Capsaicin Improves Glucose Tolerance and Insulin Sensitivity Through Modulation of the Gut Microbiota-Bile Acid-FXR Axis in Type 2 Diabetic db/db Mice.
Previous studies have linked dietary capsaicin (CAP) intake to improved glucose homeostasis and insulin sensitivity. However, the underlying mechanisms remain unclear. Type 2 diabetic db/db mice are fed a chow diet with or without CAP treatment for 8 weeks. CAP administration markedly improves glucose tolerance and insulin sensitivity through decreasing gluconeogenesis and increasing glycogen synthesis in the liver. Furthermore, CAP inhibits the increase in abundance of the genus Lactobacillus and its bile salt hydrolase (BSH) activity compared with levels in chow-fed mice, thereby leading to the accumulation of tauro-β-muricholic acid (TβMCA), a natural antagonist of the farnesoid X receptor (FXR) that is involved in the regulation of BA and glucose metabolism. CAP-induced suppression of enterohepatic FXR-fibroblast growth factor 15 (FGF15) signaling contributes to the increased BA pool size, followed by increases in the expression of cholesterol 7α-hydroxylase (CYP7A1) and hepatic BA synthesis. Additionally, depleting gut microbiota by antibiotics administration abolishes the beneficial effects of CAP on BA metabolism and glucose homeostasis. CAP-induced improvements in BA and glucose metabolism are partially mediated by the gut microbiota-BA-enterohepatic FXR axis in db/db mice.


Cardiac stress MR imaging with dobutamine.
Stress testing for detection of ischemia-induced wall-motion abnormalities has become a mainstay for noninvasive diagnosis and risk stratification of patients with suspected coronary artery disease (CAD). Recent technical developments in magnetic resonance imaging (MRI), including the adoption of balanced steady-state free precession (b-SSFP) sequences-preferentially in combination with parallel imaging techniques-have led to a significant reduction of imaging time and improved patient safety. The stress protocol includes application of high-dose dobutamine (up to 40 microg/kg/min) combined with fractionated atropine (up to a maximal dose of 1.0 mg). High-dose dobutamine stress MRI revealed good sensitivity (83-96%) and specificity (80-100%) for detection of significant CAD. Myocardial tagging methods have been shown to further increase sensitivity for CAD detection. Severe complications (sustained tachycardia, ventricular fibrillation, myocardial infarction, cardiogenic shock) are rare but may be expected in 0.1-0.3% of patients. Dobutamine stress MRI has emerged as a reliable and safe clinical alternative for noninvasive assessment of CAD. New pulse sequences, such as real-time imaging, might obviate the need for breath holding and electrocardiogram (ECG) triggering in patients with severe dyspnoea and cardiac arrhythmias, which may further improve the clinical impact and acceptance of stress MRI in the future.


Speech recognition ability as a function of duration of deafness in multichannel cochlear implant patients.
Surgical implantation of a multichannel cochlear prosthesis has become a widespread treatment for profound hearing loss. The relationship between duration of hearing loss and speech recognition ability was examined in 20 postlinguistically deafened adults using the Nucleus 22-Channel Cochlear Prosthesis. Data analysis indicated statistically significant negative correlations between duration of profound hearing loss and postoperative performance on the Central Institute for the Deaf Everyday Sentence Test and the Northwestern University Monosyllabic Word Test (NU-6). Age at implantation and age at onset of profound hearing loss were not found to be significantly correlated with performance on the two measures. These findings are discussed in terms of patient counseling and prediction of potential benefit to the patient.


Electrocardiogram machine learning for detection of cardiovascular disease in African Americans: the Jackson Heart Study.
Almost half of African American (AA) men and women have cardiovascular disease (CVD). Detection of prevalent CVD in community settings would facilitate secondary prevention of CVD. We sought to develop a tool for automated CVD detection. Participants from the Jackson Heart Study (JHS) with analysable electrocardiograms (ECGs) (n=3679; age, 6212 years; 36% men) were included. Vectorcardiographic (VCG) metrics QRS, T, and spatial ventricular gradient vectors magnitude and direction, and traditional ECG metrics were measured on 12-lead ECG. Random forests, convolutional neural network (CNN), lasso, adaptive lasso, plugin lasso, elastic net, ridge, and logistic regression models were developed in 80% and validated in 20% samples. We compared models with demographic, clinical, and VCG input (43 predictors) and those after the addition of ECG metrics (695 predictors). Prevalent CVD was diagnosed in 411 out of 3679 participants (11.2%). Machine learning models detected CVD with the area under the receiver operator curve (ROC AUC) 0.690.74. There was no difference in CVD detection accuracy between models with VCG and VCG + ECG input. Models with VCG input were better calibrated than models with ECG input. Plugin-based lasso model consisting of only two predictors (age and peak QRS-T angle) detected CVD with AUC 0.687 [95% confidence interval (CI) 0.6250.749], which was similar (P=0.394) to the CNN (0.660; 95% CI 0.5970.722) and better (P<0.0001) than random forests (0.512; 95% CI 0.4930.530). Simple model (age and QRS-T angle) can be used for prevalent CVD detection in limited-resources community settings, which opens an avenue for secondary prevention of CVD in underserved communities.


Increased biomass production and glycogen accumulation in apcE gene deleted Synechocystis sp. PCC 6803.
The effect of phycobilisome antenna-truncation in the cyanobacterium Synechocystis sp. PCC 6803 on biomass production and glycogen accumulation have not yet been fully clarified. To investigate these effects here, the apcE gene, which encodes the anchor protein linking the phycobilisome to the thylakoid membrane, was deleted in a glucose tolerant strain of Synechocystis sp. PCC 6803. Biomass production of the apcE-deleted strain under photoautotrophic and atmospheric air conditions was 1.6 times higher than that of strain PCC 6803 (1.32 ± 0.01 versus 0.84 ± 0.07 g cell-dry weight L(-1), respectively) after 15 days of cultivation. In addition, the glycogen content of the apcE-deleted strain (24.2 ± 0.7%) was also higher than that of strain PCC 6803 (11.1 ± 0.3%). Together, these results demonstrate that antenna truncation by deleting the apcE gene was effective for increasing biomass production and glycogen accumulation under photoautotrophic and atmospheric air conditions in Synechocystis sp. PCC 6803.


Policies to clean up toxic industrial contaminated sites of Gela and Priolo: a cost-benefit analysis.
Cost-benefit analysis is a transparent tool to inform policy makers about the potential effect of regulatory interventions, nevertheless its use to evaluate clean-up interventions in polluted industrial sites is limited. The two industrial areas of Gela and Priolo in Italy were declared "at high risk of environmental crisis" in 1990. Since then little has been done to clean the polluted sites and reduce the health outcomes attributable to pollution exposure. This study, aims to quantify the monetary benefits resulting from clean-up interventions in the contaminated sites of Gela and Priolo. A damage function approach was used to estimate the number of health outcomes attributable to industrial pollution exposure. Extensive one way analyses and probabilistic analyses were conducted to investigate the sensitivity of results to different model assumptions. It has been estimated that, on average, 47 cases of premature death, 281 cases of cancer and 2,702 cases of non-cancer hospital admission could be avoided each year by removing environmental exposure in these two areas. Assuming a 20 year cessation lag and a 4% discount rate we calculate that the potential monetary benefit of removing industrial pollution is €3,592 million in Priolo and €6,639 million in Gela. Given the annual number of health outcomes attributable to pollution exposure the effective clean-up of Gela and Priolo should be prioritised. This study suggests that clean-up policies costing up to €6,639 million in Gela and €3,592 million in Priolo would be cost beneficial. These two amounts are notably higher than the funds allocated thus far to clean up the two sites, €127.4 million in Gela and €774.5 million in Priolo, implying that further economic investments - even considerable ones - could still prove cost beneficial.


Corrigendum: CXCL17 Is a Specific Diagnostic Biomarker for Severe Pandemic Influenza A(H1N1) That Predicts Poor Clinical Outcome.
[This corrects the article DOI: 10.3389/fimmu.2021.633297.].


Comparison of contraceptive failures associated with CYP3A4-inducing drug-drug interactions by route of hormonal contraceptive in an adverse event reporting system.
To estimate associations between contraceptive failures and concomitant CYP3A4-inducing medications by route of administration. Comparison of unintended pregnancy outcomes within U.S. Food and Drug Administration's Adverse Event Reporting System by couse of CYP3A4-inducing drugs and route of administration for levonorgestrel and etonogestrel/desogestrel. Among 14,504 levonorgestrel case reports, the reporting odds ratio (ROR) was increased for oral (ROR = 4.2 [3.0-5.7]), implants (ROR = 8.0 [5.8-11.0]), but not intrauterine (ROR = 0.9 [0.6-1.3]) levonorgestrel products. For 9348 etonogestrel/desogestrel case reports, oral and vaginal products were not associated with contraceptive failure. Etonogestrel containing implants (ROR = 4.9 [4.1-5.9]) were associated with increased contraceptive failure. Levonorgestrel containing combination oral products and implants containing levonorgestrel or etonogestrel were prone to CYP3A4-inducing drug-drug interactions that may increase contraceptive failures. The progestin components of hormonal contraceptives are susceptible to drug-drug interactions, but this susceptibility is influenced by route of administration. This study provides evidence from an Adverse Event Reporting System that CYP3A4-inducing medications increase the risk of unintended pregnancy for oral and implant contraceptives but not intrauterine or vaginal devices.


Use of Pyromark Q96 ID pyrosequencing system in identifying bacterial pathogen directly with urine specimens for diagnosis of urinary tract infections.
Detection and identification of bacterial etiology in urine is critical for accurate diagnosis and subsequent rational treatment of urinary tract infections (UTIs). Urine culture followed by a series of biochemical reactions is currently the standard method for detecting and distinguishing microorganisms associated with UTIs. The whole procedure commonly takes more than 24h. Here we developed a new system combining 16S rRNA gene broad-range PCR with pyrosequencing technology that allows for bacteria detection and identification in urine in 5h. To evaluate this system for rapid diagnosis of bacteriuria, 768 urine specimens were collected from patients with suspected UTIs and were tested side-by-side using standard urine culture-based identification method and the pyrosequencing method. The results from pyrosequencing correlated well with those from traditional culture-based identification method. The overall agreement between these two methods reached 98.0% (753/768). In addition, we tested the sensitivity of pyrosequencing method and determined that urine bacterial numbers as low as 10(4)cfu/ml could be accurately detected and identified. In conclusion, compared with traditional biochemical method, the PCR-pyrosequencing system significantly improved the detection and identification of bacteriuria with shorter time, higher accuracy, and higher throughput, thus allowing earlier pathogen-adapted antibiotic therapy for patients.


Bone marrow-derived cell therapy stimulates endogenous cardiomyocyte progenitors and promotes cardiac repair.
Cell therapy can improve cardiac function in animals and humans after injury, but the mechanism is unclear. We performed cell therapy experiments in genetically engineered mice that permanently express green fluorescent protein (GFP) only in cardiomyocytes after a pulse of 4-OH-tamoxifen. Myocardial infarction diluted the GFP(+) cardiomyocyte pool, indicating refreshment by non-GFP(+) progenitors. Cell therapy with bone marrow-derived c-kit(+) cells, but not mesenchymal stem cells, further diluted the GFP(+) pool, consistent with c-kit(+) cell-mediated augmentation of cardiomyocyte progenitor activity. This effect could not be explained by transdifferentiation to cardiomyocytes by exogenously delivered c-kit(+) cells or by cell fusion. Therapy with c-kit(+) cells but not mesenchymal stem cells improved cardiac function. These findings suggest that stimulation of endogenous cardiogenic progenitor activity is a critical mechanism of cardiac cell therapy.


Sequencing of a second interleukin-10 gene in rainbow trout Oncorhynchus mykiss and comparative investigation of the expression and modulation of the paralogues in vitro and in vivo.
Interleukin-10 (IL-10) is a multifaceted cytokine that is produced by and effects a variety of cell populations, including macrophages, T, B and NK cells. The gene encoding for IL-10 has been isolated in mammals, birds, amphibians and recently in fish, with only single copy identified in each species. We report here a second IL-10 gene (tIL-10b) in rainbow trout that showed 92% identity in the coding region but only 50% identity in the 5'- and 3'-UTR to the known trout IL-10 paralogue, which we have now called tIL-10a. There is a short upstream open reading frame (uORF) within the 5'-untranslated region (UTR) of tIL-10a that may inhibit its translation, whilst in tIL-10b multiple mRNA instability motifs exist in the 3'-UTR, suggesting that the two IL-10 paralogues may have different mechanisms to regulate their expression post-transcriptionally. The expression of tIL-10a is generally higher than that of tIL-10b in most of the fourteen tissues examined and in the RTS-11, RTL and RTGill cell lines. However, the expression level of tIL-10b can exceed that of tIL-10a, as seen in vivo in the ovary of healthy fish and in the gills of Yersinia ruckeri challenged fish, and in vitro in head kidney (HK) leucocytes cultured for ≥ 8 h. The expression of the trout IL-10 paralogues can be up-regulated by LPS and polyIC in RTS-11 cells and by LPS, polyIC, PHA, PMA, calcium ionophore (CI) and IL-21 in head kidney leucocytes, as well as by Y. ruckeri infection, and can be modulated positively or negatively by IFN-γ. Synergistic effects on up-regulation of IL-10 expression were also seen between PHA and IL-21, as well as between PMA and CI. The expression kinetics of the IL-10 paralogues was also found to be different, suggesting that rainbow trout has evolved different pathways to regulate the expression of the two IL-10 paralogues at the transcriptional level.


Comment to: Effectiveness of contrast-enhanced ultrasound for detecting the staging and grading of bladder cancer: a systematic review and meta-analysis.
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Evidence for heme pi cation radical species in compound I of horseradish peroxidase and catalase.
Magnetic circular dichroism spectra are reported for the compound I species of beef liver catalase (hydrogen-peroxide: hydrogen-peroxide oxidoreductase, EC 126.96.36.199) and horseradish peroxidase (donor: hydrogen-peroxide oxidoreductase, EC 188.8.131.52) and the pi cation radical derivatives of porphyrins that have been suggested as models of the electronic configuration of the heme in the compound I species of these enzymes. Comparison of the magnetic circular dichroism spectra of the compound I species with the spectra of [Co(octaethylporphyrin)]2Br and [Co(octaethylporphyrin)]2ClO4 indicates that in both the intermediate enzyme species the heme has been oxidized to a pi cation radical. While there is a clear distinction between the magnetic circular dichroism spectra of the 2A2u porphyrin [Co(III)octaethylporphyrin]2ClO4, and the 2A1u porphyrin, [Co(III)octaethylporphyrin]2Br, such specific differences are not observed in the spectra of the two enzymes. Analysis of our data suggests that the ground states in the two enzymes are far more similar than the ground states in the two model porphyrins.


Analysis of AHG-PRA and ELISA-PRA in kidney transplant patients with acute rejection episodes.
Many centers determined a significant correlation between post-transplant anti-HLA antibodies production and clinical outcome. In order to confirm this correlation and ascertain the sequential appearance of anti-HLA antibodies, we compared the ELISA (ELISA-PRA) and the anti-human globulin enhanced complement-dependent lymphocytotoxicity panel-reactive antibodies test (AHG-PRA) with the occurrence of acute rejection episodes. Thirty patients who underwent kidney transplantation between December 1998 and October 1999 were assayed. One pre-transplant and 10 post-transplant serum samples were tested from each recipient except from one of them who lost his graft on the 1 week post-transplant. The diagnosis of acute rejection episode was based on classical criteria (fever, graft swelling and tenderness, oliguria, weight gain) and a rapid rise in serum creatinine levels, confirmed by an allograft biopsy graded by the Banff working classification. The 322 pre- and post-transplant serum specimens were tested by AHG-PRA methodology and 298 of them by the ELISA-PRA. The agreement coefficient (kappa) for both methodologies was 0.63. There were 27 acute rejection episodes in 19 patients. AHG-PRA results were significantly correlated (Hazard ratio=10.06; P=0.006) with this occurrence. These data were not confirmed with the ELISA-PRA procedure. Our results suggest that a routine post-transplant AHG-PRA test offers an early risk assessment of acute rejection episodes and may be a useful method for monitoring the kidney transplant evolution.


Strain distribution and linkage relationship of a mouse embryonic hemoglobin variant.
Search for structural variants of three globin chains (x, y, z), synthesized only during mouse embryonic hematopoiesis, was carried out by electrophoretic analysis of blood from 12-day embryos, all with C57BL/6 mothers, and fathers from 115 inbred stocks selected for their diverse genetic origins. Structure of the beta-chains of adult hemoglobins differed among the tested strains, with 57 carrying the Hbbs allele, 56 the Hbbd allele, and two the Hbbp allele. The search revealed no x- or z-chain variants but confirmed and extended knowledge of a previously described y-chain variant. Blood of all embryos sired by males from the 57 Hbbs strains contained only y'-chains, while blood of au embryos sired by Hbbd or Hbbp males contained y2-chains as well as the y1-chains inherited from their C57BL/6 mother. The locus controlling structure of the y-chain of mouse embryonic hemoglobins is thus extremely closely linked to the locus controlling structure of adult hemoglobin beta-chain, with maximum possible recombination frequency less than 0.019.


Improvement and decline in health status from late middle age: modeling age-related changes in deficit accumulation.
In a prospective multi-panel cohort study, we investigated how, from late middle age, individuals' health status improves or declines. In the Canadian National Population Health Survey, transition probabilities between different health states were estimated for 4330 people (58.8% women) aged 55+ at baseline over 2-year intervals from 1994 to 2000. Health status was defined by a deficit count, using 33 health-related variables combined in a frailty index. For each time interval, the chance of accumulating deficits increased linearly with the number of deficits. Older survivors (aged 70-85) showed a slightly lower chance of stability or improvement (52%; 95% confidence interval 50-54%) compared with those in late middle age (56%; 54-58%). Changes in health states can be described with high accuracy (R2=0.92) by a modified Poisson distribution, using four parameters: the background odds of accumulating additional deficits, the chance of incurring more or fewer deficits, given the existing number, and the corresponding probabilities of dying. An age-invariant limit to deficit accumulation was observed at 22 deficits. From late middle age, transitions in health states occur with a regularity that is easily modeled. Improvements in health can occur at any age. At all ages, there is a limit to deficit accumulation.


The Cohen flexitip endobronchial blocker: an alternative to a double lumen tube.
One-lung ventilation (OLV) is usually achieved by the use of a double-lumen tubes (DLTs). With increasing need for use of OLV for video-assisted thoracoscopic procedures, the limitations of traditional DLT's, including difficult insertion and positioning, have become evident. This has led to renewed interest in devising alternative methods of achieving lung separation, such as the Univent tube or Arndt endobronchial blocker. This report describes the technical features and clinical use of a new tip-deflecting endobronchial blocker.


Opportunities for Restructuring Hospital Transfer Networks for Pediatric Asthma.
To describe the current system of pediatric asthma care and identify potential options for unloading tertiary centers. Retrospective, cross-sectional study using 2014 inpatient and emergency department all-encounter administrative datasets from Arkansas, Florida, Kentucky, Maryland, Massachusetts, and New York. Study participants included children <18 with primary diagnosis of asthma. There were 174,239 encounters for pediatric asthma, with 26,316 admissions and 3101 transfers. About 94.4% of transfers were admitted, with median stay length 2 days (interquartile range [IQR] 1.0-3.0). About 637 hospitals saw pediatric asthma, but 58.7% never admitted these patients. Fifty-four hospitals (8.5%) regularly received transfers; these hospitals were broadly capable pediatric centers (mean pediatric hospital capability indices = 0.82, IQR: 0.64-0.89). Two hundred nine facilities (32.8%) did not regularly receive transfers but were highly capable of caring for pediatric asthma (mean condition-specific capability = 0.92, IQR: 0.85-1.00). Median distance from transferring hospitals to the nearest pediatric center was 25.7 miles (IQR: 6.45-50.15) vs 18.0 miles (IQR: 8.35-29.25) to the nearest potential receiving hospital. Mean cost of a 2-day asthma admission in receiving hospitals was $3927 (IQR: $3083-$4894) versus $3427 (IQR: $2485-$4102) in potential receivers. While nearly all acute care hospitals encounter children with asthma, more than half never admit them. Children are primarily transferred to a small subset of specialized centers, despite the existence, in many regions, of closer community hospitals with high pediatric asthma capability. In settings with long transfer distances and tertiary center crowding, a tiered system of hospital care for pediatric asthma may be feasible.


Genetic engineering of circularly permuted yellow fluorescent protein reveals intracellular acidification in response to nitric oxide stimuli.
Intracellular pH (pHi) is a crucial parameter in cell biology; thus, a series of pH probes have been developed to determine pHi changes in living cells. However, more sensitive and non-perturbing ratiometric pH probes are needed for accurate pHi measurements. While the fluorescence of circular permutated YFP (cpYFP) is hypersensitive to pH changes due to its intrinsic properties, the single excitation peak of this protein restricts its capacity of becoming a rational type of pH sensor. Herein, we collected several cpYFP-based probes with dual excitation peaks and constructed their corresponding loss-of-function mutants to screen for a potential competent pH probe. The most sensitive probe was named NocPer. NocPer consists of cpYFP inserted into inactive-mutated GAF and AAA+, which are two regulatory domains of E. coli NorR, a nitric oxide (NO)-specific transcription factor. Fluorescence emission of NocPer peaks at 517 nm while exhibiting dual excitation peaks at 420 and 495 nm, which can be used for ratiometric imaging. This new pH sensor has a large ratio response dynamic (pH range of 7.0-11.0), which covers the physiological pH range (pH 7.0-8.0), and exhibits an approximately 3-fold higher fluorescent signal in response to a pH increase from 7.0 to 8.0 than that of pHluorin. Using NocPer, we discovered a new biological phenomenon in which NO exposure decreases the E. coli pHi, which led to the hypothesis that pathogens decrease their own pHi during infection. Further, we elucidated that the NO-induced inhibition of cytochrome c oxidase in the respiratory chain is responsible for the decline in pHi, which might represent a protective strategy of E. coli under NO stress conditions. Our results demonstrated that NocPer is a ratiometric pH probe with high sensitivity for the physiological pH range.


The role of radiotherapy in the management of thymic tumors.
Radiotherapy is a major therapeutic modality for thymic malignancies. The exact role of adjuvant radiotherapy after complete resection is still debated for stage II through III tumors. Histology or size, capsular invasion, and even molecular data may be included in the decision making. Radiotherapy may be recommended for stage III thymomas, thymic carcinoma, or after incomplete surgical resection. Combination with chemotherapy may be useful, and must be further evaluated using validated end points, including 5- and 10-year time-to-progression and overall survival. Several initiatives have been taken worldwide to launch collaborative studies in the field, including prospective trials specifically readdressing the role of radiotherapy for thymic malignancies.


Vitamin D Supplementation and Its Relationship with Loss of Visceral Adiposity.
An inverse relationship between vitamin D (VD) nutritional status and obesity is frequent, and the distribution of body fat is an important aspect to assess the risks of obesity-related metabolic dysfunction. The purpose of the study was to evaluate the relationship between serum VD concentrations and body fat reduction after 12 months of bariatric surgery, using two different vitamin D3 (VD3) supplementation protocols. A randomized controlled trial consisted of 41 patients divided into G1 (800 IU/day) and G2 (1800 IU/day) according to the VD3 supplementation. At baseline (T0) and follow-up (T1), 25(OH)D, waist circumference (WC), visceral adiposity index (VAI), body adiposity index (BAI), and waist/height ratio (WHtR) were evaluated. In T0, the mean of 25(OH)D was lower in G2 compared to that in G1 (22.6 vs 23.6 ng/mL; p = 0.000). At T1, it had a significant increase in G2 (32.1 vs 29.9 ng/mL; p = 0.000), with 60% sufficiency. A significant negative correlation was observed between VAI, BAI, and WHtR with 25(OH)D in G2 (r = - 0.746, p = 0.024; r = - 0.411, p = 0.036; r = - 0.441, p = 0.032) after surgery. Higher mean changes from baseline of visceral fat loss, represented by VAI, were observed in G2 (176.2 ± 149.0-75.5 ± 55.0, p = 0.000). Patients submitted to the 1800 IU/day protocol, 12 months after the surgical procedure, had a higher percentage of sufficient vitamin D levels compared to those submitted to the 800 IU/day protocol. Additionally, higher dose supplementation promoted a significant improvement in VAI.


Ehlers Danlos Syndrome Type IV and pregnancy.
A case report is presented of a 23-year-old patient who was diagnosed with Ehlers Danlos syndrome (EDS) Type IV (vascular type) in the 23rd week of her second pregnancy. EDS Type IV has one of the highest mortality rates for pregnant women of any condition with significant morbidity if the mother survives. Current literature is presented and supports the necessity for close monitoring of mother and child in a specialist unit with involvement of a multi-disciplinary team. There is no agreed consensus on the mode or timing of delivery but recent literature is supportive of delivery by caesarean section at 32 weeks. This case report demonstrates a successful outcome for both mother and child with a planned delivery at 34 weeks by caesarean section and emphasises the importance of strategic planning for complicated deliveries and the effectiveness of good communication networks. Patients with EDS Type IV should be counselled about the potential risks for both themselves and the child to enable them to make informed decisions about their obstetric care.


Thalamic modulation of aggression.
This experiment extends Pavlov's method of contrasts for 8 components of aggression were quantitatively evaluated in 11 freely moving adult cats. Aggression was elicited from the perifornix septohypothalamic areas by a series of progressively increasing and decreasing stimulation parameters. Three levels of thalamic stimulation (low, medium, and high) were combined with the perifornix stimulations. High level thalamic stimulation tended to facilitate the aggressive response elicited by low level perifornix stimulation. Thalamic lesions attenuated the aggression response, especially those elicited during high level perifornix stimulation. It was suggested that within the hypothalamic induced aggression circuitry the center median nucleus modulates the excitatory state of the system. The discussion concerns anatomic and physiologic pathways through which the center median nucleus may modulate the sensory, motor, and affective-autonomic subsystems into a well integrated aggressive state. These experimental findings are supported by the clinically established treatment of aggression by stereotaxic lesions placed in the center median nucleus.


Do the effects of adolescent employment differ by employment intensity and neighborhood context?
Research on the effects of adolescent employment on primarily middle-class youth suggests that intense employment, working more than 15 or 20 hours during the school year, is associated with increased participation in risky behavior. Despite these findings, scholars who focus on the development of youth living in low-income urban areas often hypothesize that adolescent employment will have beneficial effects on this population. There is some evidence that adolescent employment is associated with increased educational achievement and adult employment for low-income urban youth. The impact of adolescent employment on future engagement in risky behavior across levels of neighborhood deprivation and employment intensity was investigated on a sample of 1,057 adolescents from the Project on Human Development in Chicago Neighborhoods, a longitudinal study of neighborhood effects on development. After controlling for individual characteristics, intense employment during adolescence did predict increased use of cigarettes and alcohol and having a greater number of sexual partners 2 years after employment was measured. There were no significant interactions between neighborhood SES and adolescent employment status on involvement in risky behavior. These findings suggest that intense adolescent employment is associated with detrimental developmental outcomes for youth regardless neighborhood context.


Treatment of locally advanced rectal cancer with external beam radiation, surgical resection, and intraoperative radiation therapy.
To try to improve the local control and survival of patients with locally advanced rectal cancer we have used a combination of high-dose pre-operative radiation therapy to 5,040 cGy followed by surgical resection and intraoperative electron beam radiation therapy (IORT) when there was visible or palpable residual disease, microscopically positive surgical margins, or persisting tumor adherence. A total of 75 patients were taken to surgery for resection +/- IORT who did not have distant metastases. Of the 49 patients with primary tumors, 11 did not have IORT as the tumor was thought to be completely resected. Of these 11, there were two local recurrences and a 3-year survival of 71%. Thirty-six patients with primary tumors had resection (20 complete, 16 partial) plus IORT, with a 3-year survival of 58% and three local failures. Twenty-six additional patients were treated for locally advanced recurrence of whom four could not receive IORT because of pelvic size or the extent of tumor. Of the 22 who received IORT, 7/9 with complete resection, 2/8 with partial resection, and 1/5 with no resection had local control with an overall 3-year actuarial survival of 32%. The local control and survival results in the primary tumors appear favorable compared to other series in the literature and suggest benefit to the use of IORT. For patients treated for local recurrence, local control and long-term survival can be obtained, but the results are not as encouraging as for the primary tumors.


Reconstitution of Detergent-Solubilized Membrane Proteins into Proteoliposomes and Nanodiscs for Functional and Structural Studies.
Reconstitution of detergent-solubilized membrane proteins into phospholipid bilayers allows for functional and structural studies under close-to-native conditions that greatly support protein stability and function. Here we outline the detailed steps for membrane protein reconstitution to result in proteoliposomes and nanodiscs. Reconstitution can be achieved via a number of different strategies. The protocols for preparation of proteoliposomes use detergent removal via dialysis or via nonpolar polystyrene beads, or a mixture of the two methods. In this chapter, the protocols for nanodiscs apply polystyrene beads only. Proteoliposome preparation methods allow for substantial control of the lipid-to-protein ratio, from minimal amounts of phospholipid to high concentrations, type of phospholipid, and mixtures of phospholipids. In addition, dialysis affords a fairly large degree of control and variation of parameters such as rate of reconstitution, temperature, buffer conditions, and proteoliposome size. For the nanodisc approach, which is highly advantageous for ensuring equal access to both membrane sides of the protein as well as fast reconstitution of only a single membrane protein into a well-defined bilayer environment in each nanodisc, the protocols outline how a number of these parameters are more restricted in comparison to the proteoliposome protocols.


Identification of Taenia solium DNA by PCR in blood and urine samples from a tertiary care center in North India.
NCC is a neglected zoonotic disease with high endemicity and disease burden. Neurocysticercosis is a frequent cause of seizures in endemic countries. Early diagnosis and therapy helps in reducing morbidity and DALYs (daily adjusted life years) lost. Definite diagnosis still relies on neuroimaging identification of scolex or by histopathological examination. Molecular method such as PCR (Polymerase Chain Reaction) is an emerging modality to supplement or complement these Gold standard methods. To determine the utility of PCR in detecting Taenia Solium DNA in NCC patients. A total of 100 blood samples of cases of NCC and 50 control blood samples, 58 urine samples of NCC cases and 24 control samples were collected. Repetitive element PTsol9 of the Taenia Solium was targeted. The sensitivity and specificity of PCR in blood samples was 57% and 94%, while sensitivity and specificity in urine samples was 64% and 87%. PCR assay can be used as an adjunct for the diagnosis of NCC especially in ambiguous cases, this is relatively rapid and non-invasive diagnostic modality.


A crisis in US drug pricing: Consequences for patients with neuromuscular diseases, physicians, and society, part 2.
Escalating drug costs place patients at risk for financial toxicity and demand that physicians understand and act on the ethical and economic principles related to drug pricing. This manuscript reviews these principles and provides clinicians with a framework to think about the value of the drugs prescribed for patients with neuromuscular diseases. A key component of addressing the drug pricing crisis will be establishing a value based (benefit/cost) drug pricing framework. Determining the value of a drug is difficult and requires estimating the benefit and costs to patients and society while integrating indirect and contextual variables. Other considerations in drug pricing include "externality," the value to society derived from innovation. The Institute for Clinical and Economic Review (ICER) is a leading independent research organization providing clinicians with value-based price "benchmarks." All physicians must educate themselves in drug pricing principles and be prepared to have conversations regarding individual and societal value with the patients they serve.


Antitumor activity of new anthraquinone derivatives.
Seven new 9,10-anthracenedione derivatives bearing positively-charged side chains at different positions of the condensed ring system have been investigated in their interaction with DNA and their biological effects, including antitumor activity in the P 388 mouse miniscreen. The drug's affinity for DNA was found to be related to the efficacy of inhibition of cell growth and nucleic acid synthesis for a number of cell lines. Moreover, alkaline elution experiments showed a close relationship between mutagenic potential and cytotoxicity. With the exception of one, all compounds behaved like intercalating agents, as shown by the unwinding of supercoiled plasmid DNA. DNA appeared, therefore, to be the more important target for drug action. The marginal in vivo activity shown by two substances in this series suggests a number of possible structural modifications which may increase their therapeutic efficacy.


Stretching capacity of capsulorhexis and nucleus delivery.
The stretching capacity of the continuous circular capsulorhexis was studied in 30 human cadaver eyes. The capsulorhexis was found to have a remarkable stretching capacity, allowing safe nucleus delivery in planned extracapsular cataract extraction using hydroexpression. The difficulties encountered when trying to deliver the nucleus by external pressure to the sclera are discussed.


Effect of agitation intensity on the exo-biopolymer production and mycelial morphology in Cordyceps militaris.
The influence of agitation intensity on Cordyceps militaris morphology and exo-biopolymer production was investigated in a 5 litre stirred vessel using a six-blade Rushton turbine impeller. The mycelial morphology of C. militaris was characterized by means of image analysis, which included mean diameter, circularity, roughness and compactness of the pellets. The morphological parameters of the pellets grown under different stirring conditions were significantly different, which correspondingly altered exo-biopolymer production yields. The compactness of the pellets was found to be the most critical parameter affecting exo-biopolymer biosynthesis; more compact pellets were formed at 150 rev min(-1) with maximum exo-biopolymer production (15 g l(-1)). The results of this study suggest that morphological change of pellets is a good indicator for identifying the cell activity for exo-biopolymer production.


Stem cells or their exosomes: which is preferred in COVID-19 treatment?
It only took 8 months for the pneumonia caused by a previously unknown coronavirus to turn into a global pandemic of unprecedentedly far-reaching implications. Failure of the already discovered treatment measures opened up a new opportunity to evaluate the potentials of mesenchymal stem cells and their extracellular vesicles (EVs), exosomes in particular. Eventually, the initial success experienced after the use of MSCs in treating the new pneumonia by Lnge and his team backed up the idea of MSC-based therapies and pushed them closer to becoming a reality. However, MSC-related concerns regarding safety such as abnormal differentiation, spontaneous malignant and the formation of ectopic tissues have triggered the replacement of MSCs by their secreted exosomes. The issue has been further strengthened by the fact that the exosomes leave similar treatment impacts when compared to their parental cells. In recent years, much attention has been paid to the use of MSC-derived exosomes in the treatment of a variety of diseases. With a primary focus on COVID-19 and its current treatment methods, the present review looks into the potentials of MSCs and MSC-derived exosomes in battling the ongoing pandemic. Finally, the research will draw an analogy between exosomes and their parental cells, when it comes to the progresses and challenges in using exosomes as a large-scale treatment method.


Anemia with elevation of growth differentiation factor-15 level in linezolid treated multidrug-resistant tuberculosis: Case series of three patients.
Linezolid is now recommended as a first line drug for Multidrug Resistant Tuberculosis (MDR-TB). Previous studies reported hematologic toxicity as one of the main side effects. The mechanism of this toxicity is mitochondrial dysfunction, for which a biomarker is Growth differentiation factor-15 (GDF-15). There is no previous report about GDF-15 and its association with hematologic toxicity from Linezolid in the treatment of MDR-TB. We present three cases of MDR-TB involving severe anemia associated with linezolid who had GDF-15 elevation. These cases highlight the need for more research into the relationship between GDF-15 and hematologic toxicity in MDR-TB patients treated with linezolid.


Genetic mapping of the determinants of plaque morphology of coxsackievirus B4.
The genetic determinants of plaque size of two variants of coxsackie-virus B4, CB4-P and CB4-V, were identified using a panel of recombinant, chimeric viruses. When grown in monkey kidney cells, CB4-V yielded large plaques with an average size of 1.0 cm while CB4-P yielded small plaques with an average size of 0.4 cm. Two genetic domains, the 5' untranslated region and the VP4 gene sequence, independently influenced plaque size. Recombinant viruses containing the CB4-P genetic background with point mutations in either the VP1 or VP2 coding sequences had small plaque phenotypes. However, two additional chimerics containing the CB4-P genetic background with either a point mutation in the VP4 sequence or four substitutions in the 5' untranslated region, had large plaque phenotypes. Plaque size correlated with growth kinetics under single-step conditions. Large-plaque variants replicated to higher titers than small-plaque variants. Comparison of the growth kinetics of the recombinant viruses revealed some differences in viral replication. These data suggest that both the 5' untranslated region and arg-16 of VP4 influence viral replication but at different stages of the replication cycle.


Phospholipid dependence of the neutral sphingomyelinase in rat liver plasma membranes.
Investigations have been carried out on the influence of the phospholipid composition of rat liver plasma membranes and of their physico-chemical properties on the activity of membrane-bound neutral sphingomyelinase. The membrane phospholipid composition was modified by the incorporation of different phospholipids into the membrane bilayer by means of lipid transfer proteins, n-butanol delipidation or exogenous sphingomyelinase (Staphylococcus aureus) treatment. The results indicate that the activity of neutral sphingomyelinase in liver plasma membranes depends upon phosphatidyl choline presence in the membrane bilayer and not upon membrane fluidity.


The regulation of the TLR4/NF-κB and Nrf2/HO-1 signaling pathways is involved in the inhibition of lipopolysaccharide-induced inflammation and oxidative reactions by morroniside in RAW 264.7 macrophages.
Morroniside, a major iridoid glycoside isolated from Cornus officinalis, has a variety of beneficial pharmacological properties. Although morroniside has recently been reported to exhibit anti-inflammatory and antioxidant effects, the detailed mechanism has not yet been fully elucidated. In this study, we investigated the inhibitory effect of morroniside on inflammatory and oxidative stress activated by lipopolysaccharide (LPS) in RAW 264.7 macrophages. Our results indicated that morroniside pretreatment significantly inhibited the LPS-induced phagocytic activity and release of pro-inflammatory factors, which was associated with blocking the expression of their regulatory genes. Morroniside also markedly suppressed the expression of myeloid differentiation factor 88 as well as Toll-like receptor 4 (TLR4), and attenuated the translocation of nuclear factor-κB (NF-κB) to the nucleus in LPS-treated RAW 264.7 macrophages. Furthermore, morroniside prevented the binding of LPS to the TLR4 on the cell surface. In addition, morroniside abolished reactive oxygen species (ROS) generation, and enhanced the expression of heme oxygenase-1 (HO-1) following activation of nuclear factor-E2-related factor 2 (Nrf2) in LPS-stimulated RAW 264.7 macrophages. However, zinc protoporphyrin, a specific inhibitor of HO-1, reversed the morroniside-mediated inhibition of inflammatory response in LPS-treated RAW 264.7 macrophages. In conclusion, our findings suggest that morroniside exerts LPS-induced anti-inflammatory and antioxidant effects by targeting the TLR4/NF-κB and Nrf2/HO-1 signaling pathways in RAW 264.7 macrophages. Taken together, our findings suggest that morroniside interacted structurally and electrochemically with TLR4/MD2 complex, consequently can be a potential functional agent to prevent inflammatory and oxidative damage.


Neuropsychological performance in early and late onset Alzheimer's disease: comparisons in a memory clinic population.
To compare the neuropsychological performance associated with early and late onset Alzheimer's disease (AD), in order to identify differences and compare these with previous reports. Patients attending a memory clinic were given a detailed multi-disciplinary diagnostic assessment, including a battery of neuropsychological tests. From those meeting ICD-10 criteria for Alzheimer's disease (AD), an early-onset (EO) group (n = 40) and a late-onset (LO) group (n = 90) were identified, and their performances compared. Patients with mixed dementia and co-morbid depression were excluded. After adjustment, the EO and LO groups performed at a comparable level on the majority of the neuropsychological tests. The LO group performed better on the WAIS digit span test, AMIPB Complex Design and the written picture description, and the EO group performed better on the WAIS similarities test and the Boston naming test. These findings suggest that, after adjusting for overall dementia severity and pre-morbid IQ, there is greater fronto-parietal/right hemisphere involvement in early-onset AD, and greater temporal/left hemisphere involvement in late-onset AD. This may be due to different genetic risk profiles for AD at different ages.


Flexible fibreoptic bronchoscopy in Addis Ababa: a 4-year experience.
The paper describes a 4-year experience (August 1981 to July 1985) of flexible fibreoptic bronchoscopy (FFB) at Tikur Anbessa Hospital. Two hundred and eighteen bronchoscopies were done in 199 patients. There were 133 males and 66 females. The youngest patient was 14 and the oldest 70. FFB was done twice in 14 patients and three times in three patients. There were 27 primary pulmonary neoplasms, five secondaries, two tuberculosis, one interstitial fibrosis, one carcinoma of the larynx and five chronic inflammation. There was only one patient who developed haemoptysis after a transbronchial lung biopsy which resolved quickly. The flexible fibreoptic bronchoscope is a simple and useful tool to diagnose endobronchial lesions and also diffuse diseases of the lungs even in developing countries.


Analysis of molecular variation in porcine reproductive and respiratory syndrome virus in China between 2007 and 2012.
In the present study, 89 porcine reproductive and respiratory syndrome virus (PRRSV) isolates in China during 2007 to 2012 were randomly selected from the GenBank genetic sequence database. Evolutionary characteristics of these isolates were analyzed based on the sequences of non-structural protein 2 (Nsp2) and glycoprotein 5 (GP5). The genetic variations of the isolates were also compared with six representative strains. The results showed that a high degree of genetic diversity exists among the PRRSV population in China. Highly pathogenic PRRSV isolates, with a discontinuous deletion of a 30 amino acid residue in the Nsp2 region, remained the most dominant virus throughout 2007-2012 in China. Owing to the extensive use of representative vaccine strains, natural recombination events occurred between strains. Three isolates - HH08, DY, and YN-2011 - were more closely related to vaccine strains than the other isolates. Both YN-2011 and DY were the evolutionary products of recombination events between strains SP and CH-1R. The results of the present study provide useful information for the epidemiology of PRRSV as well as for vaccine development.


Fluoxetine modulates hippocampal cell signaling pathways implicated in neuroplasticity in olfactory bulbectomized mice.
The olfactory bulbectomy (OB) animal model of depression is a well-established model that is capable of detecting antidepressant activity following chronic drug therapy, and the surgery results in behavioral and biochemical changes that are reminiscent of various symptoms of depression. In the present study, we investigated the degree to which 14 days of p.o. administration of the classic antidepressant fluoxetine (10mg/kg) were able to reverse OB-induced changes in behavior (namely, hyperactivity in the open-field test and reduced motivational and self-care behaviors in the splash test) and in the activation of hippocampal cell signaling pathways that are thought to be involved in synaptic plasticity. OB caused significant increases in ERK1 and CREB (Ser(133)) phosphorylation and in the expression of BDNF immunocontent, all of which were prevented by fluoxetine administration. Moreover, fluoxetine administration also caused a significant decrease in ERK2 phosphorylation in mice that had undergone OB. Neither Akt nor GSK-3β phosphorylation was altered in any experimental condition. In conclusion, the present study shows that OB can induce significant behavioral changes that are accompanied by the activation of hippocampal signaling pathways, namely the ERK1/CREB/BDNF pathway, which is involved in the synaptic plasticity. Conversely, fluoxetine prevented these OB-induced behavioral changes and avoided the activation of ERK1/CREB/BDNF in the hippocampus. Taken together, our results extend the data from the existing literature regarding OB-induced behavioral and neurochemical changes, and suggest a possible underlying mechanism that can account for the antidepressant effect of fluoxetine in this model.


Type A aortic dissection after 'zone 0' thoracic endovascular aortic repair for type 1 hybrid aortic arch replacement of arch aneurysm.
The recent rise in minimally invasive cardiovascular procedures is being accompanied by an increase in related complications. We report on an acute type A aortic dissection performed in an 82-year-old man 1 week after staged 'zone 0' hybrid thoracic endovascular aortic repair (TEVAR). Previously, the patient had undergone type I hybrid arch debranching and staged 'zone 0' TEVAR for an aortic arch aneurysm. 'Zone 0' TEVAR after type I hybrid debranching might increase the risk for aortic injury on the residual native aorta and should, therefore, be closely followed up to enable the early diagnosis of complications.


Genome-wide analysis and functional characterization of the Dof transcription factor family in rice (Oryza sativa L.).
Exhaustive searches of the rice genome have revealed 30 different potential OsDof (Oryza sativa DNA binding with One Finger) genes. Their subcellular localization, phylogenetic relationship, conserved motifs identification, chromosomal allocation, expression patterns, and interaction networks were analyzed. The Dof (DNA binding with One Finger) family of transcription factors represents a particular class of plant-specific transcriptional regulators, contain a highly conserved region of 50-52 amino acids (Dof domain) and involved in various plant developmental processes and response to various environmental stresses. Few (Oryza sativa) OsDof genes have been demonstrated previously for their biological functions but there is no comprehensive study on most of the Dof genes of rice. In the current study, exhaustive searches of the rice genome revealed 30 different potential OsDof genes, and then their subcellular localization, phylogenetic relationship, conserved motifs identification, chromosomal allocation, expression patterns, and interaction networks were analyzed. Phylogenetic analysis of Dof proteins in rice showed that they are distributed in 4 groups. By genome-wide observation of gene expression profiles, we found that OsDof genes showed significant variances in expression levels in different tissues across multiple developmental stages. Protein-protein correlation network analysis, shows a statically significant overlap of some OsDofs, suggesting their similar functions and a high degree of co-expression. The Dof family transcription factors have been reported for their involvement in the regulation of various gene expression processes in rice but still, most of the Dof genes are not characterized for their specific physiological functions. This study revealed useful information and clues about predicting the potential roles of OsDofs in rice by combining their genome-wide characterization, expression profiling, protein-protein interactions, and for further studies to develop high-quality rice varieties.


Urinary Liver-Type Fatty Acid-Binding Protein Predicts Residual Renal Function Decline in Patients on Peritoneal Dialysis
BACKGROUND Liver-type fatty acid-binding protein (L-FABP) is a predictive marker for the early detection of acute kidney injury; however, less is known about how useful it is for predicting residual renal function (RRF) decline in patients on peritoneal dialysis (PD). MATERIAL AND METHODS The study subjects were 35 patients on PD who underwent multiple peritoneal equilibration tests (PETs) between October 2011 and October 2019. Urinary L-FABP levels were analyzed with enzyme-linked immunosorbent assay. The relationship between baseline clinical data, including urinary L-FABP levels and the subsequent annual rate of renal Kt/V decline, was investigated. RESULTS The median follow-up duration was 11 months and the rate of renal Kt/V decline was 0.29/y. Compared with outcomes in the group with renal Kt/V preservation, renal Kt/V decline was associated with both high daily levels of urinary protein excretion (0.60 g/d [range, 0.50-0.87] vs. 0.36 g/d [range, 0.19-0.48]; P=0.01) and high daily levels of urinary L-FABP excretion (111.2 mg/d [range, 76.1-188.6] vs. 61.5 mg/d [range, 35.7-96.0]; P=0.002). Multiple logistic regression analysis showed that only high daily levels of urinary L-FABP excretion were independently associated with renal Kt/V decline (odds ratio 1.03, 95% confidence interval 1.00-1.05; P=0.001). Furthermore, higher daily levels of urinary L-FABP excretion were significantly correlated with the higher annual rate of renal Kt/V decline (r=0.71, P<0.001). CONCLUSIONS We demonstrated that daily levels of urinary L-FABP are associated with RRF decline in patients on PD. The results of the present study indicate that assessment of urinary L-FABP levels may help predict RRF decline in patients on PD.


Adherence to subcutaneous biologic treatment for inflammatory bowel disease.
Nonadherence to medication is common in patients with inflammatory bowel disease (IBD) and can result in disease complications, therapy escalation, and the need for corticosteroids. The aim of this study was to assess the adherence to self-administered subcutaneous biologic medications prescribed for IBD and to identify the risk factors for nonadherence. A retrospective cohort study on IBD patients initiated on subcutaneous biologic therapy between January 2016 and July 2019 was performed. Medical records were retrospectively reviewed for collection of demographic and IBD data. Medication possession ratios (mMPRs) during the first 12 months of treatment and at the end of the follow-up period (global, 42 months) were calculated. Nonadherence was defined as an mMPR of <90%. Multiple regression analysis was performed to assess the risk factors for nonadherence to therapy. A total of 154 patients (84 male and 70 female; mean age at biologic treatment initiation, 36±14 years; Crohn's disease, n=118; ulcerative colitis, n=31; indeterminate colitis, n=5) were included; 121 received adalimumab (ADA) and 33 received ustekinumab (UST); 63% were naive to anti-TNF therapy, while 16.9% previously received more than two biologic treatments. Mean time from IBD diagnosis to subcutaneous biological agent use was 16±10 months. Mean duration of subcutaneous agent use was 17.6 (SD, 11.0) and 17.08 (SD, 6.8) months for ADA and UST, respectively. Global nonadherence (mMPR≤90%) rate was 6.6% for all patients receiving subcutaneous treatment, 6.3% for ADA, and 6.5% for UST. Nonadherence during the first 12 months of treatment (n=98) was 6.1% for all patients, 2.7% for ADA, and 16% for UST. In the multivariate analysis, UST use was independently associated with higher nonadherence only within the first 12 months (OR, 6.7; 95% CI, 1.1-39.5). High global adherence to self-administered subcutaneous biologic treatment was shown in our study, with higher rates of adherence to ADA than to UST within the first 12 months.


The polysaccharides from heterocyst and spore envelopes of a blue-green alga. Methylation analysis and structure of the backbones.
Lindberg's combined gas chromatography-mass spectrometry techniques for the analysis of partially methylated alditol acetate sugar derivatives were used to study the structures of polysaccharides from the envelopes of heterocysts and spores of Anabaena cylindrica. Polysaccharides from both envelopes are highly branched. Glucose, mannose, galactose, and xylose are at terminal positions, whereas glucose and mannose are at internal positions in these polymers. The molar percentages of the 11 partially methylated alditol acetate derivatives observed were approximately the same for both envelopes, suggesting that the envelope polysaccharides may be identical or almost identical. Smith degradation (periodate oxidation followed by reduction with sodium borohydride and mild acid hydrolysis) of the polysaccharides from the two kinds of envelopes removes the side branches without measurable fragmentation of the backbones. Gas chromatographic analysis of partially methylated alditol acetate derivatives of the sugars showed that the backbones of both envelope polysaccharides consist of glucose (Glc) and mannose (Man) linked by 1 leads to 3 glycosidic bonds. Disaccharides, trisaccharides, and tetrasaccharides obtained from the backbone polysaccharides by partial acid hydrolysis were fractionated by column chromatography and separated by high voltage paper electrophoresis. Analysis of these oligosaccharides established that the backbone polysaccharides from both heterocysts and spores consist of repetitions of the structural unit Glc leads to Glc leads to Glc leads to Glc leads to Man, and that all linkages in the backbones are in the beta configuration.


Employment status as a major determinant for lower physical activity of patients with epilepsy: A case-control study.
People with epilepsy (PWE) may have a sedentary lifestyle and less physical activity (PA) as they are often advised against engaging in sports, despite a plethora of evidence suggesting seizure control, major health and psychosocial benefits associated with PA. We aimed to investigate PWE's beliefs on PA and their level of PA compared to controls. The Baecke questionnaire for measuring habitual PA in adults, comprising three domains (occupational PA, leisure, and locomotion), was applied in 97 consecutive PWE (96.9% with focal epilepsy, 39.2% well controlled with pharmacological treatment) and 45 healthy controls matched for gender, age, and socioeconomic characteristics. The total Baecke score was significantly lower in PWE than controls (7.6 ± 1.5 versus 8.2 ± 1.2; p < 0.01). PWE showed a significantly lower employment rate than controls (34.0% versus 73.3%; p < 0.01), and consequently lower occupational PA (p < 0.01). Physical exercise during sports time (p = 0.23) and leisure activities (p = 0.55) scores were similar between patients and controls. When PWE and controls' sociodemographic characteristics were analyzed together by multiple linear regression, 21% of the Baecke total score variation was explained by diagnosis of epilepsy (B = -0.26; p = 0.05), years of education (B = -0.35; p = 0.03), and occupational status (B = -0.41; p < 0.01). However, diagnosis of epilepsy alone explained only 4% (B = -0.64; p = 0.01) of Baecke total score variation. The level of PA in PWE is only slightly lower than in controls (8% lower score) and it may be explained by lower occupational PA, probably related to lower employment rate among PWE.


Improved procedure for the anion-exchange isolation of urinary organic acids.
DEAE-Sephadex equilibrated in 0.5 M triethylammonium acetate is suitable for the quantitative isolation of lactonisable organic acids. Mono-, di- and tricarboxylic acids can be eluted sequentially from DEAE-Sephadex by the use of 0.5 M triethylamine, 0.5 M triethylamine--0.1 M acetic acid, and 1.5 M pyridinium acetate.


Repeat Rifaximin for Irritable Bowel Syndrome: No Clinically Significant Changes in Stool Microbial Antibiotic Sensitivity.
Rifaximin has demonstrated efficacy and safety for diarrhea-predominant irritable bowel syndrome (IBS-D). To determine the rifaximin repeat treatment effect on fecal bacterial antibiotic susceptibility. Patients with IBS in Trial 3 (TARGET 3) study who responded to open-label rifaximin 550 mg three times daily for 2 weeks, with symptom recurrence within 18 weeks, were randomized to double-blind treatment: two 2-week repeat courses of rifaximin or placebo, separated by 10 weeks. Prospective stool sample collection occurred before and after open-label rifaximin, before and after the first repeat course, and at the end of the study. Susceptibility testing was performed with 11 antibiotics, including rifaximin and rifampin, using broth microdilution or agar dilution methods. Of 103 patients receiving open-label rifaximin, 73 received double-blind rifaximin (n = 37) or placebo (n = 36). A total of 1429 bacterial and yeast isolates were identified, of which Bacteroidaceae (36.7%) and Enterobacteriaceae (33.9%) were the most common. In the double-blind phase, Clostridium difficile was highly susceptible to rifaximin [minimum inhibitory concentration (MIC) range 0.008-1 µg/mL] and rifampin (MIC range 0.004-0.25 µg/mL). Following double-blind rifaximin treatment, Staphylococcus isolates remained susceptible to rifaximin at all visits (MIC50 range ≤0.06-32 µg/mL). Rifaximin exposure was not associated with long-term cross-resistance of Bacteroidaceae, Enterobacteriaceae, and Enterococcaceae to rifampin or nonrifamycin antibiotics tested. In this study, short-term repeat treatment with rifaximin has no apparent long-term effect on stool microbial susceptibility to rifaximin, rifampin, and nonrifamycin antibiotics. CLINICALTRIALS. NCT01543178.


Computerized System for Safety Verification of External Beam Radiation Therapy Planning.
To report an assessment of in-house software, Verifier, developed to improve efficacy and efficiency of the radiation therapy (RT) treatment planning process and quality control review (QCR). Radiation therapy plan parameters retrieved from our treatment planning database are used by automated tests to give 75 types of warnings, such as prescription and plan discrepancies. The software is continuously updated on the basis of new issues, ideas, and planning policies. Verifier was retrospectively assessed (2007-2015) by examining impact on treatment plan revisions, frequency of quality improvement incident reports of avoidable RT plan-related safety events, unaddressed issues, and staff efficiency. Plan revisions for specific issues declined dramatically in response to implementation of corresponding Verifier tests. Between 2012 and 2015 our institution's total rate of plan revisions dropped from 18.0% to 11.2%. Between 2008 and 2015 specific tests were added to Verifier while the rate of corresponding avoidable safety events was reduced from 0.34% to 0.00% over the same period. Simulations suggest Verifier saves approximately 2 to 5 minutes per QCR. The decrease in quantifiable metrics of plan revisions and incident reports suggests automatic RT plan-checking software enhances patient safety and clinical efficiency. Although only modest time savings may be gained using Verifier for the QCR itself, the greater impact on efficiency is through avoiding late-stage plan modifications and improving documentation via automation. We encourage other institutions to consider working toward adding similar technologies to enhance their RT quality assurance programs.


[Renal filtration and reabsorption of GFP in frog Rana temporaria: effect of arginine-vasotocin].
The renal tubular uptake of green fluorescent protein (GFP) in frog Rana temporaria was studied by laser confocal microscopy. The specific green fluorescence was revealed in the proximal tubule cells 30 min after intravenous GFP injection. The GFP fluorescence was distributed predominantly in the apical part of the cytoplasm in the form of the intensively fluorescing vesicles. The GFP injections increased dose-dependently the GFP tubular uptake. This was confirmed by the quantitative assessment of intensity of the specific fluorescence, its relative vesicular density, and by correlation analysis. Preliminary administration of arginine vasotocin into the dorsal lymphatic sac decreased significantly the GFP absorption. The effect of arginine vasotocin was inhibited by pretreatment a vasopressin V1-receptor antagonist. These results suggest that a decrease in the GFP absorption is due to a fall of the AVT-dependent glomerular filtration rate and consequently a decrease in the filtered GFP amount. The effect of arginine vasotocin on the GFP absorption seems to be mediated via the V1-like receptors of preglomerular blood vessels.


Hepatotoxicity following the therapeutic use of antipyretic analgesics.
The potential for hepatic injury associated with the therapeutic use of salicylates and acetaminophen has recently attracted considerable attention. About 300 cases have been reported in which elevated transaminase levels or other evidence of hepatic injury developed following treatment with salicylates. Review of the spectrum of abnormalities reveals a group of patients (4 percent) with symptomatic liver damage in whom progressive or chronic liver disease is a possibility with continued use of the drug. In a few patients in this group, jaundice developed; several had abnormal prothrombin times; 11 (70 percent) had transaminase values in excess of 500 units; and five patients (30 percent) had encephalopathy and/or Reye's syndrome. In several reports liver damage has also been associated with the use of acetaminophen in therapeutic or near-therapeutic dosages. Of 18 patients, nine appeared to have ingested acetaminophen in amounts approaching overdose. Of the remaining nine patients, six were alcoholics. In the entire group, only five patients did not have a history of alcohol abuse; in three, glutathione depletion was suggested as a possible explanation for hepatotoxicity. The association with alcoholism or glutathione depletion suggests that host susceptibility may play a critical role. In two patients, long-term use of acetaminophen resulted in liver injury suggestive of chronic active hepatitis, possibly on the basis of an idiosyncratic reaction. In a study of chronic liver disease, acetaminophen half-life was prolonged (168 percent) without accumulation at 4 g a day over five days. In a double-blind, two-week, cross-over study, no clinical or laboratory evidence of adverse effects was found. There is, therefore, no evidence that chronic liver disease increases the risk of hepatotoxicity following the administration of acetaminophen in therapeutic doses. Thus, acetaminophen is the preferred antipyretic analgesic in patients with liver disease. Salicylates should be avoided since many of the adverse effects associated with these drugs are similar to the complications of chronic liver disease.


High levels of PEEP may improve survival in acute respiratory distress syndrome: A meta-analysis.
Positive end-expiratory pressure (PEEP) has been viewed as an essential component of mechanical ventilation in acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). However, clinical trials have not yet convincingly demonstrated that high PEEP levels improve survival. The object of this study was to test a priori hypotheses that a small but clinically important mortality benefit of high PEEP did exist, especially in patients with greater overall severity of illness and differences in PEEP protocols might have affected the study results. Meta-analysis of randomized controlled trials comparing high versus low PEEP in ARDS/ALI. Studies were identified by search of MEDLINE (1950-2008) and other sources. Five studies including 2447 patients were identified. A pooled analysis showed a significant reduction in hospital mortality in favor of high PEEP (RR=0.89; 95% CI, 0.80-0.99; p=0.03). However, significant statistical and clinical heterogeneities such as differences in disease severity and ventilator protocols were found. The differences in PEEP protocols were not associated with differences in mortality rates. A logistic analysis suggested that the beneficial effect of high PEEP was greater in patients with higher ICU severity scores. The statistical and clinical heterogeneities make proper interpretation of the results difficult. However, a small, but significant mortality benefit of high PEEP may exist. In addition, our analysis suggests the effects of high PEEP are greater in patients with higher ICU severity scores.


Variations in statin prescribing for primary cardiovascular disease prevention: cross-sectional analysis.
Statins are an important intervention for primary and secondary cardiovascular disease (CVD) prevention. We aimed to establish the variation in primary preventive treatment for CVD with statins in the English population. Cross sectional analyses of 6155 English primary care practices with 40,017,963 patients in 2006/7. Linear regression was used to model prescribing rates of statins for primary CVD prevention as a function of IMD (index of multiple deprivation) quintile, proportion of population from an ethnic minority, and age over 65 years. Defined Daily Doses (DDD) were used to calculate the numbers of patients receiving a statin. Statin prescriptions were allocated to primary and secondary prevention based on the prevalence of CVD and stroke. We estimated that 10.5% (s.d.3.7%) of the registered population were dispensed a statin for any indication and that 6.3% (s.d. 3.0%) received a statin for primary CVD prevention. The regression model explained 21.2% of the variation in estimates of prescribing for primary prevention. Practices with higher prevalence of hypertension (β co-efficient 0.299 p <0.001) and diabetes (β co-efficient 0.566 p < 0.001) prescribed more statins for primary prevention. Practices with higher levels of ethnicity (β co-efficient-0.026 p <0.001), greater deprivation (β co-efficient -0.152 p < 0.001) older patients (β co-efficient -0.032 p 0.002), larger lists (β co-efficient -0.085, p < 0.001) and were more rural (β co-efficient -0.121, p0.026) prescribed fewer statins. In a small proportion of practices (0.5%) estimated prescribing rates for statins were so low that insufficient prescriptions were issued to meet the predicted secondary prevention requirements of their registered population. Absolute estimated prescribing rates for primary prevention of CVD were 6.3% of the population. There was evidence of social inequalities in statin prescribing for primary prevention. These findings support the recent introduction of a financial incentive for primary prevention of CVD in England.


A systematic review of conflicting meta-analyses in orthopaedic surgery.
Meta-analyses are important evaluations in orthopaedic surgery, not only to create clinical guidelines, but also because their findings are included in public health and health policy decision making. However, with increasing numbers of meta-analyses, discordant and frankly conflicting conclusions have been reported. We searched for conflicting meta-analyses, ie, those arriving at different conclusions despite following the same research question, identified potential reasons for these differences, and assessed the statistical significance and clinical importance of differences. We identified conflicting meta-analyses on graft choice in ACL reconstruction and the use of hyaluronic acid. We found significant differences in individual results only for meta-analyses on hyaluronic acid, but the 95% confidence intervals of the magnitude of differences included values as much as 40% for ACL meta-analyses. However, our findings suggest most conflicts derive from differences in the interpretation of pooled results rather than in the actual results. Thus conclusions and interpretations from meta-analyses should be scrutinized as critically as those from any other type of study and subjected to reassessment if deemed necessary.


High resolution imaging of tunnels by magnetic resonance neurography.
Peripheral nerves often traverse confined fibro-osseous and fibro-muscular tunnels in the extremities, where they are particularly vulnerable to entrapment and compressive neuropathy. This gives rise to various tunnel syndromes, characterized by distinct patterns of muscular weakness and sensory deficits. This article focuses on several upper and lower extremity tunnels, in which direct visualization of the normal and abnormal nerve in question is possible with high resolution 3T MR neurography (MRN). MRN can also serve as a useful adjunct to clinical and electrophysiologic exams by discriminating adhesive lesions (perineural scar) from compressive lesions (such as tumor, ganglion, hypertrophic callous, or anomalous muscles) responsible for symptoms, thereby guiding appropriate treatment.


Can walking habits be encouraged through area-based regeneration and relocation? A longitudinal study of deprived communities in Glasgow, UK.
This paper examines changes to the walkability of the built environment and associated changes in walking behaviour following area regeneration or relocation in Glasgow, UK. The aim is to contribute to longitudinal evidence of links between the built environment and walking behaviour. Most studies to date have been cross-sectional and the evidence they provide that changing the built environment will lead to changes in walking behaviour is weak. Our study examines how changes in neighbourhood walkability influence levels of walking in the local area. We use household survey data from deprived neighbourhoods in Glasgow undergoing housing-led and area regeneration at two time points, 2011 and 2015. Measures of walkability were calculated for each year as a product of intersection density (connectivity) and dwelling density and attached to survey data. Relationships between changes in walkability and repeated measures of walking frequency are examined. We compare changes in walking between those who move house compared with those who experience changes to the built environment in their existing home location. Those who relocate ('movers') are more likely to increase their frequency of walking in the neighbourhood, but this is not necessarily as a result of changes in the built environment as measured using walkability metrics. Prior walking habits are a strong influence, with those who walk at baseline being more likely to increase their walking later. Environmental improvements through renewal programmes are often of insufficient quality or extent to stimulate increased walking. It is likely that area regeneration needs to be combined with people-based and social interventions to produce 'behavioural spillovers' that encourage walking habits.


Il-6 Involvement in pain, fatigue and mood disorders in rheumatoid arthritis and the effects of Il-6 inhibitor sarilumab.
Interleukin 6 (IL-6) is a pleiotropic cytokine that plays a role in the neuroendocrine system, insulin resistance, lipid metabolism, vascular disease, mitochondrial activities, neuropsychological behaviour, and also mediates communications between the immune and central nervous system (CNS). Treatment with anti-IL-6 or anti-IL-6R agents seems to alleviate allodynia and hyperalgesia, so it may be a valid option when treating the many conditions involving pathological pain as rheumatoid arthritis.


Effects of dexamethasone on progesterone and estrogen profiles and uterine progesterone receptor localization during pregnancy in Sahel goat in Semi-Arid region.
Despite the widespread use of dexamethasone in veterinary and human medicine, it is reported to cause some severe pregnancy related side effects like abortion in some animals. The mechanism of the response is not clear but seems to be related to interspecies and/or breed difference in response which may involve alterations in the concentrations of some reproductive hormones. Twenty Sahel goats comprising 18 does and 2 bucks were used for this study. Pregnancies were achieved by natural mating after synchronization. Repeated dexamethasone injections were given at 0.25 mg/kg body weight. Blood samples were collected biweekly for hormonal assay. Uterine biopsies were harvested at days 28 and day 78 of gestation through caesarean section for immunohistochemical analysis using 3 pregnant does randomly selected from each group at each instant. Data were expressed as Means ± Standard Deviations and analyzed using statistical soft ware package, GraphPad Instant, version 3.0 (2003) and progesterone receptor (PR) were scored semi-quantitatively. Dexamethasone treatments had no significant (p > 0.05) effect on progesterone and estrogen concentrations in pregnant Sahel goats but up regulated PR from 2+ to 3+ in second trimester. As dexamethasone adverse effect on placenta is an established fact, the lack of effect on progesterone level in this study may be due to the fact that unlike other species whose progesterone production during pregnancy is placenta - dependent, in goats is corpus luteum - dependent. Consequently dexamethasone adverse effect on placenta reported in literatures did not influence progesterone levels during pregnancy in Sahel goat. The up regulation of progesterone receptor (PR) in Sahel goat gravid uterus is a beneficial effects and that dexamethasone can safely be used in corpus luteum - dependent progesterone secreting pregnant animal species like Sahel goat and camel. Therefore source of progesterone secretions during pregnancy should be considered in clinical application of dexamethasone in pregnancy.


Pentavalent lanthanide nitride-oxides: NPrO and NPrO- complexes with N[triple bond, length as m-dash]Pr triple bonds.
The neutral molecule NPrO and its anion NPrO- are produced via co-condensation of laser-ablated praseodymium atoms with nitric oxide in a solid neon matrix. Combined infrared spectroscopy and state-of-the-art quantum chemical calculations confirm that both species are pentavalent praseodymium nitride-oxides with linear structures that contain Pr[triple bond, length as m-dash]N triple bonds and Pr[double bond, length as m-dash]O double bonds. Electronic structure studies show that the neutral NPrO molecule features a 4f0 electron configuration and a Pr(v) oxidation state similar to that of the isoelectronic PrO2 + ion, while its NPrO- anion possesses a 4f1 electron configuration and a Pr(iv) oxidation state. The neutral NPrO molecule is thus a rare lanthanide nitride-oxide species with a Pr(v) oxidation state, which follows the recent identification of the first Pr(v) oxidation state in the PrO2 + and PrO4 complexes (Angew. Chem. Int. Ed., 2016, 55, 6896). This finding indicates that lanthanide compounds with oxidation states of higher than +IV are richer in chemistry than previously recognized.


Pcyt2 deficiency causes age-dependant development of nonalcoholic steatohepatitis and insulin resistance that could be attenuated with phosphoethanolamine.
The mechanisms of NASH development in the context of age and genetics are not fully elucidated. This study investigates the age-dependent liver defects during NASH development in mice with heterozygous deletion of Pcyt2 (Pcyt2+/-), the rate limiting enzyme in phosphatidylethanolamine (PE) synthesis. Further, the therapeutic potential of Pcyt2 substrate, phosphoethanolamine (PEtn), is examined. Pcyt2+/- were investigated at 2 and 6-8 months (mo) of age and in addition, 6-mo old Pcyt2+/- with developed NASH were supplemented with PEtn for 8 weeks and glucose and fatty acid metabolism, insulin signaling, and inflammation were examined. Heterozygous ablation of Pcyt2 causes changes in liver metabolic regulators from young age, prior to the development of liver disease which does not occur until adulthood. Only older Pcyt2+/- experiences perturbed glucose and fatty acid metabolism. Older Pcyt2+/- liver develops NASH characterized by increased glucose production, accumulation of TAG and glycogen, and increased inflammation. Supplementation with PEtn reverses Pcyt2+/- steatosis, inflammation, and other aspects of NASH, showing that was directly caused by Pcyt2 deficiency. Pcyt2 deficiency is a novel mechanism of metabolic dysregulation due to reduced membrane ethanolamine phospholipid synthesis, and the metabolite PEtn offers therapeutic potential for NASH reversion.


Whole-Cell Production of Patchouli Oil Sesquiterpenes in Escherichia coli: Metabolic Engineering and Fermentation Optimization in Solid-Liquid Phase Partitioning Cultivation.
Patchouli oil is a major ingredient in perfumery, granting a dark-woody scent due to its main constituent (-)-patchoulol. The growing demand for patchouli oil has raised interest in the development of a biotechnological process to assure a reliable supply. Herein, we report the production of patchouli oil sesquiterpenes by metabolically engineered Escherichia coli strains, using solid-liquid phase partitioning cultivation. The (-)-patchoulol production was possible using the endogenous methylerythritol phosphate pathway and overexpressing a (-)-patchoulol synthase isoform from Pogostemon cablin but at low titers. To improve the (-)-patchoulol production, the exogenous mevalonate pathway was overexpressed in the multi-plasmid PTS + Mev strain, which increased the (-)-patchoulol titer 5-fold. Fermentation was improved further by evaluating several defined media, and optimizing the pH and temperature of culture broth, enhancing the (-)-patchoulol titer 3-fold. To augment the (-)-patchoulol recovery from fermentation, the solid-liquid phase partitioning cultivation was analyzed by screening polymeric adsorbers, where the Diaion HP20 adsorber demonstrated the highest (-)-patchoulol recovery from all tests. Fermentation was scaled-up to fed-batch bioreactors, reaching a (-)-patchoulol titer of 40.2 mg L-1 and productivity of 20.1 mg L-1 d-1. The terpene profile and aroma produced from the PTS + Mev strain were similar to the patchouli oil, comprising (-)-patchoulol as the main product, and α-bulnesene, trans-β-caryophyllene, β-patchoulene, and guaia-5,11-diene as side products. This investigation represents the first study of (-)-patchoulol production in E. coli by solid-liquid phase partitioning cultivation, which provides new insights for the development of sustainable bioprocesses for the microbial production of fragrant terpenes.


Analysis of poly(ADP-ribose) glycohydrolase activity in nuclear extracts from mammalian cells.
We have analysed poly(ADP-ribose) glycohydrolase, the enzyme responsible for in vivo degradation of ADP-ribose polymers, by means of a biochemical assay based on the capacity of the enzyme to use a synthetic 32P-labelled polymer as a substrate. The visualization of the reaction has been achieved by separation of poly and mono(ADP-ribose) by thin-layer chromatography followed by autoradiography, whereas polymer hydrolysis has been quantified by counting the spots corresponding to poly and mono(ADP-ribose). By addition of the enzyme inhibitor ethacridine to the reaction mixture, we have confirmed the specificity of the procedure we have developed. The protocol has been applied to study the specific activity of glycohydrolase in nuclear extracts from different mammalian cell lines and to an apoptotic experimental system, namely HL60 cells treated with etoposide. We have observed the activation of the enzyme after a two-hour drug treatment, that is concomitant with the activation of poly(ADP-ribose) polymerase, the enzyme which synthesizes the polymer. These data suggest a precise regulation of ADP-ribosylation process during cell death by apoptosis.


The relationship between kinetics of substrate-limited transitions and steady-state growth in continuous cultures of Aquaspirillum autotrophicum limited by pyruvate.
Heterotrophic growth at steady state and during transient states caused by the sudden change of the concentration of the limiting factor in the feed medium was investigated experimentally for continuous cultures of Aquaspirillum autotrophicum limited by pyruvate. A model for describing the growth at steady state was selected from three unstructured models after statistical tests of the data. This model postulates that the growth yield increases linearly with the growth rate. Growth during transitions where the substrate remained limiting at all times was fitted with first-order kinetics. Theoretical predictions of these kinetics were derived from the unstructured models used to describe steady state. The predicted rate coefficients of the transients were compared to the experimental coefficients. It appeared that the model which best described steady-state growth also provided the best predictions for growth during the transient state. It is a widespread opinion that unstructured models are adequate to describe growth under steady-state conditions but not to predict transitions in continuous culture. However, for the particular case studied here, no higher degree of complexity was required to describe transitions, provided the growth of the culture was always limited by the substrate.


Sport after Knee Replacement Surgery - a Review of Sport Habits and Key Surgical Aspects.
As an increasing number of younger patients are undergoing total knee replacement (TKR) surgery, many wish to participate in sport, but still expect that the implant will survive for a extended period. Most of the current literature shows that patients predominantly participate in low impact activities, both before and after surgery. A few studies show that with appropriate previous experience, high-impact sports are possible and might not result in increased implant failure rates. These include a decrease in point loads on the polyethylene by using more conform bearing surfaces, avoidance of varus component alignment to minimise stresses at the implant bone interface and avoiding patella resurfacing to facilitate activities in deep knee flexion.A TKR is no longer an absolute contraindication for higher impact activities such as golf, tennis and ski. What is more important than implant specific factors seem to be patient specific factors, including preoperative activity level, and preoperative sport skills.The current review paper reports on the current sport habits of TKR patients, analyses biomechanical loads on the knee during different sport activities and reports on implant selection and technical considerations for the active patient undergoing TKR.


Characterisation of the in vitro modulation of splenocyte proliferation by non-4,5-epoxymorphinan opioids.
Opioids, such as morphine, can directly alter immune function via receptors expressed on immunocompetent cells. However, several studies have questioned the classical opioid nature of this change in immune response. Therefore, it is unclear how opioids that are not from the same structural class as morphine (4,5-epoxymorphinan), will modulate the immune system, if they do not behave in a classical opioid manner. Therefore, the aim of this study was to investigate the in vitro modulatory effects of a range of non-4,5-epoxymorphinan opioids on splenocyte proliferation and compare the response characteristics to their central opioid characteristics. The modulation of concanavalin A stimulated mouse splenocyte proliferation by non-4,5-epoxymorphinan opioids resulted in three types of responses: an inhibitory concentration-response curve (e.g. methadone, inhibitory EC(50)=79.4 microM), an inverted bell shaped curve (e.g. fentanyl, inhibitory EC(50)=0.06 microM) and an induction concentration response curve (e.g. nor-binaltorphimine, induction EC(50)=0.16 microM). Non-stereoselectivity, naloxone-insensitivity, naloxone-sensitivity and non-classical opioid rank order of effect were all observed. These data support the non-classical opioid nature of direct opioid modulation of splenocyte proliferation.


Impact of prostate cancer screening on health-related quality of life in at-risk families.
To describe the impact of prostate-specific antigen (PSA) screening on the health-related quality of life (HRQOL) and anxiety of men with a family history of prostate cancer. We asked 334 brothers or sons of men with prostate cancer who agreed to undergo PSA testing to fill out HRQOL questionnaires. The questionnaires were the RAND SF-36 (generic HRQOL) and State-Trait Anxiety Inventory (anxiety-specific). Participants completed the questionnaires at the time of screening, while waiting for the results, and after receiving normal results. Sociodemographic and HRQOL variables were entered into a logistic regression model to identify factors associated with the deterioration of HRQOL, defined as a decrease of at least one standard error of measurement. Only men with normal PSA results were considered. Among 334 candidates, 273 underwent PSA measurement and 220 candidates with a PSA of 4 ng/mL or less returned completed questionnaires. Of these, in 20% their anxiety moderately deteriorated and in 20% their HRQOL minimally deteriorated during the screening process. Factors associated with HRQOL deterioration included age between 50 and 60 years, having more than two relatives with prostate cancer, an anxious personality, a high level of education, and having no children presently living at home. Screening with normal PSA results is accompanied by a minimally to moderate deterioration of HRQOL in some subjects. The identification of such individuals before screening provides opportunities to improve their HRQOL during the screening process.


Postanesthetic hemorrhagic myelopathy or myelomalacia.
Hemorrhagic myelopathy or myelomalacia is an uncommon cause of failure to stand after general anesthesia. Affected horses are usually young and have been anesthetized for relatively short times in dorsal recumbency. Clinical signs involve the hind limbs and include loss of deep pain perception. Etiology of this condition is not known. Differentiation from other forms of neuropathy and myopathy is important to the prognosis.


mTOR Inhibition Increases Transcription Factor E3 (TFE3) Activity and Modulates Programmed Death-Ligand 1 (PD-L1) Expression in Translocation Renal Cell Carcinoma.
The efficacy of programmed death ligand (PD-L)-1/PD-1 checkpoint blockade in renal cell carcinoma (RCC) remains unknown. The effects of mTOR inhibitors are uncertain, and patients may develop resistance to them. The limited understanding of cancer cell-intrinsic mTOR-mediated pathways remains a challenge in developing effective treatments. Whether transcription factor (TF)-E3 regulates PD-L1 expression and the tumor microenvironment was investigated, and the effects of an mammalian target of rapamycin (mTOR) inhibitor on translocation RCC were explored. TFE3 was overexpressed in clear cell RCC cell lines, and PD-L1 expression was analyzed by Western blot analysis. PD-L1 activity in translocation RCC was analyzed in relation to TFE3 expression via TFE3 knockdown and treatment with an mTOR inhibitor. The results were correlated with the gene expression profile, evaluated using digital multiplex analysis. TFE3 and PD-L1 expression were positively correlated in RCC cells. TFE3 overexpression was associated with the expression of PD-L1 in RCC. Furthermore, mTOR inhibition was associated with enhanced PD-L1 expression via TFE3 activation in translocation RCC. These data support the feasibility of combination therapy based on mTOR inhibition and PD-L1 blockade as a novel strategy for the treatment of patients with translocation RCC.


Psychiatric disorders and labor market outcomes: evidence from the National Comorbidity Survey-Replication.
This paper uses the National Comorbidity Survey-Replication to estimate effects of recent psychiatric disorder on employment, hours worked, and earnings. We employ methods proposed in Altonji et al. (2005a) which use selection on observable traits to provide information regarding selection along unobservable factors. Among males, disorder is associated with reductions in labor force participation and employment. When selection on observed characteristics is set equal to selection on unobserved characteristics, the magnitudes of these effects for males are 9 and 14 percentage point reductions for participation and employment, respectively. Among females, we find negative associations between disorder and labor force participation and employment, but these estimates are more sensitive to assumptions about selection. There are no effects of disorder on earnings or hours worked among employed individuals.


Transthyretin: no association between serum levels or gene variants and schizophrenia.
It has been proposed that schizophrenia results from an environmental insult in genetically predisposed individuals. Environmental factors capable of modulating transcriptional activity and their carriers could link the genetic and environmental components of schizophrenia. Among these is transthyretin (TTR), a major carrier of thyroid hormones and retinol-binding protein (RBP). Retinoids and thyroid hormones regulate the expression of several genes, both during development and in the adult brain. Decreased TTR levels have been reported in the cerebrospinal fluid of patients with depression and Alzheimer's disease, and the absence of TTR influences behavior in mice. DNA variants capable of altering TTR ability to carry its ligands, either due to reduced transcription of the gene or to structural modifications of the protein, may influence development of the central nervous system and behavior. In the present study we searched for variants in the regulatory and coding regions of the TTR gene, and measured circulating levels of TTR and RBP. We found a novel single nucleotide polymorphism (SNP), ss46566417, 18 bp upstream of exon 4. Neither this SNP nor the previously described rs1800458 were found associated with schizophrenia. In addition, serum TTR and RBP levels did not differ between mentally healthy and schizophrenic individuals. In conclusion, our data does not support an involvement of the TTR gene in the pathophysiology of schizophrenia.