Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease.
Pulmonary rehabilitation has become a cornerstone in the management of patients with stable Chronic Obstructive Pulmonary Disease (COPD). Systematic reviews have shown large and important clinical effects of pulmonary rehabilitation in these patients. In unstable COPD patients who have suffered from an exacerbation recently, however, the effects of pulmonary rehabilitation are less established. To assess the effects of pulmonary rehabilitation after COPD exacerbations on future hospital admissions (primary outcome) and other patient-important outcomes (mortality, health-related quality of life and exercise capacity). Trials were identified from searches of CENTRAL, MEDLINE, EMBASE, PEDRO and the Cochrane Central Register of Controlled Trials. Searches were current as of July 2008. Randomized controlled trials comparing pulmonary rehabilitation of any duration after exacerbation of COPD with conventional care. Pulmonary rehabilitation programmes needed to include at least physical exercise. Control groups received conventional community care without rehabilitation. We calculated pooled odds ratios and weighted mean differences (WMD) using fixed-effects models. We requested missing data from the authors of the primary studies. We identified six trials including 219 patients. Pulmonary rehabilitation significantly reduced hospital admissions (pooled odds ratio 0.13 [95% CI 0.04 to 0.35], number needed to treat (NNT) 3 [95% CI 2 to 4], over 34 weeks) and mortality (pooled odds ratio 0.29 [95% CI 0.10 to 0.84], NNT 6 [95% CI 5 to 30] over 107 weeks). Effects of pulmonary rehabilitation on health-related quality of life were well above the minimal important difference (weighted mean differences for dyspnea, fatigue, emotional function and mastery domains of the Chronic Respiratory Questionnaire between 1.15 (95% CI: 0.94, 1.36) and 1.88 (95% CI:1.67, 2.09) and between -9.9 (95% CI:-18.05, -1.73) and -17.1 (95% CI: -23.55, -10.68) for total, impact and activity limitation domains of the St. Georges Respiratory Questionnaire). In all trials, pulmonary rehabilitation improved exercise capacity (60-215 meters in six-minute or shuttle walk tests). No adverse events were reported (two studies). Evidence from small studies of moderate methodological quality suggests that pulmonary rehabilitation is a highly effective and safe intervention to reduce hospital admissions and mortality and to improve health-related quality of life in COPD patients after suffering an exacerbation.


MPYS is required for IFN response factor 3 activation and type I IFN production in the response of cultured phagocytes to bacterial second messengers cyclic-di-AMP and cyclic-di-GMP.
Cyclic-di-GMP and cyclic-di-AMP are second messengers produced by bacteria and influence bacterial cell survival, differentiation, colonization, biofilm formation, virulence, and bacteria-host interactions. In this study, we show that in both RAW264.7 macrophage cells and primary bone marrow-derived macrophages, the production of IFN-β and IL-6, but not TNF, in response to cyclic-di-AMP and cyclic-di-GMP requires MPYS (also known as STING, MITA, and TMEM173). Furthermore, expression of MPYS was required for IFN response factor 3 but not NF-κB activation in response to these bacterial metabolites. We also confirm that MPYS is required for type I IFN production by cultured macrophages infected with the intracellular pathogens Listeria monocytogenes and Francisella tularensis. However, during systemic infection with either pathogen, MPYS deficiency did not impact bacterial burdens in infected spleens. Serum IFN-β and IL-6 concentrations in the infected control and MPYS(-/-) mice were also similar at 24 h postinfection, suggesting that these pathogens stimulate MPYS-independent cytokine production during in vivo infection. Our findings indicate that bifurcating MPYS-dependent and -independent pathways mediate sensing of cytosolic bacterial infections.


Precision, accuracy, and range of perceived achromatic transparency.
How accurately do human observers perceive the properties of an achromatic transparent filter with both reflective and transmissive components? To address this question, a novel six-luminance stimulus was employed, consisting of three transparent layer luminances set against three background luminances, which satisfied the conventional constraints of perceptual transparency. In one experiment, subjects adjusted one of the three layer luminances to complete the impression of a uniform transparent disk. It was found that the luminance-based formulation of Metelli's episcotister model and a model based on ratios of Michelson contrasts best predicted the subjects' settings, which were both accurate and precise. In another experiment, pairs of stimuli selected from a range with various values of the adjustable layer luminance were presented in a series of forced-choice trials. A modified implementation of the pair comparisons method was employed to recover the distribution that describes each subject's preference pattern. Results showed that there exists a reasonably wide range of stimuli that give rise to at least some degree of perceived transparency.


Quinones as electron acceptors. X-ray structures, spectral (EPR, UV-vis) characteristics and electron-transfer reactivities of their reduced anion radicals as separated vs contact ion pairs.
Successful isolation of a series of pure (crystalline) salts of labile quinone anion radicals suitable for X-ray crystallographic analysis allows for the first time their rigorous structural distinction as "separated" ion pairs (SIPs) vs "contact" ion pairs (CIPs). The quantitative evaluation of the precise changes in the geometries of these quinones (Q) upon one-electron reduction to afford the anion radical (Q-*) is viewed relative to the corresponding (two-electron) reduction to the hydroquinone (H2Q) via the Pauling bond-length/bond-order paradigm. Structural consequences between such separated and contact ion pairs as defined in the solid state with those extant in solution are explored in the context of their spectral (EPR, UV-vis) properties and isomerization of tightly bound CIPs. Moreover, the SIP/CIP dichotomy is also examined in intermolecular interactions for rapid (self-exchange) electron transfer between Q-* and Q with second-order rate constants of kET approximately equal to 10(8) M-1 s-1, together with the spectral observation of the paramagnetic intermediates [Q,Q-*]leading to 1:1 adducts, as established by X-ray crystallography.


Comparison of two instructions for deep breathing exercise: non-specific and diaphragmatic breathing.
[Purpose] Breathing exercises are frequently prescribed to reduce pulmonary complications after abdominal and thoracic surgery. Appropriate instructions ensuring the integrity of the self-exercise are important. This study compared the effects of two instructions, focusing on non-specific breathing (NB) and diaphragmatic breathing (DB) patterns, respectively, on the ventilatory efficiency and work of breathing. [Subjects and Methods] The participants were healthy men (n=15) and women (n=15). Ventilatory parameters, heart rate, and autonomic nervous system activity were measured during natural and deep breathing phases performed under the two instructions (NB and DB), with the deep breathing phase following the natural breathing phase. [Results] For both men and women, ventilatory efficiency was increased during deep breathing relative to natural breathing, regardless of the instructions. In women, the increment in ventilatory efficiency during deep breathing was greater under NB compared to that under DB. The work of breathing decreased during deep breathing in women under both instructions, but did not change in men under DB. [Conclusion] Under NB instruction, deep breathing elicits similar or greater effects on ventilatory efficiency compared to that under DB instruction.


Coil-Protected Technique for Liquid Embolization in Neurovascular Malformations.
To evaluate the safety and efficacy of the coil-protected technique for liquid embolization in neurovascular malformations. Twenty-two patients who underwent coil-protected liquid embolization for symptomatic cranial (n = 13) and spinal (n = 9) arteriovenous fistula (AVF) or arteriovenous malformations (AVMs) were identified. A total of 36 target feeder vessels were embolized with N-butyl cyanoacrylate and/or Onyx (Medtronic). This technique was used to promote delivery of a sufficient amount of liquid embolic agent into the target shunt or nidus in cases where tortuous feeding arteries preclude a microcatheter wedging techniqu and/or to prevent reflux of the liquid embolic agent in cases with a short safety margin. The procedure was considered technically successful if the target lesion was sufficiently filled with liquid embolic agent without unintentional reflux. Angiographic and clinical outcomes were retrospectively evaluated. Technical success was achieved for all 36 target feeders. Post-embolization angiographies revealed complete occlusion in 16 patients and near-complete and partial occlusion in three patients each. There were no treatment-related complications. Of the six patients who showed near-complete or partial occlusion, five received additional treatments: two received stereotactic radiosurgery for cerebral AVM, two underwent surgical removal of cerebral AVM, and one underwent additional embolization by direct puncture for a mandibular AVM. Finally, all patients showed complete (n = 19) or near-complete (n = 3) occlusion of the target AVF or AVM on follow-up angiographies. The presenting neurological symptoms improved completely in 15 patients (68.2%) and partially in seven patients (31.8%). The coil-protected technique is a safe and effective method for liquid embolization, especially in patients with various neurovascular shunts or malformations who could not be successfully treated with conventional techniques.


Response of cat inferior colliculus neurons to binaural beat stimuli: possible mechanisms for sound localization.
The interaural phase sensitivity of neurons was studied through the use of binaural beat stimuli. The response of most cells was phase-locked to the beat frequency, which provides a possible neural correlate to the human sensation of binaural beats. In addition, this stimulus allowed the direction and rate of interaural phase change to be varied. Some neurons in our sample responded selectively to manipulations of these two variables, which suggests a sensitivity to direction or speed of movement.


LKB1 deletion with the RIP2.Cre transgene modifies pancreatic beta-cell morphology and enhances insulin secretion in vivo.
The tumor suppressor liver kinase B1 (LKB1), also called STK11, is a protein kinase mutated in Peutz-Jeghers syndrome. LKB1 phosphorylates AMP-activated protein kinase (AMPK) and several related protein kinases. Whereas deletion of both catalytic isoforms of AMPK from the pancreatic beta-cell and hypothalamic neurons using the rat insulin promoter (RIP2).Cre transgene (betaAMPKdKO) diminishes insulin secretion in vivo, deletion of LKB1 in the beta-cell with an inducible Pdx-1.CreER transgene enhances insulin secretion in mice. To determine whether the differences between these models reflect genuinely distinct roles for the two kinases in the beta-cell or simply differences in the timing and site(s) of deletion, we have therefore created mice deleted for LKB1 with the RIP2.Cre transgene. In marked contrast to betaAMPKdKO mice, betaLKB1KO mice showed diminished food intake and weight gain, enhanced insulin secretion, unchanged insulin sensitivity, and improved glucose tolerance. In line with the phenotype of Pdx1-CreER mice, total beta-cell mass and the size of individual islets and beta-cells were increased and islet architecture was markedly altered in betaLKB1KO islets. Signaling by mammalian target of rapamycin (mTOR) to eIF4-binding protein-1 and ribosomal S6 kinase was also enhanced. In contrast to Pdx1-CreER-mediated deletion, the expression of Glut2, glucose-induced changes in membrane potential and intracellular Ca(2+) were sharply reduced in betaLKB1KO mouse islets and the stimulation of insulin secretion was modestly inhibited. We conclude that LKB1 and AMPK play distinct roles in the control of insulin secretion and that the timing of LKB1 deletion, and/or its loss from extrapancreatic sites, influences the final impact on beta-cell function.


Site of extranodal metastasis impacts survival in patients with testicular germ cell tumors.
Using a large, nationally representative, population-based cancer registry, this study systematically evaluated the impact of the location and burden of extranodal testicular germ cell tumor (TGCT) metastases on survival. Men with stage III TGCTs captured by the Surveillance, Epidemiology, and End Results registry from 2010 to 2015 with distant extranodal metastases were identified. Clinicopathologic information was collected, and patients were subdivided according to the specific organ site or sites of metastatic involvement (lung, liver, bone, and/or brain). Kaplan-Meier analysis and multivariable Cox regression were used to evaluate cancer-specific survival (CSS), and model performance was assessed with Harrell's C statistic. Nine hundred sixty-nine patients with stage III TGCTs were included with predominantly nonseminomatous histology (84%). Most patients (91%) had pulmonary metastases, whereas 20%, 10%, and 10% had liver, bone, and brain metastases, respectively. Over a median follow-up of 21 months, 19% of these men died of TGCTs. When they were grouped by the primary site of metastasis, patients with more than 1 extrapulmonary metastasis exhibited the worst CSS (hazard ratio [HR] vs isolated pulmonary involvement, 4.27; 95% confidence interval [CI], 2.60-7.00; P < .01). Among patients with isolated extrapulmonary involvement, those with brain metastases had the poorest survival (HR, 3.24; 95% CI, 1.98-5.28; P < .01), and they were followed by patients with liver (HR, 2.29; 95% CI, 1.56-3.35; P < .01) and bone metastases (HR, 1.97; 95% CI, 1.11-3.50; P = .02). Harrell's C statistic (multivariable) was 0.71. The site of metastatic involvement affects survival outcomes for patients with TGCTs, and this may reflect both the aggressive biology and the challenging treatment of these tumors. Further incorporation of organotropism into current prognostic models for metastatic TGCTs warrants attention.


Dietary omega-6 fatty acid replacement selectively impairs cardiac functional recovery after ischemia in female (but not male) rats.
A definitive understanding of the role of dietary lipids in determining cardioprotection (or cardiodetriment) has been elusive. Randomized trial findings have been variable and sex specificity of dietary interventions has not been determined. In this investigation the sex-selective cardiac functional effects of three diets enriched by omega-3 or omega-6 polyunsaturated fatty acids (PUFA) or enriched to an equivalent extent in saturated fatty acid components were examined in rats after an 8-wk treatment period. In females the myocardial membrane omega-6:omega-3 PUFA ratio was twofold higher than males in the omega-6 diet replacement group. In diets specified to be high in omega-3 PUFA or in saturated fat, this sex difference was not apparent. Isolated cardiomyocyte and heart Langendorff perfusion experiments were performed, and molecular measures of cell viability were assessed. Under basal conditions the contractile performance of omega-6 fed female cardiomyocytes and hearts was reduced compared with males. Omega-6 fed females exhibited impaired systolic resilience after ischemic insult. This response was associated with increased postischemia necrotic cell damage evaluated by coronary lactate dehydrogenase during reperfusion in omega-6 fed females. Cardiac and myocyte functional parameters were not different between omega-3 and saturated fat dietary groups and within these groups there were no discernible sex differences. Our data provide evidence at both the cardiac and cardiomyocyte levels that dietary saturated fatty acid intake replacement with an omega-6 (but not omega-3) enriched diet has selective adverse cardiac effect in females. This finding has potential relevance in relation to women, cardiac risk, and dietary management.


Compaction of single DNA molecules induced by binding of integration host factor (IHF).
We studied the interaction between the integration host factor (IHF), a major nucleoid-associated protein in bacteria, and single DNA molecules. Force-extension measurements of lambda DNA and an analysis of the Brownian motion of small beads tethered to a surface by single short DNA molecules, in equilibrium with an IHF solution, indicate that: (i) the DNA-IHF complex retains a random, although more compact, coiled configuration for zero or small values of the tension, (ii) IHF induces DNA compaction by binding to multiple DNA sites with low specificity, and (iii) with increasing tension on the DNA, the elastic properties of bare DNA are recovered. This behavior is consistent with the predictions of a statistical mechanical model describing how proteins bending DNA are driven off by an applied tension on the DNA molecule. Estimates of the amount of bound IHF in DNA-IHF complexes obtained from the model agree very well with independent measurements of this quantity obtained from the analysis of DNA-IHF crosslinking. Our findings support the long-held view that IHF and other histone-like proteins play an important role in shaping the long-scale structure of the bacterial nucleoid.


Neuropsychological sequelae of obstructive sleep apnea-hypopnea syndrome: a critical review.
Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a well-recognized clinical sleep disorder that results in chronically fragmented sleep and recurrent hypoxemia. The primary daytime sequelae of the disorder include patient reports of excessive daytime sleepiness, depression, and attention and concentration problems. It has been well established that OSAHS negatively impacts certain aspects of cognitive functioning. The primary goals of this article are to (1) clarify the pattern of cognitive deficits that are specific to OSAHS; (2) identify the specific cognitive domains that improve with treatment; and (3) elucidate the possible mechanisms of cognitive dysfunction in OSAHS. At the conclusion of the paper, we propose a potential neurofunctional theory to account for the etiology of cognitive deficits in OSAHS. Thirty-seven peer-reviewed articles were selected for this review. In general, findings were equivocal for most cognitive domains. Treatment, however, was noted to improve attention/vigilance in most studies and consistently did not improve constructional abilities or psychomotor functioning. The results are discussed in the context of a neurofunctional theory for the effects of OSAHS on the brain.


International Chronic Ocular Graft-vs-Host-Disease (GVHD) Consensus Group: proposed diagnostic criteria for chronic GVHD (Part I).
The International Chronic Ocular GVHD Consensus Group held 4 working meetings to define new diagnostic metrics for chronic ocular graft-versus-host disease (GVHD). After considering the factors currently used to diagnose chronic ocular GVHD, the Consensus Group identified 4 subjective and objective variables to measure in patients following allogeneic hematopoietic stem cell transplantation (HSCT): OSDI, Schirmer's score without anesthesia, corneal staining, and conjunctival injection. Each variable was scored 0-2 or 0-3, with a maximum composite score of 11. Consideration was also given to the presence or the absence of systemic GVHD. On the basis of their composite score and the presence or absence of systemic GVHD, patients were assigned to one of three diagnostic categories: NO, PROBABLE, or DEFINITE ocular GVHD. New diagnostic criteria for chronic ocular GVHD are presented by the Consensus Group. Validation studies are needed to identify the best combination of the proposed metrics to maximize diagnostic sensitivity and specificity.


Malaria Panel Assay versus PCR: detection of naturally infected Anopheles melas in a coastal village of Equatorial Guinea.
A study was carried out in a village of the mainland region of Equatorial Guinea in order to ascertain a) which members of Anopheles gambiae complex could be involved in malaria transmission and b) the rate of infectivity for Anopheles melas comparing two different methods, a PCR able to detect sporozoite-DNA and an immunochromatographic assay MPR (Malaria Rapid Dipstick Panel Assay). Mosquitoes were sampled at night by indoor captures in two houses of a coastal village in Equatorial Guinea (Ayantang). Collected mosquitoes were identified as An. gambiae s.l. These were individually dried into silica-gel. The head-thorax of the An. gambiae s.l. mosquitoes were analysed by PCR to verify that the species was of the gambiae complex. Individual head-thorax and pools (5 pools) of homogenized mosquitoes employed in Malaria Rapid Panel assay (MRP assay) were lysed and DNA was extracted. PCR was designed from the 753 base pair insert of pBRKl-14 and DNA was amplified. The relationship between dipstick and PCR to detect Plasmodium falciparum sporozoites was measured in terms of sensitivity, specificity and test association (Cohen's kappa value). Two hundred and sixty-four An. gambiae s.l. females were studied (214 individually and five pools with 10 mosquitoes in each). PCR analysis showed that 207 mosquitoes were An. melas, 3 An. gambiae s.s. and 4 could not be identified. By using PCR as the gold standard method when dipstick assay was compared, matching results were obtained for 6 mosquitoes and, in one case MRP was positive while PCR was not reactive. MRP assay showed a low sensitivity (3.3%) when compared with falciparum-DNA detection (17,7% and 14,3%, series A and B respectively). Agreement between the two test formats was low (kappa = 0,224). It was determined that An. melas is the main anopheline vector involved in malaria transmission in Ayantang, a coastal village in mainland Equatorial Guinea. A comparison of PCR and Vec-Test Assay, concluded that the PCR method proved to be a more sensitive and useful tool than the dipstick assay to determine the malarial infection rate in mosquitoes in an area of stable and high malaria transmission like Equatorial Guinea.


Investigating the prevalence of intimate partner violence victimisation in women presenting to the emergency department in suicidal crisis.
To investigate the prevalence of intimate partner violence (IPV) and frequency of victimisation questioning by hospital staff in women presenting to EDs for suicide-related complaints and injuries. A cross-sectional survey design was used to assess IPV and ED experiences among women with a recent (<18 months) suicide-related presentation to EDs within six Local Health Districts across New South Wales. Women aged 16 years and over, residing in participating health districts were recruited in-person by hospital staff, or via Facebook advertisements. Variables assessed included demographic characteristics, psychosocial assessment coverage and exposure to IPV (Composite Abuse Scale [Revised]-Short-Form). Binary logistic regression was used to test for independent associations between variables on victimisation questioning by hospital staff. A total of 563 women completed questionnaires following presentation to the ED for a suicide attempt (n = 329; 58%) or suicide crisis (n = 234; 42%). Of these, 200 women (36%) reported IPV exposure in the 18 months prior and 141 women (25%) reported earlier lifetime victimisation. Of the 341 women with a history of IPV, 155 women (45%) were asked about victimisation by hospital staff. Younger age and lower socio-economic status were significantly associated with questioning (P = 0.03). Findings suggest a large proportion of women seeking support for suicide in the ED are affected by IPV, although few are asked about abuse experiences. Victimisation is associated with complex health issues and heightened mortality risk, which carry important implications for patient-care. Findings support routine ED screening and can be applied to stratify risk within IPV responses.


Error reporting from the da Vinci surgical system in robotic surgery: A Canadian multispecialty experience at a single academic centre.
The goal of the study is to evaluate and report on the third-generation da Vinci surgical (Si) system malfunctions. A total of 1228 robotic surgeries were performed between January 2012 and December 2015 at our academic centre. All cases were performed by using a single, dual console, four-arm, da Vinci Si robot system. The three specialties included urology, gynecology, and thoracic surgery. Studied outcomes included the robotic surgical error types, immediate consequences, and operative side effects. Error rate trend with time was also examined. Overall robotic malfunctions were documented on the da Vinci Si systems event log in 4.97% (61/1228) of the cases. The most common error was related to pressure sensors in the robotic arms indicating out of limit output. This recoverable fault was noted in 2.04% (25/1228) of cases. Other errors included unrecoverable electronic communication-related in 1.06% (13/1228) of cases, failed encoder error in 0.57% (7/1228), illuminator-related in 0.33% (4/1228), faulty switch in 0.24% (3/1228), battery-related failures in 0.24% (3/1228), and software/hardware error in 0.08% (1/1228) of cases. Surgical delay was reported only in one patient. No conversion to either open or laparoscopic occurred secondary to robotic malfunctions. In 2015, the incidence of robotic error rose to 1.71% (21/1228) from 0.81% (10/1228) in 2014. Robotic malfunction is not infrequent in the current era of robotic surgery in various surgical subspecialties, but rarely consequential. Their seldom occurrence does not seem to affect patient safety or surgical outcome.


Hsp104 targets multiple intermediates on the amyloid pathway and suppresses the seeding capacity of Abeta fibrils and protofibrils.
The heat shock protein Hsp104 has been reported to possess the ability to modulate protein aggregation and toxicity and to "catalyze" the disaggregation and recovery of protein aggregates, including amyloid fibrils, in yeast, Escherichia coli, mammalian cell cultures, and animal models of Huntington's disease and Parkinson's disease. To provide mechanistic insight into the molecular mechanisms by which Hsp104 modulates aggregation and fibrillogenesis, the effect of Hsp104 on the fibrillogenesis of amyloid beta (Abeta) was investigated by characterizing its ability to interfere with oligomerization and fibrillogenesis of different species along the amyloid-formation pathway of Abeta. To probe the disaggregation activity of Hsp104, its ability to dissociate preformed protofibrillar and fibrillar aggregates of Abeta was assessed in the presence and in the absence of ATP. Our results show that Hsp104 inhibits the fibrillization of monomeric and protofibrillar forms of Abeta in a concentration-dependent but ATP-independent manner. Inhibition of Abeta fibrillization by Hsp104 is observable up to Hsp104/Abeta stoichiometric ratios of 1:1000, suggesting a preferential interaction of Hsp104 with aggregation intermediates (e.g., oligomers, protofibrils, small fibrils) on the pathway of Abeta amyloid formation. This hypothesis is consistent with our observations that Hsp104 (i) interacts with Abeta protofibrils, (ii) inhibits conversion of protofibrils into amyloid fibrils, (iii) arrests fibril elongation and reassembly, and (iv) abolishes the capacity of protofibrils and sonicated fibrils to seed the fibrillization of monomeric Abeta. Together, these findings suggest that the strong inhibition of Abeta fibrillization by Hsp104 is mediated by its ability to act at different stages and target multiple intermediates on the pathway to amyloid formation.


First Report of Guignardia citricarpa Associated with Citrus Black Spot on Sweet Orange (Citrus sinensis) in North America.
In March 2010, citrus black spot symptoms were observed on sweet orange trees in a grove near Immokalee, FL. Symptoms observed on fruit included hard spot, cracked spot, and early virulent spot. Hard spot lesions were up to 5 mm, depressed with a chocolate margin and a necrotic, tan center, often with black pycnidia (140 to 200 μm) present. Cracked spot lesions were large (15 mm), dark brown, with diffuse margins and raised cracks. In some cases, hard spots formed in the center of lesions. Early virulent spot lesions were small (up to 7 mm long), bright red, irregular, indented, and often with many pycnidia. In addition, small (2 to 3 mm), elliptical, reddish brown leaf lesions with depressed tan centers were observed on some trees with symptomatic fruit. Chlorotic halos appeared as they aged. Most leaves had single lesions, occasionally up to four per leaf. Tissue pieces from hard spots and early virulent spots were placed aseptically on potato dextrose agar (PDA), oatmeal agar, or carrot agar and incubated with 12 h of light and dark at 24°C. Cultures that grew colonies within a week were discarded. Fourteen single-spore cultures were obtained from the isolates that grew slower than the Guignardia mangiferae reference cultures, although pycnidia formed more rapidly in the G. mangiferae cultures (1). No sexual structures were observed. Cultures on half-PDA were black and cordlike with irregular margins with numerous pycnidia, often bearing white cirrhi after 14 days. Conidia (7.1 to 7.8 × 10.3 to 11.8 μm) were hyaline, aseptate, multiguttulate, ovoid with a flattened base surrounded by a hyaline matrix (0.4 to 0.6 μm) and a hyaline appendage on the rounded apex, corresponding to published descriptions of G. citricarpa (anomorph Phyllosticta citricarpa) (1). A yellow pigment was seen in oatmeal agar surrounding G. citricarpa, but not G. mangiferae colonies as previously reported (1,2). DNA was extracted from lesions and cultures and amplified with species-specific primers (2). DNA was also extracted from G. mangiferae and healthy citrus fruit. The G. citricarpa-specific primers produced a 300-bp band from fruit lesions and pure cultures. G. mangiferae-specific primers produced 290-bp bands with DNA from G. mangiferae cultures. The internally transcribed spacer (ITS) of the rRNA gene, translation-elongation factor (TEF), and actin gene regions were sequenced from G. citricarpa isolates and deposited in GenBank. These sequences had 100% homology with G. citricarpa ITS sequences from South Africa and Brazil, 100% homology with TEF, and 99% homology with actin of a Brazilian isolate. Pathogenicity tests with G. citricarpa were not done because the organism infects immature fruit and has an incubation period of at least 6 months (3). In addition, quarantine restrictions limit work with the organism outside a contained facility. To our knowledge, this is the first report of black spot in North America. The initial infested area was ~57 km2. The disease is of great importance to the Florida citrus industry because it causes serious blemishes and significant yield reduction, especially on the most commonly grown 'Valencia' sweet orange. Also, the presence of the disease in Florida may affect market access because G. citricarpa is considered a quarantine pathogen by the United States and internationally. References: (1) R. P. Baayen et al. Phytopathology 92:464, 2002. (2) N. A. Peres et al. Plant Dis. 91:525, 2007 (3) R. F. Reis et al. Fitopath Bras. 31:29, 2006.


New germline mutations in the hypervariable minisatellite CEB1 in the parents of children with leukaemia.
Gardner and co-workers advanced the hypothesis that the Seascale leukaemia cluster could have been caused by new mutations in germ cells, induced by paternal preconceptional irradiation (PPI) exposure at the Sellafield nuclear installation. Since evidence has shown that PPI can increase the de novo germline mutation rate in hypervariable minisatellite loci, we investigated the hypothesis that sporadic childhood leukaemia might be associated with an increased parental germline minisatellite mutation rate. To test this hypothesis, we compared de novo germline mutation rates in the hypervariable minisatellite locus, CEB1, in family trios (both parents and their child) of children with leukaemia (n=135) compared with unaffected control families (n=124). The majority of case and control germline mutations were paternal (94%); the mean paternal germline mutation rates of children with leukaemia (0.083) and control children (0.156) were not significantly different (odds ratio, 95% confidence interval: 0.50, 0.23-1.08; P=0.11). There were no significant differences in case and control parental allele sizes, case and control germline mutation progenitor allele sizes (2.74 vs 2.54 kb; P=0.56), case and control mutant allele sizes (2.71 vs 2.67 kb; P=0.90), mutant allele size changes (0.13 vs 0.26 kb; P=0.10), or mutational spectra. Within the limitation of the number of families available for study, we conclude that childhood leukaemia is unlikely to be associated with increased germline minisatellite instability.


Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer.
This single institution phase I trial determined the maximum tolerated dose (MTD) of concurrent vorinostat and capecitabine with radiation in non-metastatic pancreatic cancer. Twenty-one patients received escalating doses of vorinostat (100-400mg daily) during radiation. Capecitabine was given 1000mg q12 on the days of radiation. Radiation consisted of 30Gy in 10 fractions. Vorinostat dose escalation followed the standard 3+3 design. No dose escalation beyond 400mg vorinostat was planned. Diffusion-weighted (DW)-MRI pre- and post-treatment was used to evaluate in vivo tumor cellularity. The MTD of vorinostat was 400mg. Dose limiting toxicities occurred in one patient each at dose levels 100mg, 300mg, and 400mg: 2 gastrointestinal toxicities and one thrombocytopenia. The most common adverse events were lymphopenia (76%) and nausea (14%). The apparent diffusion coefficient (ADC) increased in most tumors. Nineteen (90%) patients had stable disease, and two (10%) had progressive disease at time of surgery. Eleven patients underwent surgical exploration with four R0 resections and one R1 resection. Median overall survival was 1.1years (95% confidence interval 0.78-1.35). The combination of vorinostat 400mg daily M-F and capecitabine 1000mg q12 M-F with radiation (30Gy in 10 fractions) was well tolerated with encouraging median overall survival.


SARS-CoV-2: Is it the newest spark in the TORCH?
Amid the rapidly evolving global coronavirus disease 2019 (COVID-19) pandemic that has already had profound effects on public health and medical infrastructure globally, many questions remain about its impact on child health. The unique needs of neonates and children, and their role in the spread of the virus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) should be included in preparedness and response plans. Fetuses and newborn infants may be uniquely vulnerable to the damaging consequences of congenitally- or perinatally-acquired SARS-CoV-2 infection, but data are limited about outcomes of COVID-19 disease during pregnancy. Therefore, information on illnesses associated with other highly pathogenic coronaviruses (i.e., severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome [MERS]), as well as comparisons to common congenital infections, such as cytomegalovirus (CMV), are warranted. Research regarding the potential routes of acquisition of SARS-CoV-2 infection in the prenatal and perinatal setting is of a high public health priority. Vaccines targeting women of reproductive age, and in particular pregnant patients, should be evaluated in clinical trials and should include the endpoints of neonatal infection and disease.


Effect of Antibiotic Prophylaxis on Surgical Site Infections Following Removal of Orthopedic Implants Used for Treatment of Foot, Ankle, and Lower Leg Fractures: A Randomized Clinical Trial.
Following clean (class I, not contaminated) surgical procedures, the rate of surgical site infection (SSI) should be less than approximately 2%. However, an infection rate of 12.2% has been reported following removal of orthopedic implants used for treatment of fractures below the knee. To evaluate the effect of a single dose of preoperative antibiotic prophylaxis on the incidence of SSIs following removal of orthopedic implants used for treatment of fractures below the knee. Multicenter, double-blind, randomized clinical trial including 500 patients aged 18 to 75 years with previous surgical treatment for fractures below the knee who were undergoing removal of orthopedic implants from 19 hospitals (17 teaching and 2 academic) in the Netherlands (November 2014-September 2016), with a follow-up of 6 months (final follow-up, March 28, 2017). Exclusion criteria were an active infection or fistula, antibiotic treatment, reimplantation of osteosynthesis material in the same session, allergy for cephalosporins, known kidney disease, immunosuppressant use, or pregnancy. A single preoperative intravenous dose of 1000 mg of cefazolin (cefazolin group, n = 228) or sodium chloride (0.9%; saline group, n = 242). Primary outcome was SSI within 30 days as measured by the criteria from the US Centers for Disease Control and Prevention. Secondary outcome measures were functional outcome, health-related quality of life, and patient satisfaction. Among 477 randomized patients (mean age, 44 years [SD, 15]; women, 274 [57%]; median time from orthopedic implant placement, 11 months [interquartile range, 7-16]), 470 patients completed the study. Sixty-six patients developed an SSI (14.0%): 30 patients (13.2%) in the cefazolin group vs 36 in the saline group (14.9%) (absolute risk difference, -1.7 [95% CI, -8.0 to 4.6], P = .60). Among patients undergoing surgery for removal of orthopedic implants used for treatment of fractures below the knee, a single preoperative dose of intravenous cefazolin compared with saline did not reduce the risk of surgical site infection within 30 days following implant removal. clinicaltrials.gov Identifier: NCT02225821.


Novel determinants of antibiotic resistance: identification of mutated loci in highly methicillin-resistant subpopulations of methicillin-resistant Staphylococcus aureus.
We identified mutated genes in highly resistant subpopulations of methicillin-resistant Staphylococcus aureus (MRSA) that are most likely responsible for the historic failure of the β-lactam family of antibiotics as therapeutic agents against these important pathogens. Such subpopulations are produced during growth of most clinical MRSA strains, including the four historically early MRSA isolates studied here. Chromosomal DNA was prepared from the highly resistant cells along with DNA from the majority of cells (poorly resistant cells) followed by full genome sequencing. In the highly resistant cells, mutations were identified in 3 intergenic sequences and 27 genes representing a wide range of functional categories. A common feature of these mutations appears to be their capacity to induce high-level β-lactam resistance and increased amounts of the resistance protein PBP2A in the bacteria. The observations fit a recently described model in which the ultimate controlling factor of the phenotypic expression of β-lactam resistance in MRSA is a RelA-mediated stringent response. IMPORTANCE It has been well established that the level of antibiotic resistance (i.e., minimum concentration of a β-lactam antibiotic needed to inhibit growth) of a methicillin-resistant Staphylococcus aureus (MRSA) strain depends on the transcription and translation of the resistance protein PBP2A. Here we describe mutated loci in an additional novel set of genetic determinants that appear to be essential for the unusually high resistance levels typical of subpopulations of staphylococci that are produced with unique low frequency in most MRSA clinical isolates. We propose that mutations in these determinants can trigger induction of the stringent stress response which was recently shown to cause increased transcription/translation of the resistance protein PBP2A in parallel with the increased level of resistance.


Unilateral amygdala lesions hamper attentional orienting triggered by gaze direction.
The newly discovered deficit in a bilateral amygdala-damaged case, of not being able to allocate attention to the critical feature of a face (Adolphs R, Gosselin F, Buchanan TW, Tranel D, Schyns P, Damasio AR. 2005. A mechanism for impaired fear recognition after amygdala damage. Nature. 433:68--72.), has opened a new window into the function of the amygdala. This case implies that the amygdala might be essential in detecting potentially relevant social stimuli, and directing attention accordingly. In this study, we have sought to test this implication by investigating the behavioral performance of 5 unilateral amygdala-damaged subjects on spatial cueing tasks. The tasks employed central gaze and arrow direction as cues to trigger attentional orienting in peripheral target detection. Although age-matched normal controls demonstrated a significant congruency effect such that targets presented congruently to cue direction elicited faster detection, amygdala subjects demonstrated no such congruency effect for gaze cues in the face of a significant congruency effect for arrow cues. The results suggest that the social valence of a stimulus is critical for amygdala involvement in visual processing. The results also support the implicated role of the amygdala in detecting and analyzing relevant social stimuli, and orienting attention accordingly.


Tamm oscillations in semi-infinite nonlinear waveguide arrays.
We demonstrate the existence of nonlinear Tamm oscillations at the interface between a substrate and a one-dimensional waveguide array with either cubic or saturable, self-focusing or self-defocusing nonlinearity. Light is trapped in the vicinity of the array boundary due to the interplay between the repulsive edge potential and Bragg reflection inside the array. In the special case when this potential is linear these oscillations reduce themselves to surface Bloch oscillations.


Hospital factors associated with clinical data quality.
As chronic conditions affect the evaluation, treatment, and possible clinical outcomes of patients, accurate reporting of chronic diseases into the patient record is expected. In some countries, the reported magnitude of comorbidity inaccuracy and incompleteness is compelling. Beyond incentives provided in payment systems, the role and significance of other factors that contribute to inaccurate and incomplete reporting of chronic conditions is not well understood. A complementary approach that identifies factors associated with inaccurate and incomplete data is proposed. In a two-step process, the method links hospitalizations of patients who are repeatedly hospitalized over a determined period and identifies characteristics associated with accurate and complete reporting of chronic conditions. These methods leverage the high prevalence of chronic conditions amongst patients with multiple hospitalizations. The study is based on retrospective analysis of longitudinal hospital discharge data from a cohort of Ontario (Canada) patients. There are a multitude of factors associated with incomplete clinical data reporting. Patients discharged from community or small hospitals, discharged alive, or transferred to another acute inpatient hospital tend to have less complete comorbidity reporting. For some chronic diseases, very old age affects chronic disease reporting. Longitudinally analyzing chronically ill patients is a novel approach to identifying incompletely reported clinical data. Using these results, coding quality initiatives can be focused in a directed manner.


Divisive normalization image quality metric revisited.
Structural similarity metrics and information-theory-based metrics have been proposed as completely different alternatives to the traditional metrics based on error visibility and human vision models. Three basic criticisms were raised against the traditional error visibility approach: (1) it is based on near-threshold performance, (2) its geometric meaning may be limited, and (3) stationary pooling strategies may not be statistically justified. These criticisms and the good performance of structural and information-theory-based metrics have popularized the idea of their superiority over the error visibility approach. In this work we experimentally or analytically show that the above criticisms do not apply to error visibility metrics that use a general enough divisive normalization masking model. Therefore, the traditional divisive normalization metric 1 is not intrinsically inferior to the newer approaches. In fact, experiments on a number of databases including a wide range of distortions show that divisive normalization is fairly competitive with the newer approaches, robust, and easy to interpret in linear terms. These results suggest that, despite the criticisms of the traditional error visibility approach, divisive normalization masking models should be considered in the image quality discussion.


Embryonic stem cells and the challenge of transplantation tolerance.
Isolated from early blastocysts, embryonic stem (ES) cells capture the brief moment of pluripotency in the developing embryo, as evidenced by their differentiation into many somatic cell types in vitro. Although these properties might help meet the growing demand for 'spare parts' to replace diseased or worn-out tissues, their use in so-called cell replacement therapy (CRT) poses several challenges, not least of which is the prevention of their subsequent rejection. Here we explore the notion that ES cells might spawn cell types necessary for the treatment of disease while acting as a plentiful source of hematopoietic stem cells (HSCs) or terminally differentiated dendritic cells (DCs) that might facilitate the induction of transplantation tolerance to the replacement tissues.


Comparison of standardized versus individualized caloric prescriptions in the nutritional rehabilitation of inpatients with anorexia nervosa.
Sparse research informs how caloric prescriptions should be advanced during nutritional rehabilitation of inpatients with anorexia nervosa (AN). This study compared the impact of a standardized caloric increase approach, in which increases occurred on a predetermined schedule, to an individualized approach, in which increases occurred only following insufficient weight gain, on rate, pattern, and cumulative amount of weight gain and other weight restoration outcomes. This study followed a natural experiment design comparing AN inpatients consecutively admitted before (n = 35) and after (n = 35) an institutional change from individualized to standardized caloric prescriptions. Authors examined the impact of prescription plan on weekly weight gain in the first treatment month using multilevel modeling. Within a subsample remaining inpatient through weight restoration (n = 40), multiple regressions examined the impact of caloric prescription plan on time to weight restoration, length of hospitalization, maximum caloric prescription, discharge BMI, and incidence of activity restriction and edema. There were significant interactions between prescription plan and quadratic time on average weekly weight gain (p = .03) and linear time on cumulative weekly weight gain (p < .001). Under the standardized plan, patients gained in an accelerated curvilinear pattern (p = .04) and, therefore, gained cumulatively greater amounts of weight over time (p < .001). Additionally, 30% fewer patients required activity restriction under the standardized plan. Standardized caloric prescriptions may confer advantage by facilitating accelerated early weight gain and lower incidence of bedrest without increasing the incidence of refeeding syndrome.


Neuronal synchrony during anesthesia: a thalamocortical model.
There is growing evidence in favor of the temporal-coding hypothesis that temporal correlation of neuronal discharges may serve to bind distributed neuronal activity into unique representations and, in particular, that theta (3.5-7.5 Hz) and delta (0.5 < 3.5 Hz) oscillations facilitate information coding. The theta- and delta-rhythms are shown to be involved in various sleep stages, and during anesthesia, they undergo changes with the depth of anesthesia. We introduce a thalamocortical model of interacting neuronal ensembles to describe phase relationships between theta- and delta-oscillations, especially during deep and light anesthesia. Asymmetric and long-range interactions among the thalamocortical neuronal oscillators are taken into account. The model results are compared with experimental observations. The delta- and theta-activities are found to be separately generated and are governed by the thalamus and cortex, respectively. Changes in the degree of intraensemble and interensemble synchrony imply that the neuronal ensembles inhibit information coding during deep anesthesia and facilitate it during light anesthesia.


Empirical evaluation of the genetic similarity of samples from twin registries in Australia and the Netherlands using 359 STRP markers.
One way to achieve the large sample sizes required for genetic studies of complex traits is to combine samples collected by different groups. It is not often clear, however, whether this practice is reasonable from a genetic perspective. To assess the comparability of samples from the Australian and the Netherlands twin studies, we estimated Fst (the proportion of total genetic variability attributable to genetic differences between cohorts) based on 359 short tandem repeat polymorphisms in 1068 individuals. Fst was estimated to be 0.30% between the Australian and the Netherlands cohorts, a smaller value than between many European groups. We conclude that it is reasonable to combine the Australian and the Netherlands samples for joint genetic analyses.


Insights into DNA polymerization mechanisms from structure and function analysis of HIV-1 reverse transcriptase.
When the single-stranded RNA genome of HIV-1 is copied into double-stranded DNA, the viral enzyme reverse transcriptase (RT) catalyzes the addition of approximately 20,000 nucleotides; however, the precise mechanism of nucleotide addition is unknown. In this study, we attempt to integrate the genetic data and biochemical mechanism of DNA polymerization with the structure of HIV-1 RT complexed with a dsDNA template-primer. The first step of polymerization involves the physical association of a polymerase with its nucleic acid substrate. A comparison of the structures of HIV-1 RT in the presence and absence of DNA indicates that the tip of the p66 thumb moves approximately 30 A upon DNA binding. This conformational change permits numerous interactions between residues of alpha-helices H and I in the thumb subdomain and the DNA. Measurements of DNA binding affinity for nucleic acids with double-stranded DNAs that have an increasing number of bases in the template overhang and molecular modeling suggest that portions of beta 3 and beta 4 within the fingers subdomain bind single-stranded regions of the template. Measurements of nucleotide incorporation efficiency (kcat/Km) show that the binding and incorporation of the next complementary nucleotide are not dependent on the length of the template overhang. Molecular modeling of an incoming nucleotide triphosphate (dTTP), based in part on the position of mercury atoms in a RT/DNA/Hg-UTP/Fab structure, suggests that portions of secondary structural elements alpha C-beta 6, alpha E, beta 11b, and beta 9-beta 10 determine the topology of the dNTP-binding site. These results also suggest that nucleotide incorporation is accompanied by a protein conformational change that positions the dNTP for nucleophilic attack. Nucleophilic attack by the oxygen atom of the 3'-OH group of the primer strand could be metal-mediated, and Asp185 may be directly involved in stabilizing the transition state. The translocation step may be characterized by rotational as well as translational motions of HIV-1 RT relative to the DNA double helix. Some of the energy required for translocation could be provided by dNTP hydrolysis and could be coupled with conformational changes within the nucleic acid. A structural comparison of HIV-1 RT, Klenow fragment, and T7 RNA polymerase identified regions within T7 RNA polymerase which are not present in the other two polymerases that might help this polymerase to remain bound with nucleic acids and contribute to the ability of the T7 RNA polymerase to polymerize processively.


Optical correlation of spatial-frequency-shifted images in a photorefractive BSO correlator.
The optical cross correlation of an image with another image that was spatial-frequency shifted in one dimension was demonstrated in a photorefractive VanderLugt correlator. The first image was stored as a Fourier-transform hologram in a photorefractive Bi12SiO20 crystal (BSO) and was successively correlated with different spatial-frequency-shifted versions of a second image. We implemented the spatial-frequency shift by rotating a galvanometer mirror in an image plane, causing the Fourier transform to be shifted laterally in the BSO. We verified that the resulting operation in the BSO was an accurate complex multiplication of the shifted and the stored Fourier transforms. As many as 20 successive readouts were conducted without measurable erasure of the stored hologram. The dynamic range, saturation behavior, and other performance parameters were measured and are discussed.


Exposure to psychosocial work strain and changes in smoking behavior during pregnancy - a longitudinal study within the Danish National Birth Cohort.
Objective Knowledge of the relationship between psychosocial strain in the work environment and smoking during pregnancy is scarce. This study aimed to examine the association between psychosocial job strain and change in smoking behavior during pregnancy. Methods The cohort included 65 645 pregnancies from the Danish National Birth Cohort (1996-2002), where pregnant women were interviewed on job factors and lifestyle during the first and third trimesters. Smoking was categorized into non-, non-daily, and daily smoking at each interview. Psychosocial job strain was categorized into four groups based on the concept of Karasek's demand-control model: low strain (reference), passive, active and high strain. Associations between psychosocial strain and change in smoking status between the first and second interviews were analyzed by multinomial logistic regression, separately for each smoking category at first interview. Results Non-smoking women exposed to high strain work were more likely to become daily smokers [adjusted odds ratio (OR adj) 1.41, (95% confidence interval (CI) 1.08-1.83)] compared to non-smoking women exposed to low strain work. Non-smoking women exposed to passive work were more likely to become both non-daily and daily smokers [OR adj1.59 (95% CI 1.21-2.08) and OR adj1.32 (95% CI 1.03-1.70), respectively]. Daily smoking women exposed to high strain work were less likely to decrease their smoking [OR adj0.57 (95% CI 0.32-0.99)] compared to daily smoking women exposed to low strain work. Conclusions Psychosocial strain influenced the women's smoking behavior during pregnancy, especially in job types with low control.


Loss of stem cell regenerative capacity within aged niches.
This work uncovers novel mechanisms of aging within stem cell niches that are evolutionarily conserved between mice and humans and affect both embryonic and adult stem cells. Specifically, we have examined the effects of aged muscle and systemic niches on key molecular identifiers of regenerative potential of human embryonic stem cells (hESCs) and post-natal muscle stem cells (satellite cells). Our results reveal that aged differentiated niches dominantly inhibit the expression of Oct4 in hESCs and Myf-5 in activated satellite cells, and reduce proliferation and myogenic differentiation of both embryonic and tissue-specific adult stem cells (ASCs). Therefore, despite their general neoorganogenesis potential, the ability of hESCs, and the more differentiated myogenic ASCs to contribute to tissue repair in the old will be greatly restricted due to the conserved inhibitory influence of aged differentiated niches. Significantly, this work establishes that hESC-derived factors enhance the regenerative potential of both young and, importantly, aged muscle stem cells in vitro and in vivo; thus, suggesting that the regenerative outcome of stem cell-based replacement therapies will be determined by a balance between negative influences of aged tissues on transplanted cells and positive effects of embryonic cells on the endogenous regenerative capacity. Comprehensively, this work points toward novel venues for in situ restoration of tissue repair in the old and identifies critical determinants of successful cell-replacement therapies for aged degenerating organs.


Composition dependent multiple structural transformations of myoglobin in aqueous ethanol solution: a combined experimental and theoretical study.
Experimental studies (circular dichroism and ultra-violet (UV) absorption spectra) and large scale atomistic molecular dynamics simulations (accompanied by order parameter analyses) are combined to establish a number of remarkable (and unforeseen) structural transformations of protein myoglobin in aqueous ethanol mixture at various ethanol concentrations. The following results are particularly striking. (1) Two well-defined structural regimes, one at xEtOH ∼ 0.05 and the other at xEtOH ∼ 0.25, characterized by formation of distinct partially folded conformations and separated by a unique partially unfolded intermediate state at xEtOH ∼ 0.15, are identified. (2) Existence of non-monotonic composition dependence of (i) radius of gyration, (ii) long range contact order, (iii) residue specific solvent accessible surface area of tryptophan, and (iv) circular dichroism spectra and UV-absorption peaks are observed. Interestingly at xEtOH ∼ 0.15, time averaged value of the contact order parameter of the protein reaches a minimum, implying that this conformational state can be identified as a molten globule state. Multiple structural transformations well known in water-ethanol binary mixture appear to have considerably stronger effects on conformation and dynamics of the protein. We compare the present results with studies in water-dimethyl sulfoxide mixture where also distinct structural transformations are observed along with variation of co-solvent composition.


Structural and Functional Brain Abnormalities Associated With Exposure to Different Childhood Trauma Subtypes: A Systematic Review of Neuroimaging Findings.
Background: Childhood trauma subtypes sexual abuse, physical abuse, emotional maltreatment, and neglect may have differential effects on the brain that persist into adulthood. A systematic review of neuroimaging findings supporting these differential effects is as yet lacking. Objectives: The present systematic review aims to summarize the findings of controlled neuroimaging trials regarding long-term differential effects of trauma subtypes on the human brain. Methods: A systematic literature search was performed using the PubMed and PsycINFO databases from January 2017 up to and including January 2018. Additional papers were identified by a manual search in the reference lists of selected papers and of relevant review articles retrieved by the initial database search. Studies were then assessed for eligibility by the first author. Only original human studies directly comparing neuroimaging findings of exposed and unexposed individuals to well-defined emotional, physical or sexual childhood maltreatment while controlling for the effects of other subtypes were included. A visual summary of extracted data was made for neuroimaging modalities for which comparison between trauma subtypes was feasible, taking the studies' numbers and sample sizes into account. Results: The systematic literature search yielded 25 publications. Sexual abuse was associated with structural deficits in the reward circuit and genitosensory cortex and amygdalar hyperreactivity during sad autobiographic memory recall. Emotional maltreatment correlated with abnormalities in fronto-limbic socioemotional networks. In neglected individuals, white matter integrity and connectivity were disturbed in several brain networks involved in a variety of functions. Other abnormalities, such as reduced frontal cortical volume, were common to all maltreatment types. Conclusions: There is some evidence for long-term differential effects of trauma subtypes on the human brain. The observed alterations may result from both protective adaptation of and damage to the brain following exposure to threatening life events. Though promising, the current evidence is incomplete, with few brain regions and neuroimaging modalities having been investigated in all subtypes. The comparability of the available evidence is further limited by the heterogeneity of study populations regarding gender, age and comorbid psychopathology. Future neuroimaging studies should take this potentially differential role of childhood trauma subtypes into account.


[Minimizing losses and maximizing efficiency in the detection of acute severe malnutrition].
One of the many challenges faced by epidemiologists is to adequately plan and optimize subject selection procedures in terms of effectiveness and efficiency. In the context of a case-control study involving severe acute malnutrition, a two-step subject selection procedure is used. The aim of the article is to establish an appropriate cut-off point for the screening phase and to achieve a common ground for standards, efficiency in detecting severe malnutrition and the two-step procedure. The study includes 154 children under the age of 2 from two different hospitals. To determine the ideal cut-off point of weight-for-age (WFA), the following estimators are of interest: the proportion of false negatives (PFN), false positives (PFP) and the percentage of total gain by time (ptg). Weight-for-height (WFH) (cut-off point at -2 SDs) is used as reference for establishing severe acute malnutrition. The magnitude of false negatives declines steadily until the 3rd WFA percentile (P3) and reaches zero close to P9. At this point, the PFP is around 0.4. The ptg decreases sharply up to P4, declining smoothly towards P10 thereafter (54.5%). The WFA P10 can be recommended for the screening phase. At this cut-off point, there is still efficiency whereas losses of true cases of severe acute malnutrition are minimized.


The emerging role of vitamin D binding protein in multiple sclerosis.
Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS). A growing body of evidence supports a role for vitamin D in MS aetiology. Vitamin D binding protein (DBP) is the major plasma carrier of vitamin D metabolites and genetic differences in DBP gene have been found to influence vitamin D levels. We review here evidence supporting a role of DBP in MS. Several recent studies show that DBP levels in the cerebrospinal fluid correlate with MS course, being lower during relapses and higher in the secondary progressive phase. Further studies are needed to elucidate the potential use of DBP as a biological marker of MS course, but may be of use given the current lack of diagnostic tools for the prediction of MS development and progression.


LRRK2 secretion in exosomes is regulated by 14-3-3.
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset Parkinson's disease (PD). Emerging evidence suggests a role for LRRK2 in the endocytic pathway. Here, we show that LRRK2 is released in extracellular microvesicles (i.e. exosomes) from cells that natively express LRRK2. LRRK2 localizes to collecting duct epithelial cells in the kidney that actively secrete exosomes into urine. Purified urinary exosomes contain LRRK2 protein that is both dimerized and phosphorylated. We provide a quantitative proteomic profile of 1673 proteins in urinary exosomes and find that known LRRK2 interactors including 14-3-3 are some of the most abundant exosome proteins. Disruption of the 14-3-3 LRRK2 interaction with a 14-3-3 inhibitor or through acute LRRK2 kinase inhibition potently blocks LRRK2 release in exosomes, but familial mutations in LRRK2 had no effect on secretion. LRRK2 levels were overall comparable but highly variable in urinary exosomes derived from PD cases and age-matched controls, although very high LRRK2 levels were detected in some PD affected cases. We further characterized LRRK2 exosome release in neurons and macrophages in culture, and found that LRRK2-positive exosomes circulate in cerebral spinal fluid (CSF). Together, these results define a pathway for LRRK2 extracellular release, clarify one function of the LRRK2 14-3-3 interaction and provide a foundation for utilization of LRRK2 as a biomarker in clinical trials.


Comparative ultrastructure of Mycobacterium leprae and Mycobacterium lepraemurium cell envelopes.
The structural properties of the cell envelopes of Mycobacterium leprae and Mycobacterium lepraemurium were investigated by freeze-fracture, freeze-etching, and negative-staining techniques. Freeze-fracture split the cell wall and exposed the internal features of the peptidoglycolipid mycosidic filamentous network. The cell membrane was also split into two asymmetric faces. The external fracture face was characterized by linear arrays of intramembranous particles, whereas the protoplasmic fracture face showed randomly distributed clusters of particulate entities. Comparative analysis of the ultrastructural features observed in M. leprae and M. lepraemurium indicated that the organization of the cell envelope in these two species differed particularly with respect to the amount and complexity of the superficial peptidoglycolipid and mycosidic integument, which is poorly developed in the mycobacterium responsible for human disease.


Thermochemical pretreatment of lignocellulose residues: assessment of the effect on operational conditions and their interactions on the characteristics of leachable fraction.
Annually, large amounts of agricultural residues are produced in Chile, which can be turned into a good opportunity to diversify the energy matrix. These residues have a slow hydrolysis stage during anaerobic digestion; therefore, the application of a pretreatment seems to be an alternative to improve the process. This work focused on applying a thermochemical pretreatment with NaOH on two lignocellulosic residues. The experiments were performed according to a 2(4) factorial design. The factors studied in a 2(4) factorial design were: temperature (60 and 120 °C), pretreatment time (10 and 30 minutes), NaOH dose (2 and 4%), and residue size (<1 and 1-3 mm for wheat straw; 1-5 and 5-10 mm for corn stover). The analyzed response variables were the solubilization of organic matter, and the biodegradability of the lignocellulose hydrolysate. The statistical analysis of the data allowed the identification of the experimental conditions that maximized solubilization of organic matter and biodegradability. The main results showed that more aggressive experimental conditions could increase the breaking down of the structure; in addition, the time of pretreatment was not significant. Conversely, the less aggressive experimental conditions, regarding regent dosage and downsizing, favored the release of biodegradable organic matter. The main conclusion of this study was the identification of the operational conditions of the thermochemical pretreatment that promote maximum biogas production, which was caused due to the solubilization of a large amount of organic matter, but not because of the increase in biodegradability of the released organic matter.


Differential expression analysis of RNA-seq data at single-base resolution.
RNA-sequencing (RNA-seq) is a flexible technology for measuring genome-wide expression that is rapidly replacing microarrays as costs become comparable. Current differential expression analysis methods for RNA-seq data fall into two broad classes: (1) methods that quantify expression within the boundaries of genes previously published in databases and (2) methods that attempt to reconstruct full length RNA transcripts. The first class cannot discover differential expression outside of previously known genes. While the second approach does possess discovery capabilities, statistical analysis of differential expression is complicated by the ambiguity and variability incurred while assembling transcripts and estimating their abundances. Here, we propose a novel method that first identifies differentially expressed regions (DERs) of interest by assessing differential expression at each base of the genome. The method then segments the genome into regions comprised of bases showing similar differential expression signal, and then assigns a measure of statistical significance to each region. Optionally, DERs can be annotated using a reference database of genomic features. We compare our approach with leading competitors from both current classes of differential expression methods and highlight the strengths and weaknesses of each. A software implementation of our method is available on github (https://github.com/alyssafrazee/derfinder).


Pheochromocytoma in the pregnant patient: a case study.
This is a case study of a patient 32 weeks pregnant who presented with multiple endocrine neoplasia type IIa, with severe pheochromocytoma complicated by adult respiratory distress syndrome. The patient's blood pressure was labile, with systolic variations from 50 to 230 mm Hg and tachycardia ranging from 150 to 180 beats per minute. The patient was treated with a variety of alpha- and beta-blockers whose efficacy is compared. Hemodynamic measures are compared with the clinical presentation. The importance of fluid replacement is discussed.


Angulated femurs and the skeletal dysplasias: experience of the International Skeletal Dysplasia Registry (1988-2006).
Angulated or bent femur (isolated or associated with other long bone bowing) in the fetus or newborn is relatively common when evaluating patients with skeletal dysplasias. To determine the extent and heterogeneity of disorders associated with angulated or bent femurs, we analyzed cases in the radiographic database (1998-2006) of the International Skeletal Dysplasia Registry (ISDR) and determined which established skeletal dysplasias and genetic syndromes are associated with this finding. The results show that more than 40 distinct disorders with varying frequency (very rare to more commonly occurring disorders) can be associated with bowed/bent/angulated femurs. Sixty-six percent of the cases with angulated femurs belonged to three well described groups of disorders; campomelic disorders (24.4%), thanatophoric dysplasia (23.9%) and osteogenesis imperfecta (OI) (18.1%). With specific emphasis on these, this cross-sectional cohort provides discussion of data on other rare disorders associated with angulated femurs and the importance of the finding relative to its occurrence within a diagnostic group. This study aims to provide differential diagnosis of entities to be considered when a fetus or newborn is found to have congenital bowing/angulation of the femur.


The evolution of the upright posture and gait--a review and a new synthesis.
During the last century, approximately 30 hypotheses have been constructed to explain the evolution of the human upright posture and locomotion. The most important and recent ones are discussed here. Meanwhile, it has been established that all main hypotheses published until the last decade of the past century are outdated, at least with respect to some of their main ideas: Firstly, they were focused on only one cause for the evolution of bipedality, whereas the evolutionary process was much more complex. Secondly, they were all placed into a savannah scenario. During the 1990s, the fossil record allowed the reconstruction of emerging bipedalism more precisely in a forested habitat (e.g., as reported by Clarke and Tobias (Science 269:521-524, 1995) and WoldeGabriel et al. (Nature 412:175-178, 2001)). Moreover, the fossil remains revealed increasing evidence that this part of human evolution took place in a more humid environment than previously assumed. The Amphibian Generalist Theory, presented first in the year 2000, suggests that bipedalism began in a wooded habitat. The forests were not far from a shore, where our early ancestor, along with its arboreal habits, walked and waded in shallow water finding rich food with little investment. In contrast to all other theories, wading behaviour not only triggers an upright posture, but also forces the individual to maintain this position and to walk bipedally. So far, this is the only scenario suitable to overcome the considerable anatomical and functional threshold from quadrupedalism to bipedalism. This is consistent with paleoanthropological findings and with functional anatomy as well as with energetic calculations, and not least, with evolutionary psychology. The new synthesis presented here is able to harmonise many of the hitherto competing theories.


Rats exhibit aldosterone-dependent sodium appetite during 24 h hindlimb unloading.
Hindlimb unloading (HU) is an animal model of microgravity and bed rest. In these studies, we examined the role of ingestive behaviours in regulating body fluid balance during 24 h HU. In the first experiment, all rats were given distilled water to drink while two groups were also given access to a sodium chloride solution (0.9% or 1.8%). Water and saline intakes were measured before, during and after 24 h of HU. Rats reduced water intake during 24 h HU in all conditions. During HU, rats increased their intakes of both saline solutions (0.9% NaCl (n= 11): control 7.8 +/- 3 ml; HU 18.2 +/- 4 ml; recovery 8.9 +/- 2.5 ml; 1.8% NaCl (n= 7): control 1.0 +/- 0.4 ml; HU 3.8 +/- 0.3 ml; recovery 1.2 +/- 0.5 ml). Although water intake decreased there was no reduction in total fluid intake when saline was available. Plasma volumes were reduced during HU compared to rats in a normal posture when only water was available to drink (control (n= 11) versus HU (n= 11): 4.0 +/- 0.2 versus 3.4 +/- 0.2 ml (100 g body weight)(-1)). When 0.9% saline was available in addition to water, plasma volumes after 24 h HU were not different from rats in a normal posture (control (n= 11) versus HU (n= 12): 4.3 +/- 0.4 versus 4.3 +/- 0.1 ml (100 g body weight)(-1)). Plasma aldosterone but not plasma renin activity was significantly elevated after 24 h HU. Central infusions of spironolactone blocked the increased intake of 1.8% saline that was associated with 24 h HU. Thus, HU results in an aldosterone-dependent sodium appetite and the ingestion of sodium may help maintain plasma volume.


Effects of soil texture and drought stress on the uptake of antibiotics and the internalization of Salmonella in lettuce following wastewater irrigation.
Treated wastewater is expected to be increasingly used as an alternative source of irrigation water in areas facing fresh water scarcity. Understanding the behaviors of contaminants from wastewater in soil and plants following irrigation is critical to assess and manage the risks associated with wastewater irrigation. The objective of this study was to evaluate the effects of soil texture and drought stress on the uptake of antibiotics and the internalization of human pathogens into lettuce through root uptake following wastewater irrigation. Lettuce grown in three soils with variability in soil texture (loam, sandy loam, and sand) and under different levels of water stress (no drought control, mild drought, and severe drought) were irrigated with synthetic wastewater containing three antibiotics (sulfamethoxazole, lincomycin and oxytetracycline) and one Salmonella strain a single time prior to harvest. Antibiotic uptake in lettuce was compound-specific and generally low. Only sulfamethoxazole was detected in lettuce with increasing uptake corresponding to increasing sand content in soil. Increased drought stress resulted in increased uptake of lincomycin and decreased uptake of oxytetracycline and sulfamethoxazole. The internalization of Salmonella was highly dependent on the concentration of the pathogen in irrigation water. Irrigation water containing 5 Log CFU/mL Salmonella resulted in limited incidence of internalization. When irrigation water contained 8 Log CFU/mL Salmonella, the internalization frequency was significantly higher in lettuce grown in sand than in loam (p = 0.009), and was significantly higher in lettuce exposed to severe drought than in unstressed lettuce (p = 0.049). This work demonstrated how environmental factors affected the risk of contaminant uptake by food crops following wastewater irrigation.


Physician satisfaction with telemedicine and in-person visits in otolaryngology.
To investigate the differential factors associated with physician satisfaction between telemedicine and in-person visits in otolaryngology. Study data included 646 telemedicine and 365 in-person encounters delivered from May-June 2020 at a tertiary center outpatient setting. Encounter-specific physician satisfaction was rated by 15 otolaryngologists using Provider Satisfaction Questionnaire (range 0-100) consisted of 5 items (patient needs addressed, patient involvement, adequacy of information given, quality of emotion support provided, and general interaction satisfaction). A multivariable linear mixed-effects model was used to explore patient demographic and clinical factors associated with physician satisfaction. Physician satisfaction scores for telemedicine and in-person visits were 83.0 [95 % CI: 77.0-88.9] and 88.1 [95 % CI: 82.5-93.6], respectively. Among telemedicine visits, physician satisfaction scores were significantly higher for follow-up (vs. new), videoconference (vs. telephone) encounters, and English-speaking patients in a multivariable model. New encounters had significantly lower satisfaction subdomain scores for adequacy of information given to the patient (β = -4.7 [95 % CI: -7.3 to -2.0], p = 0.001) and addressing the needs of the patient among telemedicine visits (β = -4.1, [95 % CI: -7.1 to -1.1], p = 0.007) while there were no differences in satisfaction scores between new vs follow-up visits among in-person visits. For non-English speaking patients, the physician satisfaction scores were significantly lower for subdomain scores assessing active patient participation (β = -13.1, [95 % CI: -13.1 to -17.4], p < 0.001) and emotional support given to the patient (β = -7.8, [95 % CI: -11.0 to -4.5], p < 0.001) for telemedicine visits. Telemedicine has been broadly adopted as an alternative option to deliver care in otolaryngology since COVID-19 pandemic. Appropriate triaging based on patient and encounter characteristics may enhance physician satisfaction and overall experiences with telemedicine. Further efforts are needed to provide adequate interpretation and videoconference services during telemedicine visits.


Enhanced effects of secreted soluble factor preserve better pluripotent state of embryonic stem cell culture in a membrane-based compartmentalized micro-bioreactor.
Pluripotent stem cells are under the influence of soluble factors in a diffusion dominant in vivo microenvironment. In order to investigate the effects of secreted soluble factors on embryonic stem cell (ESC) behavior in a diffusion dominant microenvironment, we cultured mouse ESCs (mESCs) in a membrane-based two-chambered micro-bioreactor (MB). To avoid disturbing the cellular environment in the top chamber of the MB, only the culture medium of the bottom chamber was exchanged. Cell growth in the MB after 5 days of culture was similar to that in conventional 6-well plate (6-WP) and membrane-based Transwell insert (TW) cultures, indicating adequate nutrient supply in the MB. However, the cells retained higher expression of pluripotency markers (Oct4, Sox2 and Rex1) and secreted soluble factors (FGF4 and BMP4) in the MB. Inhibition of FGF4 activity in the MB and TW resulted in a similar cellular response. However, in contrast to the TW, inhibition of BMP4 activity revealed that autocrine action of the upregulated BMP4, which acted cooperatively with leukemia inhibitory factor (LIF), upregulated the pluripotency markers expression in the MB culture. We propose that BMP4 accumulated in the diffusion dominant microenvironment of the MB upregulated its own expression by a positive feedback mechanism-in contrast to the macro-scale culture systems-thereby enhancing the pluripotency of mESCs. The micro-scale culture platform developed in this study enables the investigation of the effects of soluble factors on ESCs in a diffusion dominant microenvironment, and is expected to be used to modulate the ESC fate choices.


Emricasan Improves Liver Function in Patients With Cirrhosis and High Model for End-Stage Liver Disease Scores Compared With Placebo.
Caspase-mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan-caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non-alcoholic steatohepatitis (NASH). We performed a multicenter study of 86 patients with cirrhosis (Child-Pugh class A or B; mean score, 6.9; 38% with alcohol-associated cirrhosis, 29% with HCV-associated cirrhosis, and 23% with NASH) and model for end-stage liver disease (MELD) scores of 11-18 (mean, 12.8). Patients were randomly assigned to groups given placebo (N = 42) or Emricasan (25 mg, N = 44), twice daily for 3 months; subjects then received open-label Emricasan (25 mg) twice-daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK-18) at month 3. Seventy-four patients completed the 3-month study period (40 given Emricasan and 34 given placebo); 69 patients received open-label Emricasan for 3 months afterward. At the 3-month timepoint, Emricasan significantly reduced mean MELD (P = .003) and Child-Pugh (P = .003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95% CI, -0.2882 to -0.0866) and total bilirubin (95% CI, -1.5069 to -0.0823) vs placebo. There were no significant differences between Emricasan and placebo groups in mean MELD (P = .466) or Child-Pugh (P = .124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given Emricasan (67%) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20%). Serum levels of full-length CK-18 (P = .02) and caspase 3/7 (P < .001), but not cleaved CK-18 (P = .092), decreased significantly at 3 months in the Emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasan's effects were generally maintained or increased after 6 months of treatment. In a randomized trial of patients with cirrhosis, we found 3 months treatment with Emricasan to improve liver function, compared with placebo, reducing MELD and Child-Pugh scores, INR, and total bilirubin in patients with MELD scores ≥15. ClinicalTrials.gov no: NCT02230670.


Environmental Chemical Diethylhexyl Phthalate Alters Intestinal Microbiota Community Structure and Metabolite Profile in Mice.
Exposure to environmental chemicals during windows of development is a potentially contributing factor in gut microbiota dysbiosis and linked to chronic diseases and developmental disorders. We used a community-level model of microbiota metabolism to investigate the effects of diethylhexyl phthalate (DEHP), a ubiquitous plasticizer implicated in neurodevelopmental disorders, on the composition and metabolite outputs of gut microbiota in young mice. Administration of DEHP by oral gavage increased the abundance of Lachnoclostridium, while decreasing Clostridium sensu stricto Addition of DEHP to in vitro-cultured cecal microbiota increased the abundance of Paenibacillus and Lachnoclostridium Untargeted metabolomics showed that DEHP broadly altered the metabolite profile in the culture. Notably, DEHP enhanced the production of p-cresol while inhibiting butyrate synthesis. Metabolic model-guided correlation analysis indicated that the likely sources of p-cresol are Clostridium species. Monoculture of Lachnoclostridium bolteae confirmed that it is capable of producing p-hydroxyphenylacetic acid, the immediate precursor of p-cresol, and that the species' growth is enhanced upon DEHP exposure. Taken together, these findings suggest a model where DEHP increases production of p-cresol, a bacterial metabolite linked with neurodevelopmental disorders, by expanding the abundance of species that synthesize the metabolite's precursor.IMPORTANCE Several previous studies have pointed to environmental chemical exposure during windows of development as a contributing factor in neurodevelopmental disorders and correlated these disorders with microbiota dysbiosis; however, little is known about how the chemicals specifically alter the microbiota to interfere with development. The findings reported in this paper unambiguously establish that a pollutant linked with neurodevelopmental disorders can directly modify the microbiota to promote the production of a potentially toxic metabolite (p-cresol) that has also been correlated with neurodevelopmental disorders. Furthermore, we used a novel modeling strategy to identify the responsible enzymes and bacterial sources of this metabolite. To the best of our knowledge, the present study is the first to characterize the functional consequence of phthalate exposure on a developed microbiota. Our results suggest that specific bacterial pathways could be developed as diagnostic and therapeutic targets against health risks posed by ingestion of environmental chemicals.


Phylogeography and population dynamics of dengue viruses in the Americas.
Changes in Dengue virus (DENV) disease patterns in the Americas over recent decades have been attributed, at least in part, to repeated introduction of DENV strains from other regions, resulting in a shift from hypoendemicity to hyperendemicity. Using newly sequenced DENV-1 and DENV-3 envelope (E) gene isolates from 11 Caribbean countries, along with sequences available on GenBank, we sought to document the population genetic and spatiotemporal transmission histories of the four main invading DENV genotypes within the Americas and investigate factors that influence the rate and intensity of DENV transmission. For all genotypes, there was an initial invasion phase characterized by rapid increases in genetic diversity, which coincided with the first confirmed cases of each genotype in the region. Rapid geographic dispersal occurred upon each genotype's introduction, after which individual lineages were locally maintained, and gene flow was primarily observed among neighboring and nearby countries. There were, however, centers of viral diversity (Barbados, Puerto Rico, Colombia, Suriname, Venezuela, and Brazil) that were repeatedly involved in gene flow with more distant locations. For DENV-1 and DENV-2, we found that a "distance-informed" model, which posits that the intensity of virus movement between locations is inversely proportional to the distance between them, provided a better fit than a model assuming equal rates of movement between all pairs of countries. However, for DENV-3 and DENV-4, the more stochastic "equal rates" model was preferred.


Oesophageal ulceration in HIV-infected patients.
To determine the aetiology of oesophageal ulceration in HIV-infected patients. A retrospective clinical, endoscopic and histopathological analysis of patients with confirmed HIV infection and an oesophageal ulcer diagnosed on endoscopy. A tertiary referral, gastrointestinal clinic in Cape Town. Fifty-one patients with HIV infection and oesophageal ulceration were seen from January 2001 to December 2007. Median CD4 count was 26 cells/microl. Mean age was 35.5 years. Sixty per cent of patients were female. Forty-nine per cent of oesophageal ulcers were idiopathic while 23% were caused by cytomegalovirus infection. The remainder were due to miscellaneous causes. A surprisingly small number of patients with HIV-associated oesophageal ulceration were seen during the study period. This may reflect local referral practices or the fact that patients with severe immunosuppression succumb before developing oesophageal ulcers. As in other series, idiopathic oesophageal ulcers and cytomegalovirus ulcers made up the majority of cases. Correct biopsy technique and appropriate histological and microbiological investigations are associated with improved diagnostic yield in these patients.


Micronutrients and Markers of Oxidative Stress and Inflammation Related to Cardiometabolic Health: Results from the EHES-LUX Study.
Metabolic syndrome (MetS) characteristics include chronic inflammation and elevated oxidative stress. This study assessed associations between circulating concentrations of micronutrients/phytochemicals and inflammatory/oxidative stress markers with MetS and MetS components. Adults (N = 606) from the European Health Examination Survey in Luxembourg (2013-2015) were randomly selected. We performed a multivariable logistic regression model using the least absolute shrinkage and selection operator to identify MetS-associated variables. Participants with MetS had higher concentrations of C-reactive protein (CRP), 8-iso-prostaglandin F2α, leptin, insulin, and vitamins E/A, but lower concentrations of adiponectin, beta-carotene, and oxidized low-density lipoprotein. A one-unit increase in log-CRP was associated with 51% greater odds of MetS (OR = 1.51 (95% CI: 1.16, 1.98)). Adults with a one-unit increase in log-leptin were 3.1 times more likely to have MetS (3.10 (2.10, 4.72)). Women with a one-unit increase in vitamin A were associated with 3% increased odds of MetS (1.03 (1.01, 1.05)), while those with a one-unit increase in log-adiponectin were associated with 82% decreased odds (0.18 (0.07, 0.46)). Chronic inflammation best characterized adults with MetS, as CRP, adiponectin, and leptin were selected as the main MetS determinants. Micronutrients did not seem to affect MetS, except for vitamin A in women.


Identification of three distinct peroxisomal protein import defects in patients with peroxisome biogenesis disorders.
Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease, and classical rhizomelic chondrodysplasia punctata are lethal genetic disorders caused by defects in peroxisome biogenesis. We report here a characterization of the peroxisomal matrix protein import capabilities of fibroblasts from 62 of these peroxisome biogenesis disorder patients representing all ten known complementation groups. Using an immunofluorescence microscopy assay, we identified three distinct peroxisomal protein import defects among these patients. Type-1 cells have a specific inability to import proteins containing the PTS1 peroxisomal targeting signal, type-2 cells have a specific defect in import of proteins containing the PTS2 signal, and type-3 cells exhibit a loss of, or reduction in, the import of both PTS1 and PTS2 proteins. Considering that the common cellular phenotype of Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum's disease has been proposed to be a complete defect in peroxisomal matrix protein import, the observation that 85% (40/47) of the type-3 cell lines imported a low but detectable amount of both PTS1 and PTS2 proteins was surprising. Furthermore, different cell lines with the type-3 defect exhibited a broad spectrum of different phenotypes; some showed a complete absence of matrix protein import while others contained 50-100 matrix protein-containing peroxisomes per cell. We also noted certain relationships between the import phenotypes and clinical diagnoses: both type-1 cell lines were from neonatal adrenoleukodystrophy patients, all 13 type-2 cell lines were from classical rhizomelic chondrodysplasia punctata patients, and the type-3 import defect was found in the vast majority of Zellweger syndrome (22/22), neonatal adrenoleukodytrophy (17/19), and infantile Refsum's disease (7/7) patients. Our finding that all type-1 cell lines were from the second complementation group (CG2), all 13 type-2 cell lines were from CG11, and that cells from the eight remaining complementation groups only exhibit the type-3 defect indicates that mutations in particular genes give rise to the different types of peroxisomal protein import defects. This hypothesis is further supported by correlations between certain complementation groups and particular type-3 subphenotypes: all patient cell lines belonging to CG3 and CG10 showed a complete absence of peroxisomal matrix protein import while those from CG6, CG7, and CG8 imported some peroxisomal matrix proteins. However, the fact that cell lines from within particular complementation groups (CG1, CG4) could have different matrix protein import characteristics suggests that allelic heterogeneity also plays an important role in generating different import phenotypes in certain patients.(ABSTRACT TRUNCATED AT 400 WORDS)


Drinking motives moderate the impact of pre-drinking on heavy drinking on a given evening and related adverse consequences--an event-level study.
To test whether (i) drinking motives predict the frequency of pre-drinking (i.e. alcohol consumption before going out); (ii) drinking motives predict HDGE (heavy drinking on a given evening: 4+ for women, 5+ for men) and related adverse consequences (hangover, injuries, blackouts, etc.), even when pre-drinking is accounted for, and (iii) drinking motives moderate the impact of pre-drinking on HDGE and consequences. Using the internet-based cellphone-optimized assessment technique (ICAT), participants completed a series of cellphone questionnaires every Thursday, Friday and Saturday evening over 5 weeks. French-speaking Switzerland. A total of 183 young adults [53% female, mean age (standard deviation) = 23.1 (3.1)] who completed 7828 questionnaires on 1441 evenings. Drinking motives assessed at baseline, alcohol consumption assessed at 8 p.m., 9 p.m., 10 p.m., 11 p.m. and midnight and consequences assessed at 11 a.m. the next day. Gender-separate multi-level models revealed that pre-drinking predicted HDGE (men: B = 2.17, P < 0.001; women: B = 2.12, P < 0.001) and alcohol-related consequences (men: B = 0.24, P < 0.01; women: B = 0.29, P < 0.001). Enhancement motives were found to predict HDGE (B = 0.48, P < 0.05) and related consequences (B = 0.09, P < 0.05) among men, while among women coping motives had the same effect (HDGE: B = 0.73, P < 0.001; consequences: B = 0.13, P < 0.01). With the exception of conformity motives among women (B = 0.54, P < 0.05), however, no drinking motive dimension predicted the frequency of pre-drinking, while coping and conformity motives moderated the impact of pre-drinking on HDGE (men, conformity: B = -1.57, P < 0.05) and its consequences (men, coping: B = -0.46, P < 0.01; women, coping: B = 0.76, P < 0.05). Among young adults in Switzerland, heavy weekend drinking and the related consequences seem to result from the combination of pre-drinking, level of negative reinforcement drinking for women and positive reinforcement drinking for men.


SCALING LIMITS OF A MODEL FOR SELECTION AT TWO SCALES.
The dynamics of a population undergoing selection is a central topic in evolutionary biology. This question is particularly intriguing in the case where selective forces act in opposing directions at two population scales. For example, a fast-replicating virus strain outcompetes slower-replicating strains at the within-host scale. However, if the fast-replicating strain causes host morbidity and is less frequently transmitted, it can be outcompeted by slower-replicating strains at the between-host scale. Here we consider a stochastic ball-and-urn process which models this type of phenomenon. We prove the weak convergence of this process under two natural scalings. The first scaling leads to a deterministic nonlinear integro-partial differential equation on the interval [0, 1] with dependence on a single parameter, λ. We show that the fixed points of this differential equation are Beta distributions and that their stability depends on λ and the behavior of the initial data around 1. The second scaling leads to a measure-valued Fleming-Viot process, an infinite dimensional stochastic process that is frequently associated with a population genetics.


Recent advances in digital holography [invited].
This article presents an overview of recent advances in the field of digital holography, ranging from holographic techniques designed to increase the resolution of microscopic images, holographic imaging using incoherent illumination, phase retrieval with incoherent illumination, imaging of occluded objects, and the holographic recording of depth-extended objects using a frequency-comb laser, to the design of an infrastructure for remote laboratories for digital-holographic microscopy and metrology. The paper refers to current trends in digital holography and explains them using new results that were recently achieved at the Institute for Applied Optics of the University Stuttgart.