, the tropical bed bug Cimex hemipterus (Fabricius). Bed bug infestations were common in hotels and public accommodations when compared to residential premises. The three most common locations of infestation within an infested premise were the bedding (31.1%), the headboard (30.3%), and cracks and crevices surrounding the baseboard, wall, or floor (23.5%). We speculate that the route of movement of bed bugs in hotels and public accommodations is more direct than in residential premises.


The social cost of investor distraction: Evidence from institutional cross-blockholding.
Institutional investors routinely hold blocks of stocks in multiple firms within an industry. While such cross-blockholding boosts a portfolio firm's financial performance, could it distract investors from attending to firm activities in a nonfinancial domain, hurting its performance in that domain? The authors answer this question in the context of corporate social responsibility (CSR). They first document that cross-held firms perform worse on social responsibility than non-cross-held firms do. A quasi-natural experiment based on mergers between institutional blockholders helps establish causality. Next and as their primary contribution, the authors demonstrate investor distraction as the mechanism. Using two proxies of distraction-EDGAR search volume and shareholder proposals on socially responsible investment-they show that the negative impact of institutional cross-blockholding on CSR mainly comes from investor distraction when investors hold multiple blocks simultaneously. By highlighting the social cost of institutional cross-blockholding, this article finds a distraction effect of institutional cross-ownership, which extends our understanding of this unique ownership structure.


Rearrangements of the MLL gene are influenced by DNA secondary structure, potentially mediated by topoisomerase II binding.
The location of MLL translocation breakpoints within therapy-related acute myeloid leukemia linked to drugs targeting Topoisomerase II and infant acute leukemia (IAL) are biased toward the intron 11-exon 12 region of MLL, although lacking a comprehensive explanation. To address this, blood samples were taken from breast cancer and lymphoma patients receiving Topoisomerase II inhibitor therapy. Inverse PCR analysis was used to interrogate the exon 12 region of MLL for rearrangements. Eleven of 19 observed translocations showed breakpoint junctions restricted to a single 5 bp location within exon 12. A similarly restricted distribution (11/20 breakpoint junctions) was observed in TK6 cells exposed to either estrogen (linked to IAL) or anti-CD95 antibody. The translocation hotspot was at the 5' edge of a 10-bp tract matched with a perfect palindrome, 101 bp distant. A high stringency Topoisomerase II consensus sequence binding site was noted at the geometric midpoint of the palindromes. Ligation-mediated PCR to screen TK6 cells exposed to anti-CD95 antibody showed 14/37 (38%) of DNA breaks adjacent to the 5' palindrome and 10/37 (27%) at the 3' partner. We propose a model whereby Topoisomerase II facilitates the organization of nuclease-sensitive secondary structures, stabilized by palindrome association, which are prone to rearrangement.


Auditory distraction by duration and location deviants: a behavioral and event-related potential study.
Auditory distractibility was investigated using four noise stimuli that differed in their duration and/or sound source. In the duration-task/location-deviant condition, participants were asked to discriminate between equiprobable short and long stimuli. Mostly, stimuli were presented from one location (Standards), but, infrequently, a stimulus was presented from another location (Deviant). In the location-task/duration-deviant condition, participants had to discriminate between stimuli presented equiprobably from the speaker in front of them or to their left. Here, most stimuli were of equal duration (Standards), but, infrequently, a stimulus duration changed (Deviant). The rare deviations in location and duration were irrelevant for the actual task. Whether they affected processes related to the actual task was assessed with performance- and event-related potential (ERP) measures. In both conditions, responses to Deviants were slowed compared to responses to Standards. Deviants elicited ERP components mismatch negativity (MMN), P3a and reorienting negativity (RON). These results show that the processing of both a sound's duration and a sound's location can be distracted by rare, but irrelevant, changes in its location and duration, respectively. Behavioral distraction effects were markedly smaller with duration Deviants. It is suggested that duration Deviants interfere with task-related processing at later stages than location Deviants, as the processing of task-relevant information (i.e. stimulus location) commences before deviation in the location-task/duration-deviant condition occurs. Interestingly, distraction effects also prevail in the first Standard stimulus after a Deviant, as indicated by the prolonged response times and late negativity in the ERPs.


Methodologies for clinical ethics.
Truly professional medical ethics requires a methodology that generates both moral discernment and consistently right judgments. In this article the author briefly reviews difficulties involved in ethical decision-making, the historical development of casuistry, and four ethical methodologies employed in clinical medicine today. These latter, which are outlined and compared, are as follows: the methodology developed by David Thomasma in the 1960s and 1970s; one created by Jonsen, Siegler, and Winslade; another developed by the author; and the Bochum Protocol authored by Hans-Martin Sass et al. of the Bochum Center for Medical Ethics in the Federal Republic of Germany.


The involvement of the canonical Wnt-signaling receptor LRP5 and LRP6 gene variants with ADHD and sexual dimorphism: Association study and meta-analysis.
Wnt-signaling is one of the most abundant pathways involved in processes such as cell-proliferation, -polarity, and -differentiation. Altered Wnt-signaling has been linked with several neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) as well as with cognitive functions, learning and memory. Particularly, lipoprotein receptor-related protein 5 (LRP5) or LRP6 coreceptors, responsible in the activation of the canonical Wnt-pathway, were associated with cognitive alterations in psychiatric disorders. Following the hypothesis of Wnt involvement in ADHD, we investigated the association of genetic variations in LRP5 and LRP6 genes with three independent child and adolescent ADHD (cADHD) samples (total 2,917 participants), followed by a meta-analysis including previously published data. As ADHD is more prevalent in males, we stratified the analysis according to sex and compared the results with the recent ADHD Psychiatric Genomic Consortium (PGC) GWAS. Meta-analyzing our data including previously published cADHD studies, association of LRP5 intronic rs4988319 and rs3736228 (Ala1330Val) with cADHD was observed among girls (OR = 1.80 with 95% CI = 1.07-3.02, p = .0259; and OR = 2.08 with 95% CI = 1.01-4.46, p = .0026, respectively), whereas in boys association between LRP6 rs2302685 (Val1062Ile) and cADHD was present (OR = 1.66, CI = 1.20-2.31, p = .0024). In the PGC-ADHD dataset (using pooled data of cADHD and adults) tendency of associations were observed only among females with OR = 1.09 (1.02-1.17) for LRP5 rs3736228 and OR = 1.18 (1.09-1.25) for LRP6 rs2302685. Together, our findings suggest a potential sex-specific link of cADHD with LRP5 and LRP6 gene variants, which could contribute to the differences in brain maturation alterations in ADHD affected boys and girls, and suggest possible therapy targets.


