Dietary protein for muscle hypertrophy.
Skeletal muscle hypertrophy is a beneficial adaptation for many individuals. The metabolic basis for muscle hypertrophy is the balance between the rates of muscle protein synthesis (MPS) and muscle protein breakdown (MPB), i.e. net muscle protein balance (NMPB = MPS - MPB). Resistance exercise potentiates the response of muscle to protein ingestion for up to 24 h following the exercise bout. Ingestion of many protein sources in temporal proximity (immediately before and at least within 24 h after) to resistance exercise increases MPS resulting in positive NMPB. Moreover, it seems that not all protein sources are equal in their capacity to stimulate MPS. Studies suggest that ∼20-25 g of a high-quality protein maximizes the response of MPS following resistance exercise, at least in young, resistance-trained males. However, more protein may be required to maximize the response of MPS with less than optimal protein sources and/or with older individuals. Ingestion of carbohydrate with protein does not seem to increase the response of MPS following exercise. The response of inactive muscle to protein ingestion is impaired. Ingestion of a high-quality protein within close temporal proximity of exercise is recommended to maximize the potential for muscle growth.


Update on the efficacy, effectiveness and safety of artemether-lumefantrine combination therapy for treatment of uncomplicated malaria.
Artemether-lumefantrine is one of the artemisisnin-based combination therapies recommended for treatment of uncomplicated falciparum malaria. The drug combination is highly efficacious against sensitive and multidrug resistant falciparum malaria. It offers the advantage of rapid clearance of parasites by artemether and the slower elimination of residual parasites by lumefantrine. The combination can be used in all populations except pregnant mothers in the first trimester where safety is still uncertain. There are still concerns about safety and pharmacokinetics of the drug combination in children, especially infants, pregnant mothers and drug interactions with mainly non-nucleoside reverse transcriptase inhibitors and protease inhibitors used for HIV therapy.


Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies). Clinical and neuropathological analysis of 53 patients from three unrelated SCA2 families.
Autosomal dominant cerebellar ataxia type I was diagnosed in three unrelated families from Martinique (French West Indies), and linkage to the locus for spinocerebellar ataxia 2 (SCA2) was established. Neuropathological findings in two patients were those of olivopontocerebellar atrophy without oligodendroglial cytoplasmic inclusions. Cerebellar ataxia was associated with hyporeflexia in 68% of 31 examined patients, with slowed and/or limited eye movements in 65% and with dementia in 29%. No patients had optic atrophy, pigmentary retinal degeneration, spasticity or parkinsonism. Mean age at onset was 33 +/- 16 years, and onset before the age of 20 years was correlated with a more rapid and severe course of the disease. Movement disorders, oculomotor disturbances, sphincter disturbances and cognitive impairment were significantly more frequent in early than in late onset patients. This explains why the phenotype was strikingly different in one family, in which mean age at onset was much earlier. Comparison with previously described SCA2 families indicated similarities, such as reduced saccade velocity, supranuclear ophthalmoplegia and decreased reflexes, although phenotypic heterogeneity remains the outstanding feature of this disorder.


Old wine, new bottle. The alcohol dependence syndrome.
The alcohol dependence syndrome is at once a fresh approach and a restatement of established clinical lore. It is, perhaps, old wine in a new bottle. Nonetheless, behavioral researchers in this field have needed some clinically sound criteria to differentiate between subjects to account for the variability of behavioral and psychophysiologic responses to alcohol in the laboratory. Cross-cultural researchers, and those interested in the genetics of alcoholism, have needed culture-free criteria for the diagnosis of alcoholism that might help them to separate aspects of the disorder that are genetically determined from those that are influenced by culture, immediate environment, and psychopathology. The beauty of the alcohol-dependence syndrome construct is its apparent specificity and its potential clinical usefulness. The difficulty with the concept is that no questionnaire has proven entirely satisfactory in defining the severity of alcohol dependence nor have biologic variables been identified that can provide valid and reliable indicators of severity. Nonetheless, advances in biomedical research frequently await the development of a nomenclature that will permit replicable scientific investigation. The evolving definition of the alcohol dependence syndrome is consistent with this tradition.


Total synthesis of myxovirescin A1.
A convergent total synthesis of the antibiotic macrolide myxovirescin A1 (1) is described that is largely based on reagent- and catalyst-controlled transformations. This includes a highly regioselective Negishi reaction of dibromo-alkene 48 with an alkynylzinc reagent, and a palladium catalyzed alkyl-Suzuki coupling of the resulting enyne derivative 12 with the 9-BBN-adduct derived from alkene 61. The latter was obtained via an asymmetric hydrogenation of the chlorinated beta-ketoester 49 and an anti-selective oxyallylation of the functionalized aldehyde 53 as the key steps. The preparation of the bis-borylated allyl-donor 57 used in the oxyallylation step, however, required careful optimization and led to important insights into the nature of the classical hydroborating agent "di(isopinocampheyl)borane (Ipc2BH)". It was unambiguously shown by X-ray crystallography that in the solid state this compound is dimeric, but it is prone to undergo an essentially quantitative mono-deborylation when dissolved in CH2Cl2 or benzene; its composition in ethereal solvents is even more complex as evident from 11B NMR data. Product 71 derived from 12 and 61 was elaborated into the enyne-yne derivative 75, which served as the substrate for an exquisitely selective ring closing alkyne metathesis reaction (RCAM) catalyzed by the molybdenum tris-amido complex 20 activated in situ with CH2Cl2. The resulting cyclic enyne 76 was subjected to a ruthenium catalyzed trans-hydrosilylation/proto-desilylation tandem. Although [Cp*Ru(MeCN)3]PF6 had previously been recommended as catalyst of choice for trans-hydrosilylation reactions of internal alkynes, this complex failed to afford the desired product, whereas its sterically less hindered congener [CpRu(MeCN)3]PF6 permitted the reaction to be performed in appreciable yield, but at the expense of a lower stereoselectivity. AgF-mediated proto-desilylation of the isomeric silanes 79 and 80 followed by cleavage of the remaining acetal protecting groups afforded myxovirescin A1 and its hitherto unknown 14Z-isomer 81, respectively.


Ultrasonogram of hepatocellular carcinoma is associated with outcome after radiofrequency ablation.
To investigate the association between B-mode ultrasound classification of small hepatocellular carcinoma (HCC) and outcome after radiofrequency ablation (RFA). Ninety-seven cases of HCC treated using RFA between April 2001 and March 2006 were reviewed. Ultrasound images were classified as follows: type 1, with halo (n = 29); and type 2, without halo (n = 68). Type 2 was further categorized into three subgroups: type 2a, homogenous hyperechoic (n = 9); type 2b, hypoechoic with smooth margins (n = 43); and type 2c (n = 16), hypoechoic with irregular or unclear margins. Patients with type 2a HCC were excluded from analysis due to the small number of cases. Two year recurrence rates for type 2b, type 1 and type 2c were 26%, 42% and 69%, respectively, with significant differences between type 2b and type 2c (P < 0.01), and between type 1 and type 2c (P < 0.05). Five year survival rates were 89%, 43% and 65%, respectively. Survival was significantly longer for type 2b than for other types (type 1 vs type 2b, P < 0.01; type 2b vs type 2c, P < 0.05). On univariate analysis, factors contributing to recurrence were number of tumors, tumor stage, serum level of lens culinaris agglutinin-reactive alpha-fetoprotein and ultrasound classification (P < 0.05). Factors contributing to survival were tumor stage and ultrasound classification (P < 0.05). Multivariate analysis identified ultrasound classification as the only factor independently associated with both recurrence and survival (P < 0.05). B-mode ultrasound classification of small HCC is a predictive factor for outcome after RFA.


The potential for BRAF V600 inhibitors in advanced cutaneous melanoma: rationale and latest evidence.
Historically, patients with advanced cutaneous melanoma have a poor prognosis and limited treatment options. The discovery of selective v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation as an oncogenic mutation in cutaneous melanoma and the importance of the mitogen-activated protein kinase (MAPK) pathway in its tumourigenesis have changed the treatment paradigm for melanoma. Selective BRAF inhibitors and now MEK inhibitors have demonstrated response rates far higher than standard chemotherapeutic options and we review the phase I-III results for these agents in this article. The understanding of mechanisms of resistance that may occur upstream, downstream, at the BRAF level or bypassing the MAPK pathway provides a platform for rational drug development and combination therapies.


DoChaP: the domain change presenter.
Alternative splicing results in multiple transcripts of the same gene, possibly encoding for different protein isoforms with different domains. Whereas it is possible to manually determine the effect of alternative splicing on the domain composition for a single event, the process requires the tedious integration of several data sources; it is error prone and not feasible for genome-wide characterization of domains affected by differential splicing. To fulfill the need for an automated solution, we developed the Domain Change Presenter (DoChaP, https://dochap.bgu.ac.il/), a web server for the visualization of exon-domain associations. DoChaP visualizes all transcripts of a given gene, the encoded proteins and their domains, and enables a comparison between the transcripts and between their protein products. The colors and organization make the structural effect of alternative splicing events on protein structures easily identified. To enable the study of the conservation of exons structure, alternative splicing, and the effect of alternative splicing on protein domains, DoChaP also provides a two-species comparison of exon-domain associations. DoChaP thus provides a unique and easy-to-use visualization of the exon-domain association and conservation, and will facilitate the study of the structural effects of alternative splicing in health and disease.


Characteristics of breast milk and serology of women donating breast milk to a milk bank.
Breast milk is the most important nutrient to all newborn babies. If the mother's milk production is insufficient, it is important to provide donor breast milk without reduction of its immunologic and antimicrobial properties. Early use of breast milk to preterm infants has shown a reduced incidence of necrotising enterocolitis, a faster tolerance of enteral feeding, and a reduced need of parenteral nutrition. It is important to have milk from a CMV-IgG negative donor to VLBW infants considered immunocompromised. Between January 1st and December 31st 2001, 69 women delivered 1.973 litres (mean 28.6 litres/woman/year). 73% had college education, were primipara, and with a mean age of 30.7 years. Those who smoked, used alcohol or any medications were refused as donors. They started to deliver approximately 7 weeks after having given birth and continued for a mean of 4 months. Each milk sample was tested for bacterial growth. Every donor was screened for HIV, CMV-IgG and hepatitis B/C before donating milk and thereafter every third month. 62.3% was CMV-IgG positive. Samples containing staphylococcus aureus, klebsialla-, enterobacter- and serratia-species or E. coli, and all samples containing > 10(4) cfu/ml were pasteurised. Overall, only 10.5% of the samples were pasteurised. It is possible and important to provide VLBW babies with fresh frozen unpasteurised CMV-IgG negative breast milk until their own mothers' milk production is sufficient.


Impact of change to a concept-based baccalaureate nursing curriculum on student and program outcomes.
The purpose of this study was to compare selected baccalaureate program outcomes for a traditional, specialty-based curriculum (TC) to a concept-based curriculum (CBC). Outcomes included NCLEX-RN licensure pass rates, graduation rates, national assessment of critical thinking, and program satisfaction. Student self-efficacy for performing nursing activities also was measured to assess the impact of the curriculum change on student confidence. The sample included 240 students enrolled in the two curricula during the last semester of the two baccalaureate nursing curricula. The TC sample (n = 104) included three cohort graduating classes, and the CBC sample (n = 136) included two cohort graduating classes. Findings indicated few differences on outcomes between the two curricula. Lack of a negative impact on program outcomes observed in this study may encourage other nursing colleges to implement newer curriculum models. Further study is needed on ways to evaluate the impact of curriculum change.


Adsorption of charged and neutral polymer chains on silica surfaces: the role of electrostatics, volume exclusion, and hydrogen bonding.
We develop an off-lattice (continuum) model to describe the adsorption of neutral polymer chains and polyelectrolytes to surfaces. Our continuum description allows taking excluded volume interactions between polymer chains and ions directly into account. To implement those interactions, we use a modified hard-sphere equation of state, adapted for mixtures of connected beads. Our model is applicable to neutral, charged, and ionizable surfaces and polymer chains alike and accounts for polarizability effects of the adsorbed layer and chemical interactions between polymer chains and the surface. We compare our model predictions to data of a classical system for polymer adsorption: neutral poly(N-vinylpyrrolidone) (PVP) on silica surfaces. The model shows that PVP adsorption on silica is driven by surface hydrogen bonding with an effective maximum binding energy of about 1.3k(B)T per PVP segment at low pH. As the pH increases, the Si-OH groups become increasingly dissociated, leading to a lower capacity for H bonding and simultaneous counterion accumulation and volume exclusion close to the surface. Together these effects result in a characteristic adsorption isotherm, with the adsorbed amount dropping sharply at a critical pH. Using this model for adsorption data on silica surfaces cleaned by either a piranha solution or an O(2) plasma, we find that the former have a significantly higher density of silanol groups.


Complete Genome Sequence of Campylobacter fetus subsp. testudinum Strain Pet-3, Isolated from a Lizard (Hydrosaurus pustulatus).
The whole-genome sequence for Campylobacter fetus subsp. testudinum, a pathogen isolated from humans and turtles, has been reported recently. We present another completed genome sequence of the C. fetus subsp. testudinum strain pet-3, which was isolated from a lizard in Taiwan, for further genomic comparison study.


The Role of MAPRE2 and Microtubules in Maintaining Normal Ventricular Conduction.
The Brugada syndrome is associated with loss-of-function SCN5A variants, yet these account for only ≈20% of cases. A recent genome-wide association study identified a novel locus within MAPRE2, which encodes EB (microtubule end-binding protein) 2, implicating microtubule involvement in the Brugada syndrome. A mapre2 knockout zebra fish model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) and validated by Western blot. Larval hearts at 5 days post-fertilization were isolated for voltage mapping and immunocytochemistry. Adult fish hearts were used for ECG, patch clamping, and immunocytochemistry. Morpholinos were injected into embryos at 1-cell stage for knockdown experiments. A transgenic zebra fish line with cdh2 tandem fluorescent timer was used to study adherens junctions. Microtubule plus-end tracking and patch clamping were performed in human iPSC-derived cardiomyocytes with MAPRE2 knockdown and knockout, respectively. Voltage mapping of mapre2 knockout hearts showed a decrease in ventricular maximum upstroke velocity of the action potential and conduction velocity, suggesting loss of cardiac voltage-gated sodium channel function. ECG showed QRS prolongation in adult knockout fish, and patch clamping showed decreased sodium current density in knockout ventricular myocytes and arrhythmias in knockout iPSC cardiomyocytes. Confocal imaging showed disorganized adherens junctions and mislocalization of mature Ncad (N-cadherin) with mapre2 loss of function, associated with a decrease of detyrosinated tubulin. MAPRE2 knockdown in iPSC cardiomyocytes led to an increase in microtubule growth velocity and distance, indicating changes in microtubule dynamics. Finally, knockdown of ttl encoding tubulin tyrosine ligase in mapre2 knockout larvae rescued tubulin detyrosination and ventricular maximum upstroke velocity of the action potential. Genetic ablation of mapre2 led to a decrease in voltage-gated sodium channel function, a hallmark of Brugada syndrome, associated with disruption of adherens junctions, decrease of detyrosinated tubulin as a marker of microtubule stability, and changes in microtubule dynamics. Restoration of the detyrosinated tubulin fraction with ttl knockdown led to rescue of voltage-gated sodium channel-related functional parameters in mapre2 knockout hearts. Taken together, our study implicates microtubule dynamics in the modulation of ventricular conduction.


Treatment preferences among depressed primary care patients.
To understand patient factors that may affect the probability of receiving appropriate depression treatment, we examined treatment preferences and their predictors among depressed primary care patients. Patient questionnaires and interviews. Forty-six primary care clinics in 7 geographic regions of the United States. One thousand one hundred eighty-seven English- and Spanish-speaking primary care patients with current depressive symptoms. Depressive symptoms and diagnoses were determined by the Composite International Diagnostic Interview (CIDI) and the Center for Epidemiological Studies Depression Scale (CES-D). Treatment preferences and characteristics were assessed using a self-administered questionnaire and a telephone interview. Nine hundred eight-one (83%) patients desired treatment for depression. Those who preferred treatment were wealthier (odds ratio [OR], 3.7; 95% confidence interval [95% CI], 1.8 to 7.9; P =.001) and had greater knowledge about antidepressant medication ( OR, 2.6; 95% CI, 1.6 to 4.4; P </=.001) than those who did not want treatment. A majority ( 67%, n = 660) of those preferring treatment preferred counseling, with African Americans (OR, 2.2; 95% CI, 1.0 to 4.8, P =. 04 compared to whites) and those with greater knowledge about counseling (OR, 2.1; 95% CI, 1.6 to 2.7, P </=.001) more likely to choose counseling. Three hundred twelve ( 47%) of the 660 desiring counseling preferred group over individual counseling. Depression severity was only a predictor of preference among those already in treatment. Despite low rates of treatment for depression, most depressed primary care patients desire treatment, especially counseling. Preferences for depression treatment vary by ethnicity, gender, income, and knowledge about treatments.


Use of fertility drugs and risk of endometrial cancer in an Italian case-control study.
The objective of this study was to analyse time-related aspects of the use of fertility drugs related to the risk of endometrial cancer using data from a case-control study conducted between 1992 and 2006 in Italy. The study included 454 cases (median age, 60 years; range, 18-79) with incident, histologically confirmed endometrial cancer and 908 female controls (median age, 61 years; range 19-79) admitted to the same network of hospitals as cases for a wide spectrum of acute, non-neoplastic conditions. Controls were frequency matched to cases with a 2:1 ratio for age and study centre. Information was collected by trained interviewers using a structured questionnaire. We calculated odds ratios (ORs) and the corresponding 95% confidence intervals (CI) using conditional logistic regression models adjusted for major relevant covariates. The OR of endometrial cancer for ever use of fertility drugs was 3.26 (95% CI, 1.07-9.95). The risk was higher for duration of use 12 months or more (OR=6.10; 95% CI, 0.96-38.6), time since last use 25 years or less before the interview (OR=5.30; 95% CI, 1.12-25.1), and for age at first use less than 30 years (OR=5.14; 95% CI, 1.13-23.4). The association was apparently stronger in ever-gravid (OR=6.50; 95% CI, 1.10-38.3) than in nulligravid (OR=2.83; 95% CI, 0.32-25.0) women. Our data support earlier findings of an increase in risk of endometrial cancer with duration of use of fertility drugs.


[Allogeneic hematopoietic stem cell transplantations for relapsed and refractory acute lymphoblastic leukemia following inotuzumab ozogamicin treatment].
Inotuzumab ozogamicin (InO) was administered in three cases of relapsed/refractory adult acute lymphoblastic leukemia (ALL) before allogeneic hematopoietic stem cell transplantation (allo-SCT). One case developed extremely severe sinusoidal obstruction syndrome (SOS) but recovered after receiving defibrotide therapy. A gap of 63 days in the SOS case was noted from the last administration of InO to allo-SCT, the duration was 133 and 86 days for the other two cases, and the remaining risk factors for SOS were comparable in the three cases. In contrast to gemtuzumab ozogamicin (GO), the interval between InO exposure and allo-SCT has not been reported as a risk for SOS. Nevertheless, this case suggests that the intervals should be as long as possible.


[The cross desensitization and modulation of Cl currents activated by gamma-aminobutyric acid and L-glutamate in the isolated neurons of Aplysia].
Chlorine conductance gated by gamma-aminobutyric acid (GABA) and L-glutamate in the medial pleural neurons of aplysia was studied using voltage clamp technique and a continuous microperfusion system that allowed rapid agonist application. Both GABA and glutamate elicited current responses that rapidly activated and then decayed. Glutamate response could be blocked by perfusion of aspartate or taurine and the GABA current showed voltage dependence. Thus the currents exhibited cross desensitization. It has been found that very low concentrations of acetylcholine (10(-8) to 10(-14) M) which have no electrophysiologic responses of their own, modulate the response to a constant application of GABA. During cooling the preparation blocked this effect, it is possible to suggest that the small doses of acetylcholine effect the membrane chemosensitivity through the cell biochemical mechanism.


Trueness assessment for serum glucose measurement using commercial systems through the preparation of commutable reference materials.
Commutable reference materials (RMs) are suitable for end-users for evaluating the metrological traceability of values obtained using routine measurement systems. We assessed the performance of 6 routine measurement systems with validated secondary RMs. We tested the homogeneity, stability, and commutability of 5 minimally processed human serum pools according to the standard guidelines. The serum pools were assigned values as per the reference procedure of the United States Centers for Disease Control and were used to evaluate the trueness of results from 6 commercial measurement systems based on enzymatic methods: 3 glucose oxidase (GOD) and 3 hexokinase (HK) methods. The prepared RMs were validated to be sufficiently homogenous, stable, and commutable with the patient samples. Method bias varied for different systems: GOD01, -0.17 to 2.88%; GOD02, 1.66 to 4.58%; GOD03, -0.17 to 3.14%; HK01, -3.48 to -0.85%; HK02, -3.83 to -0.11%, and HK03, -1.82 to -0.27%. We observed that the prepared serum glucose RMs were qualified for trueness assessment. Most of the measurement systems met the minimal quality specifications.


