Genetic inactivation of acrAB or inhibition of efflux induces expression of ramA.
The transcriptional activator RamA regulates production of the multidrug resistance efflux AcrAB-TolC system in several Enterobacteriaceae. This study investigated factors that lead to increased expression of ramA. In order to monitor changes in ramA expression, the promoter region of ramA was fused to a gfp gene encoding an unstable green fluorescence protein (GFP) on the reporter plasmid, pMW82. The ramA reporter plasmid was transformed into Salmonella Typhimurium SL1344 and a ΔacrB mutant. The response of the reporter to subinhibitory concentrations of antibiotics, dyes, biocides, psychotropic agents and efflux inhibitors was measured during growth over a 5 h time period. Our data revealed that the expression of ramA was increased in a ΔacrB mutant and also in the presence of the efflux inhibitors phenylalanine-arginine-β-naphthylamide, carbonyl cyanide m-chlorophenylhydrazone and 1-(1-naphthylmethyl)-piperazine. The phenothiazines chlorpromazine and thioridazine also increased ramA expression, triggering the greatest increase in GFP expression. However, inducers of Escherichia coli marA and soxS and 12 of 17 tested antibiotic substrates of AcrAB-TolC did not induce ramA expression. This study shows that expression of ramA is not induced by most substrates of the AcrAB-TolC efflux system, but is increased by mutational inactivation of acrB or when efflux is inhibited.


Improving diabetic control in adverse social conditions. A home blood glucose monitoring study in Soweto, South Africa.
In order to explore the feasibility of home blood glucose monitoring (HBGM) in Type 1 diabetics in developing countries, we introduced the technique to Type 1 patients below the age of 30 yr attending the Diabetic Clinic serving Soweto in South Africa. Despite initial problems, HBGM with visually-read strips was applied to 45 of the 64 young Type 1 diabetics identified ("HBGM group"). The remaining 19 were continued on urine glucose monitoring only ("HUGM group"), usually because of attendance and compliance problems. After 4 months' follow-up, glycosylated haemoglobin (HbA1) fell from 10.5 +/- 2.6% (mean +/- SD) to 9.0 +/- 1.7 (p less than 0.001) in the HBGM group, but was unchanged (10.1 +/- 2.1 vs 9.9 +/- 1.9, pn.s.) in HUGM patients. HBGM can thus be introduced in adverse social conditions, and may be associated with improved diabetic control. Costs, in terms of finance and medical time, were not excessive. Unfortunately, a significant minority were excluded by attendance and other problems, and analysis of diabetic complication rates (before the programme began) showed that these patients had significantly more complications than those deemed suitable for HBGM (42.1% vs 15.5%, p less than 0.05).


Osteogenesis imperfecta type III and hypogonadotropic hypogonadism result in severe bone loss: a case report.
We present the case of a 33-year-old male patient with multiple fractures and typical radiographical and clinical characteristics of osteogenesis imperfecta (OI) type III. Furthermore, the patient has suffered from hypogonadotropic hypogonadism since childhood. On the basis of antiresorptive therapy, no further fractures occurred within several years. Recently, recurrent nontraumatic fractures without bone healing were observed. Decreased bone mineral density was assessed by dual X-ray absorptiometry (DXA). High-resolution peripheral quantitative computed tomography (HR-pQCT) showed impaired trabecular bone structure. Due to recurrent fragility fractures and severe deterioration of bone structure, an osteoanabolic treatment with teriparatide was initiated to potentially stimulate fracture healing and to increase bone formation.


Monitoring plasma HIV-1 RNA levels in addition to CD4+ lymphocyte count improves assessment of antiretroviral therapeutic response. ACTG 241 Protocol Virology Substudy Team.
CD4+ lymphocyte counts and plasma HIV-1 RNA levels predict progression of HIV-related disease, but the relative importance of these and other virological factors in defining response to antiretroviral therapy is not yet clear. To determine the short-term variability of plasma HIV-1 RNA level during stable therapy; the relative importance of pretreatment values and early changes in CD4+ count, HIV-1 RNA levels, and infectious HIV-1 titers in mononuclear cells of peripheral blood and pretreatment syncytium-inducing phenotype of an HIV-1 isolate for prediction of disease progression and decline in CD4+ counts during therapy. Data were collected prospectively in a randomized, clinical trial comparing two combination regimens (ACTG [AIDS Clinical Trials Group] Protocol 241) and pooled across treatments. 8 AIDS Clinical Trials Units. 198 adults with HIV-1 infection and no more than 350 CD4+ lymphocytes/mm3 who had received at least 6 months of nucleoside therapy. All patients received zidovudine and didanosine; 100 received nevirapine and 98 received placebo. CD4+ lymphocyte counts, plasma HIV-1 RNA levels, and infectious HIV-1 titers in cells were measured before and 8 and 48 weeks after study treatment. Assay for the syncytium-inducing viral phenotype was done at baseline. Progression was defined as occurrence of opportunistic infection, malignancy, or death during the 48 weeks after treatment began. The difference between two measurements of HIV-1 RNA levels at baseline was within +/-0.39 log10 copies/mL (2.5-fold) for 90% of 167 patients receiving stable therapy. In a multivariate model, risk for disease progression was reduced by 56% (95% CI, 8% to 79% [P = 0.028]) for every 10-fold lower HIV-1 RNA level at baseline, by 52% (CI, 6% increase to 79% reduction [P = 0.071]) for every 10-fold reduction in HIV-1 RNA level at 8 weeks after treatment initiation, and by 67% (CI, 42% to 81% [P < 0.001]) for every 2-fold higher CD4+ count at baseline. These risk factors and syncytium-inducing viral phenotype at baseline, but not infectious HIV-1 titers in circulating cells, were associated with change in CD4+ counts over 48 weeks. For an individual patient, a change in plasma HIV-1 RNA level of 2.5-fold or more probably indicates a true biological change. Monitoring HIV-1 RNA levels and CD4+ lymphocytes before a change in antiretroviral treatment and monitoring HIV-1 RNA levels shortly thereafter improves prediction of disease progression and decline in CD4+ counts for 1 year compared with monitoring CD4+ counts of HIV-1 RNA levels alone. Additional monitoring of infectious HIV-1 titers in mononuclear cells of peripheral blood is not useful.


The dynamics of FTO binding and demethylation from the m6A motifs.
N6-methyladenosine (m6A) is considered as a reversible RNA modification occurring more frequently on the GAC than AAC context in vivo, which regulates post-transcriptional gene expression in mammalian cells. m6A 'writers' METTL3 and METTL14 demonstrate a strong preference for binding AC-containing motifs in living cells. However, this evidence is currently lacking for m6A erasers, leaving the dynamics of the internal m6A modification under debate recently. We analysed three recently published FTO CLIP-seq data sets and two generated in this study, one of the two known m6A 'erasers'. FTO binding peaks from all cell lines contain RRACH motifs. Only those from K562, 3T3-L1and HeLa cells were enriched in AC-containing motifs, while those from HEK293 were not. The exogenously overexpressed FTO effectively binds to m6A motif-containing RNA sites. FTO overexpression specifically removed m6A modification from GGACU and RRACU motifs in a concentration-dependent manner. These findings underline the dynamics of FTO in target selection, which is predicted to contribute to both the m6A dynamics and the FTO plasticity in biological functions and diseases.


Use of preliminarily prepared v. cephalica in operations of femoral-distal bypass grafting.
Presented herein is the authors'experience in using a preliminarily prepared lateral subcutaneous vein of the arm (v. cephalica) for femoral-distal reconstructions in a total of nine patients with lower-limb critical ischaemia (LLCI). The choice of the vein referred to above as a bypass graft was a forced one because of a loose-type, insufficient-diameter greater saphenous vein (GSV), varicose and postphlebitic alterations therein or merely the total lack thereof after previous phlebectomy, with such a decision also influenced by no adequate lesser saphenous vein (LSV) available. Given the anticipated level of the would-be distal anastomoses, utilizing synthetic prosthetic grafts of blood vessels seemed fterly undesirable, and immediately employing upper-limb veins as bypass grafts turned out virtually impossible owing to their small diameter. The preparation of the bypass graft consisted in first forming a fistula between the radial artery and v.cephalica in the lower third of the forearm. Theprocedure involvinga 2-to-3-week functioning of the fistula and the so-called "training", of the vein according to a specially devised technique was followed by a noticeable widening of the lumen of the v. cephalica, thus allowing us in the long run to successfully use it for femoral-distal reconstructions.


Evaluation of an iodophor teat spray in the control of infections and cellular reactions in the udder.
A strictly controlled field trial was designed to assess the value of an iodophorpost-milking teat disinfectant in the prevention of new mastitis infections in a 132 cow herd. The disinfectant was applied by a hand spray, a method acceptable, effective, and less costly than conventional teat dipping methods. Only the left side of the udder was treated, the right quarters acting as controls. Dry-cow therapy and other methods of mastitis control were already practised, and no change in routine was introduced apart from half-udder teat spraying. Fifty-eight new cases of mastitis were found to occur on the teat-sprayed side, compared with 91 in the untreated quarters; 35 and 23, respectively, were clinical. No Group B streptococci existed in the herd, and the principal reductions were in Group C streptococci and coagulase-negative staphylococci, the percentages of which were halved. The percentage of coliform infections on the teat-sprayed side was, in contrast, doubled. The incidence of new clinical and subclinical disease without infection was in reverse ratio to that of infections, being 29-9 per cent higher in the quarters which were teat-sprayed. Analysis of cumulative CMT reactions from regular monthly surveys indicated that exponential cell-count values on each side of the udder were identical. Thus, while new infections were significantly reduced, overall cell counts were not, and there is clearly a need for further research into factors other than bacteria which may initiate teat damage and inflammatory changes in the udder.


Front-Line Therapy for Elderly Chronic Lymphocytic Leukemia Patients: Bendamustine Plus Rituximab or Chlorambucil Plus Rituximab? Real-Life Retrospective Multicenter Study in the Lazio Region.
Previous studies investigated the efficacy and the safety of bendamustine (B) vs. chlorambucil (Chl) associated with rituximab (R) in fludarabine-ineligible patients with treated and untreated chronic lymphocytic leukemia (CLL). We conducted a retrospective multicenter study in the Lazio region to further evaluate and compare the efficacy and the toxicity of Chl-R and B-R regimen in CLL patients over the age of 65. We enrolled 192 untreated CLL patients: 111 treated with B-R and 81 with Chl-R. The overall response rates (ORR; 93.6% in B-R and 86.5% in Chl-R) were not statistically different between the two groups, such as progression-free survival (PFS), time to retreatment (TTR), and overall survival (OS). The B-R group showed a higher hematological (p = 0.007) and extra-hematological (p = 0.008) toxicity. When comparing the toxicities according to age, we noted that the extra-hematological toxicity was higher in patients over the age of 75 who were treated with B-R than those treated with Chl-R (p = 0.03). This retrospective study confirms the feasibility of B-R and Chl-R in elderly untreated CLL patients. Currently, patients who are over 75 and unfit are usually treated with Chl-R. This scheme allows achieving the same ORR, PFS, TTR, and OS when compared with B-R because of hematological and extra-hematological toxicities due to B, in which a greater dose reduction has been shown in comparison to Chl.


