KALK study: ultrasound guided needling and lavage (barbotage) with steroid injection versus sham barbotage with and without steroid injection - protocol for a randomized, double-blinded, controlled, multicenter study.
For the treatment of calcific tendinitis of the shoulder a variety of treatment regimes exist. Commonly used treatment measures include medication with oral analgesics, corticosteroid injections, extracorporeal shockwave therapy, ultrasound guided needling and lavage, and surgical treatment. Earlier cohort studies suggest that patients may benefit from these treatments, but there are few randomized studies and conflicting evidence about the effectiveness of the various treatments. In the present study we aim to compare the effectiveness of ultrasound guided needling and lavage (barbotage) together with a steroid injection to sham barbotage with and without an additional steroid injection. The study will be performed in six secondary-care institutions in Norway and Sweden. It is designed as a pragmatic, randomized, three-arm, parallel group, double-blinded, sham-controlled clinical trial with a 2-year follow-up. It will be performed on 210 patients, aged 30 years or older, presenting with painful arc, positive impingement sign and a calcium deposit > 5 mm. Randomization to one of the three treatment options will be performed by using an online central randomization system. The three treatment groups are barbotage together with a subacromial steroid injection (the barbotage group), sham barbotage together with a subacromial steroid injection (the steroid group) or sham barbotage without a subacromial steroid injection (the placebo group). In the placebo group the steroid injection will be replaced by a short-acting local anaesthetic. Standardized home-based post-treatment physiotherapy will be performed by all patients for 8 weeks. Follow-ups are at 2 and 6 weeks, 4, 8, 12 and 24 months after treatment was given and will be performed with the patients and the outcome assessors blinded for group assignment. Primary outcome will be the Oxford shoulder score at 4 month follow-up. Secondary outcome measures are the QuickDASH upper extremity score, the EQ-5D-5L general health score and visual analogue scales for pain at rest, during activity, and at night. The scientific evidence from this placebo-controlled trial will be of importance for future treatment recommendations in patients with calcific tendinitis. ClinicalTrials.gov: NCT02419040 , registered 10 April 2015 EudraCT: 2015-002343-34, registered 23 September 2015 (retrospectively registered).


Propofol and propofol-ketamine in pediatric patients undergoing cardiac catheterization.
We investigated the effects of propofol and propofol-ketamine on hemodynamics, sedation level, and recovery period in pediatric patients undergoing cardiac catheterization. We performed a prospective, randomized, double-blind study. The study included 60 American Society of Anesthesiologists physical status II or III (age range, 1 month-13 years) undergoing cardiac catheterization for evaluation of congenital heart disease. Propofol and ketamine were prepared in 5% glucose solution to a final concentration of 5 and 1 mg/ml, respectively; similar injectors containing 5% glucose solution only were prepared. Fentanyl (1 microg/kg) and propofol (1.5 mg/kg) were given to both groups. Then, group 1 received 0.5 ml/kg of 5% glucose and group 2 0.5 ml/kg of ketamine solution by an anesthesiologist who was unaware of the groups of patients. Local anesthesia with 1% lidocaine was administered before intervention in all patients. The noninvasively measured mean arterial pressure, heart rate, respiratory rate, and peripheral oxygen saturation were recorded at the baseline, following drug administration, at 3, 5, 10, 15, 20, and 30 minutes and then at 15-minute intervals until the end of the procedure. Additional drug and fentanyl requirements to maintain a sedation level of 4 or 5 were recorded. After the procedure, the time to a Steward recovery score of 6 and adverse effects in the first 24 hours were recorded. The number of patients with more than a 20% decrease in mean arterial pressure was 11 in group 1 and 3 in group 2 (p < 0.05). The number of patients who experienced more than a 20% decrease in heart rate was 12 in group 1 and 5 in group 2 (p = 0.054). Ten patients in group 1 and 3 patients in group 2 required additional fentanyl doses (p = 0.057). The number of additional propofol doses was lower in group 2 (p < 0.05). Propofol combined with low-dose ketamine preserves mean arterial pressure better without affecting the recovery and thus is a good option in pediatric patients undergoing cardiac catheterization.