Exploring and predicting intermolecular binding preferences in crystalline Cu(ii) coordination complexes.
A simple model focusing on electrostatic contributions to interaction energies was found to be very effective for rationalizing the appearance of specific supramolecular interactions in a series of Cu(ii) coordination compounds. The experimental space was provided by a combination of Cu(ii) cations with acac-based anions (hexafluoracetylacetonato and trifluoracetylacetonato) and a series of pyridine-oxime ligands (3-pyridinealdoxime, methyl 3-pyridyl ketoxime, 4-pyridinealdoxime, methyl 4-pyridyl ketoxime, phenyl 4-pyridyl ketoxime). The calculated molecular electrostatic potential (MEP) values at competing hydrogen-bond acceptor sites, for ten structurally characterized complexes, provided guidelines for predicting supramolecular connectivity in cases when the MEP difference exceeded certain cut-off values, while two different and well-defined outcomes are possible within the so called 'grey zone', delineated by a range of MEP differences. It was also shown that the structural outcome within this region is determined by the influence of relatively weak, but distinct, auxillary interactions.


A controlled, crossover study of a persistent antiseptic to reduce hospital-acquired infection.
Alcohol sanitizers have not been demonstrated to reduce hospital-acquired infections over handwashing alone in controlled, well-designed clinical studies. A major reason for this may be the failure of traditional alcohol sanitizers to provide any residual, or persistent, activity. Any lapse in hand hygiene protocol then leaves patients and staff open to transmitting pathogens. The purpose of the study was to determine whether a persistent sanitizer would reduce hospital-acquired infection in a hospital setting as compared to handwashing alone. A controlled, crossover study was conducted in three wards of a hospital over the course of three months. Two months were assigned as control periods, while the third month the test product was added. More than 6,000 patient-days were evaluated. Hospital staff were given a questionnaire to determine overall satisfaction with the product. The product used was a persistent, alcohol-based hand sanitizer (Zylast Antiseptic, 76% v/v ethyl alcohol). Control data showed that the hospital had a standard hospital-acquired infection rate of 23.1% across the three wards. No hospital-acquired infections were reported during use of the Antiseptic. The product was well tolerated by the staff and improved skin condition. The Antiseptic was demonstrated to significantly (p < 0.0005) reduce the hospital-acquired infection rate as compared to handwashing alone and is well-tolerated in a healthcare setting. The novel, persistent product has the ability to significantly reduce hospital-acquired infection and improve patient care in medical facilities.


Psychometric Properties of the Family Inventory of Resources for Management in a Sample of Iranian Family Caregivers of Cancer Patients.
Objective. The aim of this study was to investigate the psychometric properties of the Family Inventory of Resources for Management (FIRM) in a sample of family caregivers of cancer patients. Methods. In this methodological study, construct validity of the FIRM was evaluated by known groups and convergent validity in a convenience sample of family caregivers of cancer patients (n = 104) referred to the outpatient oncology wards of five educational hospitals in Tehran from January to April 2016. Reliability was determined by assessing the internal consistency and stability of the instrument. Results. The known-groups findings showed that there is a significant difference between the scores of the FIRM in family caregivers with different levels of caregiver burden (p < 0.001). Also, the results of convergent validity showed that there is a moderate negative correlation (r = -0.50; p < 0.001) between the total scores of the FIRM and the scores of the caregiver burden inventory (CBI). The FIRM showed a good internal consistency (α = 0.85) and a good stability of the test-retest reliability result. Conclusions. There is a sound psychometric basis for the use of the Persian translation of the FIRM for family studies in the Iranian population.


[Scheme for dispersion analysis for evaluating heritability of reproductive traits in medicinal leech Hirudo medicinalis L].
ANOVA designs for estimating heritabilities of fecundity traits in Hirudo medicinalis including batch size, the number of juveniles per cocoon, and juvenile weight. Accounting for reproduction mode of this species, different types of kinship were identified, which were taken into account in the ANOVA designs: juveniles from one batch and one cocoon were considered respectively full sibs and polyzygotic twins. Variation components were analyzed in the following kinship groups: for batch size, in full sibs; for the number of juveniles per cocoon, between sibships, full sins, and replicates; and for juvenile weight, in full sibs and polyzygotic twins. Using these designs, heritabilities of basic reproductive traits of H. medicinalis were obtained: for batch size, h2 = 0.35-0.40, H2 = 0.40-0.45; for the number of juveniles per cocoon, h2 = 0.33-0.36, H2 = 0.36-0.39; and for juvenile weight, h2 = 0.40-0.44, H2 = 0.44-0.48.


Caldendrin and myosin V regulate synaptic spine apparatus localization via ER stabilization in dendritic spines.
Excitatory synapses of principal hippocampal neurons are frequently located on dendritic spines. The dynamic strengthening or weakening of individual inputs results in structural and molecular diversity of dendritic spines. Active spines with large calcium ion (Ca2+ ) transients are frequently invaded by a single protrusion from the endoplasmic reticulum (ER), which is dynamically transported into spines via the actin-based motor myosin V. An increase in synaptic strength correlates with stable anchoring of the ER, followed by the formation of an organelle referred to as the spine apparatus. Here, we show that myosin V binds the Ca2+ sensor caldendrin, a brain-specific homolog of the well-known myosin V interactor calmodulin. While calmodulin is an essential activator of myosin V motor function, we found that caldendrin acts as an inhibitor of processive myosin V movement. In mouse and rat hippocampal neurons, caldendrin regulates spine apparatus localization to a subset of dendritic spines through a myosin V-dependent pathway. We propose that caldendrin transforms myosin into a stationary F-actin tether that enables the localization of ER tubules and formation of the spine apparatus in dendritic spines.


Phylogeographical patterns of genetic divergence and speciation in African mole-rats (Family: Bathyergidae).
African mole-rats are subterranean Hystricomorph rodents, distributed widely throughout sub-Saharan Africa, and displaying a range of social and reproductive strategies from solitary dwelling to the 'insect-like' sociality of the naked mole-rat, Heterocephalus glaber. Both molecular systematic studies of Rodentia and the fossil record of bathyergids indicate an ancient origin for the family. This study uses an extensive molecular phylogeny and mitochondrial cytochrome b and 12s rRNA molecular clocks to examine in detail the divergence times, and patterns of speciation of the five extant genera in the context of rift valley formation in Africa. Based on a value of 40-48 million years ago (Myr) for the basal divergence of the family (Heterocephalus), we estimate divergence times of 32-40 Myr for Heliophobius, 20-26 Myr for Georychus/Bathyergus and 12-17 Myr for Cryptomys, the most speciose genus. While early divergences may have been independent of rifting, patterns of distribution of later lineages may have been influenced directly by physical barriers imposed by the formation of the Kenya and Western Rift, and indirectly by accompanying climatic and vegetative changes. Rates of chromosomal evolution and speciation appear to vary markedly within the family. In particular, the genus Cryptomys appears to have undergone an extensive radiation and shows the widest geographical distribution. Of the two distinct clades within this genus, one exhibits considerable karyotypic variation while the other does not, despite comparatively high levels of sequence divergence between some taxa. These different patterns of speciation observed both within the family and within the genus Cryptomys may have been a result of environmental changes associated with rifting.


Ceiling effects prevent further improvement of transcranial stimulation in skilled musicians.
The roles of the motor cortex in the acquisition and performance of skilled finger movements have been extensively investigated over decades. Yet it is still not known whether these roles of motor cortex are expertise-dependent. The present study addresses this issue by comparing the effects of noninvasive transcranial direction current stimulation (tDCS) on the fine control of sequential finger movements in highly trained pianists and musically untrained individuals. Thirteen pianists and 13 untrained controls performed timed-sequence finger movements with each of the right and left hands before and after receiving bilateral tDCS over the primary motor cortices. The results demonstrate an improvement of fine motor control in both hands in musically untrained controls, but deterioration in pianists following anodal tDCS over the contralateral cortex and cathodal tDCS over the ipsilateral cortex compared with the sham stimulation. However, this change in motor performance was not evident after stimulating with the opposite montage. These findings support the notion that changes in dexterous finger movements induced by bihemispheric tDCS are expertise-dependent.


Evaluation and comparison of statistical methods for early temporal detection of outbreaks: A simulation-based study.
The objective of this paper is to evaluate a panel of statistical algorithms for temporal outbreak detection. Based on a large dataset of simulated weekly surveillance time series, we performed a systematic assessment of 21 statistical algorithms, 19 implemented in the R package surveillance and two other methods. We estimated false positive rate (FPR), probability of detection (POD), probability of detection during the first week, sensitivity, specificity, negative and positive predictive values and F1-measure for each detection method. Then, to identify the factors associated with these performance measures, we ran multivariate Poisson regression models adjusted for the characteristics of the simulated time series (trend, seasonality, dispersion, outbreak sizes, etc.). The FPR ranged from 0.7% to 59.9% and the POD from 43.3% to 88.7%. Some methods had a very high specificity, up to 99.4%, but a low sensitivity. Methods with a high sensitivity (up to 79.5%) had a low specificity. All methods had a high negative predictive value, over 94%, while positive predictive values ranged from 6.5% to 68.4%. Multivariate Poisson regression models showed that performance measures were strongly influenced by the characteristics of time series. Past or current outbreak size and duration strongly influenced detection performances.


An examination of the mechanisms of exercise-induced change in psychological well-being among people with spinal cord injury.
For individuals with a spinal cord injury (SCI), regular exercise training leads to significant improvements in pain, stress, and depression. The mechanisms by which exercise effects change in these variables are poorly understood. To address this issue, we examined the mediated effects of exercise on the psychological well-being of individuals with SCI according to the relationships described in the Chronic Pain Process Model. Twenty-one individuals with traumatic SCI either participated in a 9-month, twice-weekly exercise program (n = 11), or participated as nonexercising controls (n = 10). Measures of pain, stress, and depression were administered at the baseline and 3, 6, and 9 months into the intervention. Change in pain mediated exercise-induced change in stress, F(4,17) = 7.72, p < 0.01. Change in stress mediated exercise-induced change in depression, F(4,17) = 7.68, p < 0.01. With the identification of these factors as mediators of exercise-related changes in pain and well-being, exercise interventions can be designed that specifically target these mediators and possibly maximize intervention efficacy.


Ten-Year Outcome of Islet Alone or Islet After Kidney Transplantation in Type 1 Diabetes: A Prospective Parallel-Arm Cohort Study.
The long-term outcome of allogenic islet transplantation is unknown. The aim of this study was to evaluate the 10-year outcome of islet transplantation in patients with type 1 diabetes and hypoglycemia unawareness and/or a functioning kidney graft. We enrolled in this prospective parallel-arm cohort study 28 subjects with type 1 diabetes who received islet transplantation either alone (ITA) or after a kidney graft (IAK). Islet transplantation consisted of two or three intraportal infusions of allogenic islets administered within (median [interquartile range]) 68 days (43-92). Immunosuppression was induced with interleukin-2 receptor antibodies and maintained with sirolimus and tacrolimus. The primary outcome was insulin independence with A1C ≤6.5% (48 mmol/mol). Secondary outcomes were patient and graft survival, severe hypoglycemic events (SHEs), metabolic control, and renal function. The primary outcome was met by (Kaplan-Meier estimates [95% CI]) 39% (22-57) and 28% (13-45) of patients 5 and 10 years after islet transplantation, respectively. Graft function persisted in 82% (62-92) and 78% (57-89) of case subjects after 5 and 10 years, respectively, and was associated with improved glucose control, reduced need for exogenous insulin, and a marked decrease of SHEs. ITA and IAK had similar outcomes. Primary graft function, evaluated 1 month after the last islet infusion, was significantly associated with the duration of graft function and insulin independence. Islet transplantation with the Edmonton protocol can provide 10-year markedly improved metabolic control without SHEs in three-quarters of patients with type 1 diabetes, kidney transplanted or not.


Evidence for avian and human host cell factors that affect the activity of influenza virus polymerase.
Typical avian influenza A viruses do not replicate efficiently in humans. The molecular basis of host range restriction and adaptation of avian influenza A viruses to a new host species is still not completely understood. Genetic determinants of host range adaptation have been found on the polymerase complex (PB1, PB2, and PA) as well as on the nucleoprotein (NP). These four viral proteins constitute the minimal set for transcription and replication of influenza viral RNA. It is widely documented that in human cells, avian-derived influenza A viral polymerase is poorly active, but despite extensive study, the reason for this blockade is not known. We monitored the activity of influenza A viral polymerases in heterokaryons formed between avian (DF1) and human (293T) cells. We have discovered that a positive factor present in avian cells enhances the activity of the avian influenza virus polymerase. We found no evidence for the existence of an inhibitory factor for avian virus polymerase in human cells, and we suggest, instead, that the restriction of avian influenza virus polymerases in human cells is the consequence of the absence or the low expression of a compatible positive cofactor. Finally, our results strongly suggest that the well-known adaptative mutation E627K on viral protein PB2 facilitates the ability of a human positive factor to enhance replication of influenza virus in human cells.


[A professional duty to heal!].
The rules of South African law are analysed, especially any possible rules which may impose a duty upon a medical practitioner to heal in cases where the patient refuses treatment. The conclusion is reached that a refusal of medical treatment expressed on behalf of a minor child or an unconscious patient might safely be ignored by a medical practitioner, but that an express refusal by a major patient of full legal capacity should be heeded. It is also concluded that, according to South African law, there rests no legal duty upon a medical practitioner to treat a patient where such treatment--even if necessary to save the patient's life--is refused by the patient himself. Therefore, where the conditions imposed by a Jehovah's Witness preclude a medical practitioner from practising good medicine, he should refuse the case.


Emergence of a Potent Multidrug Efflux Pump Variant That Enhances Campylobacter Resistance to Multiple Antibiotics.
Bacterial antibiotic efflux pumps are key players in antibiotic resistance. Although their role in conferring multidrug resistance is well documented, the emergence of "super" efflux pump variants that enhance bacterial resistance to multiple drugs has not been reported. Here, we describe the emergence of a resistance-enhancing variant (named RE-CmeABC) of the predominant efflux pump CmeABC in Campylobacter, a major zoonotic pathogen whose resistance to antibiotics is considered a serious antibiotic resistance threat in the United States. Compared to the previously characterized CmeABC transporters, RE-CmeABC is much more potent in conferring Campylobacter resistance to antibiotics, which was shown by increased MICs and reduced intracellular accumulation of antibiotics. Structural modeling suggests that sequence variations in the drug-binding pocket of CmeB possibly contribute to the enhanced efflux function. Additionally, RE-CmeABC expands the mutant selection window of ciprofloxacin, enhances the emergence of antibiotic-resistant mutants, and confers exceedingly high-level resistance to fluoroquinolones, an important class of antibiotics for clinical therapy of campylobacteriosis. Furthermore, RE-CmeABC is horizontally transferable, shifts antibiotic MIC distribution among clinical isolates, and is increasingly prevalent in Campylobacter jejuni isolates, suggesting that it confers a fitness advantage under antimicrobial selection. These findings reveal a new mechanism for enhanced multidrug resistance and an effective strategy utilized by bacteria for adaptation to selection from multiple antibiotics. Bacterial antibiotic efflux pumps are ubiquitously present in bacterial organisms and protect bacteria from the antibacterial effects of antimicrobials and other toxic compounds by extruding them out of cells. Thus, these efflux transporters represent an important mechanism for antibiotic resistance. In this study, we discovered the emergence and increasing prevalence of a unique efflux pump variant that is much more powerful in the efflux of antibiotics and confers multidrug resistance in Campylobacter, which is a major foodborne pathogen transmitted to humans via the food chain. Unlike other specific resistance determinants that only allow bacteria to resist a particular antimicrobial, the acquisition of a functionally enhanced efflux pump will empower bacteria with simultaneous resistance to multiple classes of antibiotics. These findings reveal a previously undescribed mechanism for enhanced multidrug resistance and open a new direction for us to understand how bacteria adapt to antibiotic treatment.


Smokers' interest in using nicotine replacement to aid smoking reduction.
In recent years the public health community has considered the risks and benefits of encouraging smokers to reduce their smoking, perhaps with the aid of nicotine replacement therapy (NRT). Little is known, however, about whether smokers themselves are interested in smoking reduction; whether they see reduction as an endpoint, or primarily as a route to cessation; or whether they are receptive to the notion of using NRT to achieve reduction. We conducted a population-based national telephone survey of 1,000 current daily cigarette smokers (499 male, 501 female). Most smokers (57%) reported previously trying to reduce their smoking, and many (26%) said that they plan to reduce within the next year. Almost half of those planning to quit in the next 12 months (44%) preferred to quit via gradual cessation and most (68%) indicated that they would consider using a reduction product or medication. Respondents reported that they would prefer a product with a cessation endpoint rather than a reduction endpoint (63% vs. 21%). Interest in reduction was highest among smokers who were less interested in quitting and among heavier smokers. We conclude that many smokers are interested in gradually reducing prior to quitting and that promoting reduction is unlikely to undermine motivation to quit smoking.


Accommodation responses and ageing.
To study the impact of age on accommodation dynamics. Monocular accommodation responses were measured continuously using a modified Canon Auto Ref R1 infrared optometer. The stimulus was a single letter oscillating sinusoidally between 2.38 and 1.33 D providing a stimulus amplitude of 0.52 D, about a mean level of 1.86 D. Response characteristics were used to quantify gain and phase. Step responses were also recorded between these stimulus vergence levels for calibration purposes and to measure reaction and response times. Nineteen visually normal subjects 18 to 49 years of age participated, and 11 frequencies were used in the range 0.05 to 1.0 Hz. A key feature of the experimental design was to use a stimulus vergence range that lay within the amplitude of accommodation of all the observers. Accommodation gain reduced and phase lag increased with age, particularly at the higher frequencies used. No strongly significant change with age was found for reaction and response times or accommodation velocity, and results were similar for both far-to-near and near-to-far responses. Response amplitude for the step change in target vergence declined with age, and substantial differences were found between the measured and predicted (from reaction time) phase lags at 1.0 Hz as a function of age. Young observers showed a phase lag that was shorter than predicted, whereas older observers' measured phase lags were considerably larger than predicted. Results show that for a target oscillating sinusoidally in a predictable manner at a modest amplitude, the main ageing effects occur in phase lag, which is appreciably longer than predicted from reaction times in the older observers. The effects of ageing on gain were not as marked. Although responses to small step changes do reduce with age, there is no evidence of increased response times with ageing. In general, accommodation function in the middle-aged eye is quite robust despite a dwindling amplitude of accommodation. These results provide evidence of accommodative vigor in youth and a slowing of accommodation with ageing.


[Rapid Determination of Pinoresinol Diglucoside and Geniposidic Acid in Eucommia ulmoides with Near Infrared Spectroscopy Combined with Chemometrics Methods].
To develop a quantitative models for simultaneous determination of pinoresinol diglucoside (PDG) and geniposidic acid (GPA) in Eucommia ulmoides with near-infrared (NIR) spectroscopy combined with chemometrics. The NIR spectra were collected in diffuse reflection mode and pretreated with various spectra preprocessing methods including first-order differentiator, multiplicative scatter correction and so on. The optimal wavelength variables were screened out by competition adaptive weighted sampling method. The quantitative models for the simultaneous determination of PDG and GPA in Eucommia ulmoides were established with partial least squares (PLS) algorithm and cross validation methods. The quantitative prediction models for simultaneous determination of PDG and GPA in Eucommia ulmoides showed good predictive ability. The correlation coefficients (R(2)) of the two calibration models were 0.961 5, 0.958 3 while the roots mean square of cross-validation (RMSECV) were 0.001 5, 0.006 4, respectively. The quantitative prediction models proved that near infrared spectra method used for the quantitative analysis of PDG and GPA in Eucommia ulmoides owned high prediction accuracy and can meet the precision need of rapid determinations of PDG and GPA in Eucommia ulmoides in reality so t it provides a new method to realize the real time on line of quality control of Eucommia ulmoides.


A 7-day continuous infusion of PTH or PTHrP suppresses bone formation and uncouples bone turnover.
Human in vivo models of primary hyperparathyroidism (HPT), humoral hypercalcemia of malignancy (HHM), or lactational bone mobilization for more than 48 hours have not been described previously. We therefore developed 7-day continuous-infusion models using human parathyroid hormone(1-34) [hPTH(1-34)] and human parathyroid hormone-related protein(1-36) [hPTHrP(1-36)] in healthy human adult volunteers. Study subjects developed sustained mild increases in serum calcium (10.0 mg/dL), with marked suppression of endogenous PTH(1-84). The maximal tolerated infused doses over a 7-day period (2 and 4 pmol/kg/h for PTH and PTHrP, respectively) were far lower than in prior, briefer human studies (8 to 28 pmol/kg/h). In contrast to prior reports using higher PTH and PTHrP doses, both 1,25-dihydroxyvitamin D(3) [1,25(OH)(2) D(3) ] and tubular maximum for phosphorus (TmP/GFR) remained unaltered with these low doses despite achievement of hypercalcemia and hypercalciuria. As expected, bone resorption increased rapidly and reversed promptly with cessation of the infusion. However, in contrast to events in primary HPT, bone formation was suppressed by 30% to 40% for the 7 days of the infusions. With cessation of PTH and PTHrP infusion, bone-formation markers abruptly rebounded upward, confirming that bone formation is suppressed by continuous PTH or PTHrP infusion. These studies demonstrate that continuous exposure of the human skeleton to PTH or PTHrP in vivo recruits and activates the bone-resorption program but causes sustained arrest in the osteoblast maturation program. These events would most closely mimic and model events in HHM. Although not a perfect model for lactation, the increase in resorption and the rebound increase in formation with cessation of the infusions are reminiscent of the maternal skeletal calcium mobilization and reversal that occur following lactation. The findings also highlight similarities and differences between the model and HPT.


When and where does mortality occur in migratory birds? Direct evidence from long-term satellite tracking of raptors.
Information about when and where animals die is important to understand population regulation. In migratory animals, mortality might occur not only during the stationary periods (e.g. breeding and wintering) but also during the migration seasons. However, the relative importance of population limiting factors during different periods of the year remains poorly understood, and previous studies mainly relied on indirect evidence. Here, we provide direct evidence about when and where migrants die by identifying cases of confirmed and probable deaths in three species of long-distance migratory raptors tracked by satellite telemetry. We show that mortality rate was about six times higher during migration seasons than during stationary periods. However, total mortality was surprisingly similar between periods, which can be explained by the fact that risky migration periods are shorter than safer stationary periods. Nevertheless, more than half of the annual mortality occurred during migration. We also found spatiotemporal patterns in mortality: spring mortality occurred mainly in Africa in association with the crossing of the Sahara desert, while most mortality during autumn took place in Europe. Our results strongly suggest that events during the migration seasons have an important impact on the population dynamics of long-distance migrants. We speculate that mortality during spring migration may account for short-term annual variation in survival and population sizes, while mortality during autumn migration may be more important for long-term population regulation (through density-dependent effects).


Cardiovascular magnetic resonance tagging of the right ventricular free wall for the assessment of long axis myocardial function in congenital heart disease.
Right ventricular ejection fraction (RV-EF) has traditionally been used to measure and compare RV function serially over time, but may be a relatively insensitive marker of change in RV myocardial contractile function. We developed a cardiovascular magnetic resonance (CMR) tagging-based technique with a view to rapid and reproducible measurement of RV long axis function and applied it in patients with congenital heart disease. We studied 84 patients: 56 with repaired Tetralogy of Fallot (rTOF); 28 with atrial septal defect (ASD): 13 with and 15 without pulmonary hypertension (RV pressure > 40 mmHG by echocardiography). For comparison, 20 healthy controls were studied. CMR acquisitions included an anatomically defined four chamber cine followed by a cine gradient echo-planar sequence in the same plane with a labelling pre-pulse giving a tag line across the basal myocardium. RV tag displacement was measured with automated registration and tracking of the tag line together with standard measurement of RV-EF. Mean RV displacement was higher in the control (26 ± 3 mm) than in rTOF (16 ± 4 mm) and ASD with pulmonary hypertension (18 ± 3 mm) groups, but lower than in the ASD group without (30 ± 4 mm), P < 0.001. The technique was reproducible with inter-study bias ± 95% limits of agreement of 0.7 ± 2.7 mm. While RV-EF was lower in rTOF than in controls (49 ± 9% versus 57 ± 6%, P < 0.001), it did not differ between either ASD group and controls. Measurements of RV long axis displacement by CMR tagging showed more differences between the groups studied than did RV-EF, and was reproducible, quick and easy to apply. Further work is needed to assess its potential use for the detection of longitudinal changes in RV myocardial function.


A Turkish patient of typical Loeys-Dietz syndrome with a TGFBR2 mutation.
We describe a 2-year-old male patient with skeletal, neurological, cardiovascular, and connective tissue anomalies. Skeletal anomalies included pectus excavatum, hammer toes and hallux valgus and camptodactyly. The characteristic craniofacial findings of hypertelorism, down slanting palpebral fissures, strabismus, ptosis of eyelids, bifid uvula, high-arched palate and retrognathia were present. The proband has been operated on twice for bilateral inguinal hernia and several times for his foot deformities. Psychomotor development was retarded. At present, echocardiographic findings show aortic root dilation. The patient has important characteristics of Loeys-Dietz syndrome (LDS). Direct sequencing analysis of the transforming growth factor beta receptor I and II (TGFBR1 and 2) genes was performed and was demonstrated heterozygous missense mutation of the TGFBR2 gene in the patient, which confirms the diagnosis of LDS. This is the first Turkish patient with typical clinical signs of LDS. This report also illustrates that LDS and Shprintzen-Goldberg syndrome (SGS) have some common clinical characteristics.


ADH single nucleotide polymorphism associations with alcohol metabolism in vivo.
We have previously found that variation in alcohol metabolism in Europeans is linked to the chromosome 4q region containing the ADH gene family. We have now typed 103 single nucleotide polymorphisms (SNPs) across this region to test for allelic associations with variation in blood and breath alcohol concentrations after an alcohol challenge. In vivo alcohol metabolism was modelled with three parameters that identified the absorption and rise of alcohol concentration following ingestion, and the rate of elimination. Alleles of ADH7 SNPs were associated with the early stages of alcohol metabolism, with additional effects in the ADH1A, ADH1B and ADH4 regions. Rate of elimination was associated with SNPs in the intragenic region between ADH7 and ADH1C, and across ADH1C and ADH1B. SNPs affecting alcohol metabolism did not correspond to those reported to affect alcohol dependence or alcohol-related disease. The combined SNP associations with early- and late-stage metabolism only account for approximately 20% of the total genetic variance linked to the ADH region, and most of the variance for in vivo alcohol metabolism linked to this region is yet to be explained.


[Malignant ovarian germ cell tumors. Current status of diagnosis and treatment].
Malignant ovarian germ cell tumors (MOGCT) are extremely aggressive and rapidly growing neoplasms, with a peak incidence occurring in adolescent girls and young women. Its incidence in Mexico is three times higher than the observed in Western countries and the United States. Dysgerminoma, immature teratoma, yolk salc tumor, and mixed germ cell tumors make up more than 90% of all MOGCT.


[Effectiveness of adrenergic transmission and mechanisms of its regulation in rats exposed to prenatal effects of ethanol].
Prenatal influence of ethanol doesn't induce the changes of 3H-NA secretion intensity from rat cerebral cortex slices, but induces an increase of coefficient of variation of 3H-NA secretion intensity. The self-facilitation and stabilization of secretion are described during study of 3H-NA secretion intensity in the series of successive depolarization of control animals slices. Prenatal influence of ethanol induces self-facilitation but destabilize 3H-NA secretion. The results show that prenatal influence of ethanol breaks of autoreceptors function which are a cause of 3H-NA secretion destabilization. The break of the higher nervous activity is followed by the break of regulation mechanisms of adrenergic transmission effectiveness which is induced by prenatal influence of ethanol.


Thermal trap for DNA replication.
The hallmark of living matter is the replication of genetic molecules and their active storage against diffusion. We implement both in the simple nonequilibrium environment of a temperature gradient. Convective flow both drives the DNA replicating polymerase chain reaction while concurrent thermophoresis accumulates the replicated 143 base pair DNA in bulk solution. The time constant for accumulation is 92 s while DNA is doubled every 50 s. The experiments explore conditions in pores of hydrothermal rock which can serve as a model environment for the origin of life.


Insular cortex Hounsfield units predict postoperative neurocardiogenic injury in patients with aneurysmal subarachnoid hemorrhage.
Our study aims to investigate the association between the Hounsfield unit (Hu) value of the insular cortex (IC) during emergency admission and the subsequent occurrence of post-operative neurocardiogenic injury (NCI) among patients afflicted with aneurysmal subarachnoid hemorrhage (aSAH). Patients baseline characteristics were juxtaposed between those with and without NCI. The significant variables were incorporated into a multivariable stepwise logistic regression model. Receiver operating characteristic (ROC) curves were drafted for each significant variable, yielding cutoff values and the area under the curve (AUC). Subgroup and sensitivity analyses were performed to assess the predictive performance across various cohorts and ascertain result stability. Propensity score matching (PSM) was ultimately employed to redress any baseline characteristic disparities. Patients displaying a right IC Hu value surpassing 28.65 exhibited an escalated risk of postoperative NCI upon confounder adjustment (p < 0.001). The ROC curve eloquently manifested the predictive capacity of right IC Hu in relation to NCI (AUC = 0.650, 95%CI, 0.591-0.709, p < 0.001). Further subgroup analysis revealed significant interactions between right IC Hu and factors such as age, history of heart disease, and Graeb 5-12 score. Sensitivity analysis further upheld the results' significant (p = 0.002). The discrepancy in NCI incidence between the two groups, both prior (p < 0.002) and post (p = 0.039) PSM, exhibited statistical significance. After PSM implementation, the likelihood of NCI displayed an ascending trend with increasing right IC Hu values, from the Hu1 cohort onward, receding post the Hu4 cohort. This study definitively establishes an elevated right IC Hu value in the early stages of emergency admission as an autonomous predictor for ensuing NCI subsequent to aSAH.


Programmed death 1 expression on HIV-specific CD4+ T cells is driven by viral replication and associated with T cell dysfunction.
Functional impairment of HIV-specific CD4(+) T cells during chronic HIV infection is closely linked to viral replication and thought to be due to T cell exhaustion. Programmed death 1 (PD-1) has been linked to T cell dysfunction in chronic viral infections, and blockade of the PD-1 pathway restores HIV-specific CD4(+) and CD8(+) T cell function in HIV infection. This study extends those findings by directly examining PD-1 expression on virus-specific CD4(+) T cells. To investigate the role of PD-1 in HIV-associated CD4(+) T cell dysfunction, we measured PD-1 expression on blood and lymph node T cells from HIV-infected subjects with chronic disease. PD-1 expression was significantly higher on IFN-gamma-producing HIV-specific CD4(+) T cells compared with total or CMV-specific CD4(+) T cells in untreated HIV-infected subjects (p = 0.0001 and p < 0.0001, respectively). PD-1 expression on HIV-specific CD4(+) T cells from subjects receiving antiretroviral therapy was significantly reduced (p = 0.007), and there was a direct correlation between PD-1 expression on HIV-specific CD4(+) T cells and plasma viral load (r = 0.71; p = 0.005). PD-1 expression was significantly higher on HIV-specific T cells in the lymph node, the main site of HIV replication, compared with those in the blood (p = 0.0078). Thus, PD-1 expression on HIV-specific CD4(+) T cells is driven by persistent HIV replication, providing a potential target for enhancing the functional capacity of HIV-specific CD4(+) T cells.


Diagnosis and treatment of macrocytic anemias in adults.
Anemia is one of the most common health problems in the primary care setting. Macrocytosis in adults is defined as a red blood cell (RBC) mean corpuscular volume (MCV) >100 femtoliter (fL). Macrocytic anemias are generally classified into megaloblastic or nonmegaloblastic anemia. Megaloblastic anemia is caused by deficiency or impaired utilization of vitamin B12 and/or folate, whereas nonmegaloblastic macrocytic anemia is caused by various diseases such as myelodysplastic syndrome (MDS), liver dysfunction, alcoholism, hypothyroidism, certain drugs, and by less commonly inherited disorders of DNA synthesis. Macrocytic anemias are treated with cause-specific therapies, and it is crucial to differentiate nonmegaloblastic from megaloblastic anemia. Because MDS and myeloid neoplasms commonly affect the elderly, primary care physicians may encounter more cases of macrocytic anemias in the near future, as the older population increases. When MDS is suspected along with leukocytopenia and/or thrombocytopenia with anemia, a hematology consultation may be appropriate.


Analysis of selection effects in New York City's Medicaid managed care population prior to mandatory enrollment.
It is becoming increasingly apparent that over the next several years the majority of Medicaid patients in many states will become enrolled in managed care plans, some voluntarily, but most as the result of mandatory initiatives. An important issue related to this development is the extent to which this movement to managed care is accompanied by serious selection effects, either across the board during the phase in or among individual plans or plan types with full-scale implementation. This paper examines selection effects in New York City between 1993 and 1997 during the voluntary enrollment period prior to implementation of mandatory enrollment pursuant to a Section 1115 waiver. No substantial selection bias was documented between patients entering managed care and those remaining in the fee-for-service system among the largest rate groups, although some selection effect was found among plans and plan types (with investor-owned plans enrolling patients with lower prior utilization and expenses).


Post-traumatic stress disorder and cancer.
Being diagnosed with and treated for cancer is highly stressful and potentially traumatic. An extensive literature has evaluated the prevalence, predictors, and correlates of cancer-related post-traumatic stress disorder (PTSD) symptoms and diagnoses. In this qualitative review of cancer-related PTSD literature, we highlight conceptual, methodological, and diagnostic issues, and identify clinical implications and areas for future research. Cancer-related PTSD has been documented in a minority of patients with cancer and their family members, is positively associated with other indices of distress and reduced quality of life, and has several correlates and risk factors (eg, prior trauma history, pre-existing psychiatric conditions, poor social support). The literature on treatment of cancer-related PTSD is sparse. Existing literature on cancer-related PTSD has used DSM-IV-TR diagnostic criteria; the revised DSM-5 PTSD criteria have important implications for the assessment of cancer-related distress. Application of PTSD diagnosis to patients with cancer has been critiqued on conceptual and methodological grounds, and important differential diagnosis considerations should be taken into account. Psychosocial assessment of patients with cancer should include careful evaluation of pre-cancer diagnosis trauma and psychiatric history, and diagnostic interviewing should consider concurrent conditions (eg, adjustment disorder). Treatment of cancer-related PTSD should be approached with caution and be informed by existing evidence-based approaches for traumatic stress.


Metabolic fingerprints of serum, brain, and liver are distinct for mice with cerebral and noncerebral malaria: a ¹H NMR spectroscopy-based metabonomic study.
Cerebral malaria (CM) is a life-threatening disease in humans caused by Plasmodium falciparum, leading to high mortality. Plasmodium berghei ANKA (PbA) infection in C57Bl/6 mice induces pathologic symptoms similar to that in human CM. However, experimental CM incidence in mice is variable, and there are no known metabolic correlates/fingerprints for the animals that develop CM. Here, we have used (1)H NMR-based metabonomics to investigate the metabolic changes in the mice with CM with respect to the mice that have noncerebral malaria (NCM) of the same batchmates with identical genetic backgrounds and infected simultaneously. The metabolic profile of the infected mice (both CM and NCM) was separately compared with the metabolite profile of uninfected control mice of same genetic background. The objective of this study was to search for metabolic changes/fingerprints of CM and identify the pathways that might be differentially altered in mice that succumbed to CM. The results show that brain, liver, and sera exhibit unique metabolic fingerprints for CM over NCM mice. Some of the major fingerprints are increased level of triglycerides, VLDL-cholesterol in sera of CM mice, and decreased levels of glutamine in the sera concomitant with increased levels of glutamine in the brain of the mice with CM. Moreover, glycerophosphocholine is decreased in both the brain and the liver of animals with CM, and myo-inositol and histamine are increased in the liver of CM mice. The metabolic fingerprints in brain, sera, and liver of mice with CM point toward perturbation in the ammonia detoxification pathway and perturbation in lipid and choline metabolism in CM specifically. The study helps us to understand the severity of CM over NCM and in unrevealing the specific metabolic pathways that are compromised in CM.


Effects of neurokinin A, substance P and electrical stimulation on the rabbit iris sphincter muscle.
A mammalian tachykinin, neurokinin A (NKA), and its analogs produced concentration-dependent contractions in the isolated rabbit iris sphincter muscle. Their potencies were slightly less than substance P (SP) but the maximal efficacies were much the same as seen with SP, except that the times required for the development of the contraction and for the recovery to the original level after washout were more rapid than in the case of SP. Although preceding exposure to SP reduced the subsequent responses to SP, NKA, carbachol, electrical stimulation and capsaicin, the exposure to NKA resulted in no such desensitization in the subsequent responses. Also, no reduction in the responses to NKA, SP and carbachol was observed in the preparations which had been exposed to capsaicin beforehand. The contractile responses to NKA and its analogs were more effectively inhibited by [D-Pro2, D-Trp7,9]-SP than was the response to SP. [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-SP also inhibited the responses to NKA and its analogs but had no effect on the response to SP. Both SP-antagonists inhibited the noncholinergic, nonadrenergic contractile response to electrical transmural stimulation. These results indicate that NKA and its analogs are potent contractile tachykinins in the rabbit iris sphincter muscle and that the mode of action differs somewhat from that seen with SP. We propose that noncholinergic, nonadrenergic contraction induced by electrical transmural stimulation is mediated predominantly by NKA rather than by SP, even though both these compounds are released concomitantly from the trigeminal nerve.


Regional health inequalities: changes observed in Brazil from 2000-2016.
Advances in reducing poverty and inequalities in the 2000s had a paradoxical effect in Brazil. This article examines how socioeconomic transformations, and the complexity of health services, are expressed in the regions established for planning purposes and the inter-governmental management of the Brazilian Unified Health System. An effort was made to identify and explain differences in the compositions of the 438 existing health regions and their spatial distribution by comparing situations observed in 2016 with those in 2000. Factor analysis and grouping techniques were used to construct a typology in the two years of the series, which was based on a diverse set of secondary data sources. It was found that there was an evolution in terms of income levels and service provision within the health regions, with a significant improvement in the socioeconomic conditions of the population. These results suggest that there was a positive impact from the combination of strategies related to social, economic and regional policies for the promotion of development, which generated more widespread well-being within the affected areas. However, limitations remain regarding the policies implemented for the universalization of the health system.


Acquired haemophilia - A diagnosis not to be missed.
Acquired haemophilia is a rare , life threatening bleeding disorder characterised by the development of auto-antibodies to coagulation factor VIII. Diagnosis is based upon the clinical history of mucocutaneous haemorrhages combined with a selective prolongation of the APTT. The condition is associated with a wide range of conditions, such as autoimmune diseases , solid and haematological malignancies. Treatment involves controlling the bleeding manifestations and eliminating the inhibitor antibodies. Three cases from our recent practice are used to highlight the variable severity of this condition.


Validation of an original Behavioral Changes Scale on the Use of Digital Technologies During Social Distancing.
The social distancing (SD) adopted during the coronavirus disease 2019 (COVID-19) pandemic has transformed the internet from a convenience into a necessity. The behavioral changes caused by isolation range from adaptation of consumption, work, and teaching routines to altered leisure options to occupy idle time at home. Such transformations can be positive, expanding use of digital technologies (DT), but they can also have serious future physical and emotional consequences if there conscious use of technological devices is lacking. The study aimed to validate the Behavioral Changes Scale on the Use of Digital Technologies During Social Distancing (BCSDTSD), an instrument for assessing behavioral changes related to use of DT during SD. Validation of the BCSDTSD in five phases: 1. construction of an initial scale with 10 questions; 2. evaluation of the questions by a panel of experts; 3. application to 1,012 volunteers via the internet; 4. statistical analysis of the results; and 5. preparation of the validated final version of the BCSDTSD. Data were analyzed using the dplyr, psy , and paran packages and the REdaS statistical program. Three statistical criteria were used in the factor analysis (FA). FA confirmed that all 10 questions in the questionnaire should be maintained, confirming its robust construction, and Cronbach's alpha demonstrated its internal consistency with a value of 0.725, which is satisfactory for first-application questionnaires. The BCSDTSD instrument was validated for assessment of behavioral changes related to the use of DT during SD.


RTS,S malaria vaccine pilot studies: addressing the human realities in large-scale clinical trials.
A malaria vaccine as part of the integrated malaria control and elimination efforts will have a major impact on public health in sub-Sahara Africa. The first malaria vaccine, RTS,S, now enters pilot implementation in three African countries. These pilot implementation studies are being initiated in Kenya, Malawi, and Ghana to inform the broader roll-out recommendation. Based on the malaria vaccine clinical trial experiences, key ethical practices for effective clinical trial research in low-resource settings are described. For successful vaccine integration into malaria intervention programs, the relational dynamics between researchers and trial communities must be made explicit. Incorporating community values and returning to research practices that serve the intended benefactors are key strategies that address the human realities in large-scale clinical trials and pilot implementation, leading to positive public health outcomes.


A technetium-99m hexamethylpropylene amine oxime brain single-photon emission tomography study in adolescent patients with major depressive disorder.
We have not encountered any brain single-photon emission tomography (SPET) study performed in adolescent depressed patients in the literature. Therefore, we used technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO) brain SPET in adolescent patients with major depressive disorder (MDD) to examine the possible changes in cerebral perfusion and the possible association between perfusion indices and clinical variables. Fourteen adolescent out-patients (nine females, five males; mean+/-SD age: 13.11+/-1.43 years; range: 11-15 years) fulfilling the DSM-IV criteria for MDD and 11 age-matched healthy control subjects (six females, five males; mean+/-SD age: 13.80+/-1.60 years; range: 12-15 years) were included in the study. 99Tc-HMPAO brain SPET was performed twice in the patient group and once in the control group. The first SPET investigation was performed under non-medicated conditions and the second was performed after depressive symptoms had subsided. A relative perfusion index (PI) was calculated as the ratio of regional cortical activity to the whole brain activity. We found significant differences between the PI values of the untreated depressed patients and those of the controls, indicating relatively reduced perfusion in the left anterofrontal and left temporal cortical areas. No significant differences in regional PI values were found between the remitted depressed patients and the controls. Our study suggests that adolescent patients with MDD may have regional cerebral blood flow deficits in frontal regions and a greater anterofrontal right-left perfusion asymmetry compared with normal subjects. The fact that these abnormalities in perfusion indices have a trend toward normal values with symptomatic improvement suggests that they may be state-dependent markers for adolescent MDD.


Differential nuclear localization of complexes may underlie in vivo intrabody efficacy in Huntington's disease.
Intrabodies offer attractive options for manipulating the protein misfolding that triggers neurodegenerative diseases. In Huntington's disease, where the expanded polyglutamine tract in the extreme N-terminal region of huntingtin exon1 misfolds, two lead intrabodies have been selected against an adjacent peptide, using slightly different approaches. Both are effective at preventing aggregation of a reporter fragment in transient co-transfection assays. However, after intracranial delivery to mutant mouse brains, VL12.3, which is mainly localized to the nucleus, appears to accelerate the mutant phenotype, while C4 scFv, which is largely cytoplasmic, shows partial phenotypic correction. This comparison highlights parameters that could inform intrabody therapeutics for multiple proteostatic diseases.