Fracture resistance of simulated immature teeth after internal bleaching procedures.
The aim of this study was to evaluate the fracture resistance of simulated immature teeth after internal bleaching. The teeth were assigned as follows (n = 12/group); Group-1: The pulp chamber was filled with ProRootMTA and bleached intracoronally with sodium perborate mixed with 37% carbamide peroxide gel; Group-2: The pulp chamber was filled with ProRootMTA without bleaching; Group-3: The pulp chamber was filled with Biodentine and bleached intracoronally as Group-1; Group-4: The pulp chamber was filled with Biodentine without bleaching; and Group-5: Teeth received no intervention (control). The specimens were loaded vertically until root fracture occurred. The data were analysed with Kruskal-Wallis and Dunn tests. There was no significant difference between the fracture resistances of the experimental groups (P > 0.05). However, all experimental groups had significantly lower fracture resistance than the control group (P < 0.05). Neither the tested calcium silicate cements nor the bleaching procedures had a significant impact on fracture resistance values.


Congenital heart defects in patients with oculo-auriculo-vertebral spectrum (Goldenhar syndrome).
The oculo-auriculo-vertebral spectrum (OAVS) is a non-random association of microtia, hemifacial microsomia with mandibular hypoplasia, ocular epibulbar dermoid, and cervical vertebral malformations. Congenital heart defects (CHDs) have been reported in 5-58% of the patients. We analyze the frequency and anatomic features of CHD in a series of 87 patients with OAVS examined between January 1990 and February 2007 with normal chromosomes, ranging in age between 0.1 and 16.8 years. A twin pregnancy occurred in eight cases (dizygotic in six cases and monozygotic in two). CHDs were diagnosed in 28/87 (32%) patients, and classified into categories of postulated developmental mechanisms including 9 (32%) atrial and ventricular septal defects, 11 (39%) conotruncal defects, 4 (14%) targeted growth defects, two (7%) with situs and looping defects, one (4%) with a left-sided obstructive lesion and one (4%) with patent ductus arteriosus. As noted in other series, the most common individual CHDs were ventricular septal defect (six patients) and tetralogy of Fallot (TOF) (classic or with pulmonary atresia) (six patients). Comparing the frequencies of CHDs groups observed in the OAVS patients with the findings of the Emilia-Romagna Registry which ascertained CHDs prevalence in the general population, conotruncal defects, targeted growth defects, and heterotaxia were significantly associated with OAVS.


The Value of TTPVI in Prediction of Microvascular Invasion in Hepatocellular Carcinoma.
The objective of our study was to evaluate the value of two-trait predictor of venous invasion (TTPVI) in the prediction of pathological microvascular invasion (pMVI) in patients with hepatocellular carcinoma (HCC) from preoperative computed tomography (CT) and magnetic resonance (MR). A total of 128 preoperative patients with findings of HCC were enrolled. Tumor size, tumor margins, tumor capsule, peritumoral enhancement, and TTPVI was assessed on preoperative CT and MRI images. Histopathological features were reviewed: pathological tumor size, tumor differentiation, pMVI along with alpha-fetoprotein level (AFP). Significant imaging findings and histopathological features were determined with univariate and multivariate logistic regression analysis. Univariate analysis revealed that tumor size (p<0.01), AFP level (p=0.043), tumor differentiation (p<0.01), peritumoral enhancement (p=0.003), pathological tumor size (p<0.01), tumor margins (p<0.01) on CT and MRI, and TTPVI (p<0.01) showed statistically significant associations with pMVI. In multivariate logistic regression analysis, tumor size (odds ratio [OR] = 1.294; 95% confidence interval [CI]: 1.155, 1.451; p < 0.001), tumor differentiation (odds ratio [OR] =1.384; 95% confidence interval [CI]: 1.224, 1.564; p < 0.001), and TTPVI (odds ratio [OR] = 4.802; 95% confidence interval [CI]: 1.037, 22.233; p=0.045) were significant independent predictors of pMVI. Using 5.8 as the threshold for size, one could obtain an area-under-curve (AUC) of 0.793, 95% confidence interval [CI]: 0.715 to 0.857. Tumor size, tumor differentiation, and TTPVI depicted in preoperative CT and MRI had a statistically significant correlation with pMVI. Hence, TTPVI detected on CT and MRI may be predictive of pMVI in HCC cases.


Mycotic keratitis in Nigeria. A study of 21 cases.
A clinical and mycological study of 21 cases of mycotic keratitis, a clinical entity not yet reported from Nigeria or West Africa, showed that Fusarium solani was the predominant aetiological agent. It was isolated from 12 cases. Four of the remaining nine cases were caused by Aspergillus fumigatus, one by A. flavus, two by Penicillium citrinum, and one each by P. expansum and Penicillium sp. All the 12 isolates of F. solani grew well at 37 degrees C and survived at 40 degrees C. Two cases, one due to F. solani and the other to A. fumigatus, were accompanied by panophthalmitis.


Development and validation of a risk assessment tool for gastric cancer in a general Japanese population.
There have been very few reports of risk score models for the development of gastric cancer. The aim of this study was to develop and validate a risk assessment tool for discerning future gastric cancer risk in Japanese. A total of 2444 subjects aged 40 years or over were followed up for 14 years from 1988 (derivation cohort), and 3204 subjects of the same age group were followed up for 5 years from 2002 (validation cohort). The weighting (risk score) of each risk factor for predicting future gastric cancer in the risk assessment tool was determined based on the coefficients of a Cox proportional hazards model in the derivation cohort. The goodness of fit of the established risk assessment tool was assessed using the c-statistic and the Hosmer-Lemeshow test in the validation cohort. During the follow-up, gastric cancer developed in 90 subjects in the derivation cohort and 35 subjects in the validation cohort. In the derivation cohort, the risk prediction model for gastric cancer was established using significant risk factors: age, sex, the combination of Helicobacter pylori antibody and pepsinogen status, hemoglobin A1c level, and smoking status. The incidence of gastric cancer increased significantly as the sum of risk scores increased (P trend < 0.001). The risk assessment tool was validated internally and showed good discrimination (c-statistic = 0.76) and calibration (Hosmer-Lemeshow test P = 0.43) in the validation cohort. We developed a risk assessment tool for gastric cancer that provides a useful guide for stratifying an individual's risk of future gastric cancer.


High sensitivity sensors made of perforated waveguides.
Sensors based on surface plasmons or waveguide modes are at the focus of interest for applications in biological or environmental chemistry. Waveguide-mode spectra of 1 mum-thick pure and perforated silica films comprising isolated nanometric holes with great aspect ratio were measured before and after adhesion of streptavidin at concentrations of 500 nM. The shift of the angular position for guided modes was nine times higher in perforated films than in bulk films. Capturing of streptavidin in the nanoholes is at the origin of that largely enhanced shift in the angular position as the amplitude of the guided mode in the waveguide perfectly overlaps with the perturbation caused by the molecules. Hence, the device allows for strongly confined modes and their strong perturbation to enable ultra-sensitive sensor applications.


Pig neutrophil adherence in experimentally induced salmonellosis.
In vitro neutrophil adherence was characterized in healthy newly weaned pigs following experimentally induced infection with Salmonella choleraesuis, A typhimurium, and S anatum. The adherence of pig neutrophils to nylon fiber columns was shown to be reproducible on a day-to-day basis. Neutrophil adherence was significantly increased in a group of pigs at 6, 30, and 48 hours after S choleraesuis was inoculated (orally). Neutrophil adherence was not significantly altered in groups of pigs inoculated with S typhimurium and S anatum, although individual pigs did show an apparent increase in adherence after S typhimurium was inoculated. An association between increased neutrophil adherence and acute inflammatory disease was made.


Epitope tagging of endogenous genes in diverse human cell lines.
Epitope tagging is a powerful and commonly used approach for studying the physical properties of proteins and their functions and localization in eukaryotic cells. In the case of Saccharomyces cerevisiae, it has been possible to exploit the high efficiency of homologous recombination to tag proteins by modifying their endogenous genes, making it possible to tag virtually every endogenous gene and perform genome-wide proteomics experiments. However, due to the relative inefficiency of homologous recombination in cultured human cells, epitope-tagging approaches have been limited to ectopically expressed transgenes, with the attendant limitations of their nonphysiological transcriptional regulation and levels of expression. To overcome this limitation, a modification and extension of adeno-associated virus-mediated human somatic cell gene targeting technology is described that makes it possible to simply and easily create an endogenous epitope tag in the same way that it is possible to knock out a gene. Using this approach, we have created and validated human cell lines with epitope-tagged alleles of two cancer-related genes in a variety of untransformed and transformed human cell lines. This straightforward approach makes it possible to study the physical and biological properties of endogenous proteins in human cells without the need for specialized antibodies for individual proteins of interest.


Rosmarinic acid content in antidiabetic aqueous extract of Ocimum canum sims grown in Ghana.
Rosmarinic acid (RA) is an important antioxidant polyphenol that is found in a variety of spices and herbs, including Ocimum canum Sims (locally called eme or akokobesa in Ghana). Aqueous extracts from the leaves of O. canum are used as an antidiabetic herbal medicine in Ghana. Analytical thin-layer chromatography was used to examine the composition of the polyphenols in leaf extracts. The polyphenol content in the aqueous and methanol extracts from the leaf, as determined by the Folin-Ciocalteu method, were 314 and 315 mg gallic acid equivalent/g leaf sample, respectively. The total flavonoid concentration as determined by the aluminum(III) chloride method was 135 mg catechin equivalent/g leaf sample. High-performance liquid chromatography coupled to an electrospray Quadrupole time-of-flight mass spectrometer was also used to determine the polyphenol fingerprint profile in the leaf extracts of O. canum. Although the average RA concentration in the O. canum leaf extracts from Ghana was 1.69 mg/g dry weight (reported values range from 0.01 to 99.62 mg/g dry weight), this polyphenol was still a prominent peak in addition to caffeic acid derivatives.


Selective inhibition of inward rectifier K+ channels (Kir2.1 or Kir2.2) abolishes protection by ischemic preconditioning in rabbit ventricular cardiomyocytes.
Volume regulatory Cl- channels are key regulators of ischemic preconditioning (IPC). Because Cl- efflux must be balanced by an efflux of cations to maintain cell membrane electroneutrality during volume regulation, we hypothesize that I(K1) channels may play a role in IPC. We subjected cultured cardiomyocytes to 60-minute simulated ischemia (SI) followed by 60-minute of simulated reperfusion (SR) and assessed percent cell death using trypan blue staining. Ischemic preconditioning (10-minute SI/10-minute SR) significantly (P<0.0001) reduced the percent cell death in nontransfected cardiomyocytes [IPC(CM) 18.0+/-2.1% versus control (C(CM)) 48.3+/-1.0%]. IPC protection was not altered by overexpression of the reporter gene (enhanced green fluorescent protein, EGFP). However, overexpression of dominant-negative Kir2.1 or Kir2.2 genes using adenoviruses (AdEGFPKir2.1DN or AdEGFPKir2.2DN) encoding the reporter gene EGFP prevented IPC protection [both IPC(CM)+AdEGFPKir2.1DN 45.8+/-2.3% (mean+/-SEM) and IPC(CM)+AdEGFPKir2.2DN 47.9+/-1.4% versus IPC(CM); P<0.0001] in cultured cardiomyocytes (n=8 hearts). Transfection of cardiomyocytes with AdEGFPKir2.1DN or AdEGFPKir2.2DN did not affect cell death in control (nonpreconditioned) cardiomyocytes (both C(CM)+ AdEGFPKir2.1DN 45.8+/-0.7% and C(CM)+AdEGFPKir2.2DN 46.2+/-1.3% versus C(CM); not statistically significant). Similar effects were observed in both cultured (n=5 hearts) and freshly isolated (n=4 hearts) ventricular cardiomyocytes after I(K1) blockade with 20 micromol/L BaCl2 plus 1 micromol/L nifedipine (to prevent Ba2+ uptake). Nifedipine alone neither protected against ischemic injury nor blocked IPC protection. Our findings establish that I(K1) channels play an important role in IPC protection.


[Clinico-immunological aspects of gastrointestinal diseases in children].
The data on the status of immunoregulation in 144 children with gastroduodenal pathology are provided as are indications for differentiated immunomodulatory therapy. As many as 100 children with celiac disease treated by means of long administration of the gluten-free diet were examined for the immunogenetic aspects and changes in the immune status. The authors demonstrate the incidence of recurrent intestinal disorders among 24 children with primary immunodeficiency states.


ARF suppresses tumor angiogenesis through translational control of VEGFA mRNA.
Vascular endothelial growth factor A (VEGFA) is a specific mitogen for vascular endothelial cells that plays a critical role in cancer neoangiogenesis. Here, we report that the nucleolar tumor suppressor p19(ARF) suppresses VEGFA expression, acting at the level of mRNA translation without affecting the transcription of the VEGFA gene. Translational repression of VEGFA mRNA by p19(ARF) does not require p53, a major target of the ARF tumor suppressor pathway, but instead correlates with binding to nucleophosmin/B23. Maintaining VEGFA expression relies on nucleophosmin/B23, and downregulating this protein by RNAi or p19(ARF) leads to translational repression of VEGFA. p19(ARF) inhibits VEGFA-dependent tumor angiogenesis in nude mice. Additionally, p14(ARF) expression and microvessel density are inversely correlated in human colon carcinomas. Taken together, our results define a mechanism by which the ARF tumor suppressor targets the translational repression of specific oncogenes during neoplastic transformation.


Long-term outcomes in refractory status epilepticus.
Refractory status epilepticus (RSE) is a diagnosis that can be made when tonic-clonic status epilepticus (SE) and focal SE cannot be stopped by at least two anti-seizure medications after 30 and 60 minutes, respectively, from the time of commencement. It could result in mortality, loss of functionality, neurological deficiency, and other serious short- and long-term effects. This narrative review covers original clinical studies of any design and case series investigating long-term outcomes of RSE recorded after at least a year from the SE onset. The future of a patient with RSE rests mostly on the long-term effects of this severe pathological condition, which may be accompanied with systemic complications like hyperthermia, hyperkalemia, acidosis, and/or stress cardiomyopathy. Younger patients with less severe RSE of shorter duration, particularly of the convulsive kind, are reported to have better long-term outcomes. Previous studies on the factors influencing the long-term outcomes of RSE, however, did not link the outcomes to treatment options for the condition. Such circumstances currently prevent making any definitive recommendations on the treatment of RSE until future research with adequate statistical power is completed.


Analysis of structural diversity in wolf-like canids reveals post-domestication variants.
Although a variety of genetic changes have been implicated in causing phenotypic differences among dogs, the role of copy number variants (CNVs) and their impact on phenotypic variation is still poorly understood. Further, very limited knowledge exists on structural variation in the gray wolf, the ancestor of the dog, or other closely related wild canids. Documenting CNVs variation in wild canids is essential to identify ancestral states and variation that may have appeared after domestication. In this work, we genotyped 1,611 dog CNVs in 23 wolf-like canids (4 purebred dogs, one dingo, 15 gray wolves, one red wolf, one coyote and one golden jackal) to identify CNVs that may have arisen after domestication. We have found an increase in GC-rich regions close to the breakpoints and around 1 kb away from them suggesting that some common motifs might be associated with the formation of CNVs. Among the CNV regions that showed the largest differentiation between dogs and wild canids we found 12 genes, nine of which are related to two known functions associated with dog domestication; growth (PDE4D, CRTC3 and NEB) and neurological function (PDE4D, EML5, ZNF500, SLC6A11, ELAVL2, RGS7 and CTSB). Our results provide insight into the evolution of structural variation in canines, where recombination is not regulated by PRDM9 due to the inactivation of this gene. We also identified genes within the most differentiated CNV regions between dogs and wolves, which could reflect selection during the domestication process.


Immunoglobulin light chain amyloidosis: 2020 update on diagnosis, prognosis, and treatment.
Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light or heavy chain are deposited in tissues. Clinical features depend on organs involved but can include heart failure with preserved ejection fraction, nephrotic syndrome, hepatic dysfunction, peripheral/autonomic neuropathy, and "atypical smoldering multiple myeloma or monoclonal gammopathy undetermined significance (MGUS)." Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for diagnosis. Invasive organ biopsy is not required in 85% of patients. Verification that amyloid is composed of immunoglobulin light chains is mandatory. The gold standard is laser capture mass spectroscopy. N-terminal pro-brain natriuretic peptide (NT-proBNP), serum troponin T, and difference between involved and uninvolved immunoglobulin free light chain (FLC) values are used to classify patients into four groups of similar size; median survivals are 94.1, 40.3, 14.0, and 5.8 months. All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure. Stem cell transplant (SCT) is preferred, but only 20% of patients are eligible. Requirements for safe SCT include systolic blood pressure >90 mmHg, troponin T < 0.06 ng/mL and serum creatinine ≤1.7 mg/dL. Nontransplant candidates can be offered cyclophosphamide-bortezomib-dexamethasone or daratumumab-containing regimens as it appears to be highly active in AL amyloidosis. Delayed diagnosis remains a major obstacle to initiating effective therapy prior to the development of end-stage organ failure.


Suspended carbon nanotube nanocomposite beams with a high mechanical strength via layer-by-layer nano-self-assembly.
The fabrication and characterization of single-walled carbon nanotube (SWCNT) composite thin film micropatterns and suspended beams prepared by lithography-compatible layer-by-layer (LbL) nano-self-assembly are demonstrated. Negatively charged SWCNTs are assembled with a positively charged polydiallyldimethylammonium chloride, and the composite thin film is patterned by oxygen plasma etching with a masking layer of photoresist, resulting in a feature size of 2 µm. Furthermore, the SWCNT nanocomposite stripe pattern with a metal clamp on both ends is released by etching a sacrificial layer of silicon dioxide in the hydrofluoric acid vapor. I-V measurement reveals that the resistance of SWCNT nanocomposite film decreases by 23% upon release, presumably due to the effect of reorientation of CNTs caused by the deflection of about 50 nm. A high Young's modulus is found in a range of 500-800 GPa based on the characterization of a fixed-fixed beam using nanoindentation. This value is much higher than those of the other CNT-polymer composites reported due to organization of structures by self-assembly and higher loading of CNTs. The stiff CNT-polymer composite thin film micropattern and suspended beam have potential applications to novel physical sensors, nanoelectromechanical switches, other M/NEMS devices, etc.


Magnetic hyperthermia enhance the treatment efficacy of peri-implant osteomyelitis.
When bacteria colony persist within a biofilm, suitable drugs are not yet available for the eradication of biofilm-producing bacteria. The aim of this study is to study the effect of magnetic nano-particles-induced hyperthermia on destroying biofilm and promoting bactericidal effects of antibiotics in the treatment of osteomyelitis. Sixty 12-weeks-old male Wistar rats were used. A metallic 18G needle was implanted into the bone marrow cavity of distal femur after the injection of Methicillin-sensitive Staphylococcus aureus (MSSA). All animals were divided into 5 different treatment modalities. The microbiological evaluation, scanning electron microscope examination, radiographic examination and then micro-CT evaluation of peri-implant bone resorption were analyzed. The pathomorphological characteristics of biofilm formation were completed after 40-days induction of osteomyelitis. The inserted implants can be heated upto 75 °C by magnetic heating without any significant thermal damage on the surrounding tissue. We also demonstrated that systemic administration of vancomycin [VC (i.m.)] could not eradicate the bacteria; but, local administration of vancomycin into the femoral canal and the presence of magnetic nanoparticles hyperthermia did enhance the eradication of bacteria in a biofilm-based colony. In these two groups, the percent bone volume (BV/TV: %) was significantly higher than that of the positive control. For the treatment of chronic osteomyelitis, we developed a new modality to improve antibiotic efficacy; the protection effect of biofilms on bacteria could be destroyed by magnetic nanoparticles-induced hyperthermia and therapeutic effect of systemic antibiotics could be enhanced.


Complex Living Conditions Impair Behavioral Inhibition but Improve Attention in Rats.
Rapid adaptation to changes, while maintaining a certain level of behavioral inhibition is an important feature in every day functioning. How environmental context and challenges in life can impact on the development of this quality is still unknown. In the present study, we examined the effect of a complex rearing environment during adolescence on attention and behavioral inhibition in adult male rats. We also tested whether these effects were affected by an adverse early life challenge, maternal deprivation (MD). We found that animals that were raised in large, two floor Marlau(TM) cages, together with 10 conspecifics, showed improved attention, but impaired behavioral inhibition in the 5-choice serial reaction time task. The early life challenge of 24 h MD on postnatal day 3 led to a decline in bodyweight during adolescence, but did not by itself influence responses in the 5-choice task in adulthood, nor did it moderate the effects of complex housing. Our data suggest that a complex rearing environment leads to a faster adaptation to changes in the environment, but at the cost of lower behavioral inhibition.


[Factors associated with change in diabetes knowledge from childhood to adolescence].
A multicentric cohort of 142 children with insulin-dependent diabetes has been longitudinally studied to evaluate if their diabetes knowledge was modified by time and to assess the factors associated to this change. A knowledge scale, previously translated and validated in French (TDK), was independently completed by the children and their parents at inclusion (T0) and 4 years later (T4). Mean age of the children was 10.2 years at T0. Mean knowledge score of the parents did not differ between T0 and T4 but mean score of the children was significantly higher at T4 than at T0 (22.2 +/- 5.7 vs 26.9 +/- 3.8, p<0.001). Age-adjusted knowledge score of children at T4 was significantly correlated to compliance to treatment (r=0.23, p<0.01). The factors associated with knowledge score of the children at T4 were: age at T4 (r=0.49, p<0.001), knowledge score of children at T0 (r=0.59, p<0.001), school results of the children (r=0.18, p=0.04), educational level of the mother (r=0.21, p=0.01), family income (r=0.19, p=0.03), knowledge score of parents at T0 (r=0.16, p=0.09), number of diabetes summer camp periods (r=0.19, p=0.03). Multivariate analysis showed that these 7 factors accounted for 59% of the variance in predicting knowledge score of the children at T4 (p<0.001). After adjustment, age at T4, knowledge score of the children at T0 and educational level of the mother stayed significantly associated with the knowledge score at T4. These results emphasise the importance of diabetes education programs specifically developed for children with the aim of improving diabetes knowledge at adolescence.


Metabolic and histopathological effects of sleeve gastrectomy and gastric plication: an experimental rodent model.
Obesity has recently become a major health problem, and researchers have been directed to work toward the development of surgical techniques, with new mediators playing an important role in nutrition. Gastric plication (GP) and sleeve gastrectomy (SG) have become popular recently. These are widely used techniques in bariatric surgery. In this study, we aimed to compare the efficiency of SG and GP techniques on rats. Wistar-Hannover rats (n=18) were divided into three equal groups, namely SG, GP, and control. Blood samples were taken before the operation and on the 30th day after the operation. The weights of all rats were recorded both on first day and the 30th day after the operation. Serum gastrin, ghrelin, and leptin levels were also measured on the same days. For histopathological examination, gastrectomy was performed after the animals were sacrificed. Average weight loss was 10% for the SG group and 6.5% for the GP group. One month after the operations, the decrease in the ghrelin and leptin levels of GP and SG groups was significant compared with the levels of the control group. Gastrin levels of the SG group increased significantly compared with those of the control group. Histopathological examination revealed that there was significant decrease in the ghrelin and leptin levels of the GP and SG groups compared with those of the control group. Foveolar hyperplasia (FH), cystic glandular dilatation, and fibrosis were significantly higher in the GP and SG groups compared with the control group. Although GP is not as effective as SG in terms of weight loss, it provides the same effectiveness in decreasing ghrelin and leptin levels. Histopathological findings revealed that FH, fibrosis, and the cystic glandular dilatation development rates were similar.


cAMP activates TRPC6 channels via the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB)-mitogen-activated protein kinase kinase (MEK)-ERK1/2 signaling pathway.
cAMP is an important second messenger that executes diverse physiological function in living cells. In this study, we investigated the effect of cAMP on canonical TRPC6 (transient receptor potential channel 6) channels in TRPC6-expressing HEK293 cells and glomerular mesangial cells. The results showed that 500 μm 8-Br-cAMP, a cell-permeable analog of cAMP, elicited [Ca(2+)](i) increases and stimulated a cation current at the whole-cell level in TRPC6-expressing HEK293 cells. The effect of cAMP diminished in the presence of the PI3K inhibitors wortmannin and LY294002 or the MEK inhibitors PD98059, U0126, and MEK inhibitor I. 8-Br-cAMP also induced phosphorylation of MEK and ERK1/2. Conversion of serine to glycine at an ERK1/2 phosphorylation site (S281G) abolished the cAMP activation of TRPC6 as determined by whole-cell and cell-attached single-channel patch recordings. Experiments based on a panel of pharmacological inhibitors or activators suggested that the cAMP action on TRPC6 was not mediated by PKA, PKG, or EPAC (exchange protein activated by cAMP). Total internal fluorescence reflection microscopy showed that 8-Br-cAMP did not alter the trafficking of TRPC6 to the plasma membrane. We also found that, in glomerular mesangial cells, glucagon-induced [Ca(2+)](i) increases were mediated through the cAMP-PI3K-PKB-MEK-ERK1/2-TRPC6 signaling pathway. In summary, this study uncovered a novel TRPC6 activation mechanism in which cAMP activates TRPC6 via the PI3K-PKB-MEK-ERK1/2 signaling pathway.


Chronic methamphetamine self-administration dysregulates 5-HT2A and mGlu2 receptor expression in the rat prefrontal and perirhinal cortex: Comparison to chronic phencyclidine and MK-801.
Chronic methamphetamine (meth) abuse often turns into a compulsive drug-taking disorder accompanied by persistent cognitive deficits and re-occurring psychosis. Possible common neurobiological substrates underlying meth-induced deficits and schizophrenia remain poorly understood. Serotonin 2A (5-HT2A) and metabotropic glutamate 2 (mGlu2) receptors co-regulate psychosis-like behaviors and cognitive function in animals. Therefore, in the present study we examined the effects of chronic exposure to three different drugs known to produce persistent deficits in sensorimotor gating and cognition [meth, phencyclidine (PCP) and MK-801] on the expression of 5-HT2A and mGlu2 within the rat medial prefrontal cortex (mPFC), dorsal hippocampus (dHPC) and perirhinal cortex (PRh). Adult male rats underwent 14 days of: (a) meth self-administration (6 h/day), (b) phencyclidine (PCP; 5 mg/kg, twice/day) administration, or (c) MK-801 (0.3 mg/kg, twice/day) administration. Seven days after the discontinuation of drug administration, tissues of interest were collected for protein expression analysis. We found that despite different pharmacological mechanism of action, chronic meth, PCP, and MK-801 similarly dysregulated 5-HT2A and mGlu2, as indicated by an increase in the 5-HT2A/mGlu2 expression ratio in the mPFC (all three tested drugs), PRh (meth and PCP), and dHPC (MK-801 only). Complementary changes in G-protein expression (increase in Gαq and decrease in Gαi) were also observed in the mPFC of meth animals. Finally, we found that 5-HT2A/mGlu2 cooperation can be mediated in part by the formation of the receptor heteromer in some, but not all cortical regions. In summary, these data suggest that a shift towards increased availability (and G-protein coupling) of cortical 5-HT2A vs. mGlu2 receptors may represent a common neurobiological mechanism underlying the emergence of psychosis and cognitive deficits observed in subjects with meth use disorder and schizophrenia.


Improving Lives in Three Dimensions: The Feasibility of 3D Printing for Creating Personalized Medical Aids in a Rural Area of Sierra Leone.
The aim of this feasibility study was to investigate how a 3D printer could be put to its best use in a resource-limited healthcare setting. We have examined whether a 3D printer can contribute to making prostheses, braces, or splints for patients who underwent major limb amputation because of complex wounds, for example, due to burns and subsequent scarring, accidents, conflicts, or congenital abnormalities. During a 3-month period, we investigated the benefits of customized, 3D-printed arm prostheses, splints, and braces in Sierra Leone. Using a handheld 3D scanner and a 3D printer, patient-specific medical aids were designed, manufactured, and tested. Questionnaires regarding patient satisfaction and the functionality of the prostheses were used for a short-term follow-up. Four esthetic prostheses were designed: two prostheses of the hand, one of the forearm, and one of the entire arm. Follow-ups were conducted after 3 to 4 weeks to investigate the quality of the prostheses and to complete a patient questionnaire. Even though the prostheses primarily fulfill esthetic needs, they also exhibit some degree of functionality. In addition, four splints for hands and arms were made to prevent scar contractures after skin transplantation. Finally, a brace for a young boy with kyphoscoliosis was manufactured. The boy has accepted the brace and will be followed up in the months to come. Long-term follow-up is required to prove the sustainability of the 3D-printed brace and prosthetic arms. Further research into how to sustain and refine this project is underway.


Preparation and characterization of activated carbons from tobacco stem by chemical activation.
Activated carbons were prepared from tobacco stem by chemical activation using potassium hydroxide (KOH), potassium carbonate (K2CO3), and zinc chloride (ZnCl2). The effects of the impregnation ratio (activating agent/precursor) and activating agents on the physical and chemical properties of activated carbons were investigated. The textual structure and surface properties of activated carbons were characterized by nitrogen (N2) adsorption isotherm, scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FT-IR), x-ray photoelectron spectroscopy (XPS), and thermogravimetry (TG). ZnCl2, acting as a superior activating agent compared to the others, produced much more porosity. The maximum specific surface area reached 1347 m2/g, obtained by ZnCl2 activation with an impregnation ratio of 4.0. Moreover, ZnCl2 activation yielded products with an excellent thermostability, attributed to different activation mechanisms. Various oxygen functions were detected on the activated carbon surface, and hydroxyl and ester groups were found to be in the majority. Tobacco stem, the residue from cigarette manufacturing, is usually discarded as waste, leading to serious resource waste and environmental problems. This study provides an effective utilization available for this solid residue by using it as the starting material in the preparation of activated carbon with chemical activation. Activated carbons with high specific area and various surface functions have been prepared, and the effects of the amount and type of activating agents on the physical and chemical properties of activated carbon were investigated as well.


Cascaded all-optical operations in a hybrid integrated 80-Gb/s logic circuit.
We demonstrate logic functionalities in a high-speed all-optical logic circuit based on differential Mach-Zehnder interferometers with semiconductor optical amplifiers as the nonlinear optical elements. The circuit, implemented by hybrid integration of the semiconductor optical amplifiers on a planar lightwave circuit platform fabricated in silica glass, can be flexibly configured to realize a variety of Boolean logic gates. We present both simulations and experimental demonstrations of cascaded all-optical operations for 80-Gb/s on-off keyed data.


Simultaneous loss of E-cadherin and catenins in invasive lobular breast cancer and lobular carcinoma in situ.
Loss of expression of the intercellular adhesion molecule E-cadherin frequently occurs in invasive lobular breast carcinomas as a result of mutational inactivation. Expression patterns of E-cadherin and the molecules comprising the cytoplasmic complex of adherens junctions, alpha-, beta- and gamma-catenin, were studied in a series of 38 lobular breast carcinomas with known E-cadherin mutation status. The effect of loss of E-cadherin by mutational inactivation (or other mechanisms) on the expression of catenins was investigated. Complete loss of plasma membrane-associated E-cadherin expression was observed in 32 out of 38 invasive lobular carcinomas, for which in 21 cases a mutation was found in the extracellular domain of E-cadherin. In total, 15 frameshift mutations of small deletions or insertions, ranging from 1 to 41 bp, three non-sense mutations, and three splice mutations were identified. Mutations were scattered over the whole coding region and no hot spots could be detected. In all cases, simultaneous loss of E-cadherin and alpha- and beta-catenin expression was found; in 50 per cent of these cases, additional loss of gamma-catenin was observed. In six invasive lobular carcinomas, expression of both E-cadherin and catenins was retained. In none of these carcinomas was an E-cadherin mutation detected. Lobular carcinoma in situ adjacent to invasive lobular carcinoma showed simultaneous loss of E-cadherin and catenins in all the cases studied--remarkably, also, in four cases positive for E-cadherin and catenin expression in the invasive component. These results indicate that simultaneous loss of E-cadherin and alpha-, beta- and gamma-catenin may be an important step in the formation of lobular carcinoma in situ, as a precursor of invasive lobular breast cancer. Events additional to E-cadherin inactivation must be involved in the transition of lobular carcinoma in situ to invasive lobular carcinoma.


CNTF, not other trophic factors, promotes axonal regeneration of axotomized retinal ganglion cells in adult hamsters.
To investigate the in vivo effects of trophic factors on the axonal regeneration of axotomized retinal ganglion cells in adult hamsters. The left optic nerve was transected intracranially or intraorbitally, and a peripheral nerve graft was apposed or sutured to the axotomized optic nerve to enhance regeneration. Trophic factors were applied intravitreally every 5 days. Animals were allowed to survive for 3 or 4 weeks. Regenerating retinal ganglion cells (RGCs) were labeled by applying the dye Fluoro-Gold to the distal end of the peripheral nerve graft 3 days before the animals were killed. Intravitreal application of ciliary neurotrophic factor substantially enhanced the regeneration of damaged axons into a sciatic nerve graft in both experimental conditions (intracranial and intraorbital optic nerve transections) but did not increase the survival of distally axotomized RGCs. Basic fibroblast growth factor and neurotrophins such as nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 failed to enhance axonal regeneration of distally axotomized RGCs. Neurons of the adult central nervous system can regenerate in response to trophic supply after injury, and ciliary neurotrophic factor is at least one of the trophic factors that can promote axonal regeneration of axotomized RGCs.


Reproductive mortality in two developing countries.
Reproductive mortality includes mortality attributable to pregnancy, termination of pregnancy, childbirth and its sequelae, and contraception. Reproductive mortality has been estimated for the United Kingdom, the United States, and for states of the US. However, it has not previously been measured for developing countries, where maternal mortality often remains distressingly high. This paper reports on data from one governorate of Egypt, where reproductive mortality was 46 per 100,000 married women ages 15-49 (2.2 per cent of this was attributable to contraception), and one province of Indonesia, where reproductive mortality was 70 per 100,000 (of which 1.4 per cent was due to contraception). In both locations, complications of pregnancy and childbirth were a leading cause of death in the age group studied (the first cause in Indonesia, second in Egypt). Contraceptive prevalence was 24 per cent of married women ages 15-49 in Egypt and 48 per cent of this age group in Indonesia.


Thermodynamic compatibility of proteins in aqueous media. Part. I. Phase diagrams of some water--protein A--protein B systems.
The thermodynamic compatibility of proteins belonging to different classes according to Osborne has been investigated in aqueous media. Phase equilibrium for water--ovalbumin--soybean globulin fraction, water--ovalbumin--casein, water--casein--gliadin and water--casein--soybean globulin fraction systems has been investigated. The data obtained were analysed according to the theoretical concepts of Scott, Patterson and Prausnitz concerning the effect of polymer molar masses and the solvent quality on the phase equilibrium in similar systems. The analysis performed indicates that these concepts can be applied to the water--protein A--protein B systems. The phase equilibrium in water--protein A--protein B systems has some distinctive features as compared to that in systems containing two synthetic polymers in the single solvent. Firstly, proteins are usually compatible in a broader concentration range as compared to common polymers. Moreover, the separation of water--protein A--protein B systems into two phases often results in a considerable concentration of one of the protein components. Apparently, the latter fact can be associated with the marked difference in the interaction parameter of proteins belonging to different classes with the solvent, and, hence, with the marked difference in the hydrophilicity of the proteins investigated.


Improving standard of care through introduction of laparoscopy for the surgical management of gynecological malignancies.
This study aimed to evaluate the impact on perioperative and medium-term oncologic outcomes of the implementation of laparoscopy into a preexisting oncologic setting. Data from consecutive 736 patients undergoing surgery for apparent early stage gynecological malignancies (endometrial, cervical, and adnexal cancers) between 2000 and 2011 were reviewed. Complications were graded per the Accordion classification. Survival outcomes within the first 5 years were analyzed using Kaplan-Meier method. Overall, 493 (67%), 162 (22%), and 81 (11%) had surgery for apparent early stage endometrial, cervical, and adnexal cancer. We assisted at an increase of the number of patients undergoing surgery via laparoscopy through the years (from 10% in the years 2000-2003 to 82% in years 2008-2011; P < 0.001 for trend); while the need to perform open surgery decreased dramatically (from 83% to 10%; P < 0.001). Vaginal approach was nearly stable over the years (from 7% to 8%; P = 0.76). A marked reduction in estimated blood loss, length of hospital stay, blood transfusions as well as grade greater than or equal to 3 postoperative complications over the years was observed (P < 0.001). Surgical radicality assessed lymph nodes count was not influenced by the introduction of laparoscopic approach (P > 0.05). The introduction of laparoscopy did not adversely affect medium-term (within 5 years) survival outcomes of patients undergoing surgery for apparent early stage cancers of the endometrium, uterine cervix, and adnexa (P > 0.05 log-rank test). The introduction of laparoscopy into a preexisting oncologic service allows an improvement of standard of care due to a gain in perioperative results, without detriments of medium-term oncologic outcomes.


Hole transfer kinetics of DNA.
Not long after the discovery of the double-helical structure of DNA in 1952, researchers proposed that charge transfer along a one-dimensional π-array of nucleobases might be possible. At the end of the 1990s researchers discovered that a positive charge (a hole) generated in DNA migrates more than 200 Å along the structure, a discovery that ignited interest in the charge-transfer process in DNA. As a result, DNA became an interesting potential bottom-up material for constructing nanoelectronic sensors and devices because DNA can form various complex two-dimensional and three-dimensional structures, such as smiley faces and cubes. From the fundamental aspects of the hole transfer process, DNA is one of the most well-studied organic molecules with many reports on the synthesis of artificial nucleobase analogues. Thus, DNA offers a unique system to study how factors such as the HOMO energy and molecular flexibility affect hole transfer kinetics. Understanding the hole transfer mechanism requires a discussion of the hole transfer rate constants (kHT). This Account reviews the kHT values determined by our group and by Lewis and Wasielewski's group, obtained by a combination of the synthesis of modified DNA and time-resolved spectroscopy. DNA consists of G/C and A/T base pairs; the HOMO localizes on the purine bases G and A, and G has a lower oxidation potential and a higher energy HOMO. Typically, long-range hole transfer proceeded via sequential hole transfer between G/C's. The kinetics of this process in DNA sequences, including those with mismatches, is reproducible via kinetic modeling using the determined kHT for each hole transfer step between G/C's. We also determined the distance dependence parameter (β), which describes the steepness of the exponential decrease of kHT. Because of this value, >0.6 Å(-1) for hole transfer in DNA, DNA itself does not serve as a molecular wire. Interestingly, hole transfer proceeded exceptionally fast for some sequences in which G/C's are located close to each other, an observation that we cannot explain by a simple sequential hole transfer between G/C's but rather through hole delocalization over the nucleobases. To further investigate and refine the factors that affect kHT, we examined various artificial nucleobases. We clearly demonstrated that kHT depends strongly on the HOMO energy gap between the bases (ΔHOMO), and that kHT can be increased with decreasing ΔHOMO. We reduced ΔHOMO between the two type of base pairs by replacing adenines (A's) with deazaadenines ((z)A's) or diaminopurines (D's) and showed that the hole transfer rate through the G/C and A/T mix sequence increased by more than 3 orders of magnitude. We also investigated how DNA flexibility affects kHT. Locked nucleic acid (LNA) modification, which makes DNA more rigid, lowered kHT by more than 2 orders of magnitude. On the other hand, 5-Me-2'-deoxyzebularine (B) modification, which increases DNA flexibility, increased kHT by more than 1 order of magnitude. These new insights in hole transfer kinetics obtained from modified DNAs may aid in the design of new molecular-scale conducting materials.


The balance between Cu,Zn-superoxide dismutase and catalase affects the sensitivity of mouse epidermal cells to oxidative stress.
Oxidants are toxic, but at low doses they can stimulate rather than inhibit the growth of mammalian cells and play a role in the etiology of cancer and fibrosis. The effect of oxidants on cells is modulated by multiple interacting antioxidant defense systems. We have studied the individual roles and the interaction of Cu,Zn-superoxide dismutase (SOD) and catalase (CAT) in transfectants with human cDNAs of mouse epidermal cells JB6 clone 41. Since only moderate increases in these enzymes are physiologically meaningful, we chose the following five clones for in-depth characterization: CAT 4 and CAT 12 with 2.6-fold and 4.2-fold increased catalase activities, respectively, SOD 15 and SOD 3 with 2.3-fold and 3.6-fold increased Cu,Zn-SOD activities, respectively, and SOCAT 3 with a 3-fold higher catalase activity and 1.7-fold higher Cu,Zn-SOD activity than the parent JB6 clone 41. While the increases in enzyme activities were moderate, the human cDNAs were highly expressed in the transfectants. As demonstrated for the clone SOD 15, this discordance between message concentrations and enzyme activities may be due to the low stability of the human Cu,Zn-SOD mRNA in the mouse recipient cells. According to immunoblots the content of Mn-SOD was unaltered in the transfectants. While the activities of glutathione peroxidase were comparable in all strains, the concentrations of reduced glutathione (GSH) were significantly lower in SOD 3 and SOD 15. This decrease in GSH may reflect a chronic prooxidant state in these Cu,Zn-SOD overproducers.(ABSTRACT TRUNCATED AT 250 WORDS)


School-based Psychosocial Interventions' Effectiveness in Strengthening Refugee and Migrant Adolescents' Mental Health, Resilience, and Social Relations: A Four-country Cluster Randomized Study.
School-based psychosocial interventions are increasingly put forward as a way to support young refugees' and migrants' well-being and mental health in resettlement. However, the evidence on these interventions' effectiveness remains scarce and scholars denounce particular gaps in the evidence to date, pointing to a lack of large-scale, controlled studies and studies including social outcome measures. This cluster randomized study aims to strengthen the evidence base on school-based psychosocial interventions for refugee and migrant youth by assessing the effect of two interventions, Classroom Drama and Welcome to School, on youth's mental health, resilience, and social relations in Belgium, Denmark, Norway, and the United Kingdom. Multilevel analyses were conducted separately for the two interventions (Classroom Drama, n = 307, ages 11-19; Welcome to School, n = 251, ages 11-23), using separate no-treatment control groups. Our analyses indicated a significant main, positive effect of Classroom Drama on perceived family support, and an effect on perceived support from friends that was moderated by country: in the United Kingdom, the intervention group reported an increase in perceived friend support, whereas the control group reported a decrease. Furthermore, baseline resilience moderated the effect of the Classroom Drama intervention on behavioral difficulties and well-being. No effects of Welcome to School on any of the outcome variables were found. Overall, this study provides novel, nuanced evidence on school-based psychosocial interventions for refugee and migrant adolescents.


Accurate determination of energy needs in hospitalized patients.
To evaluate the accuracy of seven predictive equations, including the Harris-Benedict and the Mifflin equations, against measured resting energy expenditure (REE) in hospitalized patients, including patients with obesity and critical illness. A retrospective evaluation using the nutrition support service database of a patient cohort from a similar timeframe as those used to develop the Mifflin equations. All patients with an ordered nutrition assessment who underwent indirect calorimetry at our institution over a 1-year period were included. Available data was applied to REE predictive equations, and results were compared to REE measurements. Accuracy was defined as predictions within 90% to 110% of the measured REE. Differences >10% or 250 kcal from REE were considered clinically unacceptable. Regression analysis was performed to identify variables that may predict accuracy. Limits-of-agreement analysis was carried out to describe the level of bias for each equation. A total of 395 patients, mostly white (61%) and African American (36%), were included in this analysis. Mean age+/-standard deviation was 56+/-18 years (range 16 to 92 years) in this group, and mean body mass index was 24+/-5.6 (range 13 to 53). Measured REE was 1,617+/-355 kcal/day for the entire group, 1,790+/-397 kcal/day in the obese group (n=51), and 1,730+/-402 kcal/day in the critically ill group (n=141). The most accurate prediction was the Harris-Benedict equation when a factor of 1.1 was multiplied to the equation (Harris-Benedict 1.1), but only in 61% of all the patients, with significant under- and over-predictions. In the patients with obesity, the Harris-Benedict equation using actual weight was most accurate, but only in 62% of patients; and in the critically ill patients the Harris-Benedict 1.1 was most accurate, but only in 55% of patients. The bias was also lowest with Harris-Benedict 1.1 (mean error -9 kcal/day, range +403 to -421 kcal/day); but errors across all equations were clinically unacceptable. No equation accurately predicted REE in most hospitalized patients. Without a reliable predictive equation, only indirect calorimetry will provide accurate assessment of energy needs. Although indirect calorimetry is considered the standard for assessing REE in hospitalized patients, several predictive equations are commonly used in practice. Their accuracy in hospitalized patients has been questioned. This study evaluated several of these equations, and found that even the most accurate equation (the Harris-Benedict 1.1) was inaccurate in 39% of patients and had an unacceptably high error. Without knowing which patient's REE is being accurately predicted, indirect calorimetry may still be necessary in difficult to manage hospitalized patients.


Awareness of the Benefits and Risks Related to Using Fluoridated Toothpaste Among Doctors: A Population-Based Study.
BACKGROUND This study aimed to assess the awareness of dentists and non-dental doctors regarding the benefits and risks of using fluoridated toothpaste. MATERIAL AND METHODS A self-administered questionnaire was used to collect information in this study. Multistage cluster sampling method was used to enroll doctors in 5 districts or counties in Chongqing, China. A total of 403 doctors (160 dentists and 243 non-dental doctors) completed the questionnaire. RESULTS The awareness of the anti-caries efficacy and the usage of fluoridated toothpaste in dentists was significantly higher than those of non-dental doctors (P<0.001). Most (about 60%) dentists and non-dental doctors had concerns about fluoridated toothpaste. Only 31.3% of dentists and 25.9% of non-dental doctors had a good understanding of the benefits and risks of use of fluoridated toothpaste in children under 3 years of age to 49.4% of dentists and 73.3% of non-dental doctors did not understand the benefits and risks in children 3~6 years old, and 40.0% of dentists and 67.5% of non-dental doctors did not understand the risks and benefits in individuals living in high-fluoride areas. Most dentists (76.3%) and non-dental doctors (87.3%) did not understand the benefits and risks in pregnant women. CONCLUSIONS Dentists and non-dental doctors were concerned about the potential risks of use of fluoridated toothpaste, and they lacked adequate knowledge about the benefits and risks of use of fluoridated toothpaste. Health education is needed to improve doctors' knowledge about use of fluoridated toothpaste.


Diabetic serum from older women increases adipogenic differentiation in mesenchymal stem cells.
Paradoxically, elderly persons with type 2 diabetes mellitus (T2DM) fracture despite having higher bone density than nondiabetics. Systemic factors associated with aging and T2DM may have detrimental, local effects on the skeleton. One such factor could be by altering the microenvironment of the mesenchymal stem cells (MSCs), multipotent progenitors capable of differentiating into adipocytes or osteoblasts. Sera were obtained from four participant groups (n = 40 total, 10 per group): (1) young women with normal glucose tolerance (NGTY), (2) postmenopausal women with NGT), (3) postmenopausal women with impaired glucose tolerance (IGT), and (4) postmenopausal women with T2DM. Sera were incubated with human MSCs for 14 days. Cell proliferation and apoptosis were measured using EdU and TUNEL labeling assays, respectively. MSC differentiation for each group was determined using osteogenic and adipogenic gene expression markers quantified by qRT-PCR, as well as Alizarin Red and Oil Red O staining. Expression of adipogenic genes was greater than twofold higher (P < 0.05) in MSCs cultured with T2DM sera compared to those incubated with NGTY, NGT, or IGT sera. The increase in adipogenic gene expression corresponded with increased Oil Red O staining. Despite the increased adipogenic differentiation of MSCs exposed to T2DM sera, cell proliferation and apoptosis rates as well as osteoblastic activity were not significantly different among the four conditions. Systemic, circulating factors in the serum of older women with T2DM may promote MSC differentiation into adipocytes versus osteoblasts. Increased differentiation of MSCs into adipocytes is one possible mechanism by which T2DM increases fracture risk.


Serological Surveillance of COVID-19 Hospitalized Patients in Réunion Island (France) Revealed that Specific Immunoglobulin G Are Rapidly Vanishing in Severe Cases.
Humoral immunity is critically important to control COVID-19. Long-term antibody responses remain to be fully characterized in hospitalized patients who have a high risk of death. We compared specific Immunoglobulin responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between two groups, intensive care unit (ICU) and non-ICU hospitalized patients over several weeks. Plasma specific IgG, IgM, and IgA levels were assessed using a commercial ELISA and compared to an in-house cell-based ELISA. Among the patients analyzed (mean (SD) of age, 64.4 (15.9) years, 19.2% female), 12 (46.2%) were hospitalized in ICU. IgG levels increased in non-ICU cases from the second to the eighth week after symptom onset. By contrast, IgG response was blunted in ICU patients over the same period. ICU patients with hematological malignancies had very weak or even undetectable IgG levels. While both groups had comparable levels of specific IgM antibodies, we found much lower levels of specific IgA in ICU versus non-ICU patients. In conclusion, COVID-19 ICU patients may be at risk of reinfection as their specific IgG response is declining in a matter of weeks. Antibody neutralizing assays and studies on specific cellular immunity will have to be performed.


Evaluating motor function in children with Down syndrome: validity of the GMFM.
The Gross Motor Function Measure (GMFM) was developed and validated originally by Russell and colleagues as an evaluative assessment of gross motor function in children with cerebral palsy (CP). The present study reports the results of reliability and validity testing of the GMFM for use with children with Down syndrome (DS). One hundred and twenty-three children with DS were assessed twice over a 6-month period, using the GMFM and the motor scale of the Bayley Scales of Infant Development - second edition (BSID-II). In addition to the usual method of scoring the GMFM using only observed motor behaviours (standard score), parent reports of children's activities not seen by the assessor on the day of testing were also obtained and a second score (reported score) was calculated for each GMFM assessment. Test-retest and interrater reliabilities were excellent (all >0.90). Observed correlations between change on GMFM and judgements of change made independently by parents, intervenors, and masked video raters were lower than hypothesized. However, the pattern of change scores in predefined age and severity subgroups supported the contention that the GMFM was able to detect differential amounts of change as predicted. The GMFM was shown to be relatively more responsive to change in gross motor function than the motor scale of the BSID-II. The 'reported' scores on the GMFM demonstrated better evidence of reliability, validity, and responsiveness than the standard scoring method and this approach is recommended for use when assessing children with DS.


Development of a self-rating scale of self-directed learning.
In order to realise their full potential as learners, it is essential that students have good self-directed learning skills. It is also important that students develop their own roles in learning by continuously monitoring their own learning progress, identifying areas of deficit and making a conscious effort towards self-improvement. In this paper, Swapna Naskar Williamson reports on the development and testing of a self-rating scale of self-directed learning in higher education, and considers how it might be used in practice in order to enhance the requisite skills for becoming independent and lifelong learners.


Expanding the repertoire of intermuscular coordination patterns and modulating intermuscular connectivity in stroke-affected upper extremity through electromyogram-guided training: a pilot study.
Abnormal intermuscular coordination is a major stroke-induced functional motor impairment in the upper extremity (UE). Previous studies have computationally identified the abnormalities in the intermuscular coordination in the stroke-affected UE and their negative impacts on motor outputs. Therefore, targeting the aberrant muscle synergies has the potential as an effective approach for stroke rehabilitation. Recently, we verified the modifiability of the naturally expressed muscle synergies of young able-bodied adults in UE through an electromyographic (EMG) signal-guided exercise protocol. This study tested if an EMG-guided exercise will induce new muscle synergies, alter the associated intermuscular connectivity, and improve UE motor outcome in stroke-affected UE with moderate-to-severe motor impairment. The study used the six-week isometric EMG signal-guided exercise protocol that focused on independently activating two specific muscles, the biceps and brachioradialis, to develop new muscle activation groups. The study found that both the stroke and age-matched, able-bodied groups were able to develop new muscle coordination patterns through the exercise while habitual muscle activation was still available, which led to improvements in the motor control of the trained arm. In addition, the results provided preliminary evidence of increased intermuscular connectivity between targeted muscles in the beta-band frequencies for stroke patients after training, suggesting a modulation of the common neural drive. These findings suggest that our isometric exercise protocol has the potential to improve stroke survivors' performance of UE in their activities in daily lives (ADLs) and, ultimately, their quality of life through expanding their repertoire of intermuscular coordination.Clinical Relevance- This study shows the feasibility of expanding the intermuscular coordination pattern in stroke-affected UE through an isometric EMG-guided exercise which positively affects task performance and intermuscular connectivity.


Mobile Technologies and Cervical Cancer Screening in Low- and Middle-Income Countries: A Systematic Review.
Cervical cancer screening is not well implemented in many low- and middle-income countries (LMICs). Mobile health (mHealth) refers to utilization of mobile technologies in health promotion and disease management. We aimed to qualitatively synthesize published articles reporting the impact of mHealth on cervical cancer screening-related health behaviors. Three reviewers independently reviewed articles with the following criteria: the exposure or intervention of interest was mHealth, including messages or educational information sent via mobile telephone or e-mail; the comparison was people not using mHealth technology to receive screening-related information, and studies comparing multiple different mHealth interventional strategies were also eligible; the primary outcome was cervical cancer screening uptake, and secondary outcomes included awareness, intention, and knowledge of screening; appropriate research designs included randomized controlled trials and quasi-experimental or observational research; and the study was conducted in an LMIC. Of the 8 selected studies, 5 treated mobile telephone or message reminders as the exposure or intervention, and 3 compared the effects of different messages on screening uptake. The outcomes were diverse, including screening uptake (n = 4); health beliefs regarding the Papanicolaou (Pap) test (n = 1); knowledge of, attitude toward, and adherence to colpocytologic examination (n = 1); interest in receiving messages about Pap test results or appointment (n = 1); and return for Pap test reports (n = 1). Overall, our systematic review suggests that mobile technologies, particularly telephone reminders or messages, lead to increased Pap test uptake; additional work is needed to unequivocally verify whether mhealth interventions can improve knowledge regarding cervical cancer. Our study will inform mHealth-based interventions for cervical cancer screening promotion in LMICs.


Spatiotemporal Excitation Module-based CNN for Diagnosis of Hepatic Malignancy in Four-phase CT Images.
Liver cancer is a part of the common causes of cancer death worldwide, and the accurate diagnosis of hepatic malignancy is important for effective next treatment. In this paper, we propose a convolutional neural network (CNN) based on a spatiotemporal excitation (STE) module for identification of hepatic malignancy in four-phase computed tomography (CT) images. To enhance the display detail of lesion, we expand single-channel CT images into three channels by using the channel expansion method. Our proposed STE module consists of a spatial excitation (SE) module and a temporal interaction (TI) module. The SE module calculates the temporal differences of CT slices at the feature level, which is used to excite shape-sensitive channels of the lesion features. The TI module shifts a portion of the channels in the temporal dimension to exchange information among the current CT slice and adjacent CT slices. Four-phase CT images of 398 patients diagnosed with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are used for experiments and five cross-validations are performed. Our model achieved average accuracy of 85.00% and average AUC of 88.91% for classifying HCC and ICC.Clinical Relevance- The proposed deep learning-based model can perform HCC and ICC recognition tasks based on four-phase CT images, assisting doctors to obtain better diagnostic performance.


[Recommendations for cancer prevention of World Cancer Research Fund (WCRF): situational analysis for Chile].
The main diet-related cancers include colorectal, lung, breast in (postmenopausal) women, stomach, esophagus, prostate and pancreas. After tobacco, obesity is the leading cause of cancer; it accounts for one third of all cancers. Cancer is associated with high total body fat, abdominal fat and weight gain in adult life. These are all potentially modifiable risk factors. Consumption of a "healthy diet" and living an "active life" can significantly reduce the risk of cancer. The aim of this study was to analyze the recommendations published by the World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR) for the prevention of cancer in 2007. We compared the recommendations of Food, Nutrition and Physical Activity and the Prevention of Cancer: a global perspective", with the national situation in Chile, analyzing the national report on the prevalence of risk factors. Our main finding was that the pattern of consumption and lifestyles differ markedly from the WCRF recommendations: we observed an over consumption of sugary drinks and high intake of processed foods high in sodium and total fat and low consumption of legumes, vegetables, fruits high in antioxidants and fiber that protect from cancer. Chile has an increased cancer prevalence which is associated with poor quality diets, rising mean body mass index and a sedentary behavior. We recommend the strengthening programs to promote healthy diets and active living, in order to reduce cancer risk.


Identification of human liver cytochrome P450 enzymes involved in biotransformation of vicriviroc, a CCR5 receptor antagonist.
Vicriviroc (SCH 417690), a CCR5 receptor antagonist, is currently under investigation for the treatment of human immunodeficiency virus infection. The objective of this study was to identify human liver cytochrome P450 enzyme(s) responsible for the metabolism of vicriviroc. Human liver microsomes metabolized vicriviroc via N-oxidation (M2/M3), O-demethylation (M15), N,N-dealkylation (M16), N-dealkylation (M41), and oxidation to a carboxylic acid metabolite (M35b/M37a). Recombinant human CYP3A4 catalyzed the formation of all these metabolites, whereas CYP3A5 catalyzed the formation of M2/M3 and M41. CYP2C9 only catalyzed the formation of M15. There was a high correlation between the rates of formation of M2/M3, M15, and M41, which was determined using 10 human liver microsomal samples and testosterone 6beta-hydroxylation catalyzed by CYP3A4/5 (r > or = 0.91). Ketoconazole and azamulin (inhibitors of CYP3A4) were potent inhibitors of the formation of M2/M3, M15, M41, and M35b/M37a from human liver microsomes. A CYP3A4/5-specific monoclonal antibody (1 microg/microg of protein) inhibited the formation of all metabolites from human liver microsomes by 86 to 100%. The results of this study suggest that formation of the major vicriviroc metabolites in human liver microsomes is primarily mediated via CYP3A4. CYP2C9 and CYP3A5 most likely play a minor role in the biotransformation of this compound. These enzymology data will provide guidance to design clinical studies to address any potential drug-drug interactions.


Microfluidic sorting and multimodal typing of cancer cells in self-assembled magnetic arrays.
We propose a unique method for cell sorting, "Ephesia," using columns of biofunctionalized superparamagnetic beads self-assembled in a microfluidic channel onto an array of magnetic traps prepared by microcontact printing. It combines the advantages of microfluidic cell sorting, notably the application of a well controlled, flow-activated interaction between cells and beads, and those of immunomagnetic sorting, notably the use of batch-prepared, well characterized antibody-bearing beads. On cell lines mixtures, we demonstrated a capture yield better than 94%, and the possibility to cultivate in situ the captured cells. A second series of experiments involved clinical samples--blood, pleural effusion, and fine needle aspirates--issued from healthy donors and patients with B-cell hematological malignant tumors (leukemia and lymphoma). The immunophenotype and morphology of B-lymphocytes were analyzed directly in the microfluidic chamber, and compared with conventional flow cytometry and visual cytology data, in a blind test. Immunophenotyping results using Ephesia were fully consistent with those obtained by flow cytometry. We obtained in situ high resolution confocal three-dimensional images of the cell nuclei, showing intranuclear details consistent with conventional cytological staining. Ephesia thus provides a powerful approach to cell capture and typing allowing fully automated high resolution and quantitative immunophenotyping and morphological analysis. It requires at least 10 times smaller sample volume and cell numbers than cytometry, potentially increasing the range of indications and the success rate of microbiopsy-based diagnosis, and reducing analysis time and cost.


Long-term evaluation of intrapleural bacillus Calmette-Guerin with or without adjuvant chemotherapy in completely resected stages II and III non-small-cell lung cancer.
Between January 1979 and December 1980, 52 patients with completely resected stages II and III non-small-cell lung cancer (NSCLC) were randomly assigned to receive either adjuvant chemotherapy (cyclophosphamide, doxorubicin, and vincristine--CAV) plus intrapleural bacillus Calmette-Guerin (BCG) (n = 26) or adjuvant CAV alone (n = 26). Careful intraoperative staging was performed in all patients, and stratification for histology (squamous versus nonsquamous) and stage (II or III) ensured a balanced randomization for these factors. With a median follow-up time of 111 months, overall 10-year and median survival were 21% and 20 months (range 2-127 + months), respectively. Thirty-four (95%) patients relapsed in extrathoracic sites, and five (5%) developed loco-regional recurrence; their overall median disease-free interval (DFI) was 10 months (range 1-73 months). There was a 9% and 2.5 month difference in survival (p = .76) and disease-free interval (p = .67), respectively, favoring the BCG arm. There were no significant differences in the sites and patterns of first recurrence comparing the two treatment arms. In conclusion, there is no suggestion of a significant therapeutic advantage from intrapleural BCG in conjunction with adjuvant chemotherapy for completely resected stages II and III NSCLC.


Inhibition of surface induced coagulation by preadsorption of albumin-heparin conjugates.
Surface coatings of the albumin-heparin conjugates were developed to improve the blood compatibility of polymeric materials. Glass, PVC, Biomer and cellulose acetate were coated with albumin-heparin conjugate and its adsorption and desorption behavior on glass in particular was studied using 3H and 51Cr radiolabeled conjugates. Precoated materials showed a significant prolongation of the Lee-White clotting time as compared with noncoated ones. It was demonstrated that the prolonged clotting time for pretreated glass was due to surface bound conjugate. Prolonged recalcification times of plasma exposed to glass, Biomer, and PVC were obtained using albumin-heparin conjugate precoated surfaces. Albumin-heparin conjugates with high affinity for antithrombin III gave more prolonged clotting times as low affinity conjugates when used as coatings for glass. This indicates that the behaviour of heparin in preadsorbed conjugates resembles that of heparin in solution.


Prevalence and pattern of occupational exposure to whole body vibration in Great Britain: findings from a national survey.
To estimate the number of workers in Great Britain with significant occupational exposure to whole body vibration (WBV) and to identify the common sources of exposure and the occupations and industries where such exposures arise. A postal questionnaire was posted to a random community sample of 22,194 men and women of working age. Among other things, the questionnaire asked about exposure to WBV in the past week, including occupational and common non-occupational sources. Responses were assessed by occupation and industry, and national prevalence estimates were derived from census information. Estimates were also made of the average estimated daily personal dose of vibration (eVDV). From the 12,907 responses it was estimated that 7.2 million men and 1.8 million women in Great Britain are exposed to WBV at work in a 1 week period if the occupational use of cars, vans, buses, trains, and motor cycles is included within the definition of exposure. The eVDV of >374,000 men and 9000 women was estimated to exceed a proposed British Standard action level of 15 ms(-1.75). Occupations in which the estimated exposures most often exceeded 15 ms(-1.75) included forklift truck and mechanical truck drivers, farm owners and managers, farm workers, and drivers of road goods vehicles. These occupations also contributed the largest estimated numbers of workers in Great Britain with such levels of exposure. The highest estimated median occupational eVDVs were found in forklift truck drivers, drivers of road goods vehicles, bus and coach drivers, and technical and wholesale sales representatives, among whom a greater contribution to total dose was received from occupational exposures than from non-occupational ones; but in many other occupations the reverse applied. The most common sources of occupational exposure to WBV are cars, vans, forklift trucks, lorries, tractors, buses, and loaders. Exposure to whole body vibration is common, but only a small proportion of exposures exceed the action level proposed in British standards, and in many occupations, non-occupational sources are more important than those at work. The commonest occupational sources of WBV and occupations with particularly high exposures have been identified, providing a basis for targeting future control activities.


Low-dose chronic prenatal alcohol exposure abolishes the pro-cognitive effects of angiotensin IV.
Prenatal ethanol exposure (PAE) in humans results in a spectrum of disorders including deficits in learning and memory. Animal models to date have typically used high ethanol doses but have not identified the biochemical changes underlying the cognitive deficit. This study used treatment of mouse breeding harems with 5% ethanol via drinking water throughout pregnancy and lactation and explored the behavioural consequences in the progeny at 3-6 months of age using the open field test, novel object recognition test and elevated plus maze to measure anxiety and memory consolidation. The effects of angiotensin IV on behaviour of the progeny were also determined. The results indicated that PAE increased anxiety-like behaviour as determined in the open field test in male but not female progeny. In control animals, angiotensin IV enhanced memory consolidation in males, but this effect was abolished by PAE. The abolition of the pro-cognitive effect of angiotensin IV was not a consequence of increased anxiety, and there was some evidence of a long-lasting anxiolytic effect of angiotensin IV in the male PAE progeny. These results suggest that PAE may act via alteration of the actions of the brain renin-angiotensin system to impair memory consolidation, but these effects may be partially sex-dependent.


The QseE-QseF two-component system: A key mediator of epinephrine-regulated virulence in the marine pathogen Edwardsiella piscicida.
Edwardsiella piscicida is a widespread pathogen that infects various fish species and causes massive hemorrhagic septicemia, resulting in significant property damage to the global aquaculture industry. Type III and VI secretion systems (T3/T6SS), controlled by the master regulator EsrB, are important virulence factors of E. piscicida that enable bacterial colonization and evasion from host immune clearance. In this study, we demonstrate that the QseE-QseF two-component system negatively regulated esrB expression by reanalysis of Tn-seq data. Moreover, the response regulator QseF directly bound to esrB promoter and inhibited the expression of T3/T6SS genes, especially in the presence of epinephrine. Furthermore, in response to the prompt increasing of epinephrine level, the host immune genes were delayed repressed and QseE-QseF timely inhibited the expression of T3/T6SS genes to evade immune clearance. In summary, this study enhances our understanding and knowledge of the conditional pathogenesis mechanism and virulence regulation network of E. piscicida.


Paradoxical resistance to adrenolytic agents of field-stimulated bladder base of rabbit.
Isolated circulatory or longitudinally oriented strips from anterior or posterior rabbit bladder base were tested for responsiveness to agonists and sensitivity of field stimulation-induced responses to antagonists. Results were compared to the regional distribution of adrenergic and cholinergic nerves determined histochemically. Greater norepinephrine-induced responses in posterior than in anterior strips reflect denser noradrenergic innervation in posterior base. Longitudinal strips responded better to carbachol than circular strips, but no orientation-related differences in cholinergic nerve density or muscle mass were noted. Field stimulation-induced contractions were largely resistant to phenoxybenzamine (0.03 microM) and guanethidine (100 microM) and slightly reduced by phentolamine (2.6 microM). Atropine (0.4 microM) reduced maximum responses by 25 to 75%. The resistance to guanethidine suggests that the ineffectiveness of phenoxybenzamine is not due solely to atypical post synaptic receptors. Inaccessibility of the synaptic cleft to guanethidine is unlikely because the vas deferens, which possesses close contacts, was sensitive to guanethidine. Neurotransmission in bladder base may be partially noradrenergic, noncholinergic in nature. A question arises concerning the functional significance of the noradrenergic nerves in bladder base.


Single nucleotide polymorphisms in protein tyrosine phosphatase 1beta (PTPN1) are associated with essential hypertension and obesity.
Protein tyrosine phosphatase 1beta (PTP-1beta) is involved in the regulation of several important physiological pathways. It regulates both insulin and leptin signaling, and interacts with the epidermal- and platelet-derived growth factor receptors. The gene is located on human chromosome 20q13, and several rare single nucleotide polymorphisms (SNPs) have been shown to be associated with insulin resistance and diabetes in different populations. As part of our ongoing investigations into the genetic basis of hypertension, we examined common sequence variants in the gene for association with hypertension, obesity and altered lipid profile in two populations of Japanese and Chinese descent. We re-sequenced all exons, selected intronic sequences and the promoter region in 24 individuals from our cohort. Fourteen SNPs were discovered, and six of these spanning 78 kb were genotyped in 1553 individuals from 672 families. All six SNPs were in linkage disequilibrium, and we found strong association of common risk haplotypes with hypertension in Chinese and Japanese (P<0.0001). In addition, individual SNPs showed association to total plasma cholesterol, LDL-cholesterol and VLDL-cholesterol levels, as well as obesity measures (body mass index). This analysis supports that PTP-1beta affects plasma lipid levels, and may lead to obesity and hypertension in Japanese and Chinese. Given similar associations found in other populations to insulin resistance and diabetes, this gene may play a crucial role in the development of the characteristic metabolic changes seen in patients with the metabolic syndrome.


Series of mixed valent Fe(II)Fe(I) complexes that model the Hox state of [FeFe]hydrogenase: redox properties, density-functional theory investigation, and reactivities with extrinsic CO.
A series of asymmetrically disubstituted models of the active site of [FeFe]-hydrogenase, (mu-pdt)[Fe(CO) 2PMe 3][Fe(CO) 2NHC] (pdt = 1,3-propanedithiolate, NHC = IMes, 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene IMes ( 1), IMesMe, 1-methyl,3-(2,4,6-trimethylphenyl)imidazol-2-ylidene ( 2) or IMe, 1,3-bis(methyl)imidazol-2-ylidene ( 3)), have been synthesized and characterized. The one-electron oxidation of these complexes to generate mixed valent models of the H ox state of [FeFe]-hydrogenase, such as the previously reported (mu-pdt)(mu-CO)[Fe(CO) 2PMe 3][Fe(CO)IMes] (+) ( 1 ox ) (Liu, T.; Darensbourg, M. Y. J. Am. Chem. Soc. 2007, 129, 7008-7009) has been examined to explore the steric and electronic effects of different N-atom substituents on the stability and structure of the mixed valent cations. The differences in spectroscopic properties, structures, and relative stabilities of 1 ox , (mu-pdt)[Fe(CO) 2PMe 3][Fe(CO) 2IMesMe] (+) ( 2 ox ), and (mu-pdt)[Fe(CO) 2PMe 3]-[Fe(CO) 2IMe] (+) ( 3 ox ) are discussed in the context of both experimental and theoretical data. Of the three derivatives, only that with greatest steric bulk on the NHC ligand, 1 ox , shows a clear indication of a mu-CO by solution nu(CO) IR and yields to crystallization as a rotated form, commensurate with the two-Fe subsite of H ox. In addition, the reactivity of the complexes with extrinsic CO to form CO adducts and/or exchange with (13)CO is explored by experiment and by using density-functional theory calculations.


Association of urinary pH with body weight in nephrolithiasis.
The prevalence of kidney stone disease in the United States is progressively increasing, paralleling the growing rate of obesity. Uric acid nephrolithiasis, a condition associated with a low urinary pH, has been linked to obesity and insulin resistance. Based on these observations, we hypothesized that urinary pH may be inversely associated to body weight in nephrolithiasis. Data were retrieved from 4883 patients with nephrolithiasis who underwent ambulatory evaluation at two established stone clinics in Dallas and Chicago. The patients collected 24-hour urine samples on an outpatient basis, while avoiding any drug that could alter urinary pH. Patients were divided in increasing sextiles of body weight, and urinary pH was adjusted for urinary creatinine and for age. Urinary pH had a strong, graded inverse association with body weight. Urinary creatinine and age were both found to be significant covariates of urinary pH, while gender was not a significant independent variable after adjustment for urinary creatinine. Mean 24-hour urinary pH, adjusted for age and urinary creatinine, were 6.09, 6.04, 6.01, 5.99, 5.97, and 5.91 for sextiles of body weight in increasing order from Dallas (P for linear trend <0.0001), and 6.18, 6.10, 6.04, 6.02, 5.97, and 5.88 for the sextiles from Chicago (P for linear trend <0.0001). We conclude that urinary pH is inversely related to body weight among patients with stones. The results confirm the previously proposed scheme that obesity may sometimes cause uric acid nephrolithiasis by producing excessively acid urine due to insulin resistance.