Sirolimus inhibits growth of human hepatoma cells alone or combined with tacrolimus, while tacrolimus promotes cell growth.
Standard immunosuppression after organ transplantation stimulates tumor growth. Sirolimus has a strong antiproliferative and a tumor inhibiting effect. The purpose is to assess the effect on tumor growth of the immuno-suppressive compounds sirolimus and tacrolimus alone and in combination on cells of human hepatocellular carcinoma. We used the human cell lines SK-Hep 1 and Hep 3B derived from hepatocellular carcinoma. Proliferation analyses after treatment with sirolimus, tacrolimus, or the combination of both were performed. FACS analyses were done to reveal cell cycle changes and apoptotic cell death. The expression of apoptosis-related proteins was estimated by Western blots. Sirolimus alone or combined with tacrolimus inhibited the growth of both cell lines after 5 d by up to 35% in SK-Hep 1 cells, and by up to 68% in Hep 3B cells at 25 ng/mL. Tacrolimus alone stimulated the growth by 12% after 5 ng/mL and by 25% after 25 ng/mL in Hep 3B cells. We found an increase of apoptotic Hep 3B cells from 6 to 16%, and a G1-arrest in SK-Hep 1 cells with an increase of cells from 61 to 82%, when sirolimus and tacrolimus were combined. Bcl-2 was down-regulated in Hep 3B, but not in SK-Hep 1 cells after combined treatment. Sirolimus appears to inhibit the growth of hepatocellular carcinoma cells alone and in combination with tacrolimus. Sirolimus seems to inhibit the growth stimulation of tacrolimus.


Robust preprocessing for stimulus-based functional MRI of the moving fetus.
Fetal motion manifests as signal degradation and image artifact in the acquired time series of blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) studies. We present a robust preprocessing pipeline to specifically address fetal and placental motion-induced artifacts in stimulus-based fMRI with slowly cycled block design in the living fetus. In the proposed pipeline, motion correction is optimized to the experimental paradigm, and it is performed separately in each phase as well as in each region of interest (ROI), recognizing that each phase and organ experiences different types of motion. To obtain the averaged BOLD signals for each ROI, both misaligned volumes and noisy voxels are automatically detected and excluded, and the missing data are then imputed by statistical estimation based on local polynomial smoothing. Our experimental results demonstrate that the proposed pipeline was effective in mitigating the motion-induced artifacts in stimulus-based fMRI data of the fetal brain and placenta.


Noncontrast MR angiography for comprehensive assessment of abdominopelvic arteries using quadruple inversion-recovery preconditioning and 3D balanced steady-state free precession imaging.
To develop a noncontrast magnetic resonance angiography (MRA) method for comprehensive evaluation of abdominopelvic arteries in a single 3D acquisition. A noncontrast MRA (NC MRA) pulse sequence was developed using four inversion-recovery (IR) pulses and 3D balanced steady-state free precession (b-SSFP) readout to provide arterial imaging from renal to external iliac arteries. Respiratory triggered, high spatial resolution (1.3 × 1.3 × 1.7 mm(3)) noncontrast angiograms were obtained in seven volunteers and ten patients referred for gadolinium-enhanced MRA (CE MRA). Images were assessed for diagnostic quality by two radiologists. Quantitative measurements of arterial signal contrast were also performed. NC MRA imaging was successfully completed in all subjects in 7.0 ± 2.3 minutes. In controls, image quality of NC MRA averaged 2.79 ± 0.39 on a scale of 0-3, where 3 is maximum. Image quality of NC MRA (2.65 ± 0.41) was comparable to that of CE MRA (2.9 ± 0.32) in all patients. Contrast ratio measurements in patients demonstrated that NC MRA provides arterial contrast comparable to source CE MRA images with adequate venous and excellent background tissue suppression. The proposed noncontrast MRA pulse sequence provides high-quality visualization of abdominopelvic arteries within clinically feasible scan times.


Setting positive end-expiratory pressure in the severely obstructive patient.
The response to positive end-expiratory pressure (PEEP) in patients with chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation depends on the underlying pathophysiology. This review focuses on the pathophysiology of COPD, especially intrinsic PEEP (PEEPi) and its consequences, and the benefits of applying external PEEP during assisted ventilation when PEEPi is present. The presence of expiratory airflow limitation and increased airway resistance promotes the development of dynamic hyperinflation in patients with COPD during acute respiratory failure. Dynamic hyperinflation and the associated development of PEEPi increases work of breathing and contributes to ineffective triggering of the ventilator. In the presence of airflow limitation, application of external PEEP during patient-triggered ventilation has been shown to reduce inspiratory effort, facilitate ventilatory triggering and enhance patient-ventilator interaction. To minimize the risk of hyperinflation, it is advisable to limit the level of external PEEP during assisted ventilation after optimization of ventilator settings to about 70% of the level of PEEPi (measured during passive ventilation). In patients with COPD and dynamic hyperinflation receiving assisted mechanical ventilation, the application of low levels of external PEEP can minimize work of breathing, facilitate ventilator triggering and improve patient-ventilator interaction.


Depression in general practice -- consultation duration and problem solving therapy.
General practitioners have expressed concern that consultations offering psychological therapy approaches will take up too much time. However, problem solving therapy (PST) for depression may be able to be used within the time constraints of general practice. This study investigates whether GPs' concerns that PST would result in unacceptably long consultations are justified. general practitioners were observed providing PST in simulated consultations before and after PST training - PST skill and duration of consultations were measured. Twenty-four GPs participated. Problem solving therapy skill increased markedly, but mean consultation duration changed minimally: 17.3 minutes and 17.9 minutes. This research suggests that GPs can provide an evidence supported psychological treatment for depression within the time constraints of routine practice. The structured nature of PST may allow GPs to provide additional mental healthcare for depression, without significantly increasing consultation duration. It suggests GPs' concerns about the time PST may take up in practice may be unjustified and that further research into the use of PST in routine general practice should be undertaken.


Looking Māori predicts decreased rates of home ownership: institutional racism in housing based on perceived appearance.
This study examined differences in rates of home ownership among Māori (the indigenous peoples of New Zealand). We identified systematic factors that predicted why some Māori were more likely to own their own home (partially or fully) relative to other Māori. Data were drawn from a large national postal sample of 561 self-identified Māori collected as part of the New Zealand Attitudes and Values Study. As predicted, our analyses indicated that self-reported appearance as Māori, or the extent to which people thought they personally displayed features which visibly identified them as Māori to others, significantly predicted decreased rates of home ownership. This association held when adjusting for numerous demographic covariates, such as education, level of deprivation of the immediate area, household income, age, relationship status, region of residence, and so forth. Our analyses suggest there is, or at least has been in the recent past, institutional racism against Māori in New Zealand's home lending industry based on merely appearing more Māori.


Quantitation of HeLa cell monolayer invasion by Shigella and Salmonella species.
A major determinant in the virulence of Salmonella and Shigella spp. is the ability of these organisms to invade epithelial cells of the gastrointestinal mucosa and multiply intracellularly. The invasion of cell culture monolayers is a convenient experimental system to evaluate eucaryotic cell penetration and is correlated with the potential of a strain to cause human disease. We have developed an agarose-L agar overlay technique which allows for the convenient quantitation of the number of infected tissue culture cells in a monolayer. Bacterial strains were introduced onto antibiotic-free HeLa cell monolayers. Infected monolayers were washed, and noninternalized bacteria were counterselected with kanamycin (50 micrograms/ml). The number of infected HeLa cells present was determined by overlaying the monolayer with distilled water-agarose (0.5 to 1.5%) followed by an equal volume of 2X L agar. Bacterial colonies formed over infected cells in 24 h at 37 degrees C, and wells were counted with a dissecting microscope under X2 power. Bacterial colonies were not observed with noninvasive variants of Shigella spp. To obtain countable wells (20 to 200 CFU) the multiplicity of infection or invasion times were adjusted. With a 90-min invasion time, the invasive potential of a strain was reflected by the multiplicity of infection needed to produce countable wells. The quantitation of bacterium-invaded cells by using standard bacteriological methods is a convenient and rapid method to evaluate the invasive potential of bacterial strains. Additionally, parameters essential for the invasive process can easily be investigated.


Confocal fluorescence microscopy to evaluate changes in adipocytes in the tumor microenvironment associated with invasive ductal carcinoma and ductal carcinoma in situ.
Adipose tissue is a dynamic organ that provides endocrine, inflammatory and angiogenic factors, which can assist breast carcinoma cells with invasion and metastasis. Previous studies have shown that adipocytes adjacent to carcinoma, known as cancer-associated adipocytes, undergo extensive changes that correspond to an "activated phenotype," such as reduced size relative to adipocytes in non-neoplastic breast tissue. Optical imaging provides a tool that can be used to characterize adipocyte morphology and other features of the tumor microenvironment. In this study, we used confocal fluorescence microscopy to acquire images of freshly excised breast tissue stained topically with proflavine. We developed a computerized algorithm to identify and quantitatively measure phenotypic properties of adipocytes located adjacent to and far from normal collagen, ductal carcinoma in situ and invasive ductal carcinoma. Adipocytes were measured in confocal fluorescence images of fresh breast tissue collected from 22 patients. Results show that adipocytes adjacent to neoplastic tissue margins have significantly smaller area compared to adipocytes far from the margins of neoplastic lesions and compared to adipocytes adjacent to non-neoplastic collagenous stroma. These findings suggest that confocal microscopic images can be utilized to evaluate phenotypic properties of adipocytes in breast stroma which may be useful in defining alterations in microenvironment that may aid in the development and progression of neoplastic lesions.


Multipass absorption cell designed for high temperature UHV operation.
This paper describes the design and performance of a tunable diode laser system, incorporating a multipass absorption cell to allow determination of water concentration below 10 ppb and carbon dioxide concentration below 1 ppb in nitrogen semiconductor gas. The cell is used with a tunable Pb-salt diode laser spectrometer frequency locked to a first derivative error signal from an intense vibration-rotation molecular absorption line. Sample concentrations are monitored in the second derivative mode, and the system automatically compensates for laser intensity fluctuations. A flowing gas method is used to minimize adsorption/desorption effects from the sample cell walls.


Correlation between Health Literacy and Quality of Life in Iranian Menopausal Women.
Understanding the factors that promote quality of life (QOL) in menopausal women is essential for establishing educational strategies and health policies. Studies on the relationship between health literacy and QOL in menopausal women in Iran are rare. Therefore, we aimed to determine health literacy in menopausal women and its relationship with QOL. The present cross-sectional study was performed on 177 menopausal women referred to comprehensive health services in Hamadan City, Iran. Health Literacy for Iranian Adults and Menopause-Specific QOL questionnaires were used to collect information. Pearson correlation coefficient was used to assess the correlation between health literacy and QOL. The majority of menopausal women included in this study were married housewives, and 44.6% of them were 50-55 years old; furthermore, only 6.2% had adequate or good health literacy. Health literacy was significantly correlated with total QOL score and vasomotor, psychology, and physical domains (P < 0.05). Health literacy was associated with various domains of QOL. Therefore, health providers should pay more attention on improving health literacy by holding educational promotional programs for menopausal women to enhance their QOL.


Eosinophilia and eosinophil helminthotoxicity in patients treated for Schistosoma mansoni infections.
The changes in eosinophil levels and in eosinophil-mediated antibody-dependent schistosomular cytotoxicity, following treatment for Schistosoma mansoni infections, have been investigated in 2 similar groups of patients aged 15-50 years. Patients in group 1 were treated with either hycanthone or oxamniquine, and those in group 2 with hycanthone or praziquantel. Eosinophil levels were significantly increased in both groups. In group 1 peripheral blood eosinophil counts rose from a mean of 175/microliters before treatment to 745/microliters 3 weeks after treatment, and in group 2 from 181/microliters to 1066/microliters. The increase in eosinophil levels was positively correlated with a rise in circulating anti-adult worm antibodies (r = -0.587, P less than 0.05), whereas a negative correlation was recorded with anti-egg antibodies (r = -0.727). Despite some enhanced eosinophil helminthotoxicity following treatment in some of the individuals in group 1 (7/15), the change overall was not significant. In group 2, in which a different standard anti-schistosomular antibody was used, the eosinophil killing capacity recorded at 3 weeks was lower than that before commencement of treatment (t = 2.89, P less than 0.01). The eosinophil stimulating activity, detected in cultured mononuclear cell supernatants (MCS) from individual patients, correlated with eosinophil levels (r = 0.582, P less than 0.02) but there was no association with eosinophil killing. MCS activity did not appear to be boosted by treatment. These studies showed that peripheral blood eosinophil counts were increased following treatment, but their ability to kill schistosome larvae is variable and may depend on the immune serum used as the source of anti-schistosomular antibody.


Association of medical treatment nonadherence with all-cause mortality in newly treated hypertensive US veterans.
Nonadherence to antihypertensive drugs is associated with adverse outcomes; however, mediators of this relationship are poorly understood. We examined the association between the International Classification of Diseases-Ninth Revision code for medical treatment nonadherence (V15.81) assigned before initiation of antihypertensive drug therapy and all-cause mortality in a large cohort of incident hypertensive US veterans. A propensity score-matched cohort of 18 822 patients (9411 patients with and without a V15.81 code) was generated based on variables predictive of the presence of the V15.81 code to assess its independent association with all-cause mortality during 3.8 years of follow-up. We used Cox models before and after adjustment for antihypertensive drug adherence (measured as the proportion of days covered) and for measures of blood pressure to determine whether the association of nonadherence with mortality was mediated through consequences of not following prescribed antihypertensive drugs. At baseline, the mean age of patients was 50.0 years, 91.4% were men, and 33.2% were blacks. The V15.81 code presence was associated with higher all-cause mortality (hazard ratio, 1.38, 95% confidence interval, 1.26-1.52; P<0.001). Adjustment for medication adherence, blood pressure levels, and blood pressure variability during follow-up did not alter the association between the V15.81 code and all-cause mortality (hazard ratio, 1.35; 95% confidence interval, 1.20-1.52; P<0.001). In conclusion, assignment of a V15.81 code before antihypertensive drug therapy was associated with higher all-cause mortality in incident hypertensive US veterans and can be useful to identify high-risk patients in administrative databases. This association was not mediated by worse adherence to antihypertensive drugs or differences in follow-up blood pressure.


Childhood Experiences and High-Intensity Drinking Among American Indian and Alaska Native Adults: Findings From the 2000-2015 National Alcohol Surveys.
The purpose of this study was to examine associations with high-intensity drinking (HID) in American Indian/Alaska Native (AI/AN) populations and compare them to White and other minority groups using four National Alcohol Surveys, 2000 to 2015 (total N = 29,571; AI/ANs = 434). Current drinking and HID (8+ and 12+ drinks on any day) from maximum drinks in the prior 12 months were analyzed with independent variables and race/ethnicity (AI/AN, non-Hispanic White, and other racial/ethnic groups combined). Adjusted logistic regression models comprised gender, age, marital status, employment, education, survey year, rurality, and especially, childhood trauma (physical/sexual abuse), and biological family alcohol problem history (each dichotomous). In adjusted population models, Whites had twice the odds of current drinking as AI/ANs, with no difference between other racial/ethnic groups and AI/ANs. Descriptively, AI/AN drinkers consumed at higher intensity levels than other groups, with higher prevalence of childhood trauma and family problem drinking than others. However, on a population basis, adjusting for all factors, apparent differences between AI/AN and White HID were eliminated; other minority groups together, compared with AI/ANs, showed lower odds of consuming 8+ drinks. AI/ANs had a higher prevalence of childhood trauma and family alcohol problems as well as lower current drinking likelihood compared with Whites. In adjusted population models, the combined other minorities group was less likely to ever consume 8+ drinks than AI/ANs. In all populations, childhood trauma and family alcohol problems increased the risk of HID, strongly so in AI/ANs. Addressing childhood trauma and family problems is important among AI/ANs to break generational cycles of drinking extreme amounts per occasion.


A non-virion surface antigen on Moloney sarcoma virus-transformed non-producer and producer cells.
Sera from STU mice bearing sarcomas induced by cells producing the Moloney sarcoma-helper-virus (M-MSV/MLV) complex were cytotoxic for these cells as well as for M-MSV non-producer and M-MLV producer cells. Analysis by polyacrylamide gel electrophoresis of 125I-labelled surface antigens immunoprecipitated with such sera revealed the virus envelope glycoprotein gp71 on the producer cells and an additional antigen of mol. wt 55 K on the M-MSV-transformed producer and non-producer cells. This antigen was not found on non-transformed M-MLV-producing cells and was neither related serologically to structural polypeptides of murine C-type viruses nor to components of embryonal STU mouse fibroblasts and foetal bovine serum.


[Knockdown of CMTM3 promotes migration and invasion of PC3 cell in vitro].
To investigate the change of biological characteristics after stable knockdown of CKLF-like MARVEL transmembrane domain containing 3 (CMTM3) expression in PC3 by lentivirus shRNA and to reveal new therapeutic targets. The research includes two groups: sh393 is the experimental group in which CMTM3 is knocked down in PC3 cell line; shN is the control group in which CMTM3 is negatively knocked down. The expression of CMTM3 was detected by Western blot. The migration ability of PC3 after stable knockdown was detected by Transwell and Wound healing assay. The invasion ability of PC3 was detected by Matrigel assay. RESULTS were obtained from at least three individual experiments. The expression of CMTM3 in sh393 group is significant lower than shN group (0.004 0±0.000 4 vs. 0.490 0±0.055 7, P<0.001) detected by Western blot. It also had statistical significance in Matrigel assays (248.6±4.5 vs. 113.0± 3.3), Transwell (203.6±1.9 vs. 103.0±1.2) and Wound healing assays (95.0±2.9 vs. 33.0±1.5) that knockdown of CMTM3 promoted migration, and invasion of PC3 cells in vitro (P<0.001). Negative correlation exists between the stable knockdown of CMTM3 and change of biological characteristics in PC3 cells, and knocking down CMTM3 affects migration, and invasion ability in PC3 cells.


Electroconvulsive shock treatments enhance responsiveness of forebrain neurons to serotonin.
Electroconvulsive therapy remains one of the most effective treatments of major depression. The effect of electroconvulsive shocks (ECSs) on the responsiveness of hippocampal pyramidal neurons to serotonin, norepinephrine, gamma-aminobutyric acid and 5-methoxydimethyltryptamine was studied in rats pretreated with one or six ECSs. Control rats were given subconvulsive shocks. Microiontophoretic experiments were conducted 36 hr after the last shock in urethane-anesthetized or low cerveau isolé preparations. Responsiveness of hippocampal pyramidal neurons to microiontophoretic applications of serotonin was markedly enhanced in rats pretreated with six ECSs. Responsiveness to 5-methoxydimethyltryptamine, a postsynaptic agonist which is not an adequate substrate for the high-affinity serotonin reuptake process, was also enhanced in rats pretreated with six ECSs, indicating that the increased responsiveness to serotonin was due to a postsynaptic modification. The effects of norepinephrine and of gamma-aminobutyric acid applied on the same neurons were not modified by repeated ECS pretreatment. A single ECS failed to modify responsiveness to either serotonin or 5-methoxydimethyltryptamine. Inasmuch as long-term tricyclic antidepressant drug administration has been shown to produce a similar sensitization to serotonin, the present results suggest that enhancement of serotonergic neurotransmission might mediate the therapeutic effect of both types of treatment in major depression.


Granulocyte macrophage colony-stimulating factor is overproduced by keratinocytes in atopic dermatitis. Implications for sustained dendritic cell activation in the skin.
Lesional skin of atopic dermatitis (AD) harbors high numbers of dendritic cells with enhanced stimulatory capacity for T lymphocytes. In this study, lesional AD skin was shown to stain heavily in both epidermal and dermal compartments for GM-CSF, a cytokine crucial to dendritic cell functions. Keratinocyte cultures established from uninvolved skin of AD patients exhibited markedly increased spontaneous and PMA-stimulated release of GM-CSF compared with keratinocytes from nonatopic controls. Correspondingly, keratinocytes from AD patients showed higher constitutive as well as PMA-induced GM-CSF gene expression. Larger amounts of GM-CSF were produced by AD keratinocytes, also in response to IL-1alpha, but not after stimulation with LPS, lipoteichoic acid, or staphylococcal enterotoxin B. Hydrocortisone reduced GM-CSF gene expression and protein release in both atopic and control keratinocytes. Supernatants from atopic keratinocytes were able to strongly stimulate PBMC proliferation in a GM-CSF-dependent manner. Moreover, conditioned medium from PMA-treated AD keratinocytes, together with exogenous IL-4, could support phenotypical and functional maturation of peripheral blood precursors into dendritic cells. Enhanced production of GM-CSF by keratinocytes may contribute relevantly to the establishment and chronicity of AD lesions, in particular to the increased number, sustained activation, and enhanced antigen-presenting functions of dendritic cells.


Nitrogen effects on decomposition: a five-year experiment in eight temperate sites.
The influence of inorganic nitrogen (N) inputs on decomposition is poorly understood. Some prior studies suggest that N may reduce the decomposition of substrates with high concentrations of lignin via inhibitory effects on the activity of lignin-degrading enzymes, although such inhibition has not always been demonstrated. I studied the effects of N addition on decomposition of seven substrates ranging in initial lignin concentrations (from 7.4% to 25.6%) over five years in eight different grassland and forest sites in central Minnesota, USA. I predicted that N would stimulate the decomposition of lignin-poor substrates but retard the decomposition of lignin-rich substrates. Across these sites, N had neutral or negative effects on decomposition rates. However, in contrast to my hypothesis, effects of N on decomposition were independent of substrate initial lignin concentrations, and decomposition of the lignin fraction was unaffected by N fertilization. Rather, substrate-site combinations that exhibited more rapid decomposition rates in the control treatment were affected more negatively by addition of N fertilization. Taken together, these results suggest that decreased decomposition with added N did not result from inhibition of lignin-degrading enzyme activity, but may have resulted from abiotic interactions between N fertilizer and products of microbial degradation or synthesis or from N effects on the decomposer community. Low initial substrate N concentrations and N fertilization both stimulated N immobilization, but the differences among substrates were generally much larger than the effects of fertilization. This study suggests that atmospheric N addition could stimulate ecosystem carbon sequestration in some ecosystems as a result of reduced rates of forest floor decomposition.


Detection and characterization of a putative emaravirus infecting Clematis brevicaudata DC. in China.
A novel emaravirus, tentatively named "clematis yellow mottle associated virus" (CYMaV), was identified through transcriptome sequencing and RT-PCR analysis of yellow-mottled leaf samples from Clematis brevicaudata DC. The genome of CYMaV consists of five viral RNAs: RNA1 (6591 nucleotides, nt), RNA2 (1982 nt), RNA3a (1301 nt), RNA3b (1397 nt), and RNA4 (1192 nt). The 13-nt sequences at the 5'- and 3'-termini of the CYMaV RNAs are conserved and have reverse complementary, as typically seen in emaraviruses. The proteins encoded by CYMaV shared the highest amino acid sequence similarity with those of the unclassified Karaka Okahu purepure emaravirus (KOPV), with 60.2% identity in the RNA-dependent RNA polymerase (RdRp), 44.4% in the glycoprotein precursor, and 46.9% in the nucleocapsid protein. A phylogenetic tree based on amino acid sequences of the RdRp revealed that CYMaV is most closely related to KOPV and clusters with ChMaV (chrysanthemum mosaic-associated virus, LC576445) and PCLSaV (pear chlorotic leaf spot-associated virus, MK602177) in one distinct clade. Transmission electron microscopy observation of negatively stained samples from C. brevicaudata revealed spherical virus-like particles (VLPs) approximately 100 nm in diameter. Five primers, specific for each viral RNA, were used to detect CYMaV in 11 symptomatic and two asymptomatic C. brevicaudata samples, but the results failed to show a consistent association of viral infection with symptoms. CYMaV can be considered a putative new member in the genus Emaravirus, and this marks the first report of an emaravirus found infecting C. brevicaudata plants.


Pulmonary rehabilitation for interstitial lung disease.
Interstitial lung disease (ILD) is characterised by reduced functional capacity, dyspnoea and exercise-induced hypoxia. Pulmonary rehabilitation, an intervention that includes exercise training, is beneficial for people with other chronic lung conditions; however its effects in ILD have not been well characterised. • To determine whether pulmonary rehabilitation in patients with ILD has beneficial effects on exercise capacity, symptoms, quality of life and survival compared with no pulmonary rehabilitation in patients with ILD.• To assess the safety of pulmonary rehabilitation in patients with ILD. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 6), MEDLINE (Ovid), EMBASE (Ovid), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCO) and the Physiotherapy Evidence Database (PEDro) (all searched from inception to June 2014). We also searched the reference lists of relevant studies, international clinical trial registries and respiratory conference abstracts to look for qualifying studies. Randomised and quasi-randomised controlled trials in which pulmonary rehabilitation was compared with no pulmonary rehabilitation or with other therapy in people with ILD of any origin were included. Two review authors independently selected trials for inclusion, extracted data and assessed risk of bias. Study authors were contacted to provide missing data and information regarding adverse effects. A priori subgroup analyses were specified for participants with idiopathic pulmonary fibrosis (IPF) and participants with severe lung disease (low diffusing capacity or desaturation during exercise). We planned to subgroup according to training modality applied, but there were insufficient data. Nine studies were included, six of which were published as abstracts. Five studies were included in the meta-analysis (86 participants who undertook pulmonary rehabilitation and 82 control participants). One study used a blinded assessor and intention-to-treat analysis. No adverse effects of pulmonary rehabilitation were reported. Pulmonary rehabilitation improved the six-minute walk distance with weighted mean difference (WMD) of 44.34 metres (95% confidence interval (CI) 26.04 to 62.64 metres) and improved oxygen consumption (VO2) peak with WMD of 1.24 mL/kg/min(-1) (95% CI 0.46 to 2.03 mL/kg/min(-1)). Improvements in six-minute walk distance and VO2 peak were also seen in the subgroup of participants with idiopathic pulmonary fibrosis (IPF) (WMD 35.63 metres, 95% CI 16.02 to 55.23 metres; WMD 1.46 mL/kg/min(-1), 95% CI 0.54 to 2.39 mL/kg/min(-1), respectively). Reduced dyspnoea (standardised mean difference (SMD) -0.66, 95% CI -1.05 to -0.28) following pulmonary rehabilitation was also seen in the IPF subgroup (SMD -0.68, 95% CI -1.12 to -0.25). Quality of life improved following pulmonary rehabilitation for all participants on a variety of measures (SMD 0.59, 95% CI 0.20 to 0.98) and for the subgroup of people with IPF (SMD 0.59, 95% CI 0.14 to 1.03). Two studies reported longer-term outcomes, with no significant effects of pulmonary rehabilitation on clinical variables or survival at three or six months. Available data were insufficient to allow examination of the impact of disease severity or exercise training modality. Pulmonary rehabilitation seems to be safe for people with ILD. Improvements in functional exercise capacity, dyspnoea and quality of life are seen immediately following pulmonary rehabilitation, with benefits also evident in IPF. Because of inadequate reporting of methods and small numbers of included participants, the quality of evidence was low to moderate. Little evidence was available regarding longer-term effects of pulmonary rehabilitation.


Acute allergic reaction due to vincristine sulfate. A case report.
A patient suffering from Hodgkin's disease exhibiting acute allergic reaction to vincristine sulfate with mild to moderate dermatologic and cardiovascular signs is described. The change of therapy to vindesine sulfate led to relief of all symptoms. The therapeutic effectiveness of the altered protocol remained unchanged and no other or amplified side effects appeared.


Confinement-induced phase transitions in simple liquids.
The liquid-to-solid transition of a simple model liquid confined between two surfaces was studied as a function of surface separation. From large surface separations (more than 1000 angstroms) down to a separation corresponding to seven molecular layers, the confined films displayed a liquid-like shear viscosity. When the surface separation was further decreased by a single molecular spacing, the films underwent an abrupt, reversible transition to a solid. At the transition, the rigidity of the confined films (quantified in terms of an "effective viscosity") increased reversibly by at least seven orders of magnitude.


Pharmacokinetic Interactions of a Hop Dietary Supplement with Drug Metabolism in Perimenopausal and Postmenopausal Women.
Botanical dietary supplements produced from hops (Humulus lupulus) containing the chemopreventive compound xanthohumol and phytoestrogen 8-prenylnaringenin are used by women to manage menopausal symptoms. Because of the long half-lives of prenylated hop phenols and reports that they inhibit certain cytochrome P450 enzymes, a botanically authenticated and chemically standardized hop extract was tested for Phase I pharmacokinetic drug interactions. Sixteen peri- and postmenopausal women consumed the hop extract twice daily for 2 weeks, and the pharmacokinetics of tolbutamide, caffeine, dextromethorphan, and alprazolam were evaluated before and after supplementation as probe substrates for the enzymes CYP2C9, CYP1A2, CYP2D6, and CYP3A4/5, respectively. The observed area under the time-concentration curves were unaffected, except for alprazolam which decreased 7.6% (564.6 ± 46.1 h·μg/L pre-hop and 521.9 ± 36.1 h·μg/L post-hop; p-value 0.047), suggesting minor induction of CYP3A4/5. No enzyme inhibition was detected. According to FDA guidelines, this hop dietary supplement caused no clinically relevant pharmacokinetic interactions with respect to CYP2C9, CYP1A2, CYP2D6, or CYP3A4/5. The serum obtained after consumption of the hop extract was analyzed using ultra-high performance liquid chromatography-tandem mass spectrometry to confirm compliance. Abundant Phase II conjugates of the hop prenylated phenols were observed including monoglucuronides and monosulfates as well as previously unreported diglucuronides and sulfate-glucuronic acid diconjugates.


Development and testing of formal protocols for oxygen prescribing.
The absence of standardized assessment protocols with well- defined measurement properties limits comparison of outcomes among those receiving long-term oxygen therapy (LTOT). We describe simple protocols for a hospital test, a simulated home test, and an actual home test, their reliability and relationship to each other. Stable patients with exercise hypoxemia participated. In 74 patients who completed four exercise tests, correlations between tests ranged from 0.85 to 0.78. Of these 27.0% had the same prescription from all four tests. In 46% prescriptions were within 1 L/ min and in 27% within 2 L/min. During exercise the hospital tests suggested slightly higher oxygen prescriptions than did the simulated home tests (2.5 L/min versus 2.0 L/min, p < 0.001). In 23 patients who participated in actual home assessments, the correlations between the home test, the hospital, and the simulated home tests were 0.22 (95% CI -0.24 to 0.67) and 0.27 (95% CI -0.18 to 0.72). In conclusion, standardizing tests for the assessment of LTOT is important. We describe simple hospital and simulated home tests that are reproducible, easy to carry out, and correlate well with each other.


Liver regeneration and hepatocarcinogenesis in transforming growth factor-alpha-targeted mice.
Transforming growth factor-alpha (TGF alpha), a member of the epidermal growth factor receptor ligand family, has been implicated in the regeneration and transformation of liver. Our recent development of mice that are homozygous for a disrupted TGF alpha gene allowed us to assess the requirement for this growth factor in these complex processes. We report here that although a 70% hepatectomy produced a significant increase in hepatic TGF alpha protein levels in wild-type mice, liver regeneration nevertheless proceeded normally in the absence of the growth factor. The hepatocyte labeling indices determined for homozygous targeted and wild-type mice at 36 and 48 h after hepatectomy were comparable, and the total liver DNA to body weight ratios 8 d after hepatectomy were essentially identical for the two genotypes. These results indicate that TGF alpha, is not necessary for liver regeneration. To test its requirement in liver carcinogenesis, young mice were administered single doses of diethylnitrosamine (DEN) with or without subsequent chronic treatment with the promoting agent phenobarbital (PB). Both wild-type and homozygous mutant male mice treated with DEN or DEN plus PB developed multiple preneoplastic foci or tumors by 9 mo of age with relatively high incidence. However, while five of 88 tumors in wild-type mice attained a diameter greater than 5 mm and were classified as hepatocellular carcinomas, none of 132 tumors in livers of targeted mice reached this size. Furthermore, three of these large wild-type tumors expressed significantly elevated levels of TGF alpha protein compared with normal liver. These results indicate that TGF alpha is not required for early events in chemically induced hepatocarcinogenesis but suggest that it could be important in the progression from small preneoplastic foci to large tumors.


Phase I study of sorafenib in combination with everolimus (RAD001) in patients with advanced neuroendocrine tumors.
Sorafenib and everolimus are both active against neuroendocrine tumors (NET). Because of potential synergy between VEGF pathway and mTOR inhibitors, we performed a phase I study to evaluate the safety and feasibility of combining sorafenib and everolimus in patients with advanced NET. Patients were treated with everolimus 10 mg daily in combination with sorafenib (dose level 1: 200 mg twice daily; dose level 2: 200 mg per morning, 400 mg per evening) using standard phase I dose escalation design. Dose-limiting toxicity (DLT) was defined within the first cycle (28 days) of therapy. Treatment was continued until tumor progression, unacceptable toxicity, or withdrawal of consent. Twelve additional patients were treated at the maximum tolerated dose (MTD) level to further characterize safety and a preliminary assessment of activity. One patient in Cohort 1 experienced DLT (grade 3 skin rash); the cohort was expanded to 6 patients with no further DLTs. All 3 patients in Cohort 2 experienced DLT, consisting of thrombocytopenia, hand-foot skin reaction, and rash/allergic reaction. Sorafenib 200 mg twice daily in combination with everolimus 10 mg daily was established as the MTD. Independently reviewed best objective responses revealed that 62 % of patients had some degree of tumor shrinkage. By RECIST, we observed partial response in 1 patient, stable disease in 13 patients, and progressive disease in 3 patients. Sorafenib 200 mg twice daily with everolimus 10 mg daily represents the MTD of this combination in patients with advanced NET. While the combination is active, toxicity concerns may preclude more widespread use.


Growing and analyzing biofilms in flow chambers.
This unit describes the setup of flow chamber systems for the study of microbial biofilms, and methods for the analysis of structural biofilm formation. Use of flow chambers allows direct microscopic investigation of biofilm formation. The biofilms in flow chambers develop under hydrodynamic conditions, and the environment can be carefully controlled and easily changed. The protocols in this unit include construction of the flow chamber and the bubble trap, assembly and sterilization of the flow chamber system, inoculation of the flow chambers, running of the system, image capture and analysis, and disassembly and cleaning of the system. In addition, embedding and fluorescent in situ hybridization of flow chamber-grown biofilms are addressed.


Selectivity in fragmentation of N-methylacetamide after resonant K-shell excitation.
The fragmentation pattern of the peptide model system, N-methylacetamide, is investigated using ion time-of-flight (TOF) spectroscopy after resonant K-shell excitation. Corresponding near-edge X-ray absorption fine structure (NEXAFS) spectra recorded at high resolution at the C1s, N1s and O1s edges are presented. Analysis of the ion TOF data reveals a multitude of fragmentation channels and dissociation pathways. Comparison between the excitation of six different resonances in the vicinity of the C1s, N1s and O1s edges suggests evidence for site-selective bond breaking. In particular the breaking of the peptide bond and the N-C(α) bond show a clear correlation with resonant excitation at the N1s edge. Also, stronger tendencies towards site-selective bond breaking are found for the generation of single ions compared with ion pairs. Analysis of angular distributions of ions from breakage of the peptide bond yields a fragmentation time of <400 fs.


Decomposing the Mutual Information Rate of Heart Period and Respiration Variability Series to Assess Cardiorespiratory Interactions.
Heart rate variability results from the coupled activity of the cardiovascular and cardiorespiratory systems, which have their own internal regulation mechanisms but also interact with each other and with the autonomic nervous system to maintain homeostasis. In this work, the assessment of these physiological mechanisms is carried out decomposing the Mutual Information Rate (MIR), an information-theoretic measure of the interdependence between coupled processes, into terms of entropy rate or conditional mutual information related respectively to complexity and causality measures. These measures are computed using a non-parametric approach based on nearest-neighbors. The proposed framework is first tested on simulated autoregressive processes and then applied to experimental data consisting of heart period and respiratory time series measured in healthy subjects monitored at rest and during head-up tilt. Our results evidence that MIR decomposition is able to highlight the interdependence of short-term physiological mechanisms of cardiorespiratory interactions during postural stress.


Enhancing narrative clinical guidance with computer-readable artifacts: Authoring FHIR implementation guides based on WHO recommendations.
Narrative clinical guidelines often contain assumptions, knowledge gaps, and ambiguities that make translation into an electronic computable format difficult. This can lead to divergence in electronic implementations, reducing the usefulness of collected data outside of that implementation setting. This work set out to evolve guidelines-based data dictionaries by mapping to HL7 Fast Health Interoperability Resources (FHIR) and semantic terminology, thus progressing toward machine-readable guidelines that define the minimum data set required to support family planning and sexually transmitted infections. The data dictionaries were first structured to facilitate mapping to FHIR and semantic terminologies, including ICD-10, SNOMED-CT, LOINC, and RxNorm. FHIR resources and codes were assigned to data dictionary terms. The data dictionary and mappings were used as inputs for a newly developed tool to generate FHIR implementation guides. Implementation guides for core data requirements for family planning and sexually transmitted infections were created. These implementation guides display data dictionary content as FHIR resources and semantic terminology codes. Challenges included the use of a two-dimensional spreadsheet to facilitate mapping, the need to create FHIR profiles and resource extensions, and applying FHIR to a data dictionary that was created with a user interface in mind. Authoring FHIR implementation guides is a complex and evolving practice, and there are limited examples for this groundbreaking work. Moving toward machine-readable guidelines by mapping to FHIR and semantic terminologies requires a thorough understanding of the context and use of terminology, an applied information model, and other strategies for optimizing the creation and long-term management of implementation guides. Next steps for this work include validation and, eventually, real-world application. The process for creating the data dictionary and for generating implementation guides should also be improved to prepare for this expanding work. This work was supported by the World Health Organization, which also worked as a collaborative partner throughout the study.


Cost analysis of early extubation after coronary bypass surgery.
Although early extubation after coronary bypass surgery has been shown to reduce length of stay, a systematic cost analysis of its economic benefit has not been reported, and previous studies have used hospital charges that are typically confused with actual costs. A consecutive series of 690 patients undergoing coronary bypass surgery during a 24-month period were studied to determine the effect of early extubation, defined as removal of the endotracheal tube within 8 hours of arrival to the intensive care unit, on length of stay and hospital costs. Patients in group 2 (n = 362) who underwent coronary bypass surgery in 1995, subsequent to the initiation of an early extubation protocol, were compared with those in group 1 (n = 328) operated on in 1994, before implementation of early extubation. To reflect true hospital resource consumption, only costs (not charges) directly related to patient health core (variable direct cost) were analyzed. Baseline characteristics such as age, gender, previous myocardial infarctions, ejection fraction, reoperations, diabetes, and left main stenosis were similar in both groups. Operative mortality for the entire group was 3.3% and did not differ between the two groups; the incidence of serious morbidity was 10.9% for the entire group. Early extubation was accomplished in 38% of patients in group 2 versus 3% in group 1 (p < 0.001), and postoperative length of stay declined from 9.4 days to 7.7 days (p < 0.01). This was accompanied by a significant (p = 0.001) reduction in variable direct cost per case. Early extubation after coronary bypass surgery is an effective strategy of reducing length of stay and does not appear to impact on either morbidity or mortality. An additional benefit is significant cost savings realized through accelerated recovery and control of resource use.


[Calcium and bone metabolism across women's life stages. Stress fracture in female athletes.]
Stress fractures are common overuse injuries in athletes, especially in long-distance runner, jumping sports and gymnastics in female athletes. The pathology of stress fracture mainly includes repeated biomechanical loading, which leads to bone micro-damage and failure of bone structure. Female athlete triad(FAT), which includes low energy availability with or without an eating disorder, functional hypothalamic amenorrhea, and osteoporosis, is a serious healthcare concern in female athletes. For prevention and treatment of stress fracture, management of biomechanical factors modifying the load applied to a bone is important, and especially in female athletes, management for FAT is one of the important factors. This report outlines the current knowledge on the epidemiology, diagnosis, treatment and prevention of stress fracture, relating to FAT in female athletes.


Activation of Orexinergic Neurons Inhibits the Anesthetic Effect of Desflurane on Consciousness State via Paraventricular Thalamic Nucleus in Rats.
Orexin, a neuropeptide derived from the perifornical area of the hypothalamus (PeFLH), promotes the recovery of propofol, isoflurane, and sevoflurane anesthesias, without influencing the induction time. However, whether the orexinergic system also plays a similar role in desflurane anesthesia, which is widely applied in clinical practice owing to its most rapid onset and offset time among all volatile anesthetics, has not yet been studied. In the present study, we explored the effect of the orexinergic system on the consciousness state induced by desflurane anesthesia. The c-Fos staining was used to observe the activity changes of orexinergic neurons in the PeFLH and their efferent projection regions under desflurane anesthesia. Chemogenetic and optogenetic techniques were applied to compare the effect of PeFLH orexinergic neurons on the induction, emergence, and maintenance states between desflurane and isoflurane anesthesias. Orexinergic terminals in the paraventricular thalamic nucleus (PVT) were manipulated with pharmacologic, chemogenetic, and optogenetic techniques to assess the effect of orexinergic circuitry on desflurane anesthesia. Desflurane anesthesia inhibited the activity of orexinergic neurons in the PeFLH, as well as the neuronal activity in PVT, basal forebrain, dorsal raphe nucleus, and ventral tegmental area, as demonstrated by c-Fos staining. Activation of PeFLH orexinergic neurons prolonged the induction time and accelerated emergence from desflurane anesthesia but only influenced the emergence in isoflurane anesthesia, as demonstrated by chemogenetic and pharmacologic techniques. Meanwhile, optical activation of orexinergic neurons exhibited a long-lasting inhibitory effect on burst-suppression ratio (BSR) under desflurane anesthesia, and the effect may be contributed by the orexinergic PeFLH-PVT circuitry. The orexin-2 receptor (OX2R), but not orexin-1 receptor (OX1R), in the PVT, which had been inhibited most significantly by desflurane, mediated the proemergence effect of desflurane anesthesia. We discovered, for the first time, that orexinergic neurons in the PeFLH could not only influence the maintenance and emergence from isoflurane and desflurane anesthesias but also affect the induction under desflurane anesthesia. Furthermore, this specific effect is probably mediated by orexinergic PeFLH-PVT circuitry, especially OX2Rs in the PVT.


Dysfunctional CD4+,CD25+ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-alpha-producing antigen-presenting cells.
To explore whether there are extrinsic factors that impair the suppressive function of CD4+,CD25+ regulatory T cells in patients with untreated active systemic lupus erythematosus (SLE). We studied 15 patients with untreated active SLE, 10 patients with SLE in remission, and 15 healthy control subjects. Percentages of CD4+,CD25+,FoxP3+ Treg cells and levels of forkhead box P3 (FoxP3) protein were analyzed by flow cytometry. Expression of messenger RNA (mRNA) for FoxP3 in purified Treg cell populations was assessed by real-time polymerase chain reaction analysis. Experiments examining Treg cell function in SLE were designed to distinguish primary from secondary T cell dysfunction. Levels of interferon-alpha (IFNalpha) in supernatants from the function assays were determined with an IFN-stimulated response element-luciferase reporter assay. The percentage of CD4+,CD25+, FoxP3+ cells in peripheral blood was significantly increased in SLE patients as compared with controls (mean +/- SEM 9.11 +/- 0.73% versus 4.78 +/- 0.43%; P < 0.0001). We found no difference in FoxP3 expression at either the mRNA or protein level in any CD4+,CD25+ T cell subset from SLE patients as compared with controls. Antigen-presenting cells (APCs) from SLE patients were responsible for decreased Treg cell activity and could also render dysfunctional Treg cells from healthy control subjects. CD4+,CD25+ Treg cells from SLE patients exhibited normal suppressive activity when cultured with APCs from healthy controls. A partial Treg cell blockade effect was induced by the high levels of IFNalpha derived from SLE patient APCs. We suggest that blockade of Treg cell-mediated suppression by IFNalpha-producing APCs in SLE patients may contribute to a pathogenic loss of peripheral tolerance in this disease.


A clinical model for identifying radiosensitive tumor genotypes in non-small cell lung cancer.
Non-small cell lung cancer (NSCLC) includes a spectrum of radiosensitive and radioresistant tumors. However, little is known about the molecular determinants of cellular radiation responses. We examined clinical outcomes after gamma knife radiotherapy for NSCLC intracranial metastases to evaluate the use of this model for determining radiosensitive tumor genotypes. Between 2005 and 2012, 239 patients with NSCLC were enrolled in a prospective gamma knife data repository. Molecular pathology regarding EGF receptor (EGFR), ALK, and KRAS mutation status was available for 81 patients. Local and distant brain control was determined for 79 patients with 469 brain metastases. Modified Cox proportional hazards models were established to evaluate local control for treated lesions after serial gamma knife treatments. In total, 11% of patients developed in-field recurrence. No patients with metastases from tumors with EGFR mutations (0/164 lesions) or EML4-ALK translocations (0/61 lesions) recurred in-field. In contrast, 19% of patients without these mutations and 18% of patients with KRAS mutations recurred in-field (10/139 and 3/105 lesions, respectively). Rates of distant brain recurrence did not significantly differ across tumor genotypes. The predicted median in-field local control was significantly longer for EGFR-mutant and ALK-translocated tumors compared with other patients with NSCLC (P < 0.001), whereas distant brain recurrence time was equivalent (P = 0.97). On multivariate analysis, EGFR mutation, ALK translocation, and metastasis size were independent predictors for superior local control after gamma knife treatment. This study suggests that EGFR kinase domain mutations and EML4-ALK translocations are radiosensitive NSCLC genotypes, and proposes a novel model to identify radiosensitive subtypes of NSCLC.


Spatio-temporal saliency perception via hypercomplex frequency spectral contrast.
Salient object perception is the process of sensing the salient information from the spatio-temporal visual scenes, which is a rapid pre-attention mechanism for the target location in a visual smart sensor. In recent decades, many successful models of visual saliency perception have been proposed to simulate the pre-attention behavior. Since most of the methods usually need some ad hoc parameters or high-cost preprocessing, they are difficult to rapidly detect salient object or be implemented by computing parallelism in a smart sensor. In this paper, we propose a novel spatio-temporal saliency perception method based on spatio-temporal hypercomplex spectral contrast (HSC). Firstly, the proposed HSC algorithm represent the features in the HSV (hue, saturation and value) color space and features of motion by a hypercomplex number. Secondly, the spatio-temporal salient objects are efficiently detected by hypercomplex Fourier spectral contrast in parallel. Finally, our saliency perception model also incorporates with the non-uniform sampling, which is a common phenomenon of human vision that directs visual attention to the logarithmic center of the image/video in natural scenes. The experimental results on the public saliency perception datasets demonstrate the effectiveness of the proposed approach compared to eleven state-of-the-art approaches. In addition, we extend the proposed model to moving object extraction in dynamic scenes, and the proposed algorithm is superior to the traditional algorithms.


CD4+ T cells and natural killer cells: Biomarkers for hepatic fibrosis in human immunodeficiency virus/hepatitis C virus-coinfected patients.
To characterize peripheral blood natural killer (NK) cells phenotypes by flow cytometry as potential biomarker of liver fibrosis in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients. Peripheral mononuclear cells from 24 HIV/HCV (HBV negative) coinfected and 5 HIV/HCV/HBV seronegative individuals were evaluated. HIV/HCV coinfected patients were divided in to groups: G1, patients with METAVIR F0-F2 and G2, patients with METAVIR F3-F4. NK surface cell staining was performed with: Anti-CD3(APC/Cy7), anti-CD56(PE/Cy5), anti-CD57(APC), anti-CD25(PE), anti-CD69(FITC), anti-NKp30(PE), anti-NKp46(PE/Cy7), anti-NKG2D(APC), anti-DNAM(FITC); anti-CD62L (PE/Cy7), anti-CCR7(PE), anti-TRAIL(PE), anti-FasL(PE), anti CD94(FITC). Flow cytometry data acquisition was performed on BD FACSCanto, analyzed using FlowJo software. Frequency of fluorescence was analyzed for all single markers. Clinical records were reviewed, and epidemiological and clinical data were obtained. Samples from 11 patients were included in G1 and from 13 in G2. All patients were on ARV, with undetectable HIV viral load. Liver fibrosis was evaluated by transient elastography in 90% of the patients and with biopsy in 10% of the patients. Mean HCV viral load was (6.18 ± 0.7 log10). Even though, no major significant differences were observed between G1 and G2 regarding NK surface markers, it was found that patients with higher liver fibrosis presented statistically lower percentage of NK cells than individual with low to mild fibrosis and healthy controls (G2: 5.4% ± 2.3%, G1: 12.6% ± 8.2%, P = 0.002 and healthy controls 12.2% ± 2.7%, P = 0.008). It was also found that individuals with higher liver fibrosis presented lower CD4 LT count than those from G1 (G2: 521 ± 312 cells/μL, G1: 770 ± 205 cells/μL; P = 0.035). Higher levels of liver fibrosis were associated with lower percentage of NK cells and LTCD4+ count; and they may serve as noninvasive biomarkers of liver damage.


Digital printing of selective and reversible ion optodes on fabrics: toward smart clothes for epidermal chemical sensing.
While wearable chemical sensors often rely on electrochemical techniques, optical chemical sensors coupled with a smartphone or a miniaturized camera represent an attractive approach to the monitoring of sweat composition. In this paper, we modify real sports fabrics such as polyester-spandex fabrics with rational combinations of sensing chemicals including a pH indicator, an ion exchanger, and an ionophore via one-step inkjet printing. Highly selective and fully reversible pH optodes as well as Na+- and K+-selective optodes are obtained only when the most hydrophobic sensing chemicals are used (e.g., sodium ionophore VIII vs. sodium ionophore VI). These sensors exhibit large color-based responses that can be readily identified by naked eye or analyzed via an iPhone app. Their dynamic ranges well cover the physiological sweat concentrations of the analytes. Compared to most other sensors created on garments, our fabric-based optodes are cost-effective, mass-reproducible by the digital printing technology currently used in the textile industry, and do not significantly compromise the essential properties of fabrics such as flexibility, stretchability, wickability, and breathability.


Re-evaluating the Lejour Technique for Breast Reduction in Patients with Macromastia.
Limited scar Lejour technique for breast reduction is conventionally used to remove less than 500 g of breast tissue per breast, but is effective for greater macromastia. Plastic surgery residents gain limited experience with this technique, and it is infrequently performed in the United States. To understand technique selection, we surveyed board-certified plastic surgeons and compared outcomes with the Lejour technique in 1 practice to those with other methods. We surveyed American Society of Plastic Surgeons members about techniques for breast reduction and compared outcomes with procedures performed by various techniques by a single surgeon (M.C.). Of 321 survey respondents, 33% reported formal training in the Lejour technique. Over 70% used mainly the inferior pedicle Wise procedure; 14% used mainly the Lejour or modified Lejour technique. In a series of reduction mammaplasties by 1 surgeon in 119 patients between 1997 and 2006, 14 underwent inferior pedicle Wise pattern and 105 involved the Lejour technique. Mean tissue mass removal was 1,136 g/breast (range, 170-4,050 g). Major complications occurred in 1.74% overall, and 0% and 1.9% for the Wise and Lejour techniques, respectively (P = 0.46). Although most American Society of Plastic Surgeons respondents were not formally trained in the Lejour technique and seldom perform the procedure, it can be employed for reduction mammaplasty with no greater risk of complications than the Wise method. The Lejour technique should be incorporated during residency training as an alternative for reduction mammaplasty.


[Immunologic responses in the dynamics of the establishment of postvaccinal measles immunity].
The comparative study of the humoral and cellular characteristics of antimeasles immunity in children immunized with live measles vaccine Ji-16, and in children having had measles revealed that both "wild" and vaccine strains of measles virus induced similar changes in the organism of the child: the synthesis of specific antibodies belonging to different physico-chemical classes, changes in the content of different serum immunoglobulins and the suppression of the blastogenic response of peripheral blood lymphoyctes to phitohemagglutinins. The changes suggest that both T- and B-lymphocytes took part in the formation of antimeasles immunity, but all these processes were more pronounced during the formation of postinfection immunity.


Lumbar transplant of neurons genetically modified to secrete brain-derived neurotrophic factor attenuates allodynia and hyperalgesia after sciatic nerve constriction.
Chronic delivery of anti-nociceptive molecules by means of cell grafts near the pain processing centers of the spinal cord is a newly developing technique for the treatment of neuropathic pain. The rat neuronal cell line, RN33B, derived from E13 rat brainstem raphe and immortalized with the SV40 temperature-sensitive allele of large T antigen (tsTag), was transfected with rat brain-derived neurotrophic factor cDNA (BDNF), and the BDNF-synthesizing cell line, 33BDNF.4, was isolated. The 33BDNF.4 cells synthesized mature BDNF protein at permissive temperature (33 degrees C), when the cells were proliferating, and during differentiation at non-permissive temperature (39 degrees C) in vitro. The bio-active BDNF protein was also secreted by the cells during both growth conditions, as measured by ELISA analysis of BDNF content and secretion. The bio-activity of the BDNF in 33BDNF.4 cell conditioned media was assessed by neurite outgrowth from E15 dorsal root ganglion (DRG) cultures. A control cell line, 33V1, transfected with the vector alone, did not synthesize or secrete any significant BDNF at either growth condition. Both cell lines were used as grafts in a model of chronic neuropathic pain induced by unilateral chronic constriction injury (CCI) of the sciatic nerve. Pain-related behaviors, including cold and tactile allodynia and thermal and tactile hyperalgesia, were evaluated after CCI in the affected hindpaw. When 33BDNF.4 and 33V1 cells were transplanted in the lumbar subarachnoid space of the spinal cord 1 week after CCI, they survived greater than 7 weeks on the pia mater around the spinal cord and the 33BDNF.4 cells continued to synthesize BDNF in vivo. Furthermore, the tactile and cold allodynia and tactile and thermal hyperalgesia induced by CCI was significantly reduced during the 2-7 week period after grafts of 33BDNF.4 cells. The maximal effect on chronic pain behaviors with the BDNF grafts occurred 2-3 weeks after transplant and the anti-nociceptive effects of the BDNF cell grafts was permanent. Transplants of the control 33V1 cells had no effect on the allodynia and hyperalgesia induced by CCI and these cells did not synthesize BDNF in vivo. These data suggest that a chronically applied, low local dose of BDNF supplied by transplanted cells near the spinal dorsal horn was able to reverse the development of chronic neuropathic pain following CCI. The use of neural cell lines that are able to deliver anti-nociceptive molecules, such as BDNF, in a model of chronic pain offers a novel approach to pain management and such 'biologic minipumps' can be developed for safe use in humans.


Depressive symptoms lead to impaired cellular immune response.
The association between depression and immune response is not yet clear. The biological mechanisms by which depression alters the immune system is not yet understood. The purpose of this study was to investigate the longitudinal relationship between depressive symptoms and cellular immune response. A cohort study with a baseline measurement and three annual health assessments was set up in a residential home for elderly people in Rome, Italy. A total of 166 residents aged 65 years and older, mean age 81 years, were interviewed and blood samples were collected at each annual assessment. Percentage changes in lymphocytes and T-cell subsets related to depressive symptoms were estimated over a period of 4 years, using regression models for repeated measurements. Elderly people with seven or more symptoms of depression, according to the Geriatric Depression Scale, had a lower percentage of CD4+DR+ T-cells over 4 years [beta = -20.2; 95% confidence interval (CI) = -33.0 to -4.9] and CD8+DR+ T-cells (beta = -26.9; 95% CI = -42.5 to -7.0) than elderly with less than seven symptoms of depression, after adjusting for confounding factors (sex, age, marital status, education, smoking habit, nutritional status, chronic diseases, disability and the use of benzodiazepines). The results of this study suggest an adverse effect of depressive symptoms on immune response. It remains to be determined whether these depression-associated immune changes are related to the onset or course of physical illness and the increased mortality observed in depressed old people.


Appearance of melatonin receptors during embryonic life in Siberian hamsters (Phodopus sungorous).
Maternal melatonin readily crosses the placenta to provide the fetus with time-of-day and day length information. To determine if melatonin could have a broader role during development than is currently recognized, melatonin receptor expression was examined in somatic sites during Siberian hamster embryogenesis. Using 125I-labeled-2-iodomelatonin ([125I]MEL), melatonin receptor expression was examined in whole fetuses by in vitro autoradiography. [125I]MEL binding sites were first apparent at gestational day (GD) 10 over the primitive oral pharynx. From GD 12 to 14, binding was present over the nasal pharynx, Rathke's pouch, caudal arteries, and over the thyroid gland during its migration along the thyroglossal duct. By GD 16, Rathke's pouch had differentiated into the pituitary gland, which continued to express specific [125I]MEL binding until birth. From GD 16 until birth, binding was no longer detectable over the thyroid gland, but persisted over the nasal epithelium. At all ages, binding sites exhibited high affinity for [125I]MEL and appeared to be coupled with guanosine nucleotide-binding proteins. These data suggest that melatonin receptors are expressed in several somatic sites, including Rathke's pouch and the thyroid gland, during fetal development.


Syndromic and laboratory diagnosis of sexually transmitted infection: a comparative study in China.
The rate of sexually transmitted infections (STIs) has soared in China. Yet, there is no universal consensus about the accuracy of the syndromic approach to STI management. This study aims to compare the syndromic approach with laboratory tests. A randomly selected sample of market vendors in eastern China (n = 4510) was recruited and assessed for the five most common STIs (Chlamydia trachomatis infection, gonorrhoea, genital herpes [herpes simplex type 2, HSV-2] syphilis and trichomoniasis [female only]). Symptom-based assessments made by physicians were compared with laboratory tests. Laboratory test results were used as the gold standard for the comparisons. The overall sensitivity of physician symptom-based assessment was about 10%; sensitivity was lower for males (1.6%) than for females (17.2%). The sensitivity of physician assessments for those who reported STI symptoms was relatively higher (36.7%) than for those who reported no symptoms (5.1%). More than half (54.37%) of the participants were diagnosed with STI of trichomoniasis. For the other four types of STIs, physicians correctly identified only <10% of the positive cases. The study detected a low sensitivity of STI diagnosis made by physicians in an Eastern city of China. The failure in the detection of asymptomatic patients remains one of the limitations of the syndromic approach.


How conceptual overlap and modality pairings affect task-switching and mixing costs.
Manipulating the pairings of stimulus and response modalities has been shown to affect how response selection processes for distinct tasks interact. For example, Stephan and Koch (Psychol Res 75(6):491-498, 2011) found smaller performance costs when participants switched between visual-manual (VM) and auditory-vocal (AV) tasks (modality compatible; MC) compared to between visual-vocal (VV) and auditory-manual (AM) tasks (modality incompatible; MI). However, in the Stephan and Koch study, there was conceptual overlap between one set of stimuli and one set of responses. For the MC pair, these stimuli and responses belonged to the same task, whereas for the MI pair, they belonged to different tasks. To examine how conceptual overlap affected switch and mixing costs, we conducted two experiments. Experiment 1a was a near replication of Stephan and Koch in which conceptual overlap was present in the MC AV task. In contrast, Experiment 1b reduced conceptual overlap within the MC AV task and increased it in the MI VV task. In Experiment 1a, we replicated Stephan and Koch's findings: larger switch costs were observed for the MI pair; in Experiment 1b, we found numerically greater switch costs in the MC condition. In Experiment 2, we reduced conceptual overlap in both tasks and found no effect of modality compatibility on switch costs. However, mixing costs were primarily driven by modality compatibility, regardless of conceptual overlap. These results highlight the different roles that conceptual overlap and modality pairings have on switch and mixing costs.


Regulation of cardiac gene expression by KLF15, a repressor of myocardin activity.
Pathological forms of left ventricular hypertrophy (LVH) often progress to heart failure. Specific transcription factors have been identified that activate the gene program to induce pathological forms of LVH. It is likely that apart from activating transcriptional inducers of LVH, constitutive transcriptional repressors need to be removed during the development of cardiac hypertrophy. Here, we report that the constitutive presence of Krüppel-like factor 15 (KLF15) is lost in pathological hypertrophy and that this loss precedes progression toward heart failure. We show that transforming growth factor-beta-mediated activation of p38 MAPK is necessary and sufficient to decrease KLF15 expression. We further show that KLF15 robustly inhibits myocardin, a potent transcriptional activator. Loss of KLF15 during pathological LVH relieves the inhibitory effects on myocardin and stimulates the expression of serum response factor target genes, such as atrial natriuretic factor. This uncovers a novel mechanism where activated p38 MAPK decreases KLF15, an important constitutive transcriptional repressor whose removal seems a vital step to allow the induction of pathological LVH.


Leaf phosphorus influences the photosynthesis-nitrogen relation: a cross-biome analysis of 314 species.
The ecophysiological linkage of leaf phosphorus (P) to photosynthetic capacity (A (max)) and to the A (max)-nitrogen relation remains poorly understood. To address this issue we compiled published and unpublished field data for mass-based A (max), nitrogen (N) and P (n = 517 observations) from 314 species at 42 sites in 14 countries. Data were from four biomes: arctic, cold temperate, subtropical (including Mediterranean), and tropical. We asked whether plants with low P levels have low A (max), a shallower slope of the A (max)-N relationship, and whether these patterns have a geographic signature. On average, leaf P was substantially lower in the two warmer than in the two colder biomes, with the reverse true for N:P ratios. The evidence indicates that the response of A (max) to leaf N is constrained by low leaf P. Using a full factorial model for all data, A (max) was related to leaf N, but not to leaf P on its own, with a significant leaf N x leaf P interaction indicating that the response of A (max) to N increased with increasing leaf P. This was also found in analyses using one value per species per site, or by comparing only angiosperms or only woody plants. Additionally, the slope of the A (max)-N relationship was higher in the colder arctic and temperate than warmer tropical and subtropical biomes. Sorting data into low, medium, and high leaf P groupings also showed that the A (max)-N slope increases with leaf P. These analyses support claims that in P-limited ecosystems the A (max)-N relationship may be constrained by low P, and are consistent with laboratory studies that show P-deficient plants have limited ribulose-1,5-bisphosphate regeneration, a likely mechanism for the P influence upon the A (max)-N relation.


Heart regeneration.
Heart failure plagues industrialized nations, killing more people than any other disease. It usually results from a deficiency of specialized cardiac muscle cells known as cardiomyocytes, and a robust therapy to regenerate lost myocardium could help millions of patients every year. Heart regeneration is well documented in amphibia and fish and in developing mammals. After birth, however, human heart regeneration becomes limited to very slow cardiomyocyte replacement. Several experimental strategies to remuscularize the injured heart using adult stem cells and pluripotent stem cells, cellular reprogramming and tissue engineering are in progress. Although many challenges remain, these interventions may eventually lead to better approaches to treat or prevent heart failure.


Amphiregulin causes functional downregulation of adherens junctions in psoriasis.
Overexpression of amphiregulin (AR) has been linked to psoriasis in mouse and man. Since psoriasis is marked by hyperproliferation of keratinocytes and loss of epidermal barrier function with infiltration of inflammatory cells into the epidermis and dermis, we hypothesized that AR might contribute to the pathogenesis of psoriasis by affecting the integrity of cell-cell junctions. We find that there is a marked reduction of functional E-cadherin in psoriatic lesions from both INV-AR mice and individuals with psoriasis. Total E-cadherin levels are dramatically reduced in psoriatic lesions from INV-AR mice. Compared with normal skin, psoriatic lesions from individuals with psoriasis exhibit downregulation of the cytoskeletal-associated triton-insoluble pool of E-cadherin and the appearance of an 80 kDa ectodomain fragment in the cytoplasmic triton-soluble pool. There is reduced immunohistochemical staining for E-cadherin in the basal epidermis of human psoriatic lesions. Moreover, there is enhanced transmigration of human neutrophils through polarized epithelial cell monolayers of MDCK cells after administration of AR, but not transforming growth factor-alpha, further supporting a specific role for AR in the pathogenesis of psoriasis.


Sporadic Inclusion Body Myositis: MRI Findings and Correlation With Clinical and Functional Parameters.
The purpose of this prospective study is to assess MRI findings in patients with sporadic inclusion body myositis (IBM) and correlate them with clinical and functional parameters. This study included 12 patients with biopsy-proven sporadic IBM. All patients underwent MRI of the bilateral upper and lower extremities. The images were scored for muscle atrophy, fatty infiltration, and edema pattern. Clinical data included onset and duration of disease. Muscle strength was measured using the Medical Research Council (MRC) scale, and functional status was assessed using the Modified Rankin Scale. Correlation between MRI and different clinical and functional parameters was calculated using the Spearman rank test and Pearson correlation. All patients showed MRI abnormalities, which were more severe within the lower limbs and the distal segments. The most prevalent MRI finding was fat infiltration. There was a statistically significant correlation between disease duration and number of muscles infiltrated by fat (r = 0.65; p = 0.04). The number of muscles with fat infiltration correlated with the sum of the scores of MRC (r = -0.60; p = 0.04) and with the Modified Rankin Scale (r = 0.48; p = 0.03). Our findings suggest that most patients with biopsy-proven sporadic IBM present with a typical pattern of muscle involvement at MRI, more extensively in the lower extremities. Moreover, MRI findings strongly correlated with clinical and functional parameters, because both the extent and severity of muscle involvement assessed by MRI and clinical and functional parameters are associated with the early onset of the disease and its duration.


Birth control failure among patients with unwanted pregnancies: 1982-1984.
Three hundred twenty-three patients who underwent abortion counseling between 1982 and 1984 were interviewed to determine the cause of birth control failure. Twenty-three percent employed no birth control and 27 percent used diaphragms, the majority either inconsistently or incorrectly. Twenty-two percent of the pregnancies were due to oral contraceptive-related failures; and the remainder were due to spermicide, condom, rhythm method, multiple method, and intrauterine device failures. Overall, fewer than one quarter of unwanted pregnancies among the predominantly white, middle-class population studied resulted from failure to obtain contraception, and only 19 percent represented technical failure despite correct and consistent use. The majority (51 percent) occurred because of human error, ie, either incorrect or inconsistent use of available contraceptive modalities. These findings contrast sharply with those of a similar study performed between 1969 and 1974. At that time failure to obtain contraception accounted for more than one half of the failures. Whereas the development and distribution of contraceptive technology was the challenge of the 1960s and the 1970s, reducing the number of birth control failures through anticipatory patient counseling is the challenge of the current decade.


Electron microscopic studies of replicating and catenated colicin factor E1 DNA isolated from minicells (DNA replication).
Replicating and catenated DNA molecules of colicin factor E1 that were isolated from minicells were observed by electron microscopy. Two new replicating structures that have been found include: molecules that contain two untwisted replicated branches of the same length and a twisted unreplicated branch, and a twisted circular molecule with a long tail. Other molecular forms identified include circular dimers, three types of catenated dimers (open-open, open-twisted, and twisted-twisted), catenated dimers in which one of the linked molecules is replicating, catenated trimers, and a tetamer.


Caloric restriction chronically impairs metabolic programming in mice.
Although obesity rates are rapidly rising, caloric restriction remains one of the few safe therapies. Here we tested the hypothesis that obesity-associated disorders are caused by increased adipose tissue as opposed to excess dietary lipids. Fat mass (FM) of lean C57B6 mice fed a high-fat diet (HFD; FMC mice) was "clamped" to match the FM of mice maintained on a low-fat diet (standard diet [SD] mice). FMC mice displayed improved glucose and insulin tolerance as compared with ad libitum HFD mice (P < 0.001) or SD mice (P < 0.05). These improvements were associated with fewer signs of inflammation, consistent with the less-impaired metabolism. In follow-up studies, diet-induced obese mice were food restricted for 5 weeks to achieve FM levels identical with those of age-matched SD mice. Previously, obese mice exhibited improved glucose and insulin tolerance but showed markedly increased fasting-induced hyperphagia (P < 0.001). When mice were given ad libitum access to the HFD, the hyperphagia of these mice led to accelerated body weight gain as compared with otherwise matched controls without a history of obesity. These results suggest that although caloric restriction on a HFD provides metabolic benefits, maintaining those benefits may require lifelong continuation, at least in individuals with a history of obesity.


Children's Health in Brazil: orienting basic network to Primary Health Care.
This is an integrative literature review that analyzed the scientific knowledge produced on the orientation of Brazilian basic care services to primary health care focusing on child health. Searches were carried out in SciELO, Lilacs and Medline databases using descriptors "primary health care", "family health program", "child health" and "evaluation of health services". Studies published in Portuguese, English and Spanish between 2000 and 2013 were selected. A total of 32 studies were chosen and characterized in relation to the features of primary health care, region of the country, type of study and authors' practice area. A thematic review of studies was conducted and resulted in two categories: child care in the context of Brazilian primary health care and primary health care features: limitations to child care. It can be understood that Brazilian primary health care services are heterogeneous regarding the presence and scope of essential child care characteristics. There is a lack of structural and process changes in the services to substantially plan child care actions in basic care.


Structure, function, and self-assembly of single network gyroid (I4132) photonic crystals in butterfly wing scales.
Complex three-dimensional biophotonic nanostructures produce the vivid structural colors of many butterfly wing scales, but their exact nanoscale organization is uncertain. We used small angle X-ray scattering (SAXS) on single scales to characterize the 3D photonic nanostructures of five butterfly species from two families (Papilionidae, Lycaenidae). We identify these chitin and air nanostructures as single network gyroid (I4(1)32) photonic crystals. We describe their optical function from SAXS data and photonic band-gap modeling. Butterflies apparently grow these gyroid nanostructures by exploiting the self-organizing physical dynamics of biological lipid-bilayer membranes. These butterfly photonic nanostructures initially develop within scale cells as a core-shell double gyroid (Ia3d), as seen in block-copolymer systems, with a pentacontinuous volume comprised of extracellular space, cell plasma membrane, cellular cytoplasm, smooth endoplasmic reticulum (SER) membrane, and intra-SER lumen. This double gyroid nanostructure is subsequently transformed into a single gyroid network through the deposition of chitin in the extracellular space and the degeneration of the rest of the cell. The butterflies develop the thermodynamically favored double gyroid precursors as a route to the optically more efficient single gyroid nanostructures. Current approaches to photonic crystal engineering also aim to produce single gyroid motifs. The biologically derived photonic nanostructures characterized here may offer a convenient template for producing optical devices based on biomimicry or direct dielectric infiltration.


Environmental and social cues can be used in combination to develop sustainable breeding techniques for goat reproduction in the subtropics.
Goat breeds from subtropical latitudes show different annual reproductive cycles. Some of them display large seasonal variations in their annual breeding season, while others display a moderate seasonality or sexual activity all year round. This reproductive seasonality causes seasonality of milk, cheese and meat productions and, as a consequence, induces wide variation in producer incomes. To solve this problem and provide methods allowing producers to breed animals during the anestrous period and stabilize production all year round, it is necessary to have a deep knowledge of their annual sexual activity and to identify the environmental factors controlling the timing of the annual reproductive cycle. Then, it is possible to build on these knowledge sustainable breeding techniques adapted to the environmental, economic and social characteristics of the local breeding system. In this review, I will illustrate this strategy through the example of our experiments in subtropical goats. First, we determined the characteristics of the annual breeding season in both male and female goats. Second, we identified the photoperiod as the major environmental factor controlling the timing of this annual breeding season. Third, we used the photoperiod to stimulate indirectly the sexual behavior of does. Indeed, we used photoperiodic treatments to stimulate the sexual activity of bucks during the non-breeding season. These sexually active male goats were then used to induce and synchronize the estrous behavior and ovulatory activity of anestrous females in confined or grazing conditions by using the 'male effect'. Under subtropical conditions, these results constitute an original manner to control the reproductive activity of local goats using the photoperiod combined with the 'male effect.'


Nonpharmacological treatments for musculoskeletal pain.
Several types of physical therapy are used in the management of painful musculoskeletal disorders. These treatment modalities can be broadly categorized as electrotherapy modalities (e.g., transcutaneous electrical nerve stimulation), acupuncture, thermal modalities (e.g., moist heat, ultrasound), manual therapies (e.g., manipulation or massage), or exercise. Within each of these broad categories significant variations in treatment parameters are possible. To consider the evidence base for each of these main categories of physical therapy in the management of musculoskeletal pain. To consider the available evidence related to clinical effectiveness and then to review evidence from basic science studies evaluating potentially therapeutic effects of the various therapies. There seems to be evidence from basic science research to suggest that many of the therapies could have potentially therapeutic effects. However, there appears to be limited high-quality evidence from randomized clinical trials to support the therapeutic effectiveness of several of the therapies. There is some preliminary evidence to support the use of manual therapies, exercise, and acupuncture in the management of some categories of musculoskeletal pain. Limitations of the existing research base are discussed and recommendations for areas of future research are provided.


Transformation and cytopathogenic effect in an immune human T-cell clone infected by HTLV-I.
Human T-cell leukemia-lymphoma virus (HTLV) is a human C-type retrovirus that can transform T lymphocytes in vitro and is associated with certain T-cell neoplasms. Recent data suggest that, in the United States, patients with acquired immunodeficiency syndrome (AIDS), homosexual men with lymphadenopathy, and hemophiliacs have had significant exposure rates to HTLV, whereas matched and unmatched control American subjects have rarely been exposed to this agent. In the present experiments, T cells specifically reactive against HTLV were propagated from a patient whose HTLV-bearing lymphoma was in remission. The T cells were cloned in the presence of the virus and an HTLV-specific cytotoxic T-cell clone was isolated. This clone was infected and transformed by the virus, with one copy of an HTLV-I provirus being integrated into the genome. This T-cell clone did not exhibit the normal dependence on T-cell growth factor (interleukin-2) and proliferated spontaneously in vitro. Exposure of the clone to HTLV-bearing, autologous tumor cells specifically inhibited its proliferation and resulted in its death. These results may have implications for HTLV-associated inhibition of T-cell responses.


Anterior Cruciate Ligament Reconstruction Rehabilitation Clinical Practice Patterns: A Survey of the PRiSM Society.
Recovery after anterior cruciate ligament (ACL) reconstruction (ACLR) requires extensive postoperative rehabilitation. Although no ideal rehabilitation procedure exists, most experts recommend a fusion of time and strength and functional measures to guide decision making for activity progression during rehabilitation. This process is often directed by surgeon protocols; however, the adoption of contemporary rehabilitation recommendations among surgeons is unknown. To understand the current landscape of surgeon practice as it relates to ACLR rehabilitation recommendations in adolescent athletes. Cross-sectional study. An online survey was distributed among members of the Pediatric Research in Sports Medicine (PRiSM) Society in January 2017. The survey was designed to identify clinical practice patterns during 3 key transitional points of rehabilitation after ACLR: progression to jogging, modified sports activity, and unrestricted return to sports. Responses from 60 orthopaedic surgeons were analyzed. While 80% of surgeons agreed upon initiating jogging within a 1-month range (3-4 months postoperatively), similar levels of agreement were only captured when including a wider 4-month (4-8 months) and 6-month range (6-12 months) for modified sports activity and unrestricted return to sports, respectively. All respondents (100%) reported using knee strength as a determinant to progress to modified sports activity; however, the mode of testing varied, with most using manual muscle testing (60%), followed by isokinetic (28%) or isometric (12%) testing. Most surgeons (68%) reported using some form of functional testing to return to modified sports activity, but the mode of testing and required progression criteria varied considerably among all reported testing procedures. The use of patient-reported outcome measures was limited to 20% of the sample, and no respondents reported using fear or self-efficacy questionnaires. Upon completion of rehabilitation, 73% recommended injury prevention programs, and 50% recommended the use of a functional ACL brace. Rehabilitation progression practices in adolescent athletes are variable and become more inconsistent as the time from surgery increases. While the majority of the sample considered strength and functional testing important, the mode of testing and criteria thresholds for activity advancement varied considerably.


Antibacterial flavanones and dihydrochalcones from Macaranga trichocarpa.
Previously we had isolated two prenylated flavanones and two prenylated dihydrochalcones, macatrichocarpins A-D (1-4), from the acetone extract of the leaves of Macaranga trichocarpa. Re-examination of the fractions containing minor components resulted in the isolation of four more flavonoid derivatives, including two new prenylated dihydrochalcones, oxymacatrichocarpin C (5) and isomacatrichocarpin C (6). The structures of these compounds were determined by the analysis of UV, NMR, and mass spectral data. The eight isolated flavonoids were tested on eight pathogenic bacteria and found to be mostly moderate antibacterial agents, with the lowest MIC value of 26.5 μM achieved by the flavanone macatrichocarpin A (1) against Bacillus subtilis.


Clinical outcomes of immunomodulatory therapies in the management of COVID-19: A tertiary-care experience from Pakistan.
The pharmacological management of COVID-19 has evolved significantly and various immunomodulatory agents have been repurposed. However, the clinical efficacy has been variable and a search for cure for COVID-19 continues. A retrospective cohort study was conducted on 916 patients hospitalized with polymerase chain reaction (PCR)-confirmed COVID-19 between February 2020 and October 2020 at a tertiary care academic medical center in Karachi, Pakistan. The median age was 57 years (interquartile range (IQR) 46-66 years). The most common medications administered were Methylprednisolone (65.83%), Azithromycin (50.66%), and Dexamethasone (46.6%). Majority of the patients (70%) had at least two or more medications used in combination and the most frequent combination was methylprednisolone with azithromycin. Overall in-hospital mortality was 13.65% of patients. Mortality was found to be independently associated with age greater than or equal to 60 years (OR = 4.98; 95%CI: 2.78-8.91), critical illness on admission (OR = 13.75; 95%CI: 7.27-25.99), use of hydrocortisone (OR = 12.56; 95%CI: 6.93-22.7), Ferritin> = 1500(OR = 2.07; 95%CI: 1.18-3.62), Creatinine(OR = 2.33; 95%CI: 1.31-4.14) and D-Dimer> = 1.5 (OR = 2.27; 95%CI: 1.26-4.07). None of the medications whether used as monotherapy or in combination were found to have a mortality benefit. Our study highlights the desperate need for an effective drug for the management of critical COVID-19 which necessitates usage of multiple drug combinations in patients particularly Azithromycin which has long term implications for antibiotic resistance particularly in low-middle income countries.


3D Ultrasound versus Computed Tomography for Tumor Volume Measurement Compared to Gross Pathology-A Pilot Study on an Animal Model.
The margin of the removed tumor in cancer surgery has an important influence on survival. Adjuvant treatments, prognostic complications, and financial costs are required when the pathologist observes a close/positive surgical margin. Ex vivo imaging of resected cancer tissue has been suggested for margin assessment, but traditional cross-sectional imaging is not optimal in a surgical setting. Instead, three-dimensional (3D) ultrasound is a portable, high-resolution, and low-cost method to use in the operation room. In this study, we aimed to investigate the accuracy of 3D ultrasound versus computed tomography (CT) to measure the tumor volume in an animal model compared to gross pathology assessment. The specimen was formalin fixated before systematic slicing. A slice-by-slice area measurement was performed to compare the accuracy of the 3D ultrasound and CT techniques. The tumor volume measured by pathological assessment was 980.2 mm3. The measured volume using CT was 890.4 ± 90 mm3, and the volume using 3D ultrasound was 924.2 ± 96 mm3. The correlation coefficient for CT was 0.91 and that for 3D ultrasound was 0.96. Three-dimensional ultrasound is a feasible and accurate modality to measure the tumor volume in an animal model. The accuracy of tumor delineation on CT depends on the soft tissue contrast.


Clean-up Strategy for Dithiocarbamate Fungicide Determination in Soybean by GC-ITD-MS and GC-PFPD: Method Development and Validation.
Food matrices consist of many components with different physical and chemical properties that may influence instrumental robustness. The soybean contains fatty coextractives which may have a deleterious effect on the gas chromatography (GC) system. In this study, the efficiencies of PSA, C18OH, C18, silica, aluminum oxide, and Florisil, as dSPE clean-up sorbents, were evaluated by the high-performance liquid chromatography (HPLC) diode-array detector and evaporative light-scattering detector analysis. The dithiocarbamates in soybean samples are determined as CS2 using acidic hydrolysis and isooctane partitioning, followed by GC-PFPD and GC-ITD-MS analyses. The linearity of the analytical curves, the instrument limit of detection matrix effects, the trueness and precision, and the method limit of quantification (LOQ) were assessed in the validation study. Milled soybean was spiked with thiram solution at three concentration levels (corresponding to 0.05, 0.1, and 0.5 mg CS2 kg-1) for recovery determination. Silica appeared to be an effective and cheap sorbent to remove coextracted matrix components without causing any CS2 losses. Recoveries were in the range of 68-91%, with relative standard deviations ≤ 8.7%. The method LOQ was 0.05 mg CS2 kg-1, and both GC-ITD-MS and GC-PFPD systems appeared to be appropriate and complementary to determine dithiocarbamate residues in soybean extracts.


Zebrafish Model Insights into Mediterranean Diet Liquids: Olive Oil and Wine.
In this review, we explored the potential of a zebrafish model to investigate the antioxidant effects of key components of the Mediterranean diet, namely, olive oil and wine, in the context of preventing age-related diseases, particularly cardiovascular conditions. This paper explores the spectrum of observational studies to preclinical investigations and ultimately converges toward potential translational insights derived from animal experimentation. This review highlights the potential and underutilization of zebrafish as an experimental model in this domain. We highlighted the genetic proximity of zebrafish to humans, offering a unique opportunity for translational insights into the health benefits of olive oil and wine. Indeed, we wanted to focus on the potential of zebrafish to elucidate the health benefits of olive oil and wine while calling for continued exploration to unlock its full potential to advance our knowledge of age-related disease prevention within the Mediterranean diet framework.