Production of cartilage oligomeric matrix protein (COMP) by cultured human dermal and synovial fibroblasts.
Cartilage oligomeric matrix protein (COMP) is a large disulfide-linked pentameric protein. Each of its five subunits is approximately 100,000 Da in molecular weight. COMP was originally identified and characterized in cartilage and it has been considered a marker of cartilage metabolism because it is currently thought not to be present in other joint tissues, except for tendon. To confirm the tissue specificity of COMP expression we examined cultured human dermal fibroblasts, human foreskin fibroblasts, and normal human synovial cells for the synthesis of COMP in culture. Normal synovial cells and normal human dermal foreskin fibroblasts were isolated from the corresponding tissues by sequential enzymatic digestions and cultured in media containing 10% fetal bovine serum until confluent. During the final 24 h of culture, the cells were labeled with 35S-methionine and 35S-cysteine in serum- and cysteine/methionine-free medium. The newly synthesized COMP molecules were immunoprecipitated from the culture media with a COMP-specific polyclonal antiserum, or with monoclonal antibodies or affinity-purified COMP antibodies. The immunoprecipitated COMP was analyzed by electrophoresis in 5.5% polyacrylamide gels. For other experiments, synovial cells cultured from the synovium of patients with rheumatoid arthritis (RA) and osteoarthritis (OA) were similarly examined. A comparison of the amounts of COMP produced by each cell type (corrected for the DNA content) revealed that synovial cells produced > or = 9 times more COMP than chondrocytes or dermal fibroblasts. COMP could be easily detected by immunoprecipitation in all cell types. Electrophoretic analysis revealed a distinct band with an apparent MW of 115-120 kDa in samples from each of the three cell types, regardless of the antibody used. COMP expression in cultures of synoviocytes derived from OA and RA patients showed that OA and RA synovial cells produced similar amounts of monomeric COMP of identical size to those COMP monomers produced by normal synovial cells. The addition of TGF-beta to these cultures resulted in an increase in COMP production in normal, OA and RA synovial cells (45, 116 and 115% respectively). These studies demonstrate that substantial amounts of COMP are produced by several mesenchymal cells including synoviocytes and dermal fibroblasts. These findings raise important concerns regarding the utility of measurements of COMP levels in serum or in synovial fluid as markers of articular cartilage degradation because of the likelihood that a substantial proportion of COMP or COMP fragments present in serum or synovial fluid may be produced by cells other than articular chondrocytes.


Low birth weight and preterm births: etiologic fraction attributable to prenatal drug exposure.
To determine the factors that would increase the likelihood of outcomes: low birth weight (LBW), preterm births and intrauterine growth restriction (IUGR). Secondary data analysis from a multi-center study. Risk factors for each outcome were derived from logistic regression models. Odds ratios (OR), 95% confidence intervals, and population-attributable risk proportions (PAR%) were estimated. Prenatal cocaine exposure increased the likelihood of LBW (OR: 3.59), prematurity (OR: 1.25), and IUGR (OR: 2.24). Tobacco, but not marijuana, significantly influenced these outcomes. Alcohol had an effect on LBW and IUGR. Etiologic fractions (PAR%) attributable to tobacco for LBW, prematurity, and IUGR were 5.57, 3.66, and 13.79%, respectively. With additional drug exposure including cocaine, estimated summary PAR% increased to 7.20% (LBW), 5.68% (prematurity), and 17.96% (IUGR). Disease burden for each outcome increases with each added drug exposure; however, etiologic fraction attributable to tobacco is greater than for cocaine.


Duchenne muscular dystrophy: negative electroretinograms and normal dark adaptation. Reappraisal of assignment of X linked incomplete congenital stationary night blindness.
Aland Island eye disease (AIED) and X linked congenital stationary night blindness (CSNB) have been mapped to Xp11.3. Patients have been described with deletions of the Duchenne muscular dystrophy (DMD) gene who also had a negative electroretinogram (ERG) similar to that seen in patients with CSNB and AIED. This seems to confirm that some cases of AIED and CSNB map to Xp21. We examined 16 boys with DMD/BMD (Becker muscular dystrophy) of whom 10 had negative ERGs, eight of them having deletions downstream from exon 44. Normal dark adaptation thresholds were observed in all patients and there were no anomalous visual functions. Hence, CSNB cannot be assigned to Xp21 and negative ERG in DMD/BMD is not associated with eye disease. Six boys with DMD/BMD had normal ERGs. We speculate that a retinal or glial dystrophin may be truncated or absent in the boys with negative ERGs.


Predictors of herpes simplex virus type 2 prevalence and incidence among bar and hotel workers in Moshi, Tanzania.
Herpes simplex virus (HSV) type 2 increases the risk of human immunodeficiency virus (HIV) infection, and, in regions with high prevalence of both viruses, control of HSV-2 may be an effective method of HIV prevention. Identification of modifiable factors for prevention of HSV-2 infection is essential. We conducted this study among female bar and hotel workers in Moshi, Tanzania. Factors associated with prevalent infection were examined among 1039 women. Predictors of incident infection were examined among 360 women initially HSV-2 negative, with at least 1 follow-up visit. HSV-2 prevalence was 56.3% (95% confidence interval [CI], 53.3%-59.3%). Only 2.5% of women able to name a sexually transmitted infection named herpes. Incidence was 14.2 cases/100 person-years (95% CI, 10.5-18.8 cases/100 person-years). Incident HSV-2 infection was independently associated with HIV infection, younger age of sexual initiation, ethnicity, alcohol consumption, and having a male partner with other sexual partners. The occurrence of HSV-2 is high in this population, but knowledge is low. Development of education programs to increase awareness of HSV-2 is critical. The control of both HSV-2 and HIV infections is a major public health priority in Moshi. Prevention interventions in this and other high prevalence populations might most effectively target younger women, before initiation of sexual activity.


Climate variability and vulnerability to climate change: a review.
The focus of the great majority of climate change impact studies is on changes in mean climate. In terms of climate model output, these changes are more robust than changes in climate variability. By concentrating on changes in climate means, the full impacts of climate change on biological and human systems are probably being seriously underestimated. Here, we briefly review the possible impacts of changes in climate variability and the frequency of extreme events on biological and food systems, with a focus on the developing world. We present new analysis that tentatively links increases in climate variability with increasing food insecurity in the future. We consider the ways in which people deal with climate variability and extremes and how they may adapt in the future. Key knowledge and data gaps are highlighted. These include the timing and interactions of different climatic stresses on plant growth and development, particularly at higher temperatures, and the impacts on crops, livestock and farming systems of changes in climate variability and extreme events on pest-weed-disease complexes. We highlight the need to reframe research questions in such a way that they can provide decision makers throughout the food system with actionable answers, and the need for investment in climate and environmental monitoring. Improved understanding of the full range of impacts of climate change on biological and food systems is a critical step in being able to address effectively the effects of climate variability and extreme events on human vulnerability and food security, particularly in agriculturally based developing countries facing the challenge of having to feed rapidly growing populations in the coming decades.


Genetic characteristics of drug-resistant Vibrio cholerae O1 causing endemic cholera in Dhaka, 2006-2011.
Vibrio cholerae O1 biotype El Tor (ET), causing the seventh cholera pandemic, was recently replaced in Bangladesh by an altered ET possessing ctxB of the Classical (CL) biotype, which caused the first six cholera pandemics. In the present study, V. cholerae O1 strains associated with endemic cholera in Dhaka between 2006 and 2011 were analysed for major phenotypic and genetic characteristics. Of 54 representative V. cholerae isolates tested, all were phenotypically ET and showed uniform resistance to trimethoprim/sulfamethoxazole (SXT) and furazolidone (FR). Resistance to tetracycline (TE) and erythromycin (E) showed temporal fluctuation, varying from year to year, while all isolates were susceptible to gentamicin (CN) and ciprofloxacin (CIP). Year-wise data revealed erythromycin resistance to be 33.3 % in 2006 and 11 % in 2011, while tetracycline resistance accounted for 33, 78, 0, 100 and 27 % in 2006, 2007, 2008, 2009 and 2010, respectively; interestingly, all isolates tested were sensitive to TE in 2011, as observed in 2008. All V. cholerae isolates tested possessed genetic elements such as SXT, ctxAB, tcpA(ET), rstR(ET) and rtxC; none had IntlI (Integron I). Double mismatch amplification mutation assay (DMAMA)-PCR followed by DNA sequencing and analysis of the ctxB gene revealed a point mutation at position 58 (C→A), which has resulted in an amino acid substitution from histidine (H) to asparagine (N) at position 20 (genotype 7) since 2008. Although the multi-resistant strains having tetracycline resistance showed minor genetic divergence, V. cholerae strains were clonal, as determined by a PFGE (NotI)-based dendrogram. This study shows 2008-2010 to be the time of transition from ctxB genotype 1 to genotype 7 in V. cholerae ET causing endemic cholera in Dhaka, Bangladesh.


A Guided Protocol for Array Based T2C: A High-Quality Selective High-Resolution High-Throughput Chromosome Interaction Capture.
After now more than 170 years of research the dynamic three-dimensional chromatin architecture of genomes and the co-evolved interaction networks of regulatory elements which create genome function - i.e. the storage, expression, and finally replication of genetic information - involves ever more investigative efforts in respect to not only the pure understanding of living organisms, but also diagnosis, treatment, and even future genome engineering. To study genomic interactions, we developed a novel and superior high-quality selective high-resolution, high-throughput chromosome interaction capture method - T2C (targeted chromatin capture) - which allows to arbitrarily balance resolution, frequency range of interactions, and the investigated general genetic region or single interactions in a highly cost-effective manner in respect to the obtainable result and compared to other techniques. Beyond, T2C has such a high signal-to-noise ratio at high resolution that the "genomic" statistical mechanics level can be reached. With the guided T2C protocol described here, we were already able to finally determine the chromatin quasi-fiber conformation and its folding into stable multi-loop aggregates/rosettes connected by a linker. Actually, this guided T2C protocol provides the means for architectural genome sequencing from the level of the single base pair to the entire cell nucleus and thus to analyze genetic interactions in respect to genome function in a systems biological manner in general as well as in settings ranging from basic research, via diagnostics and treatment, to genome engineering. © 2018 by John Wiley & Sons, Inc.


From somatostatin to octreotide LAR: evolution of a somatostatin analogue.
Acromegaly is characterized by overproduction of growth hormone (GH) by the pituitary gland. GH stimulates the synthesis of insulin-like growth factor-I (IGF-I), and the somatic growth and metabolic dysfunction that characterize acromegaly are a consequence of elevated GH and IGF-I levels. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare, slow-growing neoplasms that have usually metastasized by the time of diagnosis. The majority of GEP-NETs are carcinoid tumors whose syndrome is caused by the hypersecretion of biogenic amines, peptides and polypeptides responsible for the principal symptoms of diarrhea and flushing. The MEDLINE and EMBASE databases were searched for preclinical and clinical studies of octreotide (Sandostatin* ), a potent synthetic somatostatin analogue, in patients with acromegaly or GEP-NETs. This article reviews the 20 years of clinical experience with octreotide and the impact it has made in patients with acromegaly or GEP-NETs. Octreotide has proven to be an essential component in the management strategy of acromegaly and GEP-NETs over the past 20 years. The multiple beneficial effects of octreotide throughout the body, combined with its established safety profile (the most common adverse effects are injection-site pain and gastrointestinal events), have made it an appealing option for clinicians. The advent of the long-acting release (LAR) formulation of octreotide provided additional benefits to patients through monthly administration, while maintaining the efficacy and tolerability profile of the daily subcutaneous formulation. Octreotide is a potent synthetic somatostatin analogue that has become the mainstay of medical therapy for tumor control in neuroendocrine disorders such as acromegaly and GEP-NETs. The development of octreotide LAR offered a further advancement; less frequent dosing provided valuable benefits in quality of life to patients, with equivalent efficacy and tolerability. Moreover, recent results from the PROMID study have confirmed the antiproliferative effect of octreotide LAR in patients with well-differentiated metastatic GEP-NETs of the midgut. New therapeutic uses of octreotide are currently under investigation in a variety of clinical settings.


The hydro-alcoholic extracts of Sardinian wild thistles (Onopordum spp.) inhibit TNFα-induced IL-8 secretion and NF-κB pathway in human gastric epithelial AGS cells.
Thistles species (Family: Compositae) are traditionally used in the Mediterranean area, particularly in Sardinia. They are usually gathered from the wild and used for both food and therapeutic purposes, including gastrointestinal disorders. This work aims to evaluate the anti-inflammatory activity of eight wild thistles from Sardinia, in an in vitro model of gastric inflammation, and to identify the major active compounds in the extracts. The hydro-alcoholic extract of the aerial part of each species was prepared. After the induction of inflammation by the addition of tumor necrosis factor-α (TNFα) (10ng/mL), AGS cells were treated with extracts/pure compounds under study. The inhibition of interleukin-8 (IL-8) release, IL-8 and NF-κB promoter activities and NF-κB nuclear translocation were evaluated. Extracts main components were identified by HPLC-PDA-MS/MS. Only Onopordum horridum Viv. and Onopordum illyricum L. hydro-alcoholic extracts reduced, in a concentration-dependent fashion, the IL-8 release and promoter activity in human gastric epithelial cells AGS. The effect was partially due to the NF-κB pathway impairment. Onopordum hydro-alcoholic extracts were also chemically profiled, and caffeoylquinic acid derivatives were the main compounds identified in the extract. Further investigations showed that 3,5 dicaffeoylquinic acid highly inhibited IL-8 secretion in AGS cells (IC50 0.65μM), thus suggesting that this compound contributed, at least in part, to the anti-inflammatory activity elicited by O. illyricum extracts. Our results suggest that Onopordum species may exert beneficial effects against gastric inflammatory diseases. Thus, these wild plants deserve further investigations as preventive or co-adjuvant agents in gastric diseases.


Preventing adverse cardiac events (PACE) in chronic obstructive pulmonary disease (COPD): study protocol for a double-blind, placebo controlled, randomised controlled trial of bisoprolol in COPD.
Heart disease in chronic obstructive pulmonary disease (COPD) is a common but neglected comorbidity. Patients with COPD are frequently excluded from clinical trials of treatments aimed at reducing cardiac morbidity and mortality, which has led to undertreatment of cardiovascular disease in patients with COPD. A particular concern in COPD is the underuse of beta (β)-blockers. There is observational evidence that cardioselective β-blockers are safe and may even reduce mortality risk in COPD, although some evidence is conflicting. There is an urgent need to answer the research question: Are cardioselective β-blockers safe and of benefit in people with moderately severe COPD? The proposed study will investigate whether cardioselective β-blocker treatment in patients with COPD reduces mortality and cardiac and respiratory morbidity. This is a double-blind, randomised controlled trial to be conducted in approximately 26 sites in Australia, New Zealand, India, Sri Lanka and other countries as required. Participants with COPD will be randomised to either bisoprolol once daily (range 1.25-5 mg, dependent on tolerated dose) or matched placebo, in addition to receiving usual care for their COPD over the study duration of 24 months.The study will enrol 1164 participants with moderate to severe COPD, aged 40-85 years. Participants will be symptomatic from their COPD and have a postbronchodilator forced expiratory volume in 1 s (FEV1) ≥30% and ≤70% predicted and a history of at least one exacerbation requiring systemic corticosteroids, antibiotics or both in the prior 24 months. The study protocol has been approved by the Sydney Local Health District Human Research Ethics Committee at The Concord Repatriation General Hospital. NCT03917914; CTRI/2020/08/027322.


Plasma Trough Concentrations of Antihypertensive Drugs for the Assessment of Treatment Adherence: A Meta-Analysis.
Biochemical drug screening by liquid chromatography-tandem mass spectrometry in plasma is an accurate method for the quantification of plasma concentrations of antihypertensive medications in patients with hypertension. Trough concentrations could possibly be used as drug-specific cutoff values in the biochemical assessment of (non-)adherence. We performed a literature review and meta-analysis of pharmacokinetic studies to determine plasma trough concentrations of amlodipine, hydrochlorothiazide, and valsartan. PubMed was searched for pharmacokinetic studies up to September 2020. Eligible studies reported steady-state mean trough concentration and their variance. Pooled trough concentrations were estimated using a three-level random effects meta-analytic model. Moderator analyses were performed to explore sources of heterogeneity. One thousand three hundred eighteen potentially relevant articles were identified of which 45 were eligible for inclusion. The pooled mean trough concentration was 9.2 ng/mL (95% CI, 7.5-10.8) for amlodipine, 41.0 ng/mL (95% CI, 17.4-64.7) for hydrochlorothiazide, and 352.9 ng/mL (95% CI, 243.5-462.3) for valsartan. Substantial heterogeneity was present for all 3 pooled estimates. Moderator analyses identified dosage as a significant moderator for the pooled trough concentration of amlodipine (β1=0.9; P<0.05), mean age, and mean body weight for the mean trough concentration of hydrochlorothiazide (β1=2.2, P<0.05, respectively, β1=-4.0, P<0.05) and no significant moderators for valsartan. Plasma trough concentrations of amlodipine, hydrochlorothiazide, and valsartan, measured with liquid chromatography-tandem mass spectrometry, are highly heterogeneous over the different studies. Use of the pooled trough concentration as a cutoff in the biochemical assessment of adherence can result in inaccurate diagnosis of (non-)adherence, which may seriously harm the patient-physician relationship, and is therefore not recommended.


Heterozygosity excess at the cattle DRB locus revealed by large scale genotyping of two closely linked microsatellites.
A method for MHC DRB typing in cattle based on two closely linked and highly polymorphic microsatellites is described. The two microsatellites DRBP1ms and DRB3ms are located in intron 2 of the corresponding DRB gene. The very strong linkage disequilibrium between the two loci made it possible to establish DRB microsatellite haplotypes. The typing results with this method on reference samples followed closely that obtained with RFLP and direct sequence analysis of DRB3 exon 2. The method is well suited for large scale genotyping and was successfully applied for typing more than 600 unrelated animals representing 23 breeds. The data were used to test whether the observed DRB allele frequency distributions were consistent with that expected for selectively neutral alleles in populations at mutation-drift equilibrium. A significant heterozygosity excess was detected and there was an obvious trend across breeds towards a more even allele frequency distribution than expected. The deviation may be due to balancing selection acting on the DRB locus or by recent population bottlenecks.


Novel Coronavirus Outbreak in Wuhan, China, 2020: Intense Surveillance Is Vital for Preventing Sustained Transmission in New Locations.
The outbreak of pneumonia originating in Wuhan, China, has generated 24,500 confirmed cases, including 492 deaths, as of 5 February 2020. The virus (2019-nCoV) has spread elsewhere in China and to 24 countries, including South Korea, Thailand, Japan and USA. Fortunately, there has only been limited human-to-human transmission outside of China. Here, we assess the risk of sustained transmission whenever the coronavirus arrives in other countries. Data describing the times from symptom onset to hospitalisation for 47 patients infected early in the current outbreak are used to generate an estimate for the probability that an imported case is followed by sustained human-to-human transmission. Under the assumptions that the imported case is representative of the patients in China, and that the 2019-nCoV is similarly transmissible to the SARS coronavirus, the probability that an imported case is followed by sustained human-to-human transmission is 0.41 (credible interval [0.27, 0.55]). However, if the mean time from symptom onset to hospitalisation can be halved by intense surveillance, then the probability that an imported case leads to sustained transmission is only 0.012 (credible interval [0, 0.099]). This emphasises the importance of current surveillance efforts in countries around the world, to ensure that the ongoing outbreak will not become a global pandemic.


Voyager 2 at neptune: imaging science results.
Voyager 2 images of Neptune reveal a windy planet characterized by bright clouds of methane ice suspended in an exceptionally clear atmosphere above a lower deck of hydrogen sulfide or ammonia ices. Neptune's atmosphere is dominated by a large anticyclonic storm system that has been named the Great Dark Spot (GDS). About the same size as Earth in extent, the GDS bears both many similarities and some differences to the Great Red Spot of Jupiter. Neptune's zonal wind profile is remarkably similar to that of Uranus. Neptune has three major rings at radii of 42,000, 53,000, and 63,000 kilometers. The outer ring contains three higher density arc-like segments that were apparently responsible for most of the ground-based occultation events observed during the current decade. Like the rings of Uranus, the Neptune rings are composed of very dark material; unlike that of Uranus, the Neptune system is very dusty. Six new regular satellites were found, with dark surfaces and radii ranging from 200 to 25 kilometers. All lie inside the orbit of Triton and the inner four are located within the ring system. Triton is seen to be a differentiated body, with a radius of 1350 kilometers and a density of 2.1 grams per cubic centimeter; it exhibits clear evidence of early episodes of surface melting. A now rigid crust of what is probably water ice is overlain with a brilliant coating of nitrogen frost, slightly darkened and reddened with organic polymer material. Streaks of organic polymer suggest seasonal winds strong enough to move particles of micrometer size or larger, once they become airborne. At least two active plumes were seen, carrying dark material 8 kilometers above the surface before being transported downstream by high level winds. The plumes may be driven by solar heating and the subsequent violent vaporization of subsurface nitrogen.


Laccase-mediated detoxification of phenolic compounds.
The ability of a polyphenoloxidase, the laccase of the fungus Rhizoctonia praticola, to detoxify phenolic pollutants was examined. The growth of the fungus could be inhibited by phenolic compounds, and the effective concentration was dependent on the substituents of the phenol. A toxic amount of a phenolic compound was added to a fungal growth medium in the presence or absence of a naturally occurring phenol, and half of the replicates also received laccase. The medium was then inoculated with R. praticola, and the levels of phenols in the medium were monitored by high-performance liquid chromatography analysis. The addition of the laccase reversed the inhibitory effect of 2,6-xylenol, 4-chloro-2-methylphenol, and p-cresol. Other compounds, e.g., o-cresol and 2,4-dichlorophenol, were detoxified only when laccase was used in conjunction with a natural phenol such as syringic acid. The toxicity of p-chlorophenol and 2,4,5-trichlorophenol could not be overcome by any additions. The ability of the laccase to alter the toxicity of the phenols appeared to be related to the capacity of the enzyme to decrease the levels of the parent compound by transformation or cross-coupling with another phenol.


'Men value their dignity': securing respect and identity construction in urban informal settlements in South Africa.
Urban informal settlements remain sites of high HIV incidence and prevalence, as well as violence. Increasing attention is paid on how configurations of young men's masculinities shape these practices through exploring how men build respect and identity. In this paper, we explore how young Black South Africans in two urban informal settlements construct respect and a masculine identity. Data are drawn from three focus groups and 19 in-depth interviews. We suggest that while young men aspire to a 'traditional' masculinity, prioritising economic power and control over the household, we suggest that a youth masculinity emerges which, in lieu of alternative ways to display power, prioritises violence and control over men's sexual partners, men seeking multiple sexual partners and men's violence to other men. This functions as a way of demonstrating masculinity and their position within a public gender order. We suggest there are three implications of the findings for working with men on violence and HIV-risk reduction. First, there exist a number of contradictions in men's discourses about masculinity that may provide spaces and opportunities for change. Second, it is important to work on multiple issues at once given the way violence, alcohol use, and sexual risk are interlinked in youth masculinity. Finally, engaging with men's exclusion from the capitalist system may provide an important way to reduce violence.


Foraminal nerve sheath tumors: intermediate follow-up after cyberknife radiosurgery.
To conduct a retrospective review of outcomes in 15 patients with 18 foraminal tumors, including 17 benign peripheral nerve sheath tumors and 1 malignant peripheral nerve sheath tumor, who underwent CyberKnife (Accuray, Inc., Sunnyvale, CA) radiosurgery at Stanford University Medical Center from 1999 to 2006. Symptoms and findings, neurofibromatosis (NF) association, previous radiation, imaging, dosimetry, tumor volume, central necrosis, and the relation of these factors to outcomes were evaluated. Before treatment, 1 asymptomatic patient had radiculopathic findings, 3 patients experienced local pain with intact neurological examinations, and 7 patients had radiculopathic complaints with intact (1 patient), radiculopathic (4 patients), or radiculomyelopathic examinations (2 patients). Five patients had myelopathic complaints and findings. Three patients had NF1-associated neurofibromas, 1 patient with NF2 had a schwannoma, and 1 patient had a schwannomatosis-related lesion. Two likely radiation-induced lesions, a neurofibroma and a malignant peripheral nerve sheath tumor, were observed. Prescribed doses ranging from 16 to 24 Gy, delivered in 1 to 3 fractions of 6 to 20 Gy, resulted in maximum tumor doses ranging from 20.9 to 30 Gy. Target volumes ranged from 1.36 to 16.9 mL. After radiosurgery, the asymptomatic case remained asymptomatic, and neurological findings improved. Thirteen of 15 symptomatic patients with (12 patients) or without (3 patients) neurological findings improved (3 cases after resection) or remained stable, and 2 patients worsened. Symptoms and examinations remained stable or improved in 8 (80%) of 10 patients with schwannomas and 3 (60%) of 5 patients with neurofibromas. Tumor volumes decreased in 12 (67%) of 18 tumors and increased in 3 tumors. Tumor volumes decreased in 8 of 10 schwannomas and 3 of 7 neurofibromas. Central necrosis developed in 8 (44%) of 18 tumors. CyberKnife radiosurgery resulted in pain relief and functional preservation in selected foraminal peripheral nerve sheath tumors and a malignant peripheral nerve sheath tumor. Symptomatic and neurological improvements were more noticeable with schwannomas. Myelopathic symptoms may necessitate surgical debulking before radiosurgery.


Effect of changes in plasma vitamin E level of vascular responses and lipid peroxidation in sickle cell anaemia subjects.
The effect of vitamin E supplementation (300 mg/day for 6 weeks) on blood pressure, forearm blood flow, forearm vascular resistance, plasma vitamin E level and lipid peroxidation status was investigated in adult sickle cell anaemia subjects. Ten adults whose ages ranged from 19.0 to 25.0 years (mean 22.8+/-0.8 years) were studied. Vitamin E supplementation had little or no effect on arterial blood pressure but significantly increased forearm blood flow (p<0.001) and plasma vitamin E level (p<0.001). However it significantly decreased lipid peroxidation status (p<0.001) and forearm vascular resistance (p<0.001). The change in plasma vitamin E concentration correlated negatively with change in lipid peroxidation status (r=-0.8; p=0.003). However, change in plasma vitamin E concentration correlated positively with change in forearm blood flow (r=0.8; p=0.006). There was an inverse correlation between change in plasma lipid peroxidation and change in forearm blood flow (r=-0.7; p=0.03). The study therefore shows that in sickle cell anaemia subjects, vitamin E supplementation increases forearm blood flow and reduces forearm vascular resistance and lipid peroxidation. The increase in forearm blood flow correlates inversely with the reduction in lipid peroxidation. This suggests that in sickle cell anaemia subjects, vitamin E supplementation could cause an increase in forearm blood flow by decreasing plasma lipid peroxidation level.


An evaluation of the effect of an angiotensin-converting enzyme inhibitor on the growth rate of small abdominal aortic aneurysms: a randomized placebo-controlled trial (AARDVARK).
The AARDVARK (Aortic Aneurysmal Regression of Dilation: Value of ACE-Inhibition on RisK) trial investigated whether ACE-inhibition reduces small abdominal aortic aneurysms (AAA) growth rate, independent of blood pressure (BP) lowering. A three-arm, multi-centre, single-blind, and randomized controlled trial (ISRCTN51383267) was conducted in 14 hospitals in England. Subjects aged ≥55 years with AAA diameter 3.0-5.4 cm were randomized 1:1:1 to receive perindopril arginine 10 mg, or amlodipine 5 mg, or placebo and followed 3-6 monthly over 2 years. The primary outcome was aneurysm growth rate (based on external antero-posterior ultrasound measurements in the longitudinal plane), determined by multi-level modelling to provide maximum likelihood estimates. Two hundred and twenty-four subjects were randomized (2011-2013) to placebo (n = 79), perindopril (n = 73), or amlodipine (n = 72). Mean (SD) changes in mid-trial systolic BP (12 months) were 0.5 (14.3) mmHg, P = 0.78 compared with baseline, -9.5 (13.1) mmHg (P < 0.001), and -6.7 (12.0) mmHg (P < 0.001), respectively. No significant differences in the modelled annual growth rates were apparent [1.68 mm (SE 0.2), 1.77 mm (0.2), and 1.81 mm (0.2), respectively]. The estimated difference in annual growth between the perindopril and placebo groups was 0.08 mm (CI -0.50, 0.65). Similar numbers of AAAs in each group reached 5.5 cm diameter and/or underwent elective surgery: 11 receiving placebo, 10 perindopril, and 11 amlodipine. Small AAA growth rates were lower than anticipated, but there was no significant impact of perindopril compared with placebo or placebo and amlodipine, combined despite more effective BP lowering.


Shifts in the Composition of the Microbiota of Stored Wheat Grains in Response to Fumigation.
While the wheat-associated microbiome is of major agricultural importance, little is known about the alterations in wheat grain microbial community composition during storage. Characterization of the bacterial and fungal communities in stored wheat grains revealed the impact of phosphine fumigation, one of the most effective methods to eliminate insects in stored commodities, on the composition of the wheat grain microbiome. High-throughput amplicon sequencing of the bacterial 16S rRNA gene and fungal internal transcribed spacer (ITS) region was used to analyze the wheat grain microbiome at different times over as 6 months period of storage. Higher bacterial diversity was found across the samples during the first (immediately after harvest) and second (3 months later) time points, with a predominance of Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes and Planctomycetes. A two-fold decrease in the number of bacterial operational taxonomic units (OTUs) was observed in wheat grains at the last time point (6 months later), following phosphine treatment. In contrast to the effect of phosphine on bacteria, it did not affect fungal diversity in stored grains. The majority of fungal sequences were assigned to Ascomycota, followed by Basidiomycota, Glomeromycota, and unidentified fungi, which were evenly distributed throughout the storage period. Alpha and beta diversity analyses were confirmed by examination of the cultured microbial taxa obtained from the stored wheat grains. Mycotoxin analysis of wheat grains collected after phosphine fumigation revealed the presence of Fusarium toxins, primarily deoxynivalenol (DON). Several mycotoxigenic Fusarium spp. were also detected in the same samples. Results of the present study indicate that microbiome of stored, whole wheat grains was strongly affected by phosphine fumigation, which changed the structure of the microbial community leading to shifts in species composition toward mycotoxigenic strains. A better understanding of the complex interactions within the microbial communities of stored grains will assist in the development of novel biocontrol strategies to overcome mycotoxin contamination.


Mimicry of emergent traits amplifies coastal restoration success.
Restoration is becoming a vital tool to counteract coastal ecosystem degradation. Modifying transplant designs of habitat-forming organisms from dispersed to clumped can amplify coastal restoration yields as it generates self-facilitation from emergent traits, i.e. traits not expressed by individuals or small clones, but that emerge in clumped individuals or large clones. Here, we advance restoration science by mimicking key emergent traits that locally suppress physical stress using biodegradable establishment structures. Experiments across (sub)tropical and temperate seagrass and salt marsh systems demonstrate greatly enhanced yields when individuals are transplanted within structures mimicking emergent traits that suppress waves or sediment mobility. Specifically, belowground mimics of dense root mats most facilitate seagrasses via sediment stabilization, while mimics of aboveground plant structures most facilitate marsh grasses by reducing stem movement. Mimicking key emergent traits may allow upscaling of restoration in many ecosystems that depend on self-facilitation for persistence, by constraining biological material requirements and implementation costs.


Smoking and psychiatric disorders: have subthreshold disorders been overlooked?
The association between smoking and mental disorders has been confirmed by several studies using cross-sectional and retrospective designs. The present study illustrates the need for differentiating subthreshold psychiatric disorders in the analysis. The analysis is based on cumulative ("lifetime") prevalences of mental disorders and smoking in the Zurich study. This is a longitudinal community study with a stratified sample of 591 participants and six interviews from 1979 to 1999. The percentage of lifetime smokers in the Zurich study was higher both in persons with a lifetime psychiatric diagnosis (72%) and in persons with subthreshold disorders (60%) than in those without any diagnosis (40%). The association between smoking and mental disorders turned out to be clearly stronger if subthreshold mental disorders were appropriately considered in the analyses. Constructing appropriate reference groups is as crucial for the analysis of mental disorders and their outcomes as constructing adequate diagnostic groups.


Severity of injuries in different modes of transport, expressed with disability-adjusted life years (DALYs).
Health impact assessment (HIA) studies are increasingly predicting the health effects of mode shifts in traffic. The challenge for such studies is to combine the health effects, caused by injuries, with the disease driven health effects, and to express the change in the health with a common health indicator. Disability-adjusted life year (DALY) combines years lived disabled or injured (YLD) and years of life lost (YLL) providing practical indicator to combine injuries with diseases. In this study, we estimate the average YLDs for one person injured in a transport crash to allow easy to use methods to predict health effects of transport injuries. We calculated YLDs and YLLs for transport fatalities and injuries based on the data from the Swedish Traffic Accident Data Acquisition (STRADA). In STRADA, all the fatalities and most of the injuries in Sweden for 2007-2011 were recorded. The type of injury was recorded with the Abbreviated Injury Scale (AIS) codes. In this study these AIS codes were aggregated to injury types, and YLDs were calculated for each victim by multiplying the type of injury with the disability weight and the average duration of that injury. YLLs were calculated by multiplying the age of the victim with life expectancy of that age and gender. YLDs and YLLs were estimated separately for different gender, mode of transport and location of the crash. The average YLDs for injured person was 14.7 for lifelong injuries and 0.012 for temporal injuries. The average YLDs per injured person for lifelong injuries for pedestrians, cyclists and car occupants were 9.4, 12.8 and 18.4, YLDs, respectively. Lifelong injuries sustained in rural areas were on average 31% more serious than injuries in urban areas. The results show that shifting modes of transport will not only change the likelihood of injuries but also the severity of injuries sustained, if injured. The results of this study can be used to predict DALY changes in HIA studies that take into account mode shifts between different transport modes, and in other studies predicting the health effects of traffic injuries.


Social rebirth and social transformation? Rebuilding social lives after ART in rural Uganda.
This paper examines how HIV diagnosis, illness and anti-retroviral therapy (ART) have an impact on the social dimensions of people's lives in rural Uganda, focusing on identity, relationships and membership of groups. Using concepts drawn from sociological research on experiences of illness and recovery, "getting back to normal", "rebirth" and "turning point", we present findings from qualitative research that explored the social changes brought about by HIV and ART among 70 men and women taking ART since 2003. With a second chance at life, some people's narratives revealed a pursuit of getting "back to normal", restoring and resuming their place in their families and communities. Others sought to change or transform their new lives, what we term a "social rebirth", moving away from old social networks and lifestyles. Regaining health was associated with a desire to make the most of life by joining social groups and civil society organisations, establishing new relationships and advising and supporting others. However, earlier losses of family and friends due to AIDS-related deaths made "social rebirth" hard for many people. Our findings also show that the process of responding to ART is not linear and the pursuit of change following diagnosis and treatment may be difficult to sustain, as the months and years on ART progress and the struggles of getting on with life take their toll. Sustaining social rebirth was challenging and complex due to the nature of HIV infection itself (for example, new intimate relationships pose challenges) and the harsh economic environment. Maintaining changed lives for those living with HIV and ART is important because this will contribute to better disease self-management and so demands an understanding by support organisations of the nature of these changes and challenges.


Impact of olive oil and honey on healing of diabetic foot: a randomized controlled trial.
Background: This study aimed 1) to examine the impact of honey on diabetic foot; 2) to examine the effect of olive oil on diabetic foot; and 3) to compare the impact of honey and olive oil in the healing of diabetic foot. Methods: In this randomized controlled trial, 45 patients took part. Patients were randomly assigned to three groups. In the honey group, the wound was dressed using gauzes with honey daily for 1 month. In the olive oil group, the wound was dressed using gauzes with olive oil (4 mL) daily for 1 month. Patients in the control group received usual dressing. Wounds were assessed before and after intervention using the Wagner scoring system and the checklist of diabetic foot healing (where a higher score indicates better wound healing). Results: Demographic characteristics of patients in the three groups were similar. Mean scores of tissue around the wound, wound grade, wound drainage, and wound healing were similar before intervention in all three groups. After intervention, means score of tissue around the wound, wound grade, wound drainage, and wound healing were significantly higher in patients in the honey and olive oil groups compared to patients in the control group. Conclusion: The results of this study reveal that honey is as effective as olive oil in the treatment of diabetic foot. Given the few studies on this topic, further investigation is needed.


Energy expenditure during 2-day trail walking in the mountains (2,857 m) and the effects of amino acid supplementation in older men and women.
We compared relative exercise intensity and active energy expenditure (AEE) on trail walking in the mountains, with those of daily exercise training, and whether branched-chain amino acid (BCAA) and arginine supplementation attenuated the release of markers indicating muscle damage and declines in physical performance. Twenty-one subjects (~63 years) were divided into two groups: amino acid (AA, 51 g of amino acids and 40 g of carbohydrate, male/female = 6/4) or placebo (PL, 91 g of carbohydrate, male/female = 6/5) supplementation during 2 days of trail walking in the mountains. We measured heart rate (HR), AEE, fatigue sensation, water and food intake, and sweat loss during walking. In addition, we measured peak aerobic capacity [Formula: see text] and heart rate (HR(peak)) with graded-intensity walking, vertical jumping height (VJ) before and after walking. We found that average HR and AEE during uphill walking were ~100% HR(peak) and ~60% [Formula: see text], while they were ~80 and ~20% during downhill walking, respectively. Moreover, average total AEE per day was sevenfold that of their daily walking training. VJ after walking remained unchanged compared with the baseline in AA (P > 0.2), while it was reduced by ~10% in PL (P < 0.01), although with no significant difference in the reduction between the groups (P > 0.4). The responses of other variables were not significantly different between groups (all, P > 0.2). Thus, trail walking in the mountains required a high-intensity effort for older people, while the effects of BCAA and arginine supplementation were modest in this condition.


Angiographic 20-year follow-up of 61 consecutive patients with internal thoracic artery grafts.
To assess the behavior of internal thoracic artery (ITA) grafts versus venous grafts in repeated angiograms up to 20 years. Use of ITA grafts to bypass left anterior descending artery stenosis has been shown to be associated with improved survival in patients undergoing coronary artery bypass grafting. Sixty-one consecutive patients who received one or two ITA grafts and who underwent surgery from Oct. 5, 1971, to Dec. 18, 1973, in Helsinki University Central Hospital, Finland, were included in this prospective follow-up series. Fifty-six of the patients (92%) also received at least one venous graft. The number of distal anastomoses was 157, of which 47.7% (75) were performed with ITA grafts. The median age of the patients was 47.7 years (range 30.0 to 63.1), and 85% (52) were men. After 20 years of follow-up, 18/20 (90%) of the survivors underwent angiography; the patency rate was 88.9% for ITA grafts and 47.8% for venous grafts. Cumulative graft patency at 20 years, using all the information obtained from repeated angiographic examinations and autopsies, was also calculated to eliminate selection bias. The cumulative 20-year patency rate was 81% for ITA-left anterior descending artery anastomoses, 53.8% for venous graft-right coronary artery anastomoses, and 48.5% for venous graft-left circumflex artery anastomoses. In paired comparisons between anastomoses, the patency time of the ITA-left anterior descending artery anastomoses was on average 2.8 years longer than the venous graft-left circumflex artery patency time and 2.6 years longer than the venous graft-right coronary artery. Internal thoracic artery grafts, especially in left anterior descending artery anastomoses, should be considered as a primary solution in coronary artery bypass grafting surgery in patients with >10 years of life expectancy; if venous grafting is preferred, further evidence is needed.


Unconjugated p-cresol activates macrophage macropinocytosis leading to increased LDL uptake.
Patients with chronic kidney disease (CKD) and end-stage renal disease suffer from increased cardiovascular events and cardiac mortality. Prior studies have demonstrated that a portion of this enhanced risk can be attributed to the accumulation of microbiota-derived toxic metabolites, with most studies focusing on the sulfonated form of p-cresol (PCS). However, unconjugated p-cresol (uPC) itself was never assessed due to rapid and extensive first-pass metabolism that results in negligible serum concentrations of uPC. These reports thus failed to consider the host exposure to uPC prior to hepatic metabolism. In the current study, not only did we measure the effect of altering the intestinal microbiota on lipid accumulation in coronary arteries, but we also examined macrophage lipid uptake and handling pathways in response to uPC. We found that atherosclerosis-prone mice fed a high-fat diet exhibited significantly higher coronary artery lipid deposits upon receiving fecal material from CKD mice. Furthermore, treatment with uPC increased total cholesterol, triglycerides, and hepatic and aortic fatty deposits in non-CKD mice. Studies employing an in vitro macrophage model demonstrated that uPC exposure increased apoptosis whereas PCS did not. Additionally, uPC exhibited higher potency than PCS to stimulate LDL uptake and only uPC induced endocytosis- and pinocytosis-related genes. Pharmacological inhibition of varying cholesterol influx and efflux systems indicated that uPC increased macrophage LDL uptake by activating macropinocytosis. Overall, these findings indicate that uPC itself had a distinct effect on macrophage biology that might have contributed to increased cardiovascular risk in patients with CKD.


Maternal caffeine intake during pregnancy and risk of obesity in offspring: a prospective cohort study.
In-utero exposures through adverse fetal programming are emerging as an important contributing factor to the epidemic of childhood obesity. This study examines the impact of in-utero exposure to caffeine on the risk of childhood obesity in offspring. A prospective study of pregnant women with 15 years follow-up of their offspring was conducted to examine the impact of in-utero exposure to caffeine on the risk of childhood obesity. Maternal caffeine intake was prospectively ascertained during pregnancy and outcome measures (body mass index (BMI)) were ascertained from medical charts, with 17 BMI measurements per child, on average, during the follow-up period. Potential confounders including known perinatal risk factors for childhood obesity were adjusted for using the generalized estimating equations model with repeated measurements. After controlling for potential confounders, compared with those without caffeine exposure, in-utero exposure to caffeine overall is associated with 87% increased risk of childhood obesity: odds ratio (OR) =1.87, 95% confidence interval (CI): 1.12-3.12. This association demonstrated a dose-response relationship: OR=1.77 (1.05-3.00) for maternal daily caffeine intake <150 mg per day, OR=2.37 (1.24-4.52) for caffeine intake ⩾150 mg per day during pregnancy, respectively. We also observed a linear relationship: every one unit increase (log10 scale) in the amount of maternal caffeine intake was associated with 23% increased risk of obesity in offspring. The dose-response relationship appears stronger for persistent obesity than for transitory obesity (occasional high BMI), and for girls than for boys. We observed an association of in-utero exposure to caffeine with increased risk of childhood obesity. If this observation is further replicated in other studies, the finding will contribute to the understanding of fetal programming of childhood diseases and development of intervention strategy to prevent childhood obesity.


Immune modulation and increased neurotrophic factor production in multiple sclerosis patients treated with testosterone.
Multiple sclerosis is a chronic inflammatory disease of the central nervous system with a pronounced neurodegenerative component. It has been suggested that novel treatment options are needed that target both aspects of the disease. Evidence from basic and clinical studies suggests that testosterone has an immunomodulatory as well as a potential neuroprotective effect that could be beneficial in MS. Ten male MS patients were treated with 10 g of gel containing 100 mg of testosterone in a cross-over design (6 month observation period followed by 12 months of treatment). Blood samples were obtained at three-month intervals during the observation and the treatment period. Isolated blood peripheral mononuclear cells (PBMCs) were used to examine lymphocyte subpopulation composition by flow cytometry and ex vivo protein production of cytokines (IL-2, IFNgamma, TNFalpha, IL-17, IL-10, IL-12p40, TGFbeta1) and growth factors (brain-derived neurotrophic factor BDNF, platelet-derived growth factor PDGF-BB, nerve growth factor NGF, and ciliary neurotrophic factor CNTF). Delayed type hypersensitivity (DTH) skin recall tests were obtained before and during treatment as an in vivo functional immune measure. Testosterone treatment significantly reduced DTH recall responses and induced a shift in peripheral lymphocyte composition by decreasing CD4+ T cell percentage and increasing NK cells. In addition, PBMC production of IL-2 was significantly decreased while TGFbeta1 production was increased. Furthermore, PBMCs obtained during the treatment period produced significantly more BDNF and PDGF-BB. These results are consistent with an immunomodulatory effect of testosterone treatment in MS. In addition, increased production of BDNF and PDGF-BB suggests a potential neuroprotective effect. NCT00405353 http://www.clinicaltrials.gov.


On The Potential of Dynamic Nuclear Polarization Enhanced Diamonds in Solid-State and Dissolution (13) C NMR Spectroscopy.
Dynamic nuclear polarization (DNP) is a versatile option to improve the sensitivity of NMR and MRI. This versatility has elicited interest for overcoming potential limitations of these techniques, including the achievement of solid-state polarization enhancement at ambient conditions, and the maximization of (13) C signal lifetimes for performing in vivo MRI scans. This study explores whether diamond's (13) C behavior in nano- and micro-particles could be used to achieve these ends. The characteristics of diamond's DNP enhancement were analyzed for different magnetic fields, grain sizes, and sample environments ranging from cryogenic to ambient temperatures, in both solution and solid-state experiments. It was found that (13) C NMR signals could be boosted by orders of magnitude in either low- or room-temperature solid-state DNP experiments by utilizing naturally occurring paramagnetic P1 substitutional nitrogen defects. We attribute this behavior to the unusually long electronic/nuclear spin-lattice relaxation times characteristic of diamond, coupled with a time-independent cross-effect-like polarization transfer mechanism facilitated by a matching of the nitrogen-related hyperfine coupling and the (13) C Zeeman splitting. The efficiency of this solid-state polarization process, however, is harder to exploit in dissolution DNP-enhanced MRI contexts. The prospects for utilizing polarized diamond approaching nanoscale dimensions for both solid and solution applications are briefly discussed.


Use of science to guide city planning policy and practice: how to achieve healthy and sustainable future cities.
Land-use and transport policies contribute to worldwide epidemics of injuries and non-communicable diseases through traffic exposure, noise, air pollution, social isolation, low physical activity, and sedentary behaviours. Motorised transport is a major cause of the greenhouse gas emissions that are threatening human health. Urban and transport planning and urban design policies in many cities do not reflect the accumulating evidence that, if policies would take health effects into account, they could benefit a wide range of common health problems. Enhanced research translation to increase the influence of health research on urban and transport planning decisions could address many global health problems. This paper illustrates the potential for such change by presenting conceptual models and case studies of research translation applied to urban and transport planning and urban design. The primary recommendation of this paper is for cities to actively pursue compact and mixed-use urban designs that encourage a transport modal shift away from private motor vehicles towards walking, cycling, and public transport. This Series concludes by urging a systematic approach to city design to enhance health and sustainability through active transport and a move towards new urban mobility. Such an approach promises to be a powerful strategy for improvements in population health on a permanent basis.


Computational fluid dynamics analysis of a high throughput viscous heater to process feces and a fecal simulant using temperature and shear rate-dependent viscosity model.
Open defecation and poor fecal management facilitates the spread of disease. Viscous heating can pasteurize fecal sludge by creating a high shear field in the annular gap between a stationary, cylindrical outer shell and a rotating inner core. As sludge flows axially through the annular gap, thorough mixing and frictional heating eliminate cool spots where microbes may survive. A viscous heater (VH) compares favorably to a conventional heat exchanger, where cool slugs may occur. Computational fluid dynamics (CFD) was used to determine the effects of geometry and fluid rheology on VH performance over a range of conditions. A shear-rate and temperature-dependent rheological model was developed from experimental data, using a sludge simulant. CFD of an existing VH used the model to improve the original naïve design by including temperature and shear rate-dependent viscosity. CFD results were compared to experimental data at 132 and 200 L/hr to predict design and operating conditions for 1,000 L/hr. Subsequent experimentation with fecal sludge indicated that the CFD approach was valid for design and operation.


Validation of machine learning models to detect amyloid pathologies across institutions.
Semi-quantitative scoring schemes like the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) are the most commonly used method in Alzheimer's disease (AD) neuropathology practice. Computational approaches based on machine learning have recently generated quantitative scores for whole slide images (WSIs) that are highly correlated with human derived semi-quantitative scores, such as those of CERAD, for Alzheimer's disease pathology. However, the robustness of such models have yet to be tested in different cohorts. To validate previously published machine learning algorithms using convolutional neural networks (CNNs) and determine if pathological heterogeneity may alter algorithm derived measures, 40 cases from the Goizueta Emory Alzheimer's Disease Center brain bank displaying an array of pathological diagnoses (including AD with and without Lewy body disease (LBD), and / or TDP-43-positive inclusions) and levels of Aβ pathologies were evaluated. Furthermore, to provide deeper phenotyping, amyloid burden in gray matter vs whole tissue were compared, and quantitative CNN scores for both correlated significantly to CERAD-like scores. Quantitative scores also show clear stratification based on AD pathologies with or without additional diagnoses (including LBD and TDP-43 inclusions) vs cases with no significant neurodegeneration (control cases) as well as NIA Reagan scoring criteria. Specifically, the concomitant diagnosis group of AD + TDP-43 showed significantly greater CNN-score for cored plaques than the AD group. Finally, we report that whole tissue computational scores correlate better with CERAD-like categories than focusing on computational scores from a field of view with densest pathology, which is the standard of practice in neuropathological assessment per CERAD guidelines. Together these findings validate and expand CNN models to be robust to cohort variations and provide additional proof-of-concept for future studies to incorporate machine learning algorithms into neuropathological practice.


New oral anticoagulants in development.
Although currently available anticoagulants are effective for the prevention and treatment of thromboembolic disorders, they have several drawbacks. Low-molecular-weight heparins and fondaparinux produce a predictable level of anticoagulation that obviates the need for coagulation monitoring, but they must be given parenterally, which renders them inconvenient for long-term use. Vitamin K antagonists, such as warfarin, are administered orally, but produce a variable anticoagulant response because genetic polymorphisms, dietary vitamin K intake and multiple drug-drug interactions affect their metabolism. Consequently, coagulation monitoring and frequent dose adjustments are needed to ensure that a therapeutic level of anticoagulation is achieved. This is burdensome for patients and physicians, and costly for the healthcare system. These limitations have prompted the development of new oral anticoagulants that target thrombin or factor Xa and can be given in fixed doses without coagulation monitoring. This paper focuses on the new oral anticoagulants in the most advanced stages of development.


T cell responses to cytomegalovirus.
Human cytomegalovirus (HCMV) establishes a latent infection that generally remains asymptomatic in immune-competent hosts for decades but can cause serious illness in immune-compromised individuals. The long-term control of CMV requires considerable effort from the host immune system and has a lasting impact on the profile of the immune system. One hallmark of CMV infection is the maintenance of large populations of CMV-specific memory CD8(+) T cells - a phenomenon termed memory inflation - and emerging data suggest that memory inflation is associated with impaired immunity in the elderly. In this Review, we discuss the molecular triggers that promote memory inflation, the idea that memory inflation could be considered a natural pathway of T cell maturation that could be harnessed in vaccination, and the broader implications of CMV infection and the T cell responses it elicits.


Lesion mapping of cognitive control and value-based decision making in the prefrontal cortex.
A considerable body of previous research on the prefrontal cortex (PFC) has helped characterize the regional specificity of various cognitive functions, such as cognitive control and decision making. Here we provide definitive findings on this topic, using a neuropsychological approach that takes advantage of a unique dataset accrued over several decades. We applied voxel-based lesion-symptom mapping in 344 individuals with focal lesions (165 involving the PFC) who had been tested on a comprehensive battery of neuropsychological tasks. Two distinct functional-anatomical networks were revealed within the PFC: one associated with cognitive control (response inhibition, conflict monitoring, and switching), which included the dorsolateral prefrontal cortex and anterior cingulate cortex and a second associated with value-based decision-making, which included the orbitofrontal, ventromedial, and frontopolar cortex. Furthermore, cognitive control tasks shared a common performance factor related to set shifting that was linked to the rostral anterior cingulate cortex. By contrast, regions in the ventral PFC were required for decision-making. These findings provide detailed causal evidence for a remarkable functional-anatomical specificity in the human PFC.


Genetic counseling and cardiac care in predictively tested hypertrophic cardiomyopathy mutation carriers: the patients' perspective.
Hypertrophic cardiomyopathy (HCM) is a common hereditary heart disease associated with sudden cardiac death. Predictive genetic counseling and testing are performed using adapted Huntington guidelines, that is, psychosocial care and time for reflection are not obligatory and the test result can be disclosed by telephone or mail. Proven mutation carriers detected by predictive DNA testing are advised to undergo regular cardiac follow-up according to international guidelines. We evaluated the opinion of 143 predictively tested HCM mutation carriers on received cardiogenetic care using questionnaires (response rate 86%). Predictive genetic counseling and DNA testing were evaluated on four domains: information provision, satisfaction with counseling, social pressure in DNA testing and regret of DNA testing. Opinions on cardiac follow-up were assessed pertaining to communication, nervous anticipation, reassurance, and general disadvantages. Genetic counseling was valued positively and only four carriers would rather not have known that they were a mutation carrier. A majority received their DNA test result by mail or telephone, and almost all were satisfied. Only 76% of carriers received regular cardiac follow-up. Those who did, had a positive attitude regarding the cardiac visits. General disadvantages of the visits were valued as low, especially by older carriers, men and carriers with manifest HCM. We conclude that our adapted Huntington guidelines are well accepted and that cardiogenetic care is generally appreciated by predictively tested HCM mutation carriers. To better understand the cause of the substantial portion of mutation carriers not receiving regular cardiac follow-up, although recommended in international guidelines, further research is needed.


The Ca2+-activated Cl- channel ANO1/TMEM16A regulates primary ciliogenesis.
Many cells possess a single, nonmotile, primary cilium highly enriched in receptors and sensory transduction machinery that plays crucial roles in cellular morphogenesis. Although sensory transduction requires ion channels, relatively little is known about ion channels in the primary cilium (with the exception of TRPP2). Here we show that the Ca(2+)-activated Cl ((-)) channel anoctamin-1 (ANO1/TMEM16A) is located in the primary cilium and that blocking its channel function pharmacologically or knocking it down with short hairpin RNA interferes with ciliogenesis. Before ciliogenesis, the channel becomes organized into a torus-shaped structure ("the nimbus") enriched in proteins required for ciliogenesis, including the small GTPases Cdc42 and Arl13b and the exocyst complex component Sec6. The nimbus excludes F-actin and coincides with a ring of acetylated microtubules. The nimbus appears to form before, or independent of, apical docking of the mother centriole. Our data support a model in which the nimbus provides a scaffold for staging of ciliary components for assembly very early in ciliogenesis and chloride transport by ANO1/TMEM16A is required for the genesis or maintenance of primary cilia.


Sedentary Behavior Is Only Marginally Associated with Physical Function in Adults Aged 40-75 Years-the Maastricht Study.
Background: In an aging population, regular physical activity (PA) and exercise have been recognized as important factors in maintaining physical function and thereby preventing loss of independence and disability. However, (older) adults spent the majority of their day sedentary and therefore insight into the consequences of sedentary behavior on physical function, independent of PA, is warranted. Objective: To examine the associations of objectively measured sedentary time (ST), patterns of sedentary behavior, overall PA, and higher intensity PA (HPA) with objective measures of physical function. Methods: This is a cross-sectional study in 1,932 men and women (aged 40-75 years) participating in The Maastricht Study. The activPAL3 was used to assess daily sedentary behavior: ST (h), sedentary breaks (n), prolonged (≥30 min) sedentary bouts (n), and to assess time spent in (H)PA (h). Measures of physical function included: covered distance during a 6 min walk test [6MWD (meters)], timed chair rise stand test performance [TCSTtime (seconds)], grip strength (kg kg-1), and elbow flexion and knee extension strength (Nm kg-1). Linear regression analyses were used to examine associations between daily sedentary behavior and PA with physical function. Results: Every additional hour ST was associated with shorter 6MWD [B = -2.69 m (95% CI = -4.69; -0.69)] and lower relative elbow extension strength (B = -0.01 Nm kg-1 (-0.02; 0.00). More sedentary breaks were associated with faster TCSTtime: B = -0.55 s (-0.85; -0.26). Longer average sedentary bout duration was associated with slower TCSTtime [B = 0.17 s (0.09; 0.25)] and lower knee extension strength [B = -0.01 Nm kg-1 (-0.02; 0.00)]. Every hour of PA and HPA were associated with greater 6MWD [BPA = 15.88 m (9.87; 21.89), BHPA = 40.72 m (30.18; 51.25)], faster TCSTtime [BPA = -0.55 s (-1.03; -0.07), BHPA = -2.25 s (-3.09; -1.41)], greater elbow flexion strength [BPA = 0.03 Nm kg-1 (0.01; 0.07)], [BHPA = 0.05 Nm kg-1 (0.01; 0.08)], and greater knee extension strength [BPA = 0.04 Nm kg-1 (0.01; 0.07)], [BHPA = 0.13 Nm kg-1 (0.06; 0.20)]. Conclusion: In adults aged 40-75 years, sedentary behavior appeared to be marginally associated with lower physical function, independent of HPA. This suggests that merely reducing sedentary behavior is insufficient to improve/maintain physical function. In contrast, engaging regularly in PA, in particular HPA, is important for physical function.


Scoliosis and Chiari malformation Type I in children.
The identification of Chiari malformations Type I (CM-Is) has increased in recent years, commonly during MR imaging for evaluation of a possible cause of scoliosis. The treatment of this abnormality remains controversial, and the expected success of treatment is unclear. The goal of the present study is to evaluate the effects of a craniotomy for CM-I decompression on scoliosis in children and adolescents. The authors conducted a 10-year retrospective review of pediatric patients who were found to have a CM-I during evaluation for scoliosis. Seventy-nine patients were identified, ranging in age from 6 months to 18 years (median 12 years). There were 42 girls (54%) and 37 boys (46%). All were noted on MR imaging to have hydrosyringomyelia of the spinal cord. Forty-nine patients had curvatures less than 20° prior to treatment. The other 30 patients had curves ranging from 25° to 80° and underwent orthopedic follow-up and treatment. None of these patients were referred for specific neurological complaints, but 12 (16%) had neurological signs on physical examination. All were treated with a craniocervical decompression in a standard fashion. Follow-up ranged from 6 to 93 months with a median of 35 months. Magnetic resonance images obtained at 6 months postoperatively and serial standing anteroposterior spine radiographs were used to evaluate outcomes. On the MR images obtained 6 months postoperatively, 70 patients (89%) had a significant reduction in the syrinx with an associated ascent of the cerebellar tonsils. Persistent large syringes were treated with reoperation in 6 patients, and shunts were inserted for hydrocephalus in 2 patients. None of the 49 patients with curves less than 20° had progression of their curvature postoperatively. Of the 30 patients with curves greater than 25°, 9 had no change in the scoliosis or had a reduction in curve magnitude after Chiari decompression. This group required no further therapy and was effectively treated by Chiari decompression alone. Twenty-one patients required further scoliosis treatment after Chiari decompression; 12 required orthotic treatment, 11 received spinal instrumentation and fusion surgery, and 2 received orthoses followed by fusion and instrumentation. The severity of the curvature beyond 20° did not predict the need for spinal surgery. This large series reports on the efficacy of treatment for scoliosis associated with a CM-I and syrinx in children. A CM-I decompression alone was adequate treatment for mild scoliosis of less than 20°. Patients with scoliosis greater than 20° required bracing and/or spinal fusion surgery 70% of the time in addition to the CM-I decompression.


The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature.
Germline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We review clinical and molecular data on WWOX-related disorders, further describing WOREE syndrome and phenotype/genotype correlations. We report clinical and molecular findings in 20 additional patients from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants in the WWOX gene. Different molecular screening approaches were used (quantitative polymerase chain reaction/multiplex ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome sequencing), genome sequencing. Two copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families. Eight novel missense pathogenic variants have been described. By aggregating our patients with all cases reported in the literature, 37 patients from 27 families with WOREE syndrome are known. This review suggests WOREE syndrome is a very severe epileptic encephalopathy characterized by absence of language development and acquisition of walking, early-onset drug-resistant seizures, ophthalmological involvement, and a high likelihood of premature death. The most severe clinical presentation seems to be associated with null genotypes. Germline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic encephalopathy. We report here the largest cohort of individuals with WOREE syndrome.


Inhibition of retinoic acid signaling induces aberrant pericyte coverage and differentiation resulting in vascular defects in congenital diaphragmatic hernia.
The mortality and morbidity of patients with congenital diaphragmatic hernia (CDH) is primarily caused by treatment-resistant, persistent pulmonary hypertension. Structural vascular changes, exemplified by extensive muscularization, are already present early in gestation, but the origin of these abnormalities is unknown. Understanding the origin of the vascular defects is important to improve treatment modalities. Here, we show that the distribution of pericytes is different and may thereby potentially initiate the vascular pathology in CDH. Transient inhibition of retinoic acid (RA) signaling early during pregnancy, the basis of the CDH mouse model, led to an increase in the number of pericytes, thereby affecting the angiogenic potential of pericytes in the fetuses. Pericytes of CDH lungs showed reduced proliferation and an increased ACTA2 expression, which indicates that these pericytes are more contractile than in control lung pericytes. This resulted in increased pericyte coverage of pulmonary vessels and reduced expansion of the capillary bed, the earliest pathological sign of the structural changes in CDH. Furthermore, the pericytes had reduced and altered collagen IV deposition in CDH, pointing to a loss of basal membrane integrity between pericytes and endothelial cells. Inhibition of RA signaling in vitro resulted in reduced migration of pericytes, reduced angiogenesis, and loss of collagen IV expression. Importantly, we confirmed our findings in lungs of human CDH patient samples. In summary, inhibition of RA signaling affects the lung pericyte population, leading to increased contractility, reduced pulmonary angiogenesis, and aberrant lung development, as observed in CDH.


Impact of insertion sequences on convergent evolution of Shigella species.
Shigella species are specialised lineages of Escherichia coli that have converged to become human-adapted and cause dysentery by invading human gut epithelial cells. Most studies of Shigella evolution have been restricted to comparisons of single representatives of each species; and population genomic studies of individual Shigella species have focused on genomic variation caused by single nucleotide variants and ignored the contribution of insertion sequences (IS) which are highly prevalent in Shigella genomes. Here, we investigate the distribution and evolutionary dynamics of IS within populations of Shigella dysenteriae Sd1, Shigella sonnei and Shigella flexneri. We find that five IS (IS1, IS2, IS4, IS600 and IS911) have undergone expansion in all Shigella species, creating substantial strain-to-strain variation within each population and contributing to convergent patterns of functional gene loss within and between species. We find that IS expansion and genome degradation are most advanced in S. dysenteriae and least advanced in S. sonnei; and using genome-scale models of metabolism we show that Shigella species display convergent loss of core E. coli metabolic capabilities, with S. sonnei and S. flexneri following a similar trajectory of metabolic streamlining to that of S. dysenteriae. This study highlights the importance of IS to the evolution of Shigella and provides a framework for the investigation of IS dynamics and metabolic reduction in other bacterial species.


Sequestration of extracellular hemoglobin within a haptoglobin complex decreases its hypertensive and oxidative effects in dogs and guinea pigs.
Release of hemoglobin (Hb) into the circulation is a central pathophysiologic event that contributes to morbidity and mortality in chronic hemolytic anemias and severe malaria. These toxicities arise from Hb-mediated vasoactivity, possibly due to NO scavenging and localized tissue oxidative processes. Currently, there is no established treatment that targets circulating extracellular Hb. Here, we assessed the role of haptoglobin (Hp), the primary scavenger of Hb in the circulation, in limiting the toxicity of cell-free Hb infusion. Using a canine model, we found that glucocorticoid stimulation of endogenous Hp synthesis prevented Hb-induced hemodynamic responses. Furthermore, guinea pigs administered exogenous Hp displayed decreased Hb-induced hypertension and oxidative toxicity to extravascular environments, such as the proximal tubules of the kidney. The ability of Hp to both attenuate hypertensive responses during Hb exposure and prevent peroxidative toxicity in extravascular compartments was dependent on Hb-Hp complex formation, which likely acts through sequestration of Hb rather than modulation of its NO- and O2-binding characteristics. Our data therefore suggest that therapies involving supplementation of endogenous Hb scavengers may be able to treat complications of acute and chronic hemolysis, as well as counter the adverse effects associated with Hb-based oxygen therapeutics.


Automated Internet-based pain coping skills training to manage osteoarthritis pain: a randomized controlled trial.
Osteoarthritis (OA) places a significant burden on worldwide public health because of the large and growing number of people affected by OA and its associated pain and disability. Pain coping skills training (PCST) is an evidence-based intervention targeting OA pain and disability. To reduce barriers that currently limit access to PCST, we developed an 8-week, automated, Internet-based PCST program called PainCOACH and evaluated its potential efficacy and acceptability in a small-scale, 2-arm randomized controlled feasibility trial. Participants were 113 men and women with clinically confirmed hip or knee OA and associated pain. They were randomized to a group completing PainCOACH or an assessment-only control group. Osteoarthritis pain, pain-related interference with functioning, pain-related anxiety, self-efficacy for pain management, and positive and negative affect were measured before intervention, midway through the intervention, and after intervention. Findings indicated high acceptability and adherence: 91% of participants randomized to complete PainCOACH finished all 8 modules over 8 to 10 weeks. Linear mixed models showed that, after treatment, women who received the PainCOACH intervention reported significantly lower pain than that in women in the control group (Cohen d = 0.33). Intervention effects could not be tested in men because of their low pain and small sample size. Additionally, both men and women demonstrated increases in self-efficacy from baseline to after intervention compared with the control group (d = 0.43). Smaller effects were observed for pain-related anxiety (d = 0.20), pain-related interference with functioning (d = 0.13), negative affect (d = 0.10), and positive affect (d = 0.24). Findings underscore the value of continuing to develop an automated Internet-based approach to disseminate this empirically supported intervention.


The programming of sequences of saccades.
Saccadic eye movements move the high-resolution fovea to point at regions of interest. Saccades can only be generated serially (i.e., one at a time). However, what remains unclear is the extent to which saccades are programmed in parallel (i.e., a series of such moments can be planned together) and how far ahead such planning occurs. In the current experiment, we investigate this issue with a saccade contingent preview paradigm. Participants were asked to execute saccadic eye movements in response to seven small circles presented on a screen. The extent to which participants were given prior information about target locations was varied on a trial-by-trial basis: participants were aware of the location of the next target only, the next three, five, or all seven targets. The addition of new targets to the display was made during the saccade to the next target in the sequence. The overall time taken to complete the sequence was decreased as more targets were available up to all seven targets. This was a result of a reduction in the number of saccades being executed and a reduction in their saccade latencies. Surprisingly, these results suggest that, when faced with a demand to saccade to a large number of target locations, saccade preparation about all target locations is carried out in parallel.


Effects of growth factors and interleukin-1 alpha on proteoglycan and type II collagen turnover in bovine nasal and articular chondrocyte pellet cultures.
The aim of this study was to investigate the effects of insulin-like growth factor-I, transforming growth factor-beta (TGF-beta), and interluekin-1 alpha (IL-1 alpha) on the deposition and degradation of a cartilage-like matrix in high-density pellet cultures of adult bovine chondrocytes. Proteoglycan was determined by toluidine blue staining and colorimetric assay. Type II collagen was determined by immunohistochemical staining and its unwinding in situ by a recently developed immunoassay. Bovine nasal chondrocytes cultured as pellets deposited a well-organized extracellular matrix of proteoglycan and type II collagen. Insulin-like growth factor-I (2-10 ng/ml) increased the synthesis and incorporation into the matrix of both these proteins. TGF-beta (2-10 ng/ml) also increased proteoglycan synthesis. However it inhibited proteoglycan deposition, presumably through increased degradation of the molecule, as shown by increased release of aggrecan fragments into the tissue culture medium. TGF-beta had no effect on type II collagen deposition. In pellet cultures of bovine nasal or articular chondrocytes, 20 ng/ml IL-1 alpha induced a significant degradation of both proteoglycan and type II collagen. The effect on collagen clearly involved proteolytic cleavage of its triple helix because there was an increase in the proportion of unwound type II collagen in the matrix, as well as a loss of total type II collagen. In explant cultures of intact bovine articular cartilage, incubation with 50 ng/ml IL-1 alpha stimulated significant degradation of the proteoglycan but no degradation of the type II collagen. These results demonstrate that although the articular chondrocytes are capable of degrading type II collagen when isolated, they do not do so in situ, presumably because of some inherent property of the mature extracellular matrix. This study demonstrates the utility of pellet cultures when investigating chondrocyte-mediated turnover of cartilage matrix and its modulation by cytokines and growth factors.


Ethical analysis of withdrawing ventricular assist device support.
To describe a series of patients with heart failure supported with a ventricular assist device (VAD) who requested (or whose surrogates requested) withdrawal of VAD support and the legal and ethical aspects pertaining to these requests. We retrospectively reviewed the medical records of patients at Mayo Clinic, Rochester, MN, from March 1, 2003, through January 31, 2009, who requested (or whose surrogates requested) withdrawal of VAD support and for whom the requests were fulfilled. We then explored the legal and ethical permissibility of carrying out such requests. The median age of the 14 patients identified (13 men, 1 woman) was 57 years. Requests were made by 2 patients and 12 surrogates. None of the patients' available advance directives mentioned the VAD. For 11 patients, multidisciplinary care conferences were held before withdrawal of VAD support. Only 1 patient had an ethics consultation. All 14 patients died within 1 day of withdrawal of VAD support. Patients have the right to refuse or request the withdrawal of any unwanted treatment, and we argue that this right extends to VAD support. We also argue that the cause of death in these cases is the underlying heart disease, not assisted suicide or euthanasia. Therefore, patients with heart failure supported with VADs or their surrogates may request withdrawal of this treatment. In our view, carrying out such requests is permissible in accordance with the principles that apply to withdrawing other life-sustaining treatments.


Distant Position of Chordae from Coaptation Causes Mitral Regurgitation in Patients with Atrial Fibrillation.
The study aim was to investigate the mechanism of mitral regurgitation (MR) in lone atrial fibrillation (AF) patients using three-dimensional (3D) transesophageal echocardiography (TEE). A retrospective analysis was conducted of 64 patients with AF and a normal left ventricle, and without prolapse of the mitral valve. Among these patients, significant MR was not identified in 33 cases (AF+MR- group) but was present in 31 cases (AF+MR+ group). The distance from the coaptation to the bending point of the anterior mitral leaflet (AML), where the chorda was attached, was termed the 'bending length'. The ratio of the bending length to the distance from coaptation to anterior mitral annulus was termed the 'bending ratio' (= bending length/coaptation-annulus length). The mitral annular area (MAA) fractional change was defined as follows: (MAA at late systole - MAA at early systole)/MAA at late systole × 100%). Other parameters relating to mitral valve morphology obtained using 3D TEE were measured with commercial software (QLAB, Phillips). The coaptation length (CL) was smaller in the AF+MR+ group than in the AF+MR- group (p<0.001), and correlated significantly with the anteriorposterior diameter of the mitral annulus (R = 0.286, p = -0.022), MAA at mid-systole (R = -0.269, p = 0.032), MAA fractional change (R = 0.434, p <0.001), and the bending ratio (R = -0.603, p <0.001). With a multivariable analysis, the correlating factors of significant MR in lone AF patients were a decrease in MAA fractional change (p = 0.022) and an increase of the bending ratio (p = 0.009). Small MAA fractional changes and the distant position of the chordae tendineae on the AML from the coaptation correlated with significant MR in AF patients with normal left ventricular systolic function.


Self-referenced spectroscopy using plasmon waveguide resonance biosensor.
A plasmon waveguide resonance (PWR) sensor is designed, fabricated, and tested for self-referenced biosensing. The PWR sensor is able to support two different polarizations, TM and TE. The TM polarization has a large sensitivity to variations in the background refractive index while the TE polarization is more sensitive to the surface properties. The ability of the PWR sensor to simultaneously operate in both TM and TE modes is used to decouple the background index variations (bulk effects) from the changes in adlayer thickness (surface effects) via multimode spectroscopy. To benchmark the performance of the PWR, a conventional surface plasmon resonance (SPR) sensor is fabricated and tested under the same conditions.


Interventional management of central vein occlusion in patients with peripherally inserted central catheter placement.
This study evaluated the incidence of central vein occlusion (CVO) and analyzed the interventional management for CVO during peripherally inserted central catheter (PICC) placement to suggest an adequate management protocol to ensure the success and patency of PICCs. We retrospectively reviewed the records of 2568 PICCs to identify CVO in two medical centers between January 2016 and June 2017. Procedural images were reviewed for the following items: date and indication for the PICC; type of catheter; accessed vein and arm; characteristics of CVO on ascending arm venography; PICC placement technique; indwelling period of the PICC; and follow-up records. A guidewire passage trial was performed to the CVO, as follows: a trial with a 0.018-inch single or double guidewire through the pretrimmed PICC lumen; and a trial with a combination of a 0.035-inch guidewire and a curved 5F diagnostic catheter through the PICC introducer sheath. The incidence of CVO was 3.2% (71/2232), and 59 patients were analyzed (23 men; mean age, 69 ± 11 years; median age, 80 years; age range, 31-92 years). Forty-four patients had thrombotic CVO, and 12 patients had acute thrombotic CVO. Thirty-six patients had occlusion of the left innominate vein, and six patients had contiguous involvement of the adjacent central vein. Forty-two patients had obtuse stump morphology of CVO, and 28 patients had grade >III collateral development. The PICC indwelling time was statistically different between the group with successful catheter advancement (n = 36, success group) and the group with failed catheter advancement (n = 18, failure group; P = .007) with ipsilateral trimmed PICCs. Eight patients had a symptomatic catheter associated with upper extremity deep venous thrombosis (UEDVT; <30 days), one in the success group and seven in the failure group. The incidence of catheter-associated UEDVT after primary PICC placement on each arm was statistically different between the success and failure groups (P = .004). A PICC passage trial for ipsilateral CVO is challenging but frequently successful with a simple guidewire technique, which can preserve catheter patency, decrease contralateral arm access, and prevent the development of new catheter-associated UEDVT.


Recombinant activated coagulation factor VII and bleeding trauma patients.
Recombinant activated coagulation factor VII (rFVIIa) is increasingly being administered to massively bleeding trauma patients. rFVIIa has been shown to correct coagulopathy and to decrease transfusion requirements. However, there is no conclusive evidence to suggest that rFVIIa improves the survival of these patients. The purpose of this study was to determine whether or not rFVIIa has an effect on the in-hospital survival of massively bleeding trauma patients. A retrospective cohort study was conducted from January 1, 2000 to January 31, 2005, at a Level I trauma center in Toronto, Canada. Inclusion criteria included trauma patients requiring transfusion of 8 or more units of packed red cells within the first 12 hours of admission. The primary exposure of interest was the administration of rFVIIa. Primary outcome was a 24-hour survival and secondary outcome was overall in-hospital survival. There were 242 trauma patients identified who met inclusion criteria; 38 received rFVIIa. rFVIIa patients were younger, had more penetrating injuries, and fewer head injuries. However, rFVIIa patients required more red cell transfusions initially, and were more acidotic. Administering rFVIIa was associated with improved 24-hour survival, after adjusting for baseline demographics and injury factors. The odds ratio (OR) for survival was 3.4 (1.2-9.8). Furthermore, there was a strong trend toward increased overall in-hospital survival. The OR of in-hospital survival was 2.5 (0.8-7.6). Also, subgroup analysis of rFVIIa patients showed that 24-hour survivors required a slower initial rate of red cell transfusion (4.5 vs. 2.9 units/hr, p = 0.002), had higher platelet counts (175 vs. 121 [x10(-9)/L], p = 0.05) and smaller base deficits (7.1 vs. 14.3, p = 0.001) compared with rFVIIa patients who died during the first 24 hours. rFVIIa may be able to improve the early survival of massively bleeding trauma patients. However, surgical control of massive hemorrhage still has primacy, as rFVIIa did not appear efficacious if extremely high red cell transfusion rates were required. Also, correction of acidosis and thrombocytopenia may be important for rFVIIa efficacy. Prospective studies are required.


The possible protective role of pumpkin seed oil in an animal model of acid aspiration pneumonia: Light and electron microscopic study.
Aspiration pneumonitis is a common problem occurring in many clinical disorders. Pumpkin seed oil (PO) is a rich source of antioxidants. This work aimed to assess the effect of PO on the lung histopathological changes induced by acid aspiration. Forty male albino rats assigned to four groups were used. Rats of control group were instilled intratracheally with normal saline 2mL/kg. HCL group instilled with 2mL/kg of HCL 0.1N, pH 1.25. PO group received pumpkin seed oil (PO) orally (∼1375mg/kgbw/day) for 7days. HCL+PO group instilled with 2mL/kg of HCL 0.1N, pH 1.25 and received PO at the same dose of PO group. Lung tissue samples were processed for light, electron microscopic and immunohistochemical study using anti inducible NO synthase (iNOS). The lung of HCL group demonstrated thickened interalveolar septa, inflammatory cell infiltration and significant increase in the area percent of collagenous fibers and immune expression of iNOS. Ultra structurally, disrupted alveolocapillay membrane, degenerated type II pneumocytes and plentiful alveolar macrophages were evident. PO administration partially attenuated these histological and ultra structural alterations and reduced iNOS immune-expression in lung tissue. In conclusion, PO has a protective effect against HCL aspiration lung injury most probably through its antioxidant activity.


Replication of wild-type and mutant clones of satellite tobacco mosaic virus in Nicotiana benthamiana protoplasts.
RNA transcribed from cloned satellite tobacco mosaic virus (STMV) cDNA replicated in Nicotiana benthamiana protoplasts when co-inoculated with tobacco mild green mosaic virus (TMGMV) genomic RNA, but degraded when inoculated alone. STMV genomic RNA extracted from wild-type virions replicated in protoplasts when co-inoculated with TMGMV, tobacco mosaic virus (TMV) or tomato mosaic virus (ToMV). Transcripts from clones of two STMV coat protein (CP) mutants accumulated to the same level as wild-type transcripts in protoplasts when co-inoculated with TMGMV, whereas a third mutant accumulated to detectable levels in some, but not all, experiments. These results confirm that STMV RNA requires helper virus for replication, and that the helper specificity exhibited by cloned STMV reflects a specific requirement for the TMGMV replicase. It also demonstrates that the low accumulation of STMV CP mutants observed previously in whole plants cannot be attributed to inefficient RNA replication.


Are hydrophobins and/or non-specific lipid transfer proteins responsible for gushing in beer? New hypotheses on the chemical nature of gushing inducing factors.
Gushing of beer is characterised by the fact that immediately after opening a bottle a great number of fine bubbles are created throughout the volume of beer and ascend quickly under foam formation, which flows out of the bottle. This infuriating gushing phenomenon has been, and still is, a problem of world-wide importance to the brewing industry. It is generally assumed that the causes of malt-derived gushing are due to the use of "weathered" barley or wheat and the growth of moulds in the field, during storage and malting. We now develop a hypothesis connecting several lines of evidence from different laboratories. These results indicate that the fungal hydrophobins, hydrophobic components of conidiospores or aerial mycelia, are gushing-inducing factors. Furthermore, increased formation of ns-LTPs (non-specific lipid transfer proteins), synthesised in grains as response to fungal infection, and their modification during the brewing process may be responsible for malt-derived gushing.


[Paradoxical effects of thiol compounds].
Thiols act as universal antimutagens and their use is promising in the treatment of free radical diseases whose list is presented in the paper. Yet it is necessary to take into account the specific features of their action, including a paradoxical effects. The latter has different manifestations and causes: production of mutagenic products (H2O2, radicals of thiols, mutagenic conjunctives-derivatives with xenobiotics), which results in the maximum phenomenon-elimination of susceptible individuals and cells, carriers of mutations or mutant cells themselves; the allele saving effect and, presumably, the diverse action of thiols on the package of characteristics of free radical diseases. There are characteristics which enter the package, involving chromosomal instability; hypersensitivity to certain mutants; DNA repair defect or deficiency; abnormalities of the systems acting before DNA-mutagen interaction; deficiency of antimutagens; immunodeficiency; increased lipid peroxidation, production of clastogenic factor(s).


Phosphorus in antique iron music wire.
Harpsichords and other wire-strung musical instruments were made with longer strings about the beginning of the 17th century. This change required stronger music wire. Although these changes coincided with the introduction of the first mass-produced steel (iron alloyed with carbon), carbon was not found in samples of antique iron harpsichord wire. The wire contained an amount of phosphorus sufficient to have impeded its conversion to steel, and may have been drawn from iron rejected for this purpose. The method used to select pig iron for wire drawing ensured the highest possible phosphorus content at a time when its presence in iron was unsuspected. Phosphorus as an alloying element has had the reputation for making steel brittle when worked cold. Nevertheless, in replicating the antique wire, it was found that lowcarbon iron that contained 0.16 percent phosphorus was easily drawn to appropriate gauges and strengths for restringing antique harpsichords.