Plasma membrane architecture protects Candida albicans from killing by copper.
The ability to resist copper toxicity is important for microbial pathogens to survive attack by innate immune cells. A sur7Δ mutant of the fungal pathogen Candida albicans exhibits decreased virulence that correlates with increased sensitivity to copper, as well as defects in other stress responses and morphogenesis. Previous studies indicated that copper kills sur7Δ cells by a mechanism distinct from the known resistance pathways involving the Crp1 copper exporter or the Cup1 metallothionein. Since Sur7 resides in punctate plasma membrane domains known as MCC/eisosomes, we examined overexpression of SUR7 and found that it rescued the copper sensitivity of a mutant that fails to form MCC/eisosomes (pil1Δ lsp1Δ), indicating that these domains act to facilitate Sur7 function. Genetic screening identified new copper-sensitive mutants, the strongest of which were similar to sur7Δ in having altered plasma membranes due to defects in membrane trafficking, cortical actin, and morphogenesis (rvs161Δ, rvs167Δ, and arp2Δ arp3Δ). Consistent with the mutants having altered plasma membrane organization, they were all more readily permeabilized by copper, which is known to bind phosphatidylserine and phosphatidylethanolamine and cause membrane damage. Although these phospholipids are normally localized to the intracellular leaflet of the plasma membrane, their exposure on the surface of the copper-sensitive mutants was indicated by increased susceptibility to membrane damaging agents that bind to these phospholipids. Increased copper sensitivity was also detected for a drs2Δ mutant, which lacks a phospholipid flippase that is involved in maintaining phospholipid asymmetry. Copper binds phosphatidylserine with very high affinity, and deleting CHO1 to prevent phosphatidylserine synthesis rescued the copper sensitivity of sur7Δ cells, confirming a major role for phosphatidylserine in copper sensitivity. These results highlight how proper plasma membrane architecture protects fungal pathogens from copper and attack by the immune system, thereby opening up new avenues for therapeutic intervention.


Growth factor gradients in vascular patterning.
Growth factor gradients regulate many developmental processes. VEGF-A is distributed in a graded fashion in growing tissues in order to direct sprouting of new vessels. Growth factor gradients can be formed by regulated production, retention, controlled release and degradation. VEGF-A production is controlled by hypoxia while its retention depends on the C-terminal heparin-binding motifs present in the longer splice-isoforms, VEGF164 and 188. This motif confers binding to the cell surface and the surrounding extracelluar matrix. The short isoform VEGF120 is diffusible and hence fails to direct endothelial tip cell migration. Conditional inactivation of heparan sulfate proteoglycans in the cells that produce VEGF results similarly in misguidance of the tip cells. Studying retinal developmental angiogenesis and pathological neovascularization side-by-side in the mouse retina, we find that endothelial tip cell guidance and stalk cell proliferation control are disrupted in neovascularization due to a loss of VEGF-A retention. The cause for this is proteolytic cleavage of VEGF-A by matrix metalloproteases (MMP) derived mostly from macrophages infiltrating the ischaemic retinal areas. Genetic or pharmacological inhibition of macrophage infiltration or MMP activity can rescue guided revascularization at the expense of pre-retinal neovascularization. Disruption of VEGF-A gradients provides a novel concept for the mechanism underlying pathological patterning in ocular disease.


English semantic feature production norms: An extended database of 4436 concepts.
A limiting factor in understanding memory and language is often the availability of large numbers of stimuli to use and explore in experimental studies. In this study, we expand on three previous databases of concepts to over 4000 words including nouns, verbs, adjectives, and other parts of speech. Participants in the study were asked to provide lists of features for each concept presented (a semantic feature production task), which were combined with previous research in this area. These feature lists for each concept were then coded into their root word form and affixes (i.e., cat and s for cats) to explore the impact of word form on semantic similarity measures, which are often calculated by comparing concept feature lists (feature overlap). All concept features, coding, and calculated similarity information is provided in a searchable database for easy access and utilization for future researchers when designing experiments that use word stimuli. The final database of word pairs was combined with the Semantic Priming Project to examine the relation of semantic similarity statistics on semantic priming in tandem with other psycholinguistic variables.


