What is the Impact of Body Mass Index on Cardiovascular and Musculoskeletal Health?
Obesity has become a major public health concern over the past several decades and has been shown to be associated with type 2 diabetes, cardiovascular diseases, dyslipidemia, hypertension, osteoarthritis (OA), and certain types of cancer. The impact of excess weight on cardiovascular and musculoskeletal health is not well-summarized in the literature, and there are some contradictory reports. Therefore, the purpose of this study was to assess the impact of body mass index (BMI) on: 1) cardiovascular outcomes; 2) osteoarthritis risk and progression; and 3) total knee arthroplasty outcomes (TKA). Three literature searches were performed to identify clinical studies that assessed how BMI affects cardiovascular and musculoskeletal health. We included reports published within last five years. A total of 138 studies on cardiovascular health and 140 studies on musculoskeletal health were identified. After reviewing the abstracts and related citations from the references, there were 29 studies included in the present study. The effect of varying levels of BMI have demonstrated a relationship to cardiovascular disease, osteoarthritis, and TKA outcomes. The evidence suggests that as BMI increases, the chance of developing cardiovascular disease, OA, and negative TKA outcomes also increases. Furthermore, there appears to be a negative effect with being underweight on outcomes as well, suggesting that being at "normal" weight may optimize outcomes. However, there are several reports which make these findings more complicated. Several beneficial factors associated with higher BMI include increased muscle mass and strength, which can potentially be beneficial through better cardiorespiratory fitness or hormonal effects. Additionally, several studies suggest that improving fitness is more important than intentional weight loss for cardiovascular health and osteoarthritis. Therefore, future studies are warranted to assess the combination of BMI and activity to assess the optimal balance and how they affect cardiovascular and musculoskeletal outcomes.


Relationship between salivary flow rate and clinical symptoms and behaviours in patients with dry mouth.
The purpose of this study was to investigate the relationship between whole salivary flow rate and dry mouth-related subjective symptoms and behaviours in patients with dry mouth. Seventy-eight patients (13 men and 65 women, 58.2 +/- 13.5 years) with dry mouth were asked a standardized series of questions concerning dry mouth-related symptoms and behaviours. Whole salivary flow rates were measured under unstimulated and stimulated conditions. The effect of oral dryness on daily life was significantly associated with the flow rate of stimulated whole saliva (r(s) = -0.30, P < 0.01) and frequency of oral dryness (r(s) = 0.46, P < 0.01). Dry mouth-related symptoms and behaviours were significantly associated with the whole salivary flow rate and the correlation was more remarkable with respect to stimulated whole saliva. The most common dry mouth-associated complaint was sensation of burning mouth. The effect of oral dryness on daily life was significantly affected by the presence of taste disturbances. Collectively, dry mouth-related symptoms and behaviours were significantly associated with whole salivary flow rate. Moreover, the severity of dry mouth-related symptoms was more closely correlated with the flow rate of stimulated saliva, compared with the unstimulated flow rate.


Attachment of marine sponge cells of Hymeniacidon perleve on microcarriers.
Toward the development of an in vitro cultivation of marine sponge cells for sustainable production of bioactive metabolites, the attachment characteristics of marine sponge cells of Hymeniacidon perleve on three types of microcarriers, Hillex, Cytodex 3, and glass beads, were studied. Mixed cell population and enriched cell fractions of specific cell types by Ficoll gradient centrifugation (6%/8%/15%/20%) were also assessed. Cell attachment ratio (defined as the ratio of cells attached on microcarrier to the total number of cells in the culture) on glass beads is much higher than that on Cytodex 3 and Hillex for both mixed cell population and cell fraction at Ficoll 15-20% interface. The highest attachment ratio of 41% was obtained for the cell fraction at Ficoll 15-20% interface on glass beads, which was significantly higher than that of a mixed cell population (18%). The attachment kinetics on glass beads indicated that the attachment was completed within 1 h. Cell attachment ratio decreases with increase in cell-to-microcarrier ratio (3-30 cells/bead) and pH (7.6-9.0). The addition of serum and BSA (bovine serum albumin) reduced the cell attachment on glass beads.


[Cancer in Madagascar. Experience of the Institut Pasteur de Madagascar from September 1992 to June 1996].
The Unit of the anatomo-pathology in the "Institut Pasteur de Madagascar" (IPM) examined in the period from September 1992 to June 1996 tissue specimens from 10,275 patients. Tumorous pathology presented 40% of the tissues and half of which were of malign etiology. 64% of the cancer diagnosed were in females. Cervical cancer was most frequently observed (17%), followed by breast cancer (16%). Cancer in the gastro-intestinal tract (15%) was most often located in the colon without sex difference. Stomach cancer occurring predominantly in males presented 25% of the total cases of cancer in the gastro-intestinal tract. Cancer of liver is rarely diagnosed despite the high prevalence of infection with hepatitis B virus. Skin cancer constituted 9% of the malign diagnosis and was mainly found in males. Children under 15 years old presented 7.4% of the total cases of malignancy with the haematopoietic tissues (30%) and the eyes (17%) as the most frequent topic locations. Due to a very low seroprevalence of the HIV in Madagascar, malign tumours associated to AIDS were only seen in a few rare cases. The review of cancer cases in the IPM may not be representative for the cancer epidemiology of Madagascar because of a general very low level of health care coverage, especially in the rural areas. Furthermore, a major part of the specimens originates from easily accessible organsystems, whereas other organs seem less investigated due to lack of appropriate available technique. Therefore, it is not feasible for the moment to establish a cancer register in Madagascar, although the Unit of Pathology in the IPM can offer a valid cancer diagnostical service.


Association between the time to surgery and survival among patients with colon cancer: A population-based study.
Factors associated with time-to-surgery (TTS) and survival in colon cancer has not been well studied. Cancer Care Ontario recommends surgery within 42 days of diagnosis and that 90% of patients meet this benchmark. We describe factors associated with TTS and survival in routine clinical practice. Retrospective population-based cohort study of patients receiving elective colonic resection after diagnosis of colon cancer in Ontario, Canada from 2002 to 2008 followed until 2012. Factors associated with TTS were identified using multivariate log-binomial and Quantile regression at 42 days and 90th percentiles. The association between TTS and cancer-specific (CSS) and overall survival (OS) were examined using multivariate Cox regression. 4326 patients; median age 71 years and 52% male. Median TTS was 24 days (IQR 14-37); at the 90th percentile 56 days. Factors associated with TTS ≥ 42 days and >90th percentile included older age, co-morbid illness, surgeon volume, and stage I disease (P < 0.05 for all). In patients whose TTS was either at 42 days or 90th percentile, those ≥80 years old waited two weeks longer than those <60 years, individuals with co-morbid illness waited 10 days longer than without co-morbidity, and patients with stage I disease waited 10 days longer than those with stage IV disease (P < 0.05 for all). Delay in TTS > 42 days or >90th percentile was not associated with OS or CSS. Age, co-morbidity, and stage of cancer are associated with TTS. There was no association between TTS and CSS or OS.


Reactive, Inelastic, and Dissociation Processes in Collisions of Atomic Oxygen with Molecular Nitrogen.
We report the results of detailed calculations of reactive, inelastic, and dissociative processes in collisions of atomic oxygen with molecular nitrogen in their respective electronic ground states. Cross sections are calculated as a function of collision energy in the range 0.001-10 eV, considering the whole rovibrational ladder. Some problems related to the vibrational energy levels of the asymptotes of 3A″ and 3A' potential energy surfaces used in this work are solved by an appropriate scaling at the level of cross sections. The results are compared with data in the literature, obtaining excellent agreement with experimental thermal data for reactive processes on a very large temperature range, and reasonable agreement with indirect dissociative data. Significant discrepancies are observed with previous reactive state-to-state results calculated on less detailed potential energy surfaces. Inelastic results are compatible with extrapolation of experimental thermal rate coefficient for temperatures higher than 4500 K but completely fail to reproduce experimental data at room temperature. The issue is discussed, indicating the reasons and possible solutions to the problem, and a resonable rate coefficient is obtained combining experimental and theoretical results in the range 300-20000 K. Complete, accurate fits are provided for both reactive and dissociative state-to-state rate coefficients to use them in applicative numerical codes concerning air kinetics.


CRP Regulates D-Lactate Oxidation in Shewanella oneidensis MR-1.
Shewanella oneidensis MR-1 is a heterotrophic facultative anaerobe that respires using various organic and inorganic compounds. This organism has served as a model to study bacterial metabolic and regulatory systems that facilitate their survival in redox-stratified environments. The expression of many anaerobic respiratory genes in MR-1, including those for the reduction of fumarate, dimethyl sulfoxide, and metal oxides, is regulated by cyclic AMP receptor protein (CRP). However, relatively little is known about how this organism regulates the expression of catabolic enzymes catalyzing the oxidation of organic compounds, including lactate. Here, we investigated transcriptional mechanisms for the lldP (SO_1522) and dld (SO_1521) genes, which encode putative lactate permease and D-lactate dehydrogenase, respectively, and demonstrate that CRP regulates their expression in MR-1. We found that a crp-deletion mutant of MR-1 (Δcrp) showed impaired growth on D-lactate. Complementary expression of dld in Δcrp restored the ability to grow on D-lactate, indicating that the deficient growth of Δcrp on D-lactate is attributable to decreased expression of dld. In vivo transcription and in vitro electrophoretic mobility shift assays reveal that CRP positively regulates the expression of the lldP and dld genes by directly binding to an upstream region of lldP. Taken together, these results indicate that CRP is a global transcriptional regulator that coordinately regulates the expression of catabolic and respiratory pathways in MR-1, including D-lactate dehydrogenase and anaerobic terminal reductases.


Meerkats (Suricata suricatta), a new definitive host of the canid nematode Angiostrongylus vasorum.
Angiostronglyus vasorum is a cardiopulmonary nematode infecting mainly canids such as dogs (Canis familiaris) and foxes (Vulpes vulpes). Natural infections have also been reported in mustelids and red pandas (Ailurus fulgens fulgens). We report the occurrence of natural A. vasorum infections in a group of captive meerkats (Suricata suricatta), housed at a university facility in Switzerland. A. vasorum first-stage larvae (L1) were initially identified in a pooled faecal sample. Individual samples, investigated with the Baermann-Wetzel technique, revealed that 41% (7/17) of the meerkats were infected, with ranges of 2-125 L1/g faeces. PCR and sequencing of part of the ITS-2 region resulted in 100% identity with A. vasorum. Infected animals did not show clinical signs. One meerkat died two days after diagnosis. Upon necropsy one adult specimen was recovered; histological examination of the lung revealed granulomatous pneumonia caused by A. vasorum larvae and eggs as well as intima and media hyperplasia and isolated arteriosclerosis of larger lung vessels. However, the cause of death was a spleen rupture with associated blood loss. All meerkats were topically treated with 10 mg imidacloprid/2.5 mg moxidectin per animal, after which they became negative in all follow up faecal examinations. Potential intermediate (gastropods) and paratenic hosts (birds) were collected from within or outside the meerkats enclosure. Gastropods were examined by PCR and bird samples by digestion. Four out of 193 (2.1%) gastropod samples were positive for A. vasorum, whereas none of the bird samples were positive. Meerkats, belonging to the Herpestidae, therefore are suitable definitive hosts for A. vasorum, with production and excretion of live L1. Meerkats kept in captivity in areas where A. vasorum is endemic and with potential contact to intermediate hosts are at risk of infection. Regular faecal examinations including Baermann-Wetzel technique should be considered.


Comparison of antimicrobial resistance genes in feedlots and urban wastewater.
The use of antibiotics in livestock production in North America and possible association with elevated abundance of detectable antimicrobial resistance genes (ARG) is a growing concern. Real-time, quantitative PCR (RT-qPCR) was used to determine the relative abundance and diversity of ARG in fecal composite and catch basin samples from 4 beef feedlots in Alberta. Samples from a surrounding waterway and municipal wastewater treatment plants were also included to compare the ARG profile of urban environments and fresh water with that of feedlots. The relative abundance of 18 resistance genes across 5 antibiotic families including sulfonamides, tetracyclines, macrolides, fluoroquinolones, and β-lactams was examined. Sulfonamide, fluoroquinolone, and β-lactam resistance genes predominated in wastewater treatment samples, while tetracycline resistance genes predominated in cattle fecal composite samples. These results reflect the types of antibiotic that are used in cattle versus humans, but other factors such as co-selection of ARG and variation in the composition of bacterial communities associated with these samples may also play a role.


Habitat fragmentation influences gene structure and gene differentiation among the Loxoblemmus aomoriensis populations in the Thousand Island Lake.
Thousand Island Lake (TIL) is a fragmented landscape consisting of more than 1000 land-bridge islands isolated during reservoir formation. To evaluate the effects of fragmentation and island attributes on insect populations, we examined the genetic structure of Loxoblemmus aomoriensis, a species of cricket widely distributed in TIL, and compared genetic diversity between islands samples. Population genetic analyses was conducted based on mitochondrial DNA haplotype frequencies of 10 sample islands. By comparing three island attributes with population genetic diversity reveals that island area influenced population genetic diversity (r2 = 0.5094, p = 0.00204). Using Pairwise Fst values, we also found that long-distance isolation increased the genetic differentiation, while short-distance isolation can be offset by dispersal. These results indicate that fragmentation can impact populations on a genetic level.


Bacteremia due to methicillin-resistant Staphylococcus aureus.
During a three-year period, Staphylococcus aureus phage type D11/83A/85 that was resistant to methicillin, cephalothin, and multiple aminoglycosides was recovered from 260 infected patients in an urban general hospital in Cincinnati, Ohio. This methicillin-resistant S. aureus (MRSA) was recovered from 30% of all blood cultures positive for S. aureus and represented 50% of all episodes of nosocomial bacteremia due to S. aureus. Bacteremia due to MRSA occurred most often in surgical patients (especially burn patients), occurred late in hospitalization, and was recovered frequently from wounds and intravascular catheters. Infection with S. aureus was the direct cause of death of 44% of the patients with bacteremia due to MRSA. Nine of 10 MRSA-infected patients who were treated with vancomycin alone responded to therapy compared with seven of 15 who were treated with other antistaphylococcal antibiotics (P less than 0.05). The present study defines the epidemiologic characteristics of bacteremia due to MRSA, demonstrates the virulence of MRSA, and proves that vancomycin is effective as therapy.


In situ molecular identification of the influenza A (H1N1) 2009 Neuraminidase in patients with severe and fatal infections during a pandemic in Mexico City.
In April 2009, public health surveillance detected an increased number of influenza-like illnesses in Mexico City's hospitals. The etiological agent was subsequently determined to be a spread of a worldwide novel influenza A (H1N1) triple reassortant. The purpose of the present study was to demonstrate that molecular detection of pandemic influenza A (H1N1) 2009 strains is possible in archival material such as paraffin-embedded lung samples. In order to detect A (H1N1) virus sequences in archived biological samples, eight paraffin-embedded lung samples from patients who died of pneumonia and respiratory failure were tested for influenza A (H1N1) Neuraminidase (NA) RNA using in situ RT-PCR. We detected NA transcripts in 100% of the previously diagnosed A (H1N1)-positive samples as a cytoplasmic signal. No expression was detected by in situ RT-PCR in two Influenza-like Illness A (H1N1)-negative patients using standard protocols nor in a non-related cervical cell line. In situ relative transcription levels correlated with those obtained when in vitro RT-PCR assays were performed. Partial sequences of the NA gene from A (H1N1)-positive patients were obtained by the in situ RT-PCR-sequencing method. Sequence analysis showed 98% similarity with influenza viruses reported previously in other places. We have successfully amplified specific influenza A (H1N1) NA sequences using stored clinical material; results suggest that this strategy could be useful when clinical RNA samples are quantity limited, or when poor quality is obtained. Here, we provide a very sensitive method that specifically detects the neuraminidase viral RNA in lung samples from patients who died from pneumonia caused by Influenza A (H1N1) outbreak in Mexico City.


[Effects of staphylococcal enterotoxin of different concentrations on the expression of GATA-3 and Th1/Th2 cytokines in the maxillary sinus mucosa of rabbits].
The aim of this study was to determine the expression of GATA-3 and the level of Th1 and Th2 cytokines upon repeated exposure to staphylococcal enterotoxin B(SEB) of different concentrations in the maxillary sinus mucosa of rabbits. The rabbits were randomly divided into 2 groups (24 rabbits per group): low-dose SEB group and high-dose SEB group. The low-dose SEB group and high-dose SEB group received daily injections of 0.6 ng of SEB (2 ml) and 60 ng of SEB (2 ml) into the left maxillary sinus of rabbits for 28 days, respectively. Concurrent treatment of the right maxillary sinus with normal saline was used as a control. Six rabbits chosen randomly in two groups were killed on days 3, 7, 14, and 28, and to obtain the sinus mucosa from the two-side maxillary sinuses for measurement. Mucosal levels of IL-2, IL-4, IL-5, and IFN-γ were measured using ABC-ELISA. Tissue expression of GATA-3 were examined using Real-time PCR and immunohistochemistry. IFN-γ and IL-2 levels were significantly elevated in the high-dose SEB group compared with the low-dose SEB and control groups on days 7, 14, and 28 (P < 0.05). However, IL-4 and IL-5 levels were markedly enhanced in the low-dose SEB group compared with the high-dose SEB and control groups on days 14 and 28 (P < 0.05). Real-time PCR showed that the expression of GATA-3 mRNA in the low-dose SEB group was markedly enhanced, and immunohistochemical staining illustrated that the number of GATA-3 positive cells was markedly increased in the low-dose SEB group as compared with the high-dose SEB group (P < 0.05). No significant differences were observed in GATA-3 expression between the high-dose SEB and the control groups (P > 0.05). SEB promoted Th1 cytokines production at high concentrations, and enhanced Th2 cytokines expression and Th2 immune response at low concentrations.


Direct wireless readout of fiber Bragg grating sensors using radio-over-fiber.
Wireless readout of optical fiber sensors is of interest for a variety of applications. In the state of the art, the sensor data are digitized before the wireless transmission. We propose a wireless evaluation scheme for fiber Bragg gratings where the sensor signal is transmitted directly without any processing in a simplified sensor node. The underlying concept is explained in detail and validated experimentally. It is based on radio-over-fiber technology and evaluates not only the magnitude of the received analog electrical sensor signal but also the phase. Additionally, signal correction and signal processing schemes are discussed. A series of experimental measurements indicates not only advantages of the phase evaluation method over the magnitude evaluation method but also approves the general feasibility of the direct interrogation approach for wireless sensing applications. Future subjects of interest involve absolute accuracy considerations and maximum achievable sampling rates.


Transfer of Neonates with Critical Congenital Heart Disease Within a Regionalized Network.
Regionalization of pediatric cardiac surgical care varies between and within states. In most geographic regions, at least some neonates with critical heart disease are transferred from their birth hospital to a different hospital for surgery. The impact of neonatal transfer for surgery, particularly over a considerable distance (>10 miles), has been largely unexplored. We sought to examine the impact of transferring neonates for cardiac surgery. We queried the New York State Cardiac Surgery database (2005-2014) from a single institution to identify neonates born within the cardiac surgery center and those transferred for surgery. Outcomes were compared between groups, with subgroup analysis of neonates with single ventricle anatomy. 113 surgical neonates were born at the cardiac surgery center, and 268 were transferred to the cardiac surgery center. Median transfer distance was 91 (IQR 73, 94) miles. Age at operation and the need for preoperative ventilation were significantly lower in neonates born at the cardiac surgery center. In addition, single ventricle anatomy was more prevalent among those born at the cardiac surgery center (48.7 vs. 31.3%; p = 0.001). However, postoperative outcomes were the same-30-day survival was similar across groups (birth: 89% vs. transfer: 90%; p = 0.7), and for those with single ventricle palliation (birth: 81% vs. transfer: 81%; p = 0.9). Within our regionalized network, we found no difference in 30-day survival between neonates either born or transferred to a cardiac surgery center, which supports the use of a regionalized network of hospitals to the care of children with congenital heart disease.


High-Pressure Metathesis of the M1- xPO3+4 xN1-4 x ( x ≈ 0.05) and M0.75PO4 ( M = Zr, Hf) Orthophosphates.
We describe the oxonitridophosphates M1- xPO3+4 xN1-4 x ( x ≈ 0.05) and the isotypic oxophosphates M0.75PO4 ( M = Zr, Hf) obtained by high-pressure metathesis. The structures (ZrSiO4-type, space group I41/ amd (no. 141), a = 6.5335(7)-6.6178(12), c = 5.7699(7)-5.8409(9) Å, Z = 4) were refined from single-crystal X-ray diffraction data, and the powder samples were examined with quantitative Rietveld refinement. Infrared spectroscopy did not indicate the presence of X-H ( X = O, N) bonds. The optical band gaps, between 3.5 and 4.3 eV, were estimated from UV-vis data using the Kubelka-Munk function under assumption of a direct band gap. Temperature-dependent powder X-ray diffraction showed a phase transformation of the M0.75PO4 ( M = Zr, Hf) compounds to ambient pressure polymorphs at 780 (Zr) and 900 °C (Hf). The preparation of the nitrogen containing compounds exemplifies the systematic access to the new class of group 4 nitridophosphates granted by high-pressure metathesis. Moreover, we show that high-pressure metathesis can also be used for the preparation of metastable oxophosphates.


Temperature-Controlled Retinal Photocoagulation Reliably Generates Uniform Subvisible, Mild, or Moderate Lesions.
Conventional retinal photocoagulation produces irregular lesions and does not allow reliable control of ophthalmoscopically invisible lesions. We applied automatically controlled retinal photocoagulation, which allows to apply uniform lesions without titration, and aimed at five different predictable lesion intensities in a study on rabbit eyes. A conventional 532-nm photocoagulation laser was used in combination with a pulsed probe laser. They facilitated real-time fundus temperature measurements and automatic exposure time control for different predefined time/temperature dependent characteristics (TTC). We applied 225 control lesions (exposure time 200 ms) and 794 TTC lesions (5 intensities, exposure times 7-800 ms) in six rabbit eyes with variable laser power (20-66.4 mW). Starting after 2 hours, we examined fundus color and optical coherence tomographic (OCT) images over 3 months and classified lesion morphologies according to a seven-stage OCT classifier. Visibility rates in funduscopy (OCT) after 2 hours were 17% (68%) for TTC intensity group 1, 38% (90%) for TTC group 2 and greater than 94% (>98%) for all consecutive groups. TTC groups 1 through 4 correlated to increasing morphological lesion intensities and increasing median funduscopic and OCT diameters. Group 5 lesions were as large as, but more intense than group 4 lesions. Automatic, temperature controlled photocoagulation allows to apply predictable subvisible, mild, or moderate lesions without manual power titration. The technique will facilitate standardized, automatically controlled low and early treatment of diabetic retinopathy study (ETDRS) intensity photocoagulation independently of the treating physician, the treated eye and lesion location.


Healing of fresh extraction sockets filled with bioactive glass particles: histological findings in humans.
The aim of the present study was to histologically evaluate fresh human sockets filled with bioactive glass after 6 months of healing. In 13 patients, 32 single extraction sites in the anterior area underwent socket ridge preservation procedure (RPP) with a bioactive glass (BioRestore™, Inion Oy, Tampere, Finland). At implant installation, 22 bone cores were trephined out and processed for histomorphometric and immunohistochemical analysis. Newly formed immature bone around residual particles of bioactive glass was found in all 22 biopsies. The histomorphometry of the amount of bone, provisional matrix, and residual graft returned a mean ± SD value of 54 ± 31%, 37.9 ± 25.6%, and 8.1 ± 7.8, respectively, 6 months after RPP. The use of this grafting material in fresh extraction sockets appears to delay the healing processes of the alveolar bone; therefore, its indication as a material for RPP when implant placement is considered within 6 months after extraction should be revised.


Relationship between the HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis.
The US Food and Drug Administration recommends screening for the HLA-B*1502 allele before initiation of carbamazepine therapy in patients of Asian ancestry, but there remains unclear evidence of a relationship between HLA-B*1502 and Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) among carbamazepine users, especially in some racial/ethnic populations. To determine the relationship between the HLA-B*1502 allele and carbamazepine-induced SJS and TEN. A comprehensive search of the following data sources was performed without language restriction from the inception of the database until January 8, 2013: EMBASE, PubMed, clinicaltrials.gov, Cochrane Library, IPA (International Pharmaceutical Abstracts), HuGENet (Human Genome Epidemiology Network), and CINAHL (Cumulative Index to Nursing and Allied Health Literature), and the reference lists of identified studies. Inclusion criteria were studies that investigated the relationship between HLA-B*1502 and carbamazepine-induced SJS and TEN and that reported sufficient data for calculating the frequency of HLA-B*1502 carriers among cases and controls. The search yielded 525 articles, of which 16 met the inclusion criteria. The studies included 227 SJS or TEN cases, 602 matched control subjects, and 2949 population control subjects. Two reviewers independently extracted the following data: study design, eligibility criteria, diagnostic criteria, patient demographics, genotype distribution, HLA-B genotyping technique, selection of cases and controls, dosage of carbamazepine and duration of use, and results of Hardy-Weinberg equilibrium in the control group. The Newcastle-Ottawa Scale was used to assess the quality of studies. The overall odds ratios (ORs) with corresponding 95% CIs were calculated using a random-effects model. The primary analysis was based on matched control studies. Subgroup analyses by race/ethnicity were also performed. The primary outcome was carbamazepine-induced SJS and TEN. The outcome measure is given as an overall OR. The summary OR for the relationship between HLA-B*1502 and carbamazepine-induced SJS and TEN was 79.84 (95% CI, 28.45-224.06). Racial/ethnic subgroup analyses yielded similar findings for Han-Chinese (115.32; 18.17-732.13), Thais (54.43; 16.28-181.96), and Malaysians (221.00; 3.85-12 694.65). Among individuals of white or Japanese race/ethnicity, no patients with SJS or TEN were carriers of the HLA-B*1502 allele. We found a strong relationship between the HLA-B*1502 allele and carbamazepine-induced SJS and TEN in Han-Chinese, Thai, and Malaysian populations. HLA-B*1502 screening in patients requiring carbamazepine therapy is warranted.


Coadministration of bedaquiline and pyrifazimine reduce exposure to toxic metabolite N-desmethyl bedaquiline.
Background: A new, effective anti-tuberculosis (TB) regimen containing bedaquiline (BDQ) and pyrifazimine (TBI-166) has been recommended for a phase IIb clinical trial. Preclinical drug-drug interaction (DDI) studies of the combination of BDQ and TBI-166 have been designed to support future clinical trials. In this study, we investigated whether a DDI between BDQ and TBI-166 affects the pharmacokinetics of BDQ. Methods: We performed in vitro quantification of the fractional contributions of the fraction of drug metabolism by individual CYP enzymes (f m) of BDQ and the inhibition potency of key metabolic pathways of TBI-166. Furthermore, we conducted an in vivo steady-state pharmacokinetics study in a murine TB model and healthy BALB/c mice. Results: The in vitro f m value indicated that the CYP3A4 pathway contributed more than 75% to BDQ metabolism to N-desmethyl-bedaquiline (M2), and TBI-166 was a moderate (IC50 2.65 µM) potential CYP3A4 inhibitor. Coadministration of BDQ and TBI-166 greatly reduced exposure to metabolite M2 (AUC0-t 76310 vs 115704 h ng/mL, 66% of BDQ alone), whereas the exposure to BDQ and TBI-166 did not changed. The same trend was observed both in healthy and TB model mice. The plasma concentration of M2 decreased significantly after coadministration of BDQ and TBI-166 and decreased further during treatment in the TB model. Conclusions: In conclusion, our results showed that the combination of BDQ and TBI-166 significantly reduced exposure to the toxic metabolite M2 by inhibiting the activity of the CYP3A4 pathway. The potential safety and efficacy benefits demonstrated by the TB treatment highly suggest that coadministration of BDQ and TBI-166 should be studied further.


Impact of Premature Senescence on Radiosensitivity Measured by High Throughput Cell-Based Assays.
In most p53 wild-type human cell types, radiosensitivity evaluated by the colony formation assay predominantly reflects stress-induced premature senescence (SIPS) and not cell death (Int. J. Mol. Sci. 2017, 18, 928). SIPS is a growth-arrested state in which the cells acquire flattened and enlarged morphology, remain viable, secrete growth-promoting factors, and can give rise to tumor-repopulating progeny. The impact of SIPS on radiosensitivity measured by short-term assays remains largely unknown. We report that in four p53 wild-type human solid tumor-derived cell lines (HCT116, SKNSH, MCF7 and A172): (i) the conventional short-term growth inhibition assay (3 days post-irradiation) generates radiosensitivity data comparable to that measured by the laborious and time-consuming colony formation assay; (ii) radiation dose-response curves obtained by multiwell plate colorimetric/fluorimetric assays are markedly skewed towards radioresistance, presumably reflecting the emergence of highly enlarged, growth-arrested and viable cells; and (iii) radiation exposure (e.g., 8 Gy) does not trigger apoptosis or loss of viability over a period of 3 days post-irradiation. Irrespective of the cell-based assay employed, caution should be exercised to avoid misinterpreting radiosensitivity data in terms of loss of viability and, hence, cell death.


uS10, a novel Npro-interacting protein, inhibits classical swine fever virus replication.
Classical swine fever (CSF) is a severe, febrile and highly contagious disease caused by classical swine fever virus (CSFV) that has resulted in huge economic losses in the pig industry worldwide. CSFV Npro has been actively studied but remains incompletely understood. Few studies have investigated the cellular proteins that interact with Npro and their participation in viral replication. Here, the yeast two-hybrid (Y2H) system was employed to screen Npro-interacting proteins from a porcine alveolar macrophage (PAM) cDNA library, and a blast search of the NCBI database revealed that 15 cellular proteins interact with Npro. The interaction of Npro with ribosomal protein S20, also known as universal S10 (uS10), was further confirmed by co-immunoprecipitation and glutathione S-transferase pull-down assays. Furthermore, uS10 overexpression inhibited CSFV replication, whereas the knockdown of uS10 promoted CSFV replication in PAMs. In addition, Npro or CSFV reduced uS10 expression in PAMs in a proteasome-dependent manner, indicating that Npro-uS10 interaction might contribute to persistent CSFV replication. Our previous research showed that CSFV decreases Toll-like receptor 3 (TLR3) expression. The results showed that uS10 knockdown reduced TLR3 expression, and that uS10 overexpression increased TLR3 expression. Notably, uS10 knockdown did not promote CSFV replication following TLR3 overexpression. Conversely, uS10 overexpression did not inhibit CSFV replication following TLR3 knockdown. These results revealed that uS10 inhibits CSFV replication by modulating TLR3 expression. This work addresses a novel aspect of the regulation of the innate antiviral immune response during CSFV infection.


African swine fever virus protein p17 promotes mitophagy by facilitating the interaction of SQSTM1 with TOMM70.
Viruses have developed different strategies to hijack mitophagy to facilitate their replication. However, whether and how African swine fever virus (ASFV) regulates mitophagy are largely unknown. Here, we found that the ASFV-encoded p17 induced mitophagy. Coimmunoprecipitation/mass spectrometry assays identified translocase of outer mitochondrial membrane 70 (TOMM70) as the protein that interacted with p17. The binding of TOMM70 to p17 promoted the binding of the mitophagy receptor SQSTM1 to TOMM70, led to engulfment of mitochondria by autophagosomes, and consequently decreased the number of mitochondria. Consistently, the levels of TOMM70 and TOMM20 decreased substantially after p17 expression or ASFV infection. Furthermore, p17-mediated mitophagy resulted in the degradation of mitochondrial antiviral signalling proteins and inhibited the production of IFN-α, IL-6 and TNFα. Overall, our findings suggest that ASFV p17 regulates innate immunity by inducing mitophagy via the interaction of SQSTM1 with TOMM70.


Semen characterization, seasonality of production, and in vitro sperm quality after chilled storage and cryopreservation in the king penguin (Aptenodytes patagonicus).
Research was conducted to examine seasonal seminal traits and to establish short-term and long-term sperm preservation methods in the king penguin (Aptenodytes patagonicus) for use in genome banking and artificial insemination (AI). Spermic ejaculates (n = 87) obtained using a cooperative method were collected across multiple (n = 6, Male 1) and a single (Male 2) breeding season(s). Non-contaminated ejaculates (n = 69) were 0.36 ± 0.32 ml at 56.3 ± 62.7 × 10(7) sperm/ml with 85.3 ± 10.6% total motility (TMot), 52.5 ± 12.9% progressive motility (PMot), 86.6 ± 24.3 µm/sec average path velocity (VAP) and 92.3 ± 3.7% plasma membrane intact. In vitro quality of chilled semen was best maintained over 48 hr at 5°C than 21°C, with decreased (P < 0.05) motility and morphology parameters observed by 24 and 6 hr, respectively. A comparison of two freezing methods (straw [STR] vs. directional [DF]) demonstrated similar effects on post-thaw quality at 0 and 3 hr, with the exception of plasma membrane integrity which was higher (P < 0.05) at 0 hr for DF (48.7 ± 6.5%) than STR (41.2 ± 7.0%). At 0 hr post-thaw, DF samples retained 46%, 69%, and 52% of their initial PMot, VAP, and plasma membrane integrity, respectively. Normal morphology of motile cells was reduced (P < 0.05) during freeze-thawing from 84% post-collection to 37% and 34% at 0 and 3 hr post-thaw, respectively. Results indicate that chilled and cryopreserved semen from the king penguin has potential for use in AI.


Mesodermal- vs. neuronal-specific expression of MafK is elicited by different promoters.
Small members of the Maf family of transcriptional regulatory proteins share similar basic-leucine zipper domains but have no intrinsic ability to activate transcription. One member of the family (MafK) has been shown to mediate both negative and positive regulation: in addition to forming a homodimer which represses transcription, MafK can also form a heterodimer with p45 (the large subunit of erythroid transcription factor NF-E2) to activate transcription. We examined the expression of mafK during murine development. mafK mRNA was first detected in 7.5 days post coitus (dpc) embryonic mesoderm and persisted in mesodermal derivatives (mesenchymal and haematopoietic cells) thereafter. However, around 13 dpc mafK was also strongly induced in neuronal cells and it is broadly expressed in neurones in postnatal mouse. The neuronal expression of mafK is directed by a distinct promoter located 6 kbp 3' to the mesoderm-specific promoter. mafK in neurones associates with a different partner molecule from p45. In transgenic mice, a regulatory domain in the immediate vicinity of the mesodermal promoter was found to direct mesenchymal, but not haematopoietic, expression of mafK. The cell type- and developmental stage-specific expression of MafK suggests that, in addition to its demonstrated role in erythroid transcriptional regulation, MafK also plays an important regulatory role in other mesodermally and neuroectodermally derived tissues during mouse embryonic development.


Early postpartum discharge: how are mothers managing?
To describe maternal concerns at 2 weeks and mothers' ability to function in various roles at 4 weeks postpartum. Subjects were mailed questionnaires at 2 and 4 weeks postpartum. A mid-Atlantic hospital that is a part of an academic health center. A convenience sample of 100 healthy women who were discharged < or = 48 hours postpartum and met the study criteria. Instruments included a demographic questionnaire, the Maternal Concerns Questionnaire, and the Inventory of Functional Status After Childbirth. Physiologic concerns during the early postpartum period related primarily to perineal sutures, breast care, body image, and fatigue. More than 25% of the women continued to experience depression at 2 weeks, and 40% had days at 1 month when they never got dressed. Much concern was expressed about the mothering role but little about interaction with the mate. Older maternal age was associated with a longer hospital stay, and the trend suggested improved functioning at 1 month with longer hospitalization. More than half of the participants said they would visit a nurse-run clinic during the 1st postpartum week if given the opportunity. The results provide descriptive information about effects of early hospital discharge. Mothers discharged in 48 hours or less adjust to motherhood without the education and assessment that was formerly possible with extended hospitalization. The current study reinforces the need for nurses to explore strategies in hospitals or communities to provide early care for postpartum mothers.


Use of a 4-week up-titration regimen of roflumilast in patients with severe COPD.
The oral selective phosphodiesterase-4 inhibitor roflumilast (ROF) reduces exacerbations in patients with severe COPD. Adverse events (AEs) can cause early ROF discontinuation. Alternative dosing strategies may help patients continue their therapy. In this multicenter, double-blind trial, 1,321 patients with severe COPD were randomized 1:1:1 to 4 weeks' treatment with ROF 250 µg once daily (OD), 500 µg every other day (EOD), or 500 µg OD, each followed by ROF 500 µg OD for 8 weeks, plus standard therapy. The primary end point was the percentage of patients prematurely discontinuing study treatment. Patients in the 250 µg OD/500 µg OD group had significantly fewer treatment discontinuations (odds ratio [OR] 0.66 [95% CI 0.47-0.93], p=0.017) and lower rates of AEs of interest such as diarrhea, nausea, headache, decreased appetite, insomnia and abdominal pain (OR 0.63 [95% CI 0.47-0.83], p=0.001) compared with those in the 500 µg OD group. Although rates of discontinuation and AEs of interest were numerically lower with ROF 500 µg EOD/500 µg OD, the difference was not significant (OR 0.76, p=0.114, and OR 0.78, p=0.091, respectively) compared with ROF 500 µg OD. A dose of ROF 250 µg OD for 4 weeks before escalation to the approved maintenance dose of 500 µg OD resulted in reduced treatment discontinuation and improved tolerability.


[Chlamydial polyarthritis in calves].
Investigations were carried out on some farms to establish the presence of Chlamydia organisms in spontaneous cases of polyarthritis in calves. Use was made of various methods--chick embryos, light and electron microscopy, and the complement-fixation test (CFT). As many as 9 C. psittaci strains were isolated from synovial liquid of calves affected with polyarthritis from 6 farms in several districts of the country. The isolated strains were identified morphologically by means of electron and light microscope, and serologically--through demonstrating the presence of a group-specific Chlamydia antigen by CFT with a known positive anti-chlamydial serum. There were in the sera of some calves with polyarthritis chlamydial KC-antibodies. Results spoke of the chlamydial etiology of some polyarthritis diseases in calves in this country, confirming and supplementing previous observations of the authors.


Donor-recipient size matching and mortality in heart transplantation: Influence of body mass index and gender.
The International Society for Heart and Lung Transplantation (ISHLT) guidelines advise against inappropriate weight match (IWM) for heart transplant, defined as donor weight <70% of recipient's weight. Few studies have explored in detail this size-matching recommendation, especially with regard to body mass index (BMI) and gender matching. We aimed to determine whether any difference could be observed between size-matching in obese and non-obese recipients with regard to mortality after cardiac transplantation. Data from 52,455 adult heart transplants (recipients ≥18 years of age) between 1994 and 2013 were obtained from the ISHLT Registry. We defined the following subgroups of patients based on BMI: underweight, BMI <18.5; non-obese, BMI 18.5 to 30; and obese, BMI >30. The end-points were all-cause 30-day mortality and cumulative mortality. IWM was associated with increased 30-day mortality (odds ratio [OR] = 1.20, 95% confidence interval [CI] 1.01 to 1.43, p = 0.041) and cumulative mortality (hazard ratio [HR] = 1.14, 95% CI 1.07 to 1.22, p < 0.001). In non-obese recipients, IWM was associated with increased 30-day mortality (OR = 1.89, 95% CI 1.48 to 2.41, p < 0.001) as well as cumulative mortality (HR = 1.27, 95% CI 1.15 to 1.41, p < 0.001), whereas, for obese recipients, IWM was not associated with 30-day or cumulative mortality. Male recipients of female allografts (HR = 1.08, 95% CI 1.04 to 1.12, p < 0.001) as well as female recipients of male allografts (HR = 1.07, 95% CI 1.02 to 1.13, p = 0.003) had increased cumulative mortality compared with gender-matched transplants. There was no interaction between IWM and gender mismatch. Our results indicate that donor weight <70% of recipient weight increases mortality in non-obese heart transplant recipients, but not in obese transplant recipients. Gender mismatch increases mortality independently of weight match.


Hybrid materials covalently incorporated with isophorone-based dyes through sol-gel process for nonlinear optical applications.
Two new push-pull type second-order nonlinear optical (NLO) active isophorone-based alkoxysilane dyes with the same acceptor were synthesized and characterized. One silane (ICTES-HEMA) bears a chromophore with a hydroxyethyl methylamino donor and the other silane (ICTES-HMPP) is a bulkier analogue with a hydroxymethyl diphenylamino donor. Transparent, homogeneous films were prepared via the copolymerization of tetraalkoxysilane (TEOS) and different NLO silanes with the ratio of 5:1. The d(33) values obtained for the HEMA and HMPP films are 46.3 and 20.6 pm/V, respectively. Normalized UV-vis spectra reveal that the introduction of a diaryl group would help to prevent unfavorable organization of the chromophores. The reorientation dynamic stabilities of the samples were studied by second-harmonic generation (SHG) measurements, demonstrating that bulkier chromophores incorporated in sol-gel materials would not necessarily lead to higher stabilities over time.


A Recombinant 12-His Tagged Pyrococcus furiosus Soluble [NiFe]-Hydrogenase I Overexpressed in Thermococcus kodakarensis KOD1 Facilitates Hydrogen-Powered in vitro NADH Regeneration.
Soluble hydrogenase I (SHI) from the hyperthermophilic archaeon Pyrococcus furiosus is a heterotetrameric [NiFe] hydrogenase that catalyzes the reversible reduction of protons by NADPH into hydrogen gas (H2 ). Here, the authors expressed the four αβγδ subunits of SHI encoded by one gene cluster in another hyperthermophilic archaeon, Thermococcus kodakarensis KOD1, which uses its hydrogenase maturation apparatus without the coexpression of native P. furiosus hydrogenase endopeptidases (maturation proteases). The SHI overexpression of T. kodakarensis resulted in more than 1200-fold enhancement in the hydrogenase activity of the cell lysate compared to that of the host strain with an empty vector. An active, purified 12-His tagged recombinant SHI (rSHI) is obtained by one-step affinity adsorption on nickel-charged resin. Size-exclusion chromatography show that purified rSHI is heterotetrameric and has a molecular mass of 150 kDa. The purified rSHI has a half-life of 70 h at 80 °C. This rSHI is used to design a novel in vitro synthetic enzymatic biosystem to convert pyruvate and H2 gas into lactate in a theoretical yield, whereas rSHI is used for NADPH regeneration; an FMN-containing diaphorase (DI) is used to match NADP-preferred SHI and NAD-preferred lactate dehydrogenase (LDH). This study provides a cost-efficient method to obtain hyperthermostable hydrogenases, which can be used in in vitro synthetic enzymatic biosystems for cofactor regeneration and hydrogen production.


Selection and separation of viable cells based on a cell-lethal assay.
A method to select and separate viable cells based on the results of a cell-lethal assay was developed. Cells were plated on an array of culture sites with each site composed of closely spaced, releasable micropallets. Clonal colonies spanning multiple micropallets on individual culture sites were established within 72 h of plating. Adjacent sites were widely spaced with 100% of the colonies remaining sequestered on a single culture site during expansion. A laser-based method mechanically released a micropallet underlying a colony to segment the colony into two genetically identical colonies. One portion of the segmented colony was collected with 90% efficiency while viability of both fractions was 100%. The segmented colonies released from the array were fixed and subjected to immunofluorescence staining of intracellular phospho-ERK kinase to identify colonies that were highly resistant or sensitive to phorbol ester-induced activation of ERK. These resistant and sensitive cells were then matched to the corresponding viable colonies on the array. Sensitive and resistant colonies on the array were released and cultured. When these cultured cells were reanalyzed for phorbol ester-induced ERK activity, the cells retained the sensitive or resistant phenotype of the originally screened subcolony. Thus, cells were separated and collected based using the result of a cell-lethal assay as selection criteria. These microarrays enabling clonal colony segmentation permitted sampling and manipulation of the colonies at very early times and at small cell numbers to reduce reagent, time, and manpower requirements.


Kidney preservation in pigs with University of Wisconsin and Celsior solution.
Although University of Wisconsin (UW) solution continues to be the most commonly used for intra-abdominal organs a new solution, Celsior, already utilized for heart and lungs, has been proposed for kidney and liver preservation. The aim of this research was to assess the effect of Celsior compared to UW on the immediate graft function of pig autotransplanted kidneys. We used an autotransplantation pig model to avoid immunological interferences. After harvesting the graft was immediately bench perfused through the renal artery with 200 cc of solution and preserved for 24, 32 and 48 hrs. After cold ischemia grafts were autotransplanted on cava vein and aorta and a ureteral-ureteral anastomosis was performed. Contralateral nephrectomy was carried out at the end of this procedure. Each experimental group was composed of 5 animals. All animals were sacrificed after 1 week. All animals with 24 hr and 32 hr preserved grafts survived up to sacrifice; kidney function was recovered in all animals of 24 hr groups and in most of the animals of 32 hr preserved grafts (4/5) without any differences between the 2 solutions. In Celsior and UW 48 hr groups only 5 animals survived (3 and 2, respectively) and in all these animals kidney function was not totally recovered. Our data show that preservation of kidneys with the Celsior solution in the experimental setting is equivalent to UW solution.


Evaluating public commentary and scientific evidence submitted in the development of a risk assessment.
Risk assessments form the methodological basis for many public policies. A key component of the risk assessment process is the public commentary period. We conducted a case study of the California environmental tobacco smoke risk assessment to describe the contribution of the commentary to the risk assessment process. We used content analysis to examine the sources, quantity, and quality of public commentary, as well as the agency's response to the commentary. We examined the type and quality of publications cited in the commentary. Most of the comments were from critics of the risk assessment (36/44, 80%), especially tobacco industry affiliates (30/36, 83%). Critics were more likely to evoke the science evaluation criteria of study quality, reliability, and validity than were supporters. More than half the critics argued that appropriate procedures were not followed (13/23, 57%). Of the 29 commentaries on the respiratory, carcinogenic, and cardiovascular chapters, four resulted in changes to the risk assessment, such as the addition of new references or reanalysis of data. Journal articles were the most frequently cited type of reference, cited by critics (1,022/1,526 of references, 67%) and supporters (39/60, 65%). However, journal articles submitted by critics had lower impact factors than those cited by supporters (2.6 vs. 3.6, p=0.03). Participation in the public input process was not balanced among all interested parties, although this may reflect different opportunities for stakeholders to participate in stages of the process. Critics and supporters of the risk assessment used different criteria to evaluate the scientific evidence, suggesting that they were socially constructing the evidence to support their positions.


Exploratory biomarker analysis for treatment response in KRAS wild type metastatic colorectal cancer patients who received cetuximab plus irinotecan.
More than half of the patients selected based on KRAS mutation status fail to respond to the treatment with cetuximab in metastatic colorectal cancer (mCRC). We designed a study to identify additional biomarkers that could act as indicators for cetuximab treatment in mCRC. We investigated 58 tumor samples from wild type KRAS CRC patients treated with cetuximab plus irinotecan (CI). We conducted the genotyping for mutations in either BRAF or PIK3CA and profiled comprehensively the expression of 522 kinase genes. BRAF mutation was detected in 5.1 % (3/58) of patients. All 50 patients showed wild type PIK3CA. Gene expression patterns that categorized patients with or without the disease control to CI were compared by supervised classification analysis. PSKH1, TLK2 and PHKG2 were overexpressed significantly in patients with the disease control to IC. The higher expression value of PSKH1 (r = 0.462, p < 0.001) and TLK2 (r = 0.361, p = 0.005) had the significant correlation to prolonged PFS. The result of this work demonstrated that expression nature of kinase genes such as PSKH1, TLK2 and PHKG2 may be informative to predict the efficacy of CI in wild type KRAS CRC. Mutations in either BRAF or PIK3CA were rare subsets in wild type KRAS CRC.


A vibro-tactile display for clinical monitoring: real-time evaluation.
Vibro-tactile displays use human skin to convey information from physiological monitors to anesthesiologists, providing cues about changes in the status of the patient. In this investigation, we evaluated, in a real-time clinical environment, the usability and wearability of a novel vibro-tactile display belt recently developed by our group, and determined its accuracy in identifying events when used by anesthesiologists. A prospective observational study design was used. During routine anesthesia, a standard physiological monitor was connected to a software tool that used algorithms to automatically identify changing trends in mean noninvasive arterial blood pressure, expired minute ventilation, peak airway pressure, and end-tidal carbon dioxide partial pressure. The software was wirelessly interfaced to a vibro-tactile belt worn by the anesthesiologist. Each physiological variable was mapped to 1 of 4 tactor locations within the belt. The direction (increase/decrease) and 2 levels of change (small/large) were encoded in the stimulation patterns. A training session was completed by each anesthesiologist. The system was activated in real-time during anesthesia alongside routine physiological monitors. When the algorithms detected changes in the patient, the belt vibrated at the appropriate location with the pattern corresponding to the level and direction of change. Using a touch screen monitor the anesthesiologist was to enter the vibro-tactile message by first identifying the variable, then identifying the level and direction of change. Usability and wearability questionnaires were to be completed. The percentage of correct identification of the physiological trend, the direction of change, and the level of change were primary outcome variables. The mean usability score and wearability results were secondary outcome variables. We hypothesized that anesthesiologists would correctly identify the events communicated to them through the vibro-tactile belt 90% of the time, and that anesthesiologists would find the vibro-tactile belt usable and wearable. Seventeen anesthesiologists evaluated the display during 57 cases. The belt was operational for a mean (SD) duration of 75 (41) minutes per case. Seven cases were excluded from analysis because of technical failures. Eighty-one percent (confidence interval [CI], 77% to 84%) of all stimuli were decoded. The physiological trend, the direction of change, and the level of change were correctly identified for 97.7% (CI 96%-99%), 94.9% (CI 92%-97%), and 93.5% of these stimuli (CI, 91%-96%), respectively. Fourteen anesthesiologists completed the usability and wearability questionnaires. The mean usability score was 4.8 of a maximum usability score of 7. Anesthesiologists found a vibro-tactile belt to be wearable and usable and could accurately decode vibro-tactile messages in a real-time clinical environment.


[The value of searching for additional prognostic factors in combination with Nottingham Prognostic Index in breast carcinoma patients].
One of prognostic factors known as Nottingham Prognostic Index (NPI), which is combination of known prognostic factors such as tumor size, grade and axillary node status, is recently in usage in some European countries in clinical practice in prediction of breast carcinoma patients' survival. Therefore, the aim of this study was to verify, according to our experience, the prognostic significance of Nottingham Prognostic Index (NPI) in breast carcinoma patients in association with other new prognostic factors. In this study 148 consecutive specimens of breast carcinoma patients were analyzed. The following data for each patient were collected: age, tumor size, histological grade, axillary lymph node status, overall survival, estrogen (ER), progesterone (PR) receptor expression as well as expression of bcl-2, Ki-67, nm23, HER-2/neu, and p53. The Nottingham Prognostic Index (NPI) was calculated from the pathological information and patients were grouped according to the standard NPI index into: good prognostic group (GPG), moderate prognostic group (MPG), and poor prognostic group (PPG). The correlation of prognostic groups according to the NPI with other prognostic and predictive factors such as age, ER, PR, p53, bcl-2, Ki-67, nm23, Ki-67, Cathepsin D and HER-2/neu on overall survival was analyzed. The results of univariate analysis showed statistically significant correlation between patients' age, NPI prognostic groups and stage of disease with patients survival. When other prognostic factors were correlated with NPI prognostic groups there was not additional prognostic discrimination in given prognostic groups. Only marginally statistically significant influence of p53 expression was found on patient survival between MPG and PPG. It seems that other prognostic factors in combination with NPI prognostic groups do not have in our group of patients practical clinical relevance for the management of patients with breast carcinoma.


Cryo-EM reveals a previously unrecognized structural protein of a dsRNA virus implicated in its extracellular transmission.
Mosquito viruses cause unpredictable outbreaks of disease. Recently, several unassigned viruses isolated from mosquitoes, including the Omono River virus (OmRV), were identified as totivirus-like viruses, with features similar to those of the Totiviridae family. Most reported members of this family infect fungi or protozoans and lack an extracellular life cycle stage. Here, we identified a new strain of OmRV and determined high-resolution structures for this virus using single-particle cryo-electron microscopy. The structures feature an unexpected protrusion at the five-fold vertex of the capsid. Disassociation of the protrusion could result in several conformational changes in the major capsid. All these structures, together with some biological results, suggest the protrusions' associations with the extracellular transmission of OmRV.


Histological and immunophenotypic changes in 59 cases of B-cell non-Hodgkin's lymphoma after rituximab therapy.
Rituximab is a chimeric monoclonal antibody that recognizes the CD20 antigen. It has been used to treat B-cell non-Hodgkin lymphoma (B-NHL), but recently rituximab resistance has been a cause for concern. We examined histological and immunohistochemical changes in 59 patients with B-NHL after rituximab therapy. The patients comprised 32 men and 27 women with a median age of 59 years. Pre-rituximab specimens comprised 34 follicular lymphomas (FL), 11 diffuse large B-cell lymphomas (DLBCL), 10 mantle cell lymphomas, two marginal zone B-cell lymphomas (MZBCL), and two chronic lymphocytic leukemias (CLL). CD20 expression in lymphoma cells was evaluated by immunohistochemistry or flow cytometry. Post-rituximab materials were taken a median of 6 months (4 days to 59 months) after rituximab therapy. Sixteen cases (27%) showed loss of CD20 expression with four histological patterns: pattern 1, no remarkable histological change (FL, 5; DLBCL, 3; and CLL, 2); pattern 2, proliferation of plasmacytoid cells (FL, 2; DLBCL, 1; and MZBCL, 1); pattern 3, transformation to classical Hodgkin's lymphoma (FL, 1); and pattern 4, transformation to anaplastic large cell lymphoma-like undifferentiated lymphoma (FL, 1). Loss of CD20 was unrelated to the interval of biopsies, treatment regimen, clinical response, and frequency of rituximab administration. Loss of CD20 within 1 month of rituximab therapy (3/14, 21%) and regain of CD20 (2/7, 29%) were not frequent. CD20-positive relapse with transformation occurred most frequently in cases of early relapse. In conclusion, B-NHL showed various histological and immunophenotypic changes after rituximab therapy, including not only CD20 loss but also proliferation of plasmacytoid cells or transformation to special subtypes of lymphoma.


An abscisic acid-induced protein, HVA22, inhibits gibberellin-mediated programmed cell death in cereal aleurone cells.
Plant HVA22 is a unique abscisic acid (ABA)/stress-induced protein first isolated from barley (Hordeum vulgare) aleurone cells. Its yeast homolog, Yop1p, functions in vesicular trafficking and in the endoplasmic reticulum (ER) network in vivo. To examine the roles of plant HVA22, barley HVA22 was ectopically expressed in barley aleurone cells. Overexpression of HVA22 proteins inhibited gibberellin (GA)-induced formation of large digestive vacuoles, which is an important aspect of GA-induced programmed cell death in aleurone cells. The effect of HVA22 was specific, because overexpression of green fluorescent protein or another ABA-induced protein, HVA1, did not lead to the same effect. HVA22 acts downstream of the transcription factor GAMyb, which activates programmed cell death and other GA-mediated processes. Moreover, expression of HVA22:green fluorescent protein fusion proteins showed network and punctate fluorescence patterns, which were colocalized with an ER marker, BiP:RFP, and a Golgi marker, ST:mRFP, respectively. In particular, the transmembrane domain 2 was critical for protein localization and stability. Ectopic expression of the most phylogenetically similar Arabidopsis (Arabidopsis thaliana) homolog, AtHVA22D, also resulted in the inhibition of vacuolation to a similar level as HVA22, indicating function conservation between barley HVA22 and some Arabidopsis homologs. Taken together, we show that HVA22 is an ER- and Golgi-localized protein capable of negatively regulating GA-mediated vacuolation/programmed cell death in barley aleurone cells. We propose that ABA induces the accumulation of HVA22 proteins to inhibit vesicular trafficking involved in nutrient mobilization to delay coalescence of protein storage vacuoles as part of its role in regulating seed germination and seedling growth.


Alcohol and sexual risk behaviors as mediators of the sexual victimization-revictimization relationship.
Women who experience sexual victimization, whether in childhood, adolescence, or adulthood, are at elevated risk of sexual revictimization. The mechanism responsible for this robust association is unclear, however. The present study proposed and tested a prospective, mediated model that posited that the association between adolescent and college victimization is mediated via 2 types of risk exposure in the first semester of college: alcohol-related and sexual risk behaviors. Female adolescents (N = 469) were recruited from the community at the time of high school graduation. They completed baseline assessments as well as follow-ups at the end of the first and second semesters of college. Consistent with hypotheses, adolescent sexual victimization was associated indirectly, via high school risk behaviors, with increased first-semester college risk behaviors (i.e., sexual partners, hookups, heavy episodic drinking, and heavy drinking contexts), which were, in turn, strongly predictive of sexual victimization experiences in the first year of college. College risk behaviors partially mediated the significant association between adolescent and first-year college victimization; however, even women without prior victimization faced elevated risk of college victimization with higher levels of college risk behaviors. Women who have experienced adolescent sexual victimization engage in higher levels of risk taking in college, thereby increasing vulnerability to college victimization. Intervention to reduce these primarily alcohol-related risk-taking behaviors may reduce vulnerability to college sexual victimization.


Trapping charges at grain boundaries and degradation of CH3NH3Pb(I1-x Br x )3 perovskite solar cells.
The electrical properties of CH3NH3Pb(I1-x Br x )3 (x = 0.13) perovskite materials were investigated under ambient conditions. The local work function and the local current were measured using Kelvin probe force microscopy and conductive atomic force microscopy, respectively. The degradation of the perovskite layers depends on their grain size. As the material degrades, an additional peak in the surface potential appears simultaneously with a sudden increase and subsequent relaxation of the local current. The potential bending at the grain boundaries and the intragrains is the most likely reason for the change of the local current surface of the perovskite layers. The improved understanding of the degradation mechanism garnered from this study helps pave the way toward an improved photo-conversion efficiency in perovskite solar cells.


Lymphedema of the arm after surgery for breast cancer: new physiotherapy.
Secondary lymphedema of the upper limb is a complication which can be found in patients who have undergone surgical breast cancer treatment with an axillary dissection. Lymphedema following breast cancer treatment remains a long-term disabling complication which cannot be treated in a decisive and radical manner. The objective of the treatment is to limit complications, to try to preserve the remaining lymphatic system and to develop new anastomosis. It consists of a specific decongestive physiotherapy, which may include a specific lymphatic drainage and skin mobilization, reducing bandages including Mobiderm (Thuasne), and sub-bandage muscular exercises. However variations in the therapy have been recorded by different teams. Our experience in treating lymphedema in Tunisia takes into consideration the epidemiological, climatic, cultural and socio-economic conditions of the country. The difference in our treatment compared to what is being advocated elsewhere essentially consists of the no muscular exercise while wearing a bandage. This is compensated for by daily domestic activities, by prolonging the first two phases of treatment (the intensive phase and the stabilization phase), and by the use of the hydro gel dressing Hydrosob (Hartmann) to prevent blisters induced by the pressure imposed by Mobiderm studs of the bandage on the skin, and also by the superimposition of two types of Mobiderm bandages (small and large blocks).


Alcohol, tobacco, and prescription drugs: the relationship with illicit drugs in the treatment of substance users.
Alcohol, tobacco, prescription drug, and illicit drug use frequently co-occur. This paper reviews the extent of this co-occurrence in both general population samples and clinical samples, and its impact on treatment outcome. We argue that the research base for understanding comorbidity among tobacco, alcohol, prescription, and illicit drugs needs to be broadened. We specifically advocate for: (1) more epidemiological studies of relationships among alcohol, tobacco, and other illicit drug use; and (2) increased research on treatment options that address the problematic use of all of these drugs.


[How widespread is resistance to invermectin among gastrointestinal nematodes in sheep in The Netherlands?].
In Autumn 2009, a faecal egg count reduction test (FERCT) was carried out on three sheep farms. Groups of 8-11 lambs were treated with ivermectin or moxidectin, with a 14-day interval between treatment and sampling. Ivermectin resistance was present on all three farms. Treatment with ivermectin resulted in a reduction in faecal egg numbers of 94.6%, 63%, and 59%. On two farms, 14 days after treatment pooled faecal samples yielded predominantly larvae of Hamonchus contortus (100% and 98%, respectively). On the third farm, H. contortus and (probably) Teladorsagia circumcincta were resistant to ivermectin (64% and 36% of the larvae, respectively). Treatment with moxidectin resulted in a 100% reduction in egg output in sheep on all three farms. More sensitive culture techniques failed to detect any larvae in samples taken from two farms, but a few Ostertagia-type larvae, probably of T. circumcincta, were detected in samples from the third farm. It can be concluded that gastrointestinal nematodes in sheep from these three farms were resistant to ivermectin, whereas resistance to moxidectin was not detected.


Boosted X waves in nonlinear optical systems.
X waves are spatiotemporal optical waves with intriguing superluminal and subluminal characteristics. Here we theoretically show that for a given initial carrier frequency of the system localized waves with genuine superluminal or subluminal group velocity can emerge from initial X waves in nonlinear optical systems with normal group velocity dispersion. Moreover, we show that this temporal behavior depends on the wave detuning from the carrier frequency of the system and not on the particular X-wave biconical form. A spatial counterpart of this behavior is also found when initial X waves are boosted in the plane transverse to the direction of propagation, so a fully spatiotemporal motion of localized waves can be observed.


Association of proinflammatory molecules with apoptotic markers and survival in critically ill multiple organ dysfunction patients.
Recent evidence supports the involvement of apoptosis in multiple organ dysfunction (MODS). The authors examined the hypothesis that nitric oxide (NO), interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and cortisol correlate with Fas and Fas ligand (FasL) expression on peripheral blood mononuclear cells and that Fas and FasL, therefore, mediate their association with MODS severity. Thirty-five critically ill adult MODS patients were followed for up to 14 days and were compared to non-MODS matched controls. Fas, FasL, nitrate, cortisol, and IL-6 were elevated in MODS patients (P < 0.05). Nitrate and cortisol correlated with Fas expression (P < 0.05). All factors studied, except for TNF-alpha, correlated with MODS severity (P < 0.05); however, by multivariate analyses, Fas and FasL were independently associated with severity and survival (P < 0.05). The inflammatory molecules studied may mediate the association of apoptotic constituents with MODS severity and survival only in part.


Are we undertreating carotid stenoses diagnosed by ultrasound alone?
Clinical management of carotid disease is primarily based on results of national trials (ACAS and NASCET) that used the distal internal carotid artery diameter as a reference. However, commonly accepted ultrasound (US) criteria for carotid stenosis were derived from the correlation of velocity measurements with angiographic bulb diameter reductions (BDR). This study was undertaken to compare the degree of carotid stenosis determined by conventional velocity criteria to the degree of stenosis measured by B-mode (gray scale) diameter at both the carotid bulb and at the distal internal carotid artery, and, second, to evaluate US imaging to derive distal diameter reductions (DDR) noninvasively. During a 3-month period patients referred for carotid US were prospectively analyzed for standard velocity criteria and plaque morphology. Minimum carotid diameter was measured by longitudinal and transverse B-mode measurements and compared to carotid bulb diameter and internal carotid diameter distal to all disease. B-mode diameter reductions were compared to the degree of stenosis determined by velocity criteria and to patient symptoms and the decision for carotid endarterectomy. In total, 131 carotid arteries in 74 patients were evaluated. Based on the University of Washington velocity criteria, lesions were classified as grade I (n = 61, 46%), IIA (n = 58, 44%), IIB (n = 7, 5%), or III (n = 5, 4%). BDR measured by B-mode predicted the grade of disease based on velocity criteria (p < 0.001) with an overall accuracy of 95%. With use of the B-mode for DDR (NASCET style), 18 patients exceeded the 60% threshold for surgical intervention. Of these, only 3 patients were symptomatic and were operated on. An additional 3 operated-on patients had an asymptomatic grade III stenosis, our usual threshold for intervention. Twelve additional patients were appropriate for surgical intervention by B-mode but were not treated based on conventional velocity criteria alone. Bulb diameter reduction by B-mode imaging correlates strongly with diameter reduction determined by velocity criteria, and independently predicts the grade of carotid disease. With this in mind, the accuracy of B-mode imaging may be extended to the measurement of carotid stenosis based on DDR. By B-mode criteria, many patients appropriate for intervention were not offered treatment based on conventional velocity criteria. Modern B-mode imaging provides a noninvasive method to obtain 'arteriographic equivalent'' measurements and should be added as a routine to carotid ultrasound interrogation.


[Benign osteoblastoma of the parietal bones].
Benign osteoblastoma accounts for less than 1% of the primary bone tumors and the calvarial lesion is extremely rare. There are only 12 reported cases in the literature as far as we could collect. We have presented a case of benign osteoblastoma originated from the parietal bone. This 9-year-old boy struck his head on the parietal region and noticed the bulging at the same site. A month later he visited to Fukuoka University Hospital because of persistent bulging of the same site. Neurological examinations were normal. Plain skull roentgenogram on Towne view showed radiolucent area in the midline of parietal bones with irregular margins and in tangential view the outer table revealed thinning and expanding. Coronal CT scan demonstrated same abnormality and intact inner table. The tumor was located within the dipole in the bilateral parietal bones and was removed by a simple curettage. The microscopic feature showed numerous osteoblasts, osteoblastic rimming and many multinucleated giant cells. These indicated a typical benign osteoblastoma. He has been doing well one year after the operation without any evidence of recurrence.


Polymeric Composite Matrix with High Biobased Content as Pharmaceutically Relevant Molecular Encapsulation and Release Platform.
Drug delivery systems (DDS) that can temporally control the rate and extent of release of therapeutically active molecules find applications in many clinical settings, ranging from infection control to cancer therapy. With an aim to design a locally implantable, controlled-release DDS, we demonstrated the feasibility of using cellulose nanocrystal (CNC)-reinforced poly (l-lactic acid) (PLA) composite beads. The performance of the platform was evaluated using doxorubicin (DOX) as a model drug for applications in triple-negative breast cancer. A facile, nonsolvent-induced phase separation (NIPS) method was adopted to form composite beads. We observed that CNC loading within these beads played a critical role in the mechanical stability, porosity, water uptake, diffusion, release, and pharmacological activity of the drug from the delivery system. When loaded with DOX, composite beads significantly controlled the release of the drug in a pH-dependent pattern. For example, PLA/CNC beads containing 37.5 wt % of CNCs showed a biphasic release of DOX, where 41 and 82% of the loaded drug were released at pH 7.4 and pH 5.5, respectively, over 7 days. Drug release followed Korsmeyer's kinetics, indicating that the release mechanism was mostly diffusion and swelling-controlled. We showed that DOX released from drug-loaded PLA/CNC composite beads locally suppressed the growth and proliferation of triple-negative breast cancer cells, MBA-MB-231, via the apoptotic pathway. The efficacy of the DDS was evaluated in human tissue explants. We envision that such systems will find applications for designing biobased platforms with programmed stability and drug delivery functions.


[Diagnosis and management of Crohn disease complicated with gastrointestinal fistulae].
To investigate the diagnosis and treatment of patients with Crohn disease (CD) complicated with gastrointestinal fistulae. Clinical data of sixty-two cases with CD complicated with gastrointestinal fistula e from 1978 to 2004 were analyzed. These were 68 external fistulae in 6 2 patients including recurrent fistulae in 6 cases, internal fistulae in 8 cases . Twenty- seven fistulae were located in the terminal ileum and 21 fistulae wer e located in ileocolic anastomosis site. The main surgery included 14 ileocecal resections with primary anastomosis and 26 resections of original ileocolic anastomosis with fistula and re-anastomosis. The incidence of recurrence was lower (15.4% ) in patients with postoperative medication including sulfasalazine and immunomodulator than that (34.8% ) in patients without postoperative immunomodulator,but the recurrence time was longer [(40+/- 17) months] in patients with postoperative medication than that [(8+/- 3)months] in the patients without postoperative specific medication. Most CD fistulae are external fistulae,most of the external fistulae are treated by resection of the fistula and anastomosis. Specific medication including sulfasalazine,mesalamine and immunomodulators should be used to prevent postoperative complications and CD recurrence.


Haplotype analysis of beta-actin gene for its association with sperm quality and boar fertility.
beta-actin (ACTB) was examined as a direct functional candidate gene for the possible association with sperm concentration, motility (MOT), semen volume per ejaculate, plasma droplet rate, abnormal sperm rate (ASR) and the fertility traits, non-return rate and number of piglets born alive (NBA). Three polymorphisms in intron 3 (T>C) and one polymorphism in exon 4 (T>C) of porcine ACTB gene were identified by comparative sequencing of animals of the breeds Pietrain and Hampshire. Association analysis revealed that haplotypes affected the variation of the traits MOT, ASR and NBA. The beneficial haplotypes may provide considerable improvement of sperm quality and fertility in the tested commercial boar population.


Toward robust phase-locking in Melibe swim central pattern generator models.
Small groups of interneurons, abbreviated by CPG for central pattern generators, are arranged into neural networks to generate a variety of core bursting rhythms with specific phase-locked states, on distinct time scales, which govern vital motor behaviors in invertebrates such as chewing and swimming. These movements in lower level animals mimic motions of organs in higher animals due to evolutionarily conserved mechanisms. Hence, various neurological diseases can be linked to abnormal movement of body parts that are regulated by a malfunctioning CPG. In this paper, we, being inspired by recent experimental studies of neuronal activity patterns recorded from a swimming motion CPG of the sea slug Melibe leonina, examine a mathematical model of a 4-cell network that can plausibly and stably underlie the observed bursting rhythm. We develop a dynamical systems framework for explaining the existence and robustness of phase-locked states in activity patterns produced by the modeled CPGs. The proposed tools can be used for identifying core components for other CPG networks with reliable bursting outcomes and specific phase relationships between the interneurons. Our findings can be employed for identifying or implementing the conditions for normal and pathological functioning of basic CPGs of animals and artificially intelligent prosthetics that can regulate various movements.


Liquid gradient in two-dimensional matrix for high throughput screening.
Based on the ingenious combination of two different gradient generation mechanisms, this work reports a novel approach for a high throughput linear liquid gradient in a two-dimensional (2D) matrix. Specifically, a typical Christmas Tree structure with two inlets was designed as the first mixture gradient generator, upon which the second diffusion gradient generator was coupled to produce the desired concentration series on the basis of the distance difference. Rather than a simple 1D line, the integration of the two generators would result in an innovative 2D matrix of reservoirs, which was then characterized both theoretically and experimentally. Theoretically, calculation of fluid field demonstrated the formation of a concentration gradient, which was then confirmed by the dye solution visualization analysis. For high throughput screening application, doxorubicin (Dox) was then selected as model medicine to treat the acute myeloblastic leukemia (HL-60) cells. Cell viability displayed that cell death rate enhanced with the increase of drug concentration, and this result was higher than that on a 96-well plate, and the corresponding mechanism was properly discussed. Subsequently, Dox and quercetin were employed simultaneously to generate an overlapping gradient and its effect on HL-60 cells was investigated. Due to the automatic formation of concentration gradient that could improve the work efficiency, this work provides a promising tool for future high throughput drug screening.


Increased frequency of Sjögren's syndrome in patients with spondyloarthropathy.
To determine the prevalence of sicca symptoms and Sjögren's syndrome (SS) in spondyloarthropathy (SpA) patients with ankylosing spondylitis (AS) and undifferentiated SpA (uSpA). Patients with SpA with inflammatory back pain and/or peripheral arthritis presenting to the university outpatient clinic were diagnosed as AS (n = 40) and uSpA (n = 65) according to established criteria. Patients with SpA with sicca symptoms and/or positive antinuclear antibody (ANA) were investigated for SS by minor salivary gland biopsy and/or sialography. To assess sicca symptoms in this cohort systematically we mailed a validated questionnaire with 6 questions on dryness of eyes and mouth to all 105 SpA patients and 150 healthy controls, a positive answer to > or = 3 questions was taken as suggestive of SS. There was no significant difference in baseline characteristics between patients and controls. In 8/105 SpA patients (5 uSpA, 3 AS; 6 female, 2 male) SS diagnosis by the European criteria indicated a frequency of 7.6%. Of 105 SpA patients, 12 were ANA+ (11.4%), of whom 7 had SS; thus, ANA were detected in 7/8 SpA patients with SS (88%). Of the 84 SpA patients responding to the questionnaire (80%), 10 gave a positive answer to > or = 3 questions (11.9%) compared to 2 of 131 (1.5%) controls (87.3%) (odds ratio = 8.7, 95% CI 2.3-32.5, p < 0.01). The data suggest increased prevalence of sicca symptoms and SS in SpA patients with AS and uSpA. The occurrence of a secondary SS in a variety of inflammatory diseases suggests that salivary gland involvement in these conditions results from as yet unidentified shared pathogenic mechanisms resulting in nonspecific inflammation in this location.


Harmonic forcing of an extended oscillatory system: homogeneous and periodic solutions.
In this paper we study the effect of external harmonic forcing on a one-dimensional oscillatory system described by the complex Ginzburg-Landau equation (CGLE). For a sufficiently large forcing amplitude, a homogeneous state with no spatial structure is observed. The state becomes unstable to a spatially periodic "stripe" state via a supercritical bifurcation as the forcing amplitude decreases. An approximate phase equation is derived, and an analytic solution for the stripe state is obtained, through which the asymmetric behavior of the stability border of the state is explained. The phase equation, in particular the analytic solution, is found to be very useful in understanding the stability borders of the homogeneous and stripe states of the forced CGLE.


Factors affecting mechanical nociceptive thresholds in healthy sows.
To describe anatomical and methodological factors influencing mechanical nociceptive thresholds (MNTs) and intra-site variability in healthy sows. Prospective, randomized validation. Eight pregnant, healthy, mixed-parity sows (176-269 kg). Repeated MNT measurements were taken: 1) with a hand-held probe and a limb-mounted actuator connected to a digital algometer; 2) at nine landmarks on the limbs and tail; and 3) at 1 and 3 minute intervals. Data were analysed using linear mixed regression models. The MNTs (±SEM) of the limbs were lower with the probe (14.7 ± 1.2 N) than with the actuator (21.3 ± 1.2 N; p < 0.001), in the pelvic versus the thoracic limbs (16.7 ± 1.2 versus 19.2 ± 1.2 N; p < 0.001), and in the lateral versus the dorsal metatarsi and metacarpi (17.6 ± 1.2 versus 18.4 ± 1.2 N; p = 0.002). MNTs were higher in all subsequent measurements compared with the first (p < 0.001) and in the morning compared with the afternoon (p = 0.04). We found no evidence of MNT differences based on interval between consecutive measurements (1 versus 3 minutes). Variability was lower in the thoracic limbs [mean back-transformed log10 coefficient of variation (CV) ± SE = 25.5 ± 1.5% versus 30.6 ± 1.5% in the pelvic limbs; p < 0.001], with the actuator (22.7 ± 1.5% versus 33.4 ± 1.5% with the probe; p < 0.001), and on the left (CV = 26.9 ± 1.5% versus 29.3 ± 1.5% on the right; p = 0.01). Tail data (probe only) were analysed separately: mean MNT (± SE) was 11.7 (±1.8); MNT increased in days 3-6 of testing compared with day 1 (p < 0.001). The mean CV (±SE) was 38.9% (±1.1%). MNTs and intra-site variability in healthy sows were affected by several factors, indicating that this methodology requires considerable attention to detail.


Surface-based laminar analysis of diffusion abnormalities in cortical and white matter layers in neocortical epilepsy.
Microstructural alterations seen in the epileptic cortex have been implicated as a cause and also result of multiple seizure activity. In the present study, we evaluated water diffusion changes at different cortical thickness fractions and in the underlying white matter of the epileptic cortex and compared them with electrographically normal cortex and also with corresponding cortical regions of healthy controls. We selected 18 children with normal magnetic resonance imaging (MRI) who underwent two-stage epilepsy surgery to control seizures of neocortical origin, and compared their MR images with those of 18 age-matched healthy controls. First, delineation of the gray-white and gray-pial intersection surfaces was performed on high-resolution volumetric T1 MR images. Using the delineated surfaces as reference, diffusion values were measured at different cortical thickness fractions and in the underlying white matter at various depths, using diffusion tensor imaging (DTI). Cortical regions representing seizure onset and electrographically normal cortex were differentiated by electrocorticography in the epilepsy patients. We observed different patterns of diffusion abnormalities in both the seizure onset and electrographically normal cortical regions when compared to healthy controls. In the seizure-onset regions, a marked increase in diffusivity was noted in the cortical gray matter, and this increase was most pronounced in the outer fraction of the gray matter. Similarly, increased diffusivity was noted in the white matter underlying the epileptic cortex. The electrographically normal cortex, in contrast, showed decreased diffusivity in inner and middle cortical fractions compared to the controls. The white matter underlying the electrographically normal cortex did not show any difference in diffusivity between the children with epilepsy and controls. Finally, both the cortical gray matter and the underlying white matter regions showed decreased anisotropy in epileptic as well as electrographically normal regions when compared to controls. Our results suggest specific patterns of diffusion changes in the cortical fractions and the underlying white matter of the epileptic region compared to electrographically normal and normal control regions. The abnormal increase in diffusivity of the superficial cortex might be associated with microstructural abnormalities commonly seen in layers II through IV of epileptic cortex. Such combined use of a high-resolution structural image to extract the laminar diffusion values, which are highly sensitive to microstructural alterations, could be of clinical value in localizing epileptogenic cortex.


A new bis-seco-abietane diterpenoid from Hyptis crenata Pohl ex Benth.
A new, highly oxidized, bis-seco-abietane diterpenoid named hyptisolide A (1) was isolated from Hyptis crenata Pohl ex Benth. Its structure and stereochemistry were elucidated on the basis of data obtained by HRESIMS, NMR, and X-ray diffraction analyses, and its absolute configuration was determined with vibrational circular dichroism spectroscopy. By reporter gene assay, 1 was demonstrated to induce cAMP-responsive element-dependent transcription in Neuro2A cells.


Suppressing the activity of trehalase with validamycin disrupts the trehalose and chitin biosynthesis pathways in the rice brown planthopper, Nilaparvata lugens.
Trehalase (TRE) is a key enzyme in trehalose degradation and has important functions in insect growth and chitin synthesis. Though validamycin has the potential for pest control by suppressing TRE activities, it is not known whether validamycin acts on both trehalose and chitin metabolism. TRE1 and TRE2 activities and glucose and glycogen contents decreased significantly after the injection of different doses of validamycin solution compared with the control group, while the trehalose content increased significantly. Overall, it showed that about 13 to 38% insects was appeared abnormal phenotypes, and 10 to 57% of insects died 48h after injection of solutions with different concentrations of validamycin; the chitin content also decreased significantly. Validamycin altered the relative expression levels of trehalose, glycogen and chitin metabolism-related genes by suppressing the activities of two TREs. We showed that the expression levels of three TRE and two trehalose-6-phosphate synthase (TPS) genes increased, while the expression levels of GP; CHS1 and its two transcripts, CHS1a, CHS1b; six chitinases, including Cht3, Cht4, Cht5, Cht6, Cht7, Cht9; and the HK, G6PI2, GFAT, GNPNA, PAGM1, UAP, VVL, CI and AP genes decreased significantly 48h after the injection of any validamycin concentration compared with the control group. These results demonstrate that by inhibiting the activities of two TREs, validamycin alters N. lugens chitin synthesis and degradation and affects trehalose and chitin metabolism-related gene expression. The development of TRE inhibitors may provide effective pest control in the future.


The clinical outcomes of neonatal and childhood stroke: review of the literature and implications for future research.
A detailed assessment of clinical outcomes after ischemic stroke in childhood is necessary to evaluate prognostic factors. Previous studies are difficult to compare because of differences in test instruments, study design, heterogeneity of cohorts and number of included cases. Depending on neurodevelopmental assessment methods, major and subtle/minor disabilities, especially in infants, may not have been detected. Most outcome studies reveal only limited information about behavioral changes and quality of life in children with ischemic stroke. Thus the assumption that children make a better recovery from stroke than adults due to the immature brain's capacity to reorganize function is not evidence-based. We systematically review the current literature with regard to the neurological and psychosocial development of affected children as well as their quality of life. Implications for future research strategies follow the review to encourage further clinical study of the neurobehavioral trajectory of childhood stroke.


What can be learned from the experience with the fixed low-dose combination of perindopril/indapamide in the treatment of hypertension?
The association of low doses of perindopril and indapamide in a single pill has been developed to meet the criteria required for a fixed-dose combination to be used as first-line therapy. The experience accumulated so far has demonstrated a greater antihypertensive efficacy of this preparation compared with various monotherapies, but not at the expense of a worsening of tolerability. The perindopril/indapamide combination is particularly effective in lowering systolic and pulse blood pressure. Starting treatment with this fixed-dose combination improves arterial stiffness and allows a better regression of cardiac hypertrophy than angiotensin-converting enzyme-inhibition or beta-adrenoceptor blockade alone. In hypertensive patients with Type 2 diabetes, a greater reduction of urinary albumin excretion can be obtained with the perindopril/indapamide association compared with an angiotensin-converting enzyme inhibitor administered as monotherapy. There is evidence that a first-line management of hypertension based on a low-dose perindopril/indapamide combination can provide a better efficacy/safety ratio than other well-established therapeutic strategies.


[Transient expression and characterization of intracellular single chain Fv against the nucleocapsid protein of Hantavirus].
To transiently express an intracellular single chain Fv of monoclonal antibody 1A8 against nucleocapsid protein of Hantavirus and characterize the immunological activities of the expressed products. COS-7 cells were transfected with mammalian expression vector 1A8-scFv-Ckappa/pCI-neo via lipofectin. The expressed product was identified by indirect immunofluorescence and immunoprecipitation. A diffuse pattern fluorescence was observed in less than 1% cytoplasm of transfected COS-7 cells. The binding of intracellular antibody fragments to NP antigen was confirmed by immunoprecipitation analysis. Transiently expressed single chain intrabodies can effectively target NP antigen in the cytoplasm. The present study may provide a new approach for treatment of Hantavirus.


Peritoneal Dialysis to Treat Patients with Acute Kidney Injury-The Saving Young Lives Experience in West Africa: Proceedings of the Saving Young Lives Session at the First International Conference of Dialysis in West Africa, Dakar, Senegal, December 2015.
In December 2015, as part of the First African Dialysis Conference organized in Dakar, Senegal, 5 physicians from West African countries who have participated in the Saving Young Lives Program reviewed their experiences establishing peritoneal dialysis (PD) programs to treat patients with acute kidney injury (AKI). Thus far, nearly 200 patients have received PD treatment in these countries. The interaction and discussion amongst the participants at the meeting was meaningful and informative. The presentations highlighted the creativity, conviction, and determination of the physicians in overcoming the various barriers and challenges they encountered to establish PD/AKI programs. Hopefully, these successes and the increased awareness of the importance of early diagnosis and treatment of AKI will inspire much needed support from government, hospital, and international organizations.


Determination of gestational age by beta-subunit HCG measurement.
The accurate knowledge of gestational age is important in most Obstetric decisions near term. Gestational age estimation by a single measurement of beta-subunit HCG in early pregnancy was assessed in 164 Nigerian Women attending the antenatal clinic of Jos University Teaching Hospital. The mean difference between estimated gestational age by HCG concentrations and by recorded dates of last menstrual period was 2.8 +/- 1.6 days (mean +/- SD). This relationship was valid only for samples randomly selected between 35 and 56 days of gestation. We conclude that single measurement of HCG in early pregnancy provides accurate estimation of gestational age.


Skills training treatment for adaptive affect regulation in a woman with binge-eating disorder.
This case study describes a skills training treatment for binge eating which focused on teaching adaptive affect regulation. A 36-year-old obese woman with a long history of severe binge eating received individual treatment specifically aimed at enhancing her emotion regulation abilities. By treatment end she no longer met criteria for binge eating disorder.