Achieving durable compliance with venous thromboembolism prophylaxis in bariatric surgery: 3-year data from a major academic medical center.
Metabolic and bariatric surgery (MBS) venous thromboembolism (VTE) prescribing practices vary widely. Our institutional VTE prophylaxis protocol has historically been unstandardized. To create a standardized MBS VTE prophylaxis protocol, track protocol compliance, and identify barriers to protocol compliance and address them with Plan-Do-Study-Act (PDSA) cycles. Single Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program-accredited academic hospital. We conducted a retrospective study for all patients undergoing MBS (January 2019 to September 2022). A multidisciplinary group of bariatric clinicians reviewed literature and developed the following standardized VTE prophylaxis protocol: 5000 units preoperative subcutaneous (SC) heparin within 60 minutes of anesthesia induction and postoperative 40 mg SC low molecular weight heparin (LMWH) within 24 hours of surgery. This protocol was distributed to relevant clinical stakeholders. We assessed monthly compliance rates through chart review. Goal compliance was ≥90%. We identified sources of noncompliance and addressed them with PDSA methodology. A total of 796 patients were included. Preoperative heparin administration increased from a mean of 47% (107/228) preintervention to 96% (545/568) postintervention (P < .0001), and postoperative LMWH administration increased from 71% (47/66) to 96% (573/597, P = .0002). These compliance rates were sustained for 3 years. Barriers to protocol noncompliance included order set timing errors (n = 45), surgeon error (n = 44), surgeon discretion (n = 40), and nursing error (n = 20). No change in bleeding or VTE rates was observed. Developing a standardized VTE prophylaxis protocol, monitoring process measures, and engaging relevant stakeholders in PDSA cycles resulted in drastic and durable improvement in VTE prophylaxis compliance rates.


Three dimensional analysis of the retinal vasculature using immunofluorescent staining and confocal laser scanning microscopy.
To undertake a qualitative and quantitative analysis in three dimensions of the human retinal vasculature. Fixed and excised whole retinas were permeabilised and subjected to immunofluorescent staining for blood vessel components followed by confocal laser scanning microscopy. Single projection and stereoimages were constructed using computer software. XZ sections through the retina were constructed and the vasculature analysed using appropriate software. Immunofluorescent staining with no discontinuities was present in vessels of all sizes, the confocal images of the capillary network being free of out of focus blur at all depths. Quantitative analysis of XZ sections confirmed the qualitative impression of sharp delineation of the deep retinal capillary plexus, an absence of laminar arrangement of capillaries within the inner retina, and a truncated cone of capillaries around the foveal avascular zone (FAZ) wherein the superficial capillaries approached the FAZ more closely than those in the deeper retina. Immunofluorescent staining of the retina and confocal laser scanning microscopy were shown to be useful in analysing accurate three dimensional reconstructions of the normal retinal vasculature without affecting overall tissue architecture.


Assessing the role of anal intercourse in the epidemiology of AIDS in Africa.
Public health authorities have long believed that the preponderance of AIDS cases in Africa are attributable to 'heterosexual transmission'; most people silently assume this rubric to indicate penile-vaginal intercourse only. Recent epidemiologic analyses suggest that the majority of HIV cases in sub-Saharan Africa may be due to non-sterile health care practices. The present paper reviews the anthropological, proctologic, and infectious disease literature, and argues that both homosexuality and heterosexual anal intercourse are more prevalent in Africa than has traditionally been believed. The authors hypothesize that perhaps the majority of HIV transmission not accounted for by iatrogenic exposure could be accounted for by unsuspected and unreported penile-anal intercourse. Given the authors' findings, properly conducted studies to measure this HIV transmission vector, while controlling for iatrogenic exposure confound, are clearly warranted in Africa and in countries with similar epidemiologic characteristics.


The National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network Beneficial Effects of Antenatal Repeated Steroids study: impact of repeated doses of antenatal corticosteroids on placental growth and histologic findings.
In utero exposure to repeated doses of antenatal corticosteroids (ACSs) has been shown to reduce fetal growth. Our goal was to evaluate whether weekly betamethasone (R-ACS) alters placental growth and histologic findings. In a multicenter randomized controlled trial of R-ACS vs a single course of ACS followed by weekly placebo (S-ACS), placentas were weighed after removal of the membranes and umbilical cord. A single pathologist who was masked to study group and pregnancy outcomes performed histologic evaluation for placental calcifications, infarction, fibrin deposition, and hemorrhage or thrombus formation, acute and chronic chorioamnionitis, fibromuscular vascular hyperplasia, nucleated red blood cells, and villous crowding, edema, fibrosis, or fibrinoid necrosis. Findings were compared between study groups and according to the number of courses of ACS. One hundred ninety-four placentas were available for evaluation. Univariable analyses revealed no differences between study groups in any of the 19 evaluated histologic parameters between R-ACS and S-ACS groups overall or in analyses that were restricted to deliveries at < 32 or > or = 32 weeks of gestation. Calcifications were more common (P = .045) in the R-ACS group after controlling for other factors. Multivariable analysis revealed increasing gestational age at delivery, but not increasing ACS courses, to be associated with decreasing chorionic inflammation, villous edema, and fibrosis and with increasing villus crowding, fibrin deposition, and calcifications. Ninety-three placentas were weighed before formalin fixation. After controlling for delivery gestation and infant gender, placental weight was significantly lower in the R-ACS group (P = .017) and was related inversely to the number of ACS courses (P = .037). This finding was confirmed only for deliveries at > or = 32 weeks of gestation (525 vs 441 g for R-ACS and S-ACS group, respectively; P = .036). Repeated antenatal corticosteroid treatments in pregnancy are associated with decreased placental growth in a dose-dependent fashion, but not with evident differences in histologic markers of placental inflammation, ischemia, or infarction. Histologic placental abnormalities should not be attributed to repeated courses of corticosteroids.


Yields of Soviet underground nuclear explosions at Novaya Zemlya, 1964-1976, from seismic body and surface waves.
Surface and body wave magnitudes are determined for 15 U.S.S.R. underground nuclear weapons tests conducted at Novaya Zemlya between 1964 and 1976 and are used to estimate yields. These events include the largest underground explosions detonated by the Soviet Union. A histogram of body wave magnitude (m(b)) values indicates a clustering of explosions at a few specific yields. The most pronounced cluster consists of six explosions of yield near 500 kilotons. Several of these seem to be tests of warheads for major strategic systems that became operational in the late 1970s. The largest Soviet underground explosion is estimated to have a yield of 3500 +/- 600 kilotons, somewhat smaller than the yield of the largest U.S. underground test. A preliminary estimation of the significance of tectonic release is made by measuring the amplitude of Love waves. The bias in m(b) for Novaya Zemlya relative to the Nevada test site is about 0.35, nearly identical to that of the eastern Kazakhstan test site relative to Nevada.


Immunotherapy of tumors with α2-macroglobulin-antigen complexes pre-formed in vivo.
The cell surface receptor CD91/LRP-1 binds to immunogenic heat shock proteins (HSP) and α(2)M ligands to elicit T cell immune responses. In order to generate specific immune responses, the peptides chaperoned by HSPs or α(2)M are cross-presented on MHC molecules to T cells. While the immunogenic HSPs naturally chaperone peptides within cells and can be purified as an intact HSP-peptide complex, the peptides have had to be complexed artificially to α(2)M in previous studies. Here, we show that immunogenic α(2)M-peptide complexes can be isolated from the blood of tumor-bearing mice without further experimental manipulation in vitro demonstrating the natural association of tumor antigens with α(2)M. The naturally formed immunogenic α(2)M-peptide complexes are effective in prophylaxis and therapy of cancer in mouse models. We investigate the mechanisms of cross-presentation of associated peptides and co-stimulation by APCs that interact with α(2)M. These data have implications for vaccine design in immunotherapy of cancer and infectious disease.


Perinatal/maternal-fetal-infant dermatologic manifestations of SARS-CoV-2. An Overview and Implications for diagnosis, treatment, and prognosis.
Early identification of the dermatologic manifestations of SARS-CoV-2 in perinatal and maternal-fetal-infant populations is essential for early intervention in the diagnosis, treatment, and prevention of short and long term sequelae. Although cutaneous signs of SARS-CoV-2 are less common in pregnant women, neonates, and infants, the recognition of related skin lesions with regard to timing, location, duration, and pattern can lead to determining disease severity. While many pediatric patients may be asymptomatic with negative SARS-CoV-2 testing, skin lesions may be the only clue of infection. SARS-CoV-2 infection in pregnancy can lead to severe life threatening illness and by understanding the cutaneous manifestations associated with SARS-CoV-2 infection, early diagnosis can be made with improved maternal-fetal outcomes. A wide array of dermatologic presentations associated with SARS-CoV-2 are reported in the literature. This review explores the expanding reports in the literature of the dermatologic presentations of skin lesions related to SARS-CoV-2 specifically in perinatal and maternal-fetal-infant health and the implications for management. The collaboration of the specialties of dermatology, pediatrics, obstetrics/gynecology, and infectious disease in the approach to SARS-CoV-2 disease can lead to a better understanding of the scope and presentation of this disease.


Adoption of evidence-based practices among substance abuse treatment providers.
This research was conducted at a Substance Abuse Forum designed to address local community needs by focusing on Evidence-Based Practices (EBPs) in addiction treatment. The purpose of the study was to assess substance abuse treatment professionals' readiness to adopt EBPs, experience with EBPs, and attitudes toward EBPs, as well as agency support for EBPs. A total of 119 addiction treatment providers completed pre-test measures, and 82% completed a post-test. Eighty-three percent of participants reported using some EBPs in the past year, and 75% reported currently using EBPs. Participants who were currently licensed or certified in addictions had less negative attitudes toward EBPs than those without credentials. While respondents reported agency support for EBPs, most expressed interest in further training. This study underscores the movement toward EBPs in addiction treatment and the need for effective dissemination and training in this area.


Antisocial behavior and post-traumatic stress disorder in Vietnam veterans.
Assessment data from 118 Vietnam-era veterans seeking psychological services at two Los Angeles Veterans Administration Medical Centers were analyzed to examine the potential relationships between number of preadult and adult antisocial behaviors, as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-III; American Psychiatric Association, 1980) criteria for antisocial personality disorder, level of combat exposure, and development of combat-related post-traumatic stress disorder (PTSD). Results of hierarchical regression analyses indicated that combat exposure level was related significantly to PTSD symptomatology, whereas number of preadult antisocial behaviors was not. However, both combat exposure level and preadult behaviors, which were not correlated significantly, were related significantly to number of adult antisocial behaviors. There were no significant interaction effects. Results were consistent with a theoretical model of PTSD development that emphasizes the role of trauma vs. premorbid characterological factors. In addition, the significant association between combat exposure and adult antisocial behavior indicates that trauma may play a role in the development and/or maintenance of adult antisocial behaviors observed in some Vietnam veterans.


Impact of round-the-clock, rapid oral fluid HIV testing of women in labor in rural India.
Testing pregnant women for HIV at the time of labor and delivery is the last opportunity for prevention of mother-to-child HIV transmission (PMTCT) measures, particularly in settings where women do not receive adequate antenatal care. However, HIV testing and counseling of pregnant women in labor is a challenge, especially in resource-constrained settings. In India, many rural women present for delivery without any prior antenatal care. Those who do get antenatal care are not always tested for HIV, because of deficiencies in the provision of HIV testing and counseling services. In this context, we investigated the impact of introducing round-the-clock, rapid, point-of-care HIV testing and counseling in a busy labor ward at a tertiary care hospital in rural India. After they provided written informed consent, women admitted to the labor ward of a rural teaching hospital in India were offered two rapid tests on oral fluid and finger-stick specimens (OraQuick Rapid HIV-1/HIV-2 tests, OraSure Technologies). Simultaneously, venous blood was drawn for conventional HIV ELISA testing. Western blot tests were performed for confirmatory testing if women were positive by both rapid tests and dual ELISA, or where test results were discordant. Round-the-clock (24 h, 7 d/wk) abbreviated prepartum and extended postpartum counseling sessions were offered as part of the testing strategy. HIV-positive women were administered PMTCT interventions. Of 1,252 eligible women (age range 18 y to 38 y) approached for consent over a 9 mo period in 2006, 1,222 (98%) accepted HIV testing in the labor ward. Of these, 1,003 (82%) women presented with either no reports or incomplete reports of prior HIV testing results at the time of admission to the labor ward. Of 1,222 women, 15 were diagnosed as HIV-positive (on the basis of two rapid tests, dual ELISA and Western blot), yielding a seroprevalence of 1.23% (95% confidence interval [CI] 0.61%-1.8%). Of the 15 HIV test-positive women, four (27%) had presented with reported HIV status, and 11 (73%) new cases of HIV infection were detected due to rapid testing in the labor room. Thus, 11 HIV-positive women received PMTCT interventions on account of round-the-clock rapid HIV testing and counseling in the labor room. While both OraQuick tests (oral and finger-stick) were 100% specific, one false-negative result was documented (with both oral fluid and finger-stick specimens). Of the 15 HIV-infected women who delivered, 13 infants were HIV seronegative at birth and at 1 and 4 mo after delivery; two HIV-positive infants died within a month of delivery. In a busy rural labor ward setting in India, we demonstrated that it is feasible to introduce a program of round-the-clock rapid HIV testing, including prepartum and extended postpartum counseling sessions. Our data suggest that the availability of round-the-clock rapid HIV testing resulted in successful documentation of HIV serostatus in a large proportion (82%) of rural women who were unaware of their HIV status when admitted to the labor room. In addition, 11 (73%) of a total of 15 HIV-positive women received PMTCT interventions because of round-the-clock rapid testing in the labor ward. These findings are relevant for PMTCT programs in developing countries.


Mechanism of ethanol inhibition of NMDA receptor function in primary cultures of cerebral cortical cells.
Ethanol is a potent inhibitor of the function of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in various neuronal preparations. In primary cultures of cerebellar granule cells, ethanol was suggested to interact with the glycine co-agonist site of the receptor by a mechanism involving protein kinase C. In the present study, the interaction of ethanol with various sites on the NMDA receptor was examined in primary cultures of cerebral cortical cells from embryonic rats. NMDA receptor function was determined by measuring increases in intracellular Ca2+ with fura-2 fluorescence. Ethanol inhibited the function of the NMDA receptor in cerebral cortical cells, but in contrast to the results in cerebellar granule cells, phorbol ester treatment did not inhibit the NMDA response, and ethanol did not alter the effect of glycine on NMDA receptor function. Ethanol also did not affect inhibition of the NMDA response by Mg2+ or dizocilpine. The results support the hypothesis that the mechanism of ethanol inhibition of NMDA receptor function can vary in neurons from different brain regions.


Risk factors associated with kanamycin-resistant tuberculosis in a Beijing tuberculosis referral hospital.
The rapidly increasing number of multidrug-resistant tuberculosis (MDR-TB) cases worldwide underlines the necessity for the rational use of key second-line drugs such as kanamycin. In this study, we determined the prevalence of, and risk factors associated with, kanamycin-resistant tuberculosis (TB) in 309 Hospital, Beijing, China, with the aim of providing information for better case management in order to minimize further development of extensively drug-resistant TB (XDR-TB). Drug susceptibility testing results and clinical data were retrospectively analysed for hospitalized TB patients for whom such data were available in 309 Hospital for the period 1997-2009. Univariate and multivariate analyses were used to determine the risk factors associated with kanamycin-resistant TB. During 1997-2009, 553 (14.4 %) of 3843 tested Mycobacterium tuberculosis isolates from hospitalized TB patients were kanamycin-resistant. The increasing trend of resistance to kanamycin was reversed since 2000. The independent risk factors associated with kanamycin-resistant TB included living in urban areas [adjusted odds ratio (OR) = 1.89], being retreated for repeat cases (adjusted OR = 1.60), being smear-positive for acid-fast bacilli at admission to the hospital (adjusted OR = 1.39), having ofloxacin-resistant (adjusted OR = 1.61) or para-aminosalicylic acid-resistant TB (adjusted OR = 1.47), having MDR-TB (adjusted OR = 5.10), having MDR-TB plus ofloxacin resistance (adjusted OR = 4.27) and having poly-resistant TB (adjusted OR = 3.94). The remaining rate of kanamycin resistance is still high despite the reversal of the increasing trend during the past decade. Surveillance of kanamycin resistance, especially among high-risk populations, should be continued to closely monitor trends so that appropriate action can be taken.


Increased Risk of Colorectal Cancer Among Family Members of All Ages, Regardless of Age of Index Case at Diagnosis.
It is not clear whether familial risk of colorectal cancer (CRC) varies with age of index CRC patients or their relatives. We quantified the risk of CRC in first-degree relatives (FDRs), second-degree relatives, and first-cousin relatives of individuals with CRC, stratified by ages and sexes of index patients and ages of relatives. CRCs diagnosed between 1980 and 2010 were identified from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Age- and sex-matched CRC-free individuals were selected to form the comparison group. CRC risk in relatives was determined by Cox regression analysis. Of 18,208 index patients diagnosed with CRC, the highest familial risk was observed in FDRs of index CRC patients who were diagnosed at an age younger than 40 years (hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.7-3.79). However, familial risk was increased in FDRs even when the index case was diagnosed with cancer at an advanced age (>80 years; HR, 1.76; 95% CI, 1.59-1.94). Ages of relatives and ages of index cases of CRC each affected familial cancer risk; the highest risk was found in young relatives (<50 years) of individuals with early-onset CRC (<40 years; HR, 7.0; 95% CI, 2.86-17.09). All relatives of individuals with CRC are at increased risk for this cancer, regardless of the age of diagnosis of the index patient. Although risk is greatest among young relatives of early-onset CRC cases, relatives of patients diagnosed at advanced ages also have an increased risk.


Impact of a generalizable reminder system on colorectal cancer screening in diverse primary care practices: a report from the prompting and reminding at encounters for prevention project.
Computerized reminder systems (CRS) show promise for increasing preventive services such as colorectal cancer (CRC) screening. However, prior research has not evaluated a generalizable CRS across diverse, community primary care practices. We evaluated whether a generalizable CRS, ClinfoTracker, could improve screening rates for CRC in diverse primary care practices. The study was a prospective trial to evaluate ClinfoTracker using historical control data in 12 Great Lakes Research In Practice Network community-based, primary care practices distributed from Southeast to Upper Peninsula Michigan. Our outcome measures were pre- and post-study practice-level CRC screening rates among patients seen during the 9-month study period. Ability to maintain the CRS was measured by days of reminder printing. Field notes were used to examine each practice's cohesion and technology capabilities. All but one practice increased their CRC screening rates, ranging from 3.3% to 16.8% improvement. t tests adjusted for within practice correlation showed improvement in screening rates across all 12 practices, from 41.7% to 50.9%, P = 0.002. Technology capabilities impacted printing days (74% for high technology vs. 45% for low technology practices, P = 0.01), and cohesion demonstrated an impact trend for screening (15.3% rate change for high cohesion vs. 7.9% for low cohesion practices). Implementing a generalizable CRS in diverse primary care practices yielded significant improvements in CRC screening rates. Technology capabilities are important in maintaining the system, but practice cohesion may have a greater influence on screening rates. This work has important implications for practices implementing reminder systems.


YopH inhibits early pro-inflammatory cytokine responses during plague pneumonia.
Yersinia pestis is the causative agent of pneumonic plague; recently, we and others reported that during the first 24-36 hours after pulmonary infection with Y. pestis pro-inflammatory cytokine expression is undetectable in lung tissues. Here, we report that, intranasal infection of mice with CO92 delta yopH mutant results in an early pro-inflammatory response in the lungs characterized by an increase in the pro-inflammatory cytokines Tumor Necrosis Factor-alpha and Interleukin one-beta 24 hours post-infection. CO92 delta yopH colonizes the lung but does not disseminate to the liver or spleen and is cleared from the host within 72 hours post-infection. This is different from what is observed in a wild-type CO92 infection, where pro-inflammatory cytokine expression and immune cell infiltration into the lungs is not detectable until 36-48 h post-infection. CO92 rapidly disseminates to the liver and spleen resulting in high bacterial burdens in these tissues ultimately cumulating in death 72-94 h post-infection. Mice deficient in TNF-alpha are more susceptible to CO92 delta yopH infection with 40% of the mice succumbing to infection. Altogether, our results suggest that YopH can inhibit an early pro-inflammatory response in the lungs of mice and that this is an important step in the pathogenesis of infection.


Two Cases of Duchenne Muscular Dystrophy That Showed Different Reactions to Nerve Stimulation During Peripheral Nerve Block: A Case Report.
In recent years, the technique of combined ultrasound and electrical stimulation-guided nerve block has been recommended. We present 2 patients with Duchenne muscular dystrophy who exhibited different muscle responses to nerve stimulation during the performance of peripheral nerve blocks for surgeries. Whereas a 2-year-old boy without severe disability showed the expected muscle contraction to electrical nerve stimulation, a 14-year-old boy with severe disability showed no muscle response. Our experience suggests that muscle responses to electrical nerve stimulation will vary with the stage of Duchenne muscular dystrophy.


A distinct endosomal Ca2+/Mn2+ pump affects root growth through the secretory process.
Ca(2+) is required for protein processing, sorting, and secretion in eukaryotic cells, although the particular roles of the transporters involved in the secretory system of plants are obscure. One endomembrane-type Ca-ATPase from Arabidopsis (Arabidopsis thaliana), AtECA3, diverges from AtECA1, AtECA2, and AtECA4 in protein sequence; yet, AtECA3 appears similar in transport activity to the endoplasmic reticulum (ER)-bound AtECA1. Expression of AtECA3 in a yeast (Saccharomyces cerevisiae) mutant defective in its endogenous Ca(2+) pumps conferred the ability to grow on Ca(2+)-depleted medium and tolerance to toxic levels of Mn(2+). A green fluorescent protein-tagged AtECA3 was functionally competent and localized to intracellular membranes of yeast, suggesting that Ca(2+) and Mn(2+) loading into internal compartment(s) enhanced yeast proliferation. In mesophyll protoplasts, AtECA3-green fluorescent protein associated with a subpopulation of endosome/prevacuolar compartments based on partial colocalization with the Ara7 marker. Interestingly, three independent eca3 T-DNA disruption mutants showed severe reduction in root growth normally stimulated by 3 mm Ca(2+), indicating that AtECA3 function cannot be replaced by an ER-associated AtECA1. Furthermore, root growth of mutants is sensitive to 50 microm Mn(2+), indicating that AtECA3 is also important for the detoxification of excess Mn(2+). Curiously, Ateca3 mutant roots produced 65% more apoplastic protein than wild-type roots, as monitored by peroxidase activity, suggesting that the secretory process was altered. Together, these results demonstrate that the role of AtECA3 is distinct from that of the more abundant ER AtECA1. AtECA3 supports Ca(2+)-stimulated root growth and the detoxification of high Mn(2+), possibly through activities mediated by post-Golgi compartments that coordinate membrane traffic and sorting of materials to the vacuole and the cell wall.


An Influenza Virus M2 Protein Specific Chimeric Antigen Receptor Modulates Influenza A/WSN/33 H1N1 Infection In Vivo.
A potential target for the development of universal vaccine strategies against Influenza A is the M2 protein - a membrane protein with a highly conserved extracellular domain. In this study we developed engineered T-cell receptors, by fusing M2-specific antibody sequences with T-cell receptor transmembrane and signaling domains to target influenza infected cells. When expressed on T-cells, these novel T-cell receptors (chimeric antigen receptors - CARs) are able to recognize specific antigens on the surface of target cells via an MHC-independent mechanism. Using an existing monoclonal antibody (14C2) specific for the M2 ectodomain (M2e), we generated an M2-specific CAR. We tested the specificity of this M2 CAR in vitro by measuring the activation of T-cells in response to M2-specific peptides or M2-expressing cell lines. Both Jurkat T-cells and peripheral blood mononuclear cells expressing the M2-specific CAR responded to specific antigen stimulation by upregulating NFAT and producing γ-interferon. To test whether the M2-specific CAR are effective at recognizing influenza infected cells in vivo we used an established BALB/c murine infection model. At day 4 post-infection, when M2 CAR expressing splenocytes could be detected in the lung, the Influenza A/WSN/33 virus titre was around 50% of that in control mice. Although the lung virus titre later increased in the treated group, virus was cleared in both groups of mice by day 8. The results provide support for the development of M2e as a target for cell mediated immunotherapy.


Investigation of lifestyle choices of individuals following a vegan diet for health and ethical reasons.
The proportion of individuals choosing to follow a vegan diet has increased in recent years. The choice is made for different reasons, primarily concern for animals (ethics) and health, which may impact both specific food choices and other lifestyle behaviors linked to health outcomes. To determine the extent to which the reason for following a vegan diet was associated with health behaviors, we conducted an online survey recruiting an international sample of 246 individuals who reported adhering to a vegan diet. We hypothesized that compared to those following the diet for ethical reasons, those doing so for health reasons would consume foods with higher nutritional value and engage in other healthier lifestyle behaviors. Our hypotheses were partially supported in that those citing health reasons (n = 45) reported eating more fruit (U = 3503.00, p = 0.02) and fewer sweets (U = 3347.00, p <0.01) than did those citing ethical reasons (n = 201). Individuals endorsing ethical reasons reported being on the diet longer (U = 3137.00, p <0.01), and more frequent consumption of soy (U = 2936.00, p <0.01), foods rich in vitamin D (U = 3441.00, p = 0.01), high-polyphenol beverages (U = 3124.50, p <0.01), and vitamin supplements (vitamin D: χ(2)=4.65, p = 0.04; vitamin B12: χ(2)=4.46, p = 0.03) than did those endorsing health reasons. As these factors may affect outcome in studies investigating the impact of vegan diets on health, they should be taken into account when studying persons following a vegan diet.


Parallel transverse-sigmoid sinus harboring dural arteriovenous malformation. How to differentiate the pathological and normal sinus in order to treat and preserve patency and function.
An unusual case of dural arteriovenous malformation (DAVM) harboring a parallel transverse-sigmoid sinus (TSS) is presented. The patient had a 2-year history of left-sided pulsatile tinnitus in the left ear refractory to medical management. Angiography demonstrated a DAVM involving the left TSS. Super-selective transvenous dural sinus occlusion of the DAVM situated at the pathological compartment of the TSS provided cure. We were able to spare the normal compartment providing anatomical venous drainage from this system.


ADP-ribosylation factor 6 mediates E-cadherin recovery by chemical chaperones.
E-cadherin plays a powerful tumor suppressor role. Germline E-cadherin mutations justify 30% of Hereditary Diffuse Gastric Cancer (HDGC) and missense mutations are found in 30% of these families. We found possible to restore in vitro mutant E-cadherin associated to HDGC syndrome by using Chemical Chaperones (CCs). Herein, our aim was to disclose the molecular mechanisms underlying the CCs effects in E-cadherin regulation. Using cells stably expressing WT E-cadherin or two HDGC-associated missense mutations, we show that upon DMSO treatment, not only mutant E-cadherin is restored and stabilized at the plasma membrane (PM), but also Arf6 and PIPKIγ expressions are altered. We show that modulation of Arf6 expression partially mimics the effect of CCs, suggesting that the cellular effects observed upon CCs treatment are mediated by Arf6. Further, we show that E-cadherin expression recovery is specifically linked to Arf6 due to its role on endocytosis and recycling pathways. Finally, we demonstrated that, as DMSO, several others CCs are able to modulate the trafficking machinery through an Arf6 dependent mechanism. Interestingly, the more effective compounds in E-cadherin recovery to PM are those that simultaneously inhibit Arf6 and stimulate PIPKIγ expression and binding to E-cadherin. Here, we present the first evidence of a direct influence of CCs in cellular trafficking machinery and we show that this effect is of crucial importance in the context of juxtamembrane E-cadherin missense mutations associated to HDGC. We propose that this influence should be taken into account when exploring the therapeutic potential of this type of chemicals in genetic diseases associated to protein-misfolding.


New treatment options for lower respiratory tract infections.
Community-acquired pneumonia (CAP) and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) are among the most frequent lower respiratory tract infections (LRTIs). They represent an increased morbidity and mortality rate in adults. Areas covered: This review describes recent advances regarding solithromycin, zabofloxacin and delafoxacin antibacterial agents that have been recently developed for treatment of CAP and in AECOPD. All of them have been introduced into phase III clinical trials. We will be summarising chemical structures, pharmacokinetics, antibacterial efficacy and toxicity of these agents. The manuscript has been prepared based on available scientific publications. Expert opinion: Novel agents of known antimicrobial classes have been developed that demonstrate treatment options in CAP and in AECOPD. Antimicrobials discussed in this review showed bactericide effect against major respiratory tract pathogens. Each has multiple targets in bacteria, thus enabling them for more potency, even against strains exhibiting resistance to commonly used antibiotics. Solithromycin, delafloxacin and zabofloxcian demonstrate broad-spectrum antibacterial activity together with other beneficial features like intracellular accumulation, anti-inflammatory effect and inhibition of biofilm production. These agents showed moderately severe or mild adverse events and demonstrated favourable tissue penetration. These features can make solithromycin, zabofloxacin and delafloxacin treatment options in LRTIs.


The effects of different dietary protein sources on live weight, sperm quality and the histology of the testes and accessory glands in male rats.
This study was aimed at determining the effects of corn and wheat gluten, used as dietary protein sources, on live weight gain, sperm quality and the histology of the testes and accessory glands in male rats. For this purpose, 20-day-old 24 male Wistar albino rats were randomly assigned to three groups. Group 1 (Control), Group 2 and Group 3 were fed on a basal ration supplemented with high levels of soybean meal, corn gluten and wheat gluten, respectively, as a protein source. At the end of the study, when compared to Group 1, live weight values were determined to have increased in Group 3 and to have decreased in Group 2 (p < .05). Furthermore, sperm density, sperm motility, the dead/ live sperm ratio and testes weight were determined to have significantly decreased in Group 2, in comparison to Groups 1 and 3 (p < .05). The percentages of abnormal spermatozoon, and head, acrosome, mid-piece and tail abnormalities were high in Group 2 (p < .05). Histological examination demonstrated that, in Group 2, the diameter of the Tubulus Seminiferous Contortus (TSC) and the size of the Tubular Epithelial Cells (TE) were small, and the tubular and anatomical structure of the testes were shrunken and altered. Group 2 also presented with connective tissue increase and alveolar lumen enlargement in the prostate gland, and with connective tissue thickening, muscle tissue increase and secretory capacity decrease in the seminal vesicle (p < .05). Moreover, in Group 2, the Gl. Bulbourethral (Cowper's gland) presented with a decreased size and dilatations in the mucous structures. In a result, based on the findings obtained in this study, it is suggested that high levels of dietary corn gluten adversely affect live weight, sperm quality, and the testes and accessory glands.


Comparison of kits for SARS-CoV-2 extraction in liquid and passive samples.
Effective extraction and detection of viral nucleic acids from sewage are fundamental components of a successful SARS-CoV-2 sewage surveillance program. As there is no standard method employed in sewage surveillance, understanding the performance of different extraction kits in the recovery of SARS-CoV-2 and the impact that PCR inhibitors have on quantification is essential to minimise data discrepancies caused by sample extraction. Three commercial nucleic acid extraction kits: RNeasy PowerSoil Total RNA kit (PS), RNeasy PowerMicrobiome Kit (PMB), and MagMAX™ Microbiome Ultra Nucleic Acid Isolation Kit (MM), with minor modification, were evaluated. Their efficacy in recovering viral ribonucleic acid and removal of PCR inhibitors was assessed using two South Australian wastewater matrices-one from a major metropolitan site and one from a regional centre. Both had SARS-CoV-2 present due to active COVID-19 cases in these communities. Overall, the MM kit had a higher recovery of SARS-CoV-2 from the samples tested, followed by PMB and PS. The PMB kit performance was strongly influenced by sample matrix when compared to the MM kit. It is recommended to assess the performance of extraction kits using different local wastewater matrices to ensure the accuracy and reliability of monitoring results to avoid false reporting.


Applications of methodologies of the Veterans Health Study in the VA healthcare system: conclusions and summary.
The Veterans Health Study (VHS) had as its overarching goal the development, testing, and application of patient-centered assessments for monitoring patient outcomes in ambulatory care in large integrated care systems such as the Department of Veterans Affairs (VA). Unlike other previous studies, the VHS has capitalized on rich administrative databases restricted to the VA and linked to patient-centered outcomes. The VHS has developed a comprehensive set of general and disease-specific measures for use by systems of care for ambulatory patients. Chief among these assessments is the Veterans SF-36 Health Survey for measuring health-related quality of life in veteran ambulatory populations. The Veterans SF-36 Health Survey provides the cornerstone for this study and historically has been extensively disseminated and used in the VA with close to 2 million administrations nationally as part of its quality management system. National surveys administered by the VA since 1996 using the Veterans SF-36 Health Survey indicate important regional differences with implications for varying resource needs. Based upon the rich foundation provided by the VHS methodology, the VA has implemented some of these approaches as part of its quality monitoring system and can serve as a model for other large integrated systems of care.


Transcranial Doppler ultrasound: technique and application.
Transcranial Doppler (TCD) ultrasound provides rapid, noninvasive, real-time measures of cerebrovascular function. TCD can be used to measure flow velocity in the basal arteries of the brain to assess relative changes in flow, diagnose focal vascular stenosis, or to detect embolic signals within these arteries. TCD can also be used to assess the physiologic health of a particular vascular territory by measuring blood flow responses to changes in blood pressure (cerebral autoregulation), changes in end-tidal CO2 (cerebral vasoreactivity), or cognitive and motor activation (neurovascular coupling or functional hyperemia). TCD has established utility in the clinical diagnosis of a number of cerebrovascular disorders such as acute ischemic stroke, vasospasm, subarachnoid hemorrhage, sickle cell disease, as well as other conditions such as brain death. Clinical indication and research applications for this mode of imaging continue to expand. In this review, the authors summarize the basic principles and clinical utility of TCD and provide an overview of a few TCD research applications.


Targeted transcranial theta-burst stimulation alters fronto-insular network and prefrontal GABA.
Repetitive transcranial magnetic stimulation (rTMS) has been used worldwide to treat depression. However, the exact physiological effects are not well understood. Pathophysiology of depression involves crucial limbic structures (e.g. insula), and it is still not clear if these structures can be modulated through neurostimulation of surface regions (e.g. dorsolateral prefrontal cortex, DLPFC), and whether rTMS-induced excitatory/inhibitory transmission alterations relate to fronto-limbic connectivity changes. Therefore, we sought proof-of-concept for neuromodulation of insula via prefrontal intermittent theta-burst stimulation (iTBS), and how these effects relate to GABAergic and glutamatergic systems. In 27 healthy controls, we employed a single-blind crossover randomised-controlled trial comparing placebo and real iTBS using resting-state functional MRI and magnetic resonance spectroscopy. Granger causal analysis was seeded from right anterior insula (rAI) to locate individualized left DLPFC rTMS targets. Effective connectivity coefficients within rAI and DLPFC were calculated, and levels of GABA/Glx, GABA/Cr and Glx/Cr in DLPFC and anterior cingulate voxels were also measured. ITBS significantly dampened fronto-insular connectivity and reduced GABA/Glx in both voxels. GABA/Glx had a significant mediating effect on iTBS-induced changes in DLPFC-to-rAI connectivity. We demonstrate modulation of the rAI using targeted iTBS through alterations of excitatory/inhibitory interactions, which may underlie therapeutic effects of rTMS, offering promise for rTMS treatment optimization.


Relationship between cognitive impairment and nutritional assessment on functional status in Calabrian long-term-care.
The interaction between dementia and nutritional state is very complex and not yet fully understood. The aim of the present study was to assess the interaction between cognitive impairment and nutritional state in a cohort of residential elderly in relationship with functional condition of patients and their load of assistance in long-term-care facilities of the National Association of Third Age Structures (ANASTE) Calabria. One hundred seventy-four subjects (122 female and 52 male) were admitted to the long-term-care ANASTE Calabria study. All patients underwent multidimensional geriatric assessment. Nutritional state was assessed with the Mini Nutritional Assessment (MNA), whereas cognitive performance was evaluated by the Mini-Mental State Examination (MMSE). The functional state was assessed by Barthel Index (BI) and Activity Daily Living (ADL). The following nutritional biochemical parameters were also evaluated: albumin, cholesterol, iron, and hemoglobin. All patients were reassessed 180 days later. A severe cognitive impairment in MMSE performance was displayed in 49.7% patients, while 39.8% showed a moderate deficit; 6.9% had a slight deficit; and 3.4% evidenced no cognitive impairment. In MNA, 30% of patients exhibited an impairment of nutritional state; 56% were at risk of malnutrition; and 14% showed no nutritional problems. Malnutrition was present in 42% of patients with severe cognitive impairment, but only 4% of malnourished patients showed moderate cognitive deficit. The statistical analysis displayed a significant correlation between MNA and MMSE (P<0.001), as did MMSE correlated with Activity Daily Living (P<0.001) and BI (P<0.05). MNA correlated with BI (P<0.001) and albumin (P<0.001). The follow-up showed a strong correlation between cognitive deterioration and worsening of nutritional state (P<0.005) as well as with the functional state (P<0.05) and mortality (P<0.01). The present study clearly shows that malnutrition may play an important role in the progression of cognitive loss.


Ligand-protein docking: cancer research at the interface between biology and chemistry.
In recent years there has been a growing interest in computer-based screening. One of the driving forces has been the increased efficiency of protein crystallography leading to the real possibility of using structure-based design as a significant contributor to the discovery of novel ligands. In 1957 after 22 years of work the first protein structure, determined by x-ray crystallography was produced. Now the process has become increasingly automated and nearly 20,000 protein structures are available in the Protein Data Bank (PDB). Equally, progress in genomics will result in a great expansion of validated targets for cancer therapy. The understanding of the relationships between structure and function of gene products will be one of the key routes to new therapeutic advances. The challenge now is to use this data in the discovery of novel therapeutics. One approach is obviously to synthesize molecules and co-crystallize or soak them into the protein crystal and so determine the position and interaction of the molecule with the protein. The structural information obtained (where does the molecule bind; what are the ligand/protein/solvent interactions?) can be invaluable in the generation of novel molecules or in the re-design of existing molecules whose drug properties are not optimal. However, when dealing with large numbers (millions) of molecules, when crystallization is difficult or in testing hypotheses, a significant contribution can be made using computer based screening methods. In order to use the structural information derived from x-ray crystallography (or other sources, for example NMR or homology modelling) when evaluating the utility of a novel ligand, we need to understand where in the protein (or other macromolecule such as RNA) the ligand is likely to bind and also if possible, the strength of the binding interactions. This problem is known as the 'docking problem'. There have been many approaches to the solution of this problem over the last ten years. For example, some methods rely on complex molecular dynamics simulations while others use less costly graph matching approaches. There is generally a compromise between speed and accuracy, with some methods giving much more information and insight into the nature of the protein/ligand interactions and other methods optimised for speed of docking thousands of putative ligands. We will describe some of the more common methods and algorithms used to solve the docking problem and in particular, we will review recent applications in cancer research.


DNA barcoding discriminates echinoderm species.
DNA barcode sequences (a 657-bp segment of the mtDNA cytochrome oxidase I gene, COI) were collected from 191 species (503 specimens) of Echinodermata. All five classes were represented: Ophiuroidea, Asteroidea, Echinoidea, Holothuroidea and Crinoidea. About 30% of sequences were collected specifically for this study, the remainder came from GenBank. Fifty-one species were represented by multiple samples, with a mean intraspecific divergence of 0.62%. Several possible instances of cryptic speciation were noted. Thirty-two genera were represented by multiple species, with a mean congeneric divergence of 15.33%. One hundred and eighty-seven of the 191 species (97.9%) could be distinguished by their COI barcodes. Those that could not were from the echinoid genus Amblypneustes. Neighbour-joining trees of COI sequences generally showed low bootstrap support for anything other than shallow splits, although with very rare exceptions, members of the same class clustered together. Two ophiuran species, in both nucleotide and amino acid neighbour-joining trees, grouped loosely as sister taxa to Crinoidea rather than Ophiuroidea; sequences of these two species appear to have evolved very quickly. Results suggest that DNA barcoding is likely to be an effective, accurate and useful method of species diagnosis for all five classes of Echinodermata.


The 20th ion channel meeting: September 2009, France.
The French Ion Channel society has existed since 1989 and its main goal is to annually organize a scientific meeting. This meeting, which gathers young and senior French scientists, provides a great opportunity for exchange and interaction among the ion channel research community. Additionally, for many years, the French ion channel meeting has attracted a significant number of scientists from different European countries, promoting the discussion of new insights and advances, as well as aiding in the establishment of collaborations. In this report, we summarize the five symposia selected for their novelty and importance in human channelopathies, neuroplasticity, ion channel regulations, intracellular ion channels and plant physiology.


The health and social service needs of gay and lesbian elders and their families in Canada.
This article reports the findings of a study, undertaken in 2000, whose purpose was to gather information about the experiences and realities of gay and lesbian seniors and their families from across Canada in accessing a broad range of health and social services in the community, and to examine the role of health care and social service organizations in shaping access and service delivery. This study used a qualitative exploratory design based on focus group interviews. Perspectives of older gay men and lesbians and their families involved in organizations addressing these issues, as well as professionals from both gay and lesbian health organizations and mainstream elder care organizations were sought. Specific reference was made to the impact of discrimination on the health and access to health services of these populations. Issues relating to invisibility, historic and current barriers to care, and the nature of service options are identified. Recommendations for change are highlighted, including those related to best practice programs and policies in the long-term care sector.


Fer kinase/FerT and adherens junction dynamics in the testis: an in vitro and in vivo study.
Fer kinase is a 94-kDa cytoplasmic cell-cell actin-based adherens junction (AJ)-associated nonreceptor protein tyrosine kinase (PTK) found in multiple epithelia including the testis, whereas FerT kinase (51 kDa) is the truncated testis-specific form of Fer kinase, lacking the Fps/Fes/Fer/CIP4 (products of oncogenes identified in avian and feline sarcoma, encoding tyrosine protein kinases) and the three coiled-coil domains versus Fer kinase. Yet the role(s) of Fer kinase in AJ dynamics in the testis remains largely unexplored. We have used an in vitro model of AJ assembly with Sertoli-germ cell cocultures and an in vivo model of AJ disassembly in which adult rats were treated with 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide (AF-2364) to study changes in the expression and/or localization of Fer kinase during AJ restructuring. Fer kinase/FerT was expressed by Sertoli and germ cells when cultured in vitro. Using an antibody prepared against a synthetic peptide, NH2-SAPQNCPEEIFTIMMKCWDYK-COOH, corresponding to residues 779-799 of Fer kinase in the rat, which failed to cross-react with FerT kinase, for immunohistochemistry, Fer kinase was detected in the seminiferous epithelium in virtually all stages of the epithelial cycle. At stages XIII-VI, Fer kinase was associated largely with round and elongating spermatids. At stages VII-VIII, Fer kinase associated almost exclusively with round spermatids with very weak staining associated with elongated spermatids. This stage-specific localization of Fer kinase in the epithelium was confirmed by using staged tubules for semiquantitative reverse transcription-polymerase chain reaction. Studies by immunoprecipitation revealed that Fer kinase associated with N-cadherin, gamma-catenin, p120ctn, c-Src (a putative PTK and the product of the transforming, sarcoma-inducing gene of Rous sarcoma virus), Rab 8 (a GTPase), actin, vimentin, but not E-cadherin, afadin, nectin-3, and integrin beta1, suggesting Fer kinase associates not only with the actin-based cell-cell AJ structures, such as the N-cadherin/catenin complex (but not the alpha6beta1 integrin/laminin and the afadin/nectin complex), but also with intermediate filament-based cell-cell desmosomes. An induction in Fer kinase expression was detected during Sertoli-germ cell AJ assembly in vitro but not during AF-2364-induced AJ disruption in vivo. Yet this AF-2364-induced Fer kinase plummeting associated with an induction in N-cadherin, beta-catenin, and p120ctn, particularly at the base of the seminiferous epithelium. In summary, Fer kinase structurally associates with the N-cadherin/catenin protein complex in the testis and can possibly be used to mediate signaling function via the cadherin/catenin protein complex.


Insulinoma Presenting with Reactive Hypoglycemia: Evaluating the Effect of Tumor Resection via Continuous Glucose Monitoring.
A 71-year-old woman previously diagnosed with reactive hypoglycemia was transferred to our emergency unit because of loss of consciousness. Her plasma glucose level was 27 mg/dL, and continuous glucose monitoring (CGM) revealed postprandial asymptomatic hypoglycemia. A hypervascular tumor was identified via computed tomography in the distal pancreas, and the diagnosis of insulinoma was confirmed using the selective arterial calcium stimulation test. Although no episodes of hypoglycemia were observed during CGM after resection, a pathological examination identified regional lymph node metastasis. It is important to consider insulinoma as a cause of postprandial hypoglycemia, and CGM is useful for evaluating treatment outcomes.


Laparoscopic metroplasty: reconstructive surgery for unicornuate uterus with noncommunicating, functional uterine horn.
To demonstrate laparoscopic surgery for a patient with unicornuate uterus and a large hematometra in the noncommunicating uterine horn. Narrated video featuring the diagnostic tests and surgical management. Academic tertiary hospital. A 13-year-old woman, gravida 0 with menarche at 9 years old, had severe dysmenorrhea during her recent menstrual cycles. The results of transrectal three-dimensional sonography, hysteroscopy, and magnetic resonance imaging (MRI) were consistent for a uterine didelphys composed of a right unicornuate uterus and a left hemiuterus with hematometra and no connection to the cervix. Left adnexal endometrioma and ipsilateral renal agenesis were also noted. Laparoscopic adhesiolysis and enucleation of the left ovarian endometrioma were first performed. Then, implementing the concepts of Strassman unification method, a horizontal incision was made on the medial side of each hemicorpus, starting from the left rudimentary horn and ending at the fundal area of the right hemiuterus. The incision was carried deep enough to reach the endometrium. The opposing, reverted myometrium was then reapproximated from the lower end of the uterus to the upper fundal part in two layers, using absorbable bidirectional monofilament barbed suture. The outer serosal layer was closed with 1-0 Monocryl via a running continuous suture. On postoperative day 2, the patient was discharged uneventfully. Symptomatic relief and restoration of normal and functional anatomy. The patient has regular menstrual cycles with no recurrence of dysmenorrhea or ovarian endometrioma. At a 2-year postoperative follow-up evaluation, hysteroscopic examination revealed a single uterine cavity with a small fundal septum. The MRI scans showed an anteverted, symmetrical uterus. In comparison with the widely applied hemihysterectomy, reconstructive laparoscopic metroplasty not only effectively achieves symptomatic relief but also offers better uterine symmetry and a larger intrauterine cavity via unification of the uterus.


[Rheumatoid arthritis, methothrexate, and pulmonary fibrosis: which evidences?].
Pulmonary fibrosis is an extraarticular manifestation of rheumatoid arthritis (RA), which appears between 20 to 40% of cases. MTX is an ordinary treatment used for patients with RA. It has been suggested in some studies that a link between the use of MTX and the appearance of pulmonary fibrosis exists. Furthermore, the chronic use of MTX has been associated with the development of hepatic cirrhosis. Adenosine, a key molecule in the anti-inflammatory action of MTX seems to have a pro-fibrotic effect in some experimental models, thereby suggesting a mechanism through which MTX could lead to a fibrotic process. However, in spite of these experimental models, clinical studies have not permitted to confirm the pathogenic role of MTX in pulmonary fibrosis.


At the European union's door: a Hungarian team's experiences of participating in the Project Leonardo for better nursing care.
The aim of this paper is to provide information about the work completed by Hungarian nurses and professors of baccalaureate nurses, in the framework of Leonardo project, organized and sponsored by the European Union. The goal of the project was to increase the effectiveness of chief nurses through a further training programme in the field of management. The team in Szeged (Hungary) chose as their area of interest, human resource management, as in this field, it is possible to achieve the greatest improvement with the smallest financial investment. We measured fluctuations and the absenteeism of nurses, changes in their qualifications, and nurse and patient satisfaction at the beginning and end of the period studied. Almost all parameters showed improvement by the end of the tested period. A book of two volumes (available on the WEB in English and in French) was prepared containing the recommendations of EU.


Cryptosporidium, enterocytozoon, and cyclospora infections in pediatric and adult patients with diarrhea in Tanzania.
Cryptosporidiosis, microsporidiosis, and cyclosporiasis were studied in four groups of Tanzanian inpatients: adults with AIDS-associated diarrhea, children with chronic diarrhea (of whom 23 of 59 were positive [+] for human immunodeficiency virus [HIV]), children with acute diarrhea (of whom 15 of 55 were HIV+), and HIV control children without diarrhea. Cryptosporidium was identified in specimens from 6/86 adults, 5/59 children with chronic diarrhea (3/5, HIV+), 7/55 children with acute diarrhea (0/7, HIV+), and 0/20 control children. Among children with acute diarrhea, 7/7 with cryptosporidiosis were malnourished, compared with 10/48 without cryptosporidiosis (P < .01). Enterocytozoon was identified in specimens from 3/86 adults, 2/59 children with chronic diarrhea (1 HIV+), 0/55 children with acute diarrhea, and 4/20 control children. All four controls were underweight (P < .01). Cyclospora was identified in specimens from one adult and one child with acute diarrhea (HIV-). Thus, Cryptosporidium was the most frequent and Cyclospora the least frequent pathogen identified. Cryptosporidium and Enterocytozoon were associated with malnutrition. Asymptomatic fecal shedding of Enterocytozoon in otherwise healthy, HIV children has not been described previously.


Let's face it: facial emotion processing is impaired in bipolar disorder.
Patients with bipolar disorder (BD) have difficulty in recognizing and discriminating facial emotions. However, beyond this broad finding, existing literature is equivocal about the specific nature of impairments, and progress toward adequately profiling facial emotion processing in BD is hampered by methodological inconsistencies. The current study aimed to advance the literature by comparing 50 BD patients and 52 controls on a series of facial emotion processing tasks. Results indicated that patients with BD had a small, yet consistent impairment in emotion processing overall. This impairment did not vary as a function of specific emotions, tasks, or intensities between groups, and was not influenced by current mood state. These results suggest that past inconsistencies in the literature are unlikely to be attributable to task related artifacts influencing the estimation of an effect. These findings add to our understanding of social cognition in BD, and have important implications for clinicians treating patients with the disorder.


Tissue engineering penoplasty with biodegradable scaffold Maxpol-T cografted autologous fibroblasts for small penis syndrome.
In this study, we investigated the safety and efficacy of a poly acid-co-glycolide biodegradable scaffold (Maxpol-T) coated by autologous fibroblasts (AF) for penile girth enlargement in small penis syndrome (SPS). Eighty patients with SPS were enrolled in a clinical study at 2 medical centers; 69 patients completed the study protocol. Scrotal skin was harvested under local anesthesia, and AFs were cultured and seeded on a Maxpol-T scaffold; the cografted scaffold was implanted under the Buck's fascia of penile shaft via a circumcising incision. Patients were followed up at 1, 3, and 6 months to evaluate penile girth changes. Patient satisfaction was assessed via Visual Analogue Scale and scored on the International Index of Erectile Function-5 (IIEF-5). Mean preoperative penile girth in the flaccid and erect state was 8.18 ± 0.83 cm and 10.26 ± 1.22 cm, respectively. At the 6-month postoperative follow-up, mean penile girth in the flaccid and erect state was increased to 12.19 ± 1.27 cm and 13.18 ± 1.31 cm, respectively (P < .001 for change in both flaccid and erect state). Sixty-five patients (94.2%) reported satisfaction with the procedure. Among them, 4 cases (5.8%) were dissatisfied, 7 cases (10.1%) were satisfied, 26 cases (37.7%) were very satisfied, and 32 cases (46.4%) were extremely satisfied. All men maintained IIEF-5 scores of more than 22. Complications included prolonged subcutaneous edema in 3 patients (4.3%) and pinpoint erosion at the suture area in 3 patients (4.3%). Implantation of autologous fibroblasts seeded on a Maxpol-T collagen scaffold holds promise as a safe and novel technique for penile girth enhancement in patients with SPS.


The function of the p190 Rho GTPase-activating protein is controlled by its N-terminal GTP binding domain.
p190 is a GTPase-activating protein (GAP) for the Rho family of GTPases. The GAP domain of p190 is at the C terminus of the protein. At its N terminus, p190 contains a GTP binding domain of unknown significance. We have introduced a mutation (Ser36 --> Asn) into this domain of p190 that decreased its ability to bind guanine nucleotide when expressed as a hemagglutinin (HA)-tagged protein in COS cells. In vitro, both the wild type and S36N mutant HA-p190 proteins showed similar GAP activities toward RhoA, but when expressed in NIH 3T3 fibroblasts only wild type p190 appeared able to function as a RhoGAP. Wild type HA-p190 induced a phenotype of rounded cells with long, beaded extensions similar to that seen when Rho function is disrupted by ADP-ribosylation. HA-p190(S36N), although expressed at a similar level to the wild type protein, had no discernible effect on the cells. The beaded extension phenotype induced by wild type HA-p190 required GAP function. A GAP-defective mutant, p190(R1283A), had no effect on cell morphology. Moreover, the beaded extension phenotype could be suppressed by co-expression of a gain-of-function Rho mutant, RhoA(G14V), or Rac mutant, Rac1(G12V). Activation of the Jun kinase (JNK) via muscarinic receptors was inhibited by wild type HA-p190, but JNK activity was enhanced by the S36N mutant. Co-expression of HA-p190 with a fragment containing only the mutated GTP binding domain partially inhibited the beaded extension phenotype, suggesting that it may sequester a factor required for p190 function. Taken together these data demonstrate that within the cell, the Rho/Rac GAP activity of p190 can be regulated by the N-terminal GTP binding domain.


Minimal and optimal mechanisms for GroE-mediated protein folding.
We have analyzed the effects of different components of the GroE chaperonin system on protein folding by using a nonpermissive substrate (i.e., one that has very low spontaneous refolding yield) for which rate data can be acquired. In the absence of GroES and nucleotides, the rate of GroEL-mediated refolding of heat- and DTT-denatured mitochondrial malate dehydrogenase was extremely low, but some three times higher than the spontaneous rate. This GroEL-mediated rate was increased 17-fold by saturating concentrations of ATP, 11-fold by ADP and GroES, and 465-fold by ATP and GroES. Optimal refolding activity was observed when the dissociation of GroES from the chaperonin complex was dramatically reduced. Although GroEL minichaperones were able to bind denatured mitochondrial malate dehydrogenase, they were ineffective in enhancing the refolding rate. The spectrum of mechanisms for GroE-mediated protein folding depends on the nature of the substrate. The minimal mechanism for permissive substrates (i.e., having significant yields of spontaneous refolding), requires only binding to the apical domain of GroEL. Slow folding rates of nonpermissive substrates are limited by the transitions between high- and low-affinity states of GroEL alone. The optimal mechanism, which requires holoGroEL, physiological amounts of GroES, and ATP hydrolysis, is necessary for the chaperonin-mediated folding of nonpermissive substrates at physiologically relevant rates under conditions in which retention of bound GroES prevents the premature release of aggregation-prone folding intermediates from the chaperonin complex. The different mechanisms are described in terms of the structural features of mini- and holo-chaperones.


A beginner's guide to getting involved in science advocacy.
Every scientist in the United States likely has a story of how the federal funding crisis for biomedical research has affected him or her personally. The sharing of these powerful anecdotes will enable policy makers to fully grasp the extent to which the decline in federal funding has negatively affected the scientific community. However, many scientists do not know where to begin or are uncertain that their advocacy efforts will have an impact. In an effort to encourage more scientists to become involved in science advocacy, we describe how to form and maintain a student science advocacy group.


Prevention and Treatment of Venous Thromboembolism in Patients with Cancer: Focus on Drug Therapy.
Venous thromboembolism (VTE) is a frequent complication in patients with cancer and is associated with significant morbidity and mortality. The use of anticoagulants for the prevention and treatment of VTE in this population is challenging given the high risk of both recurrent VTE and bleeding complications. Thromboprophylaxis with subcutaneous low-molecular-weight heparin (LMWH) is recommended in cancer patients hospitalized for an acute medical illness and in those undergoing major surgery. In ambulatory cancer patients with or without central venous catheters, routine thromboprophylaxis is not recommended because of the relatively low benefit-to-risk ratio. To identify cancer outpatients at very high risk of VTE who may benefit from thromboprophylaxis, VTE risk stratification tools based on tumour type, clinical parameters, or coagulation biomarkers have been proposed, but their clinical utility needs validation. The mainstay of treatment for cancer-associated VTE is LMWH for at least 6 months or longer in case of active disease. The same initial and long-term treatment for incidental VTE as for symptomatic VTE can be suggested while awaiting additional studies in this area.


World Pneumonia Day 2011-2016: Twitter contents and retweets.
Twitter is used for World Pneumonia Day (WPD; November 12) communication. We evaluate if themes of #pneumonia tweets were associated with retweet frequency. A total of 28 181 original #pneumonia tweets were retrieved (21 November 2016), from which six subcorpora, 1 mo before and 1 mo after WPD 2011-2016, were extracted (n=6721). Underlying topics were identified via latent Dirichlet allocation and were manually coded into themes. The association of themes with retweet count was assessed via multivariable hurdle regression. Compared with personal experience tweets, tweets that both raised awareness and promoted intervention were 2.62 times as likely to be retweeted (adjusted odds ratio [aOR] 2.62 [95% 1.79 to 3.85]) and if retweeted had 37% more retweets (adjusted prevalence ratio [aPR] 1.37 [95% CI 1.06 to 1.78]). Tweets that raised concerns about vaccine price were twice as likely to be retweeted (aOR 2.29 [95% CI 1.36 to 3.84]) and if retweeted, had double the retweet count (aPR 2.05 [95% CI 1.27 to 3.29]) of tweets sharing personal experience. The #pneumonia tweets that both raised awareness and promoted interventions and those discussing vaccine price were more likely to engage users than tweets about personal experience. These results help health professionals craft WPD messages that will engage the audience.


Assessing the polarization of a quantum field from stokes fluctuations.
We propose an operational degree of polarization in terms of the variance of the Stokes vector minimized over all the directions of the Poincaré sphere. We examine the properties of this second-order definition and carry out its experimental determination. Quantum states with the same standard (first-order) degree of polarization are correctly discriminated by this new measure. We argue that a comprehensive quantum characterization of polarization properties requires a whole hierarchy of higher-order degrees.


Fluidic measurement of electric field sensitivity of Ti-GaAs Schottky junction gated field effect biosensors.
We report the electric field and pH sensitivity of fluid gated metal-semiconductor hybrid (MSH) Schottky structures consisting of a Titanium layer on n-type GaAs. Compared to standard field-effect sensors, the MSH Schottky structures are 21 times more sensitive to electric field of -46.6 V/cm and show about six times larger resistance change as pH of the solution is decreased from 8.17 to 5.54. The potential change at the fluidic gate and passivation layer interface by bias voltages and pH are mirrored by the metal shunt, resulting in larger depletion widths under the Schottky junction and resistance change as compared to sensors with no Schottky junction. 2D numerical simulation results are in good agreement with the measured data and suggest thinner mesa with lower doping density can further increase device sensitivity.


The long-term prediction of return to work following serious accidental injuries: a follow up study.
Considerable indirect costs are incurred by time taken off work following accidental injuries. The aim of this study was to predict return to work following serious accidental injuries. 121 severely injured patients were included in the study. Complete follow-up data were available for 85 patients. Two weeks post trauma (T1), patients rated their appraisal of the injury severity and their ability to cope with the injury and its job-related consequences. Time off work was assessed at one (T2) and three years (T3) post accident. The main outcome was the number of days of sick leave taken due to the accidental injury. The patients' appraisals a) of the injury severity and b) of their coping abilities regarding the accidental injury and its job-related consequences were significant predictors of the number of sick-leave days taken. Injury severity (ISS), type of accident, age and gender did not contribute significantly to the prediction. Return to work in the long term is best predicted by the patients' own appraisal of both their injury severity and the ability to cope with the accidental injury.


The continuous flow culture as an in vitro model in experimental mycology.
We used the model of continuous flow culture (cfc) to study the growth of Candida species. This model allows special test conditions: a long generation time of 15-20 hs, controlled limitation of nitrogen sources and carbohydrates, comparison of the growth under aerobic and anaerobic conditions simultaneously. These conditions were used to study the effect of antimycotic drugs, mainly during a long time of 7 to 10 days. Germ tube formation as a virulence factor was more abundant and faster in cfc of strains with a stronger adherence to buccal epithelium cells. Co-cultivation of C. albicans and C. glabrata allowed conclusions for their colonization in vivo. A biofilm on the glass wall of the culture vessel led to mycelium formation by C. albicans. Concomitantly the growth of C. glabrata was favoured. Growth of C. albicans in the gastrointestinal flora was reduced by masses of bacteria and their multiple metabolic activities. A remarkable growth of C. albicans was only to be seen if the ecosystem was destroyed e.g. by antibacterial antibiotics. The influence of fluconazole in a long-term follow up study under anaerobic conditions showed an inhibition of C. albicans in 99.9 %. This means fungicidal efficacy.