Mildly oxidized low density lipoprotein induces contraction of human endothelial cells through activation of Rho/Rho kinase and inhibition of myosin light chain phosphatase.
Mildly oxidized low density lipoprotein (mox-LDL) is critically involved in the early atherogenic responses of the endothelium and increases endothelial permeability through an unknown signal pathway. Here we show that (i) exposure of confluent human endothelial cells (HUVEC) to mox-LDL but not to native LDL induces the formation of actin stress fibers and intercellular gaps within minutes, leading to an increase in endothelial permeability; (ii) mox-LDL induces a transient decrease in myosin light chain (MLC) phosphatase that is paralleled by an increase in MLC phosphorylation; (iii) phosphorylated MLC stimulated by mox-LDL is incorporated into stress fibers; (iv) cytoskeletal rearrangements and MLC phosphorylation are inhibited by C3 transferase from Clostridium botulinum, a specific Rho inhibitor, and Y-27632, an inhibitor of Rho kinase; and (v) mox-LDL does not increase intracellular Ca(2+) concentration. Our data indicate that mox-LDL induces endothelial cell contraction through activation of Rho and its effector Rho kinase which inhibits MLC phosphatase and phosphorylates MLC. We suggest that inhibition of this novel cell signaling pathway of mox-LDL could be relevant for the prevention of atherosclerosis.


Pancreatitis-associated protein 2 modulates inflammatory responses in macrophages.
Pancreatitis-associated proteins (PAP) are stress-induced secretory proteins that are implicated in immunoregulation. Previous studies have demonstrated that PAP is up-regulated in acute pancreatitis and that gene knockdown of PAP correlated with worsening severity of pancreatitis, suggesting a protective effect for PAP. In the present study, we investigated the effect of PAP2 in the regulation of macrophage physiology. rPAP2 administration to clonal (NR8383) and primary macrophages were followed by an assessment of cell morphology, inflammatory cytokine expression, and studies of cell-signaling pathways. NR8383 macrophages which were cultured in the presence of PAP2 aggregated and exhibited increased expression of IL-1, IL-6, TNF-alpha, and IL-10; no significant change was observed in IL-12, IL-15, and IL-18 when compared with controls. Chemical inhibition of the NFkappaB pathway abolished cytokine production and PAP facilitated nuclear translocation of NF-kappaB and phosphorylation of IkappaB alpha inhibitory protein suggesting that PAP2 signaling involves this pathway. Cytokine responses were dose dependent. Interestingly, similar findings were observed with primary macrophages derived from lung, peritoneum, and blood but not spleen. Furthermore, PAP2 activity was inhibited by the presence of serum, inhibition which was overcome with increased PAP2. Our results demonstrate a new function for PAP2: it stimulates macrophage activity and likely modulates the inflammatory environment of pancreatitis.


The experimental determination of reliable biodegradation rates for mono-aromatics towards evaluating QSBR models.
Quantitative Structure Biodegradation Relationships (QSBRs) are a tool to predict the biodegradability of chemicals. The objective of this work was to generate reliable biodegradation data for mono-aromatic chemicals in order to evaluate and verify previously developed QSBRs models. A robust biodegradation test method was developed to estimate specific substrate utilization rates, which were used as a proxy for biodegradation rates of chemicals in pure culture. Five representative mono-aromatic chemicals were selected that spanned a wide range of biodegradability. Aerobic biodegradation experiments were performed for each chemical in batch reactors seeded with known degraders. Chemical removal, degrader growth and CO2 production were monitored over time. Experimental data were interpreted using a full carbon mass balance model, and Monod kinetic parameters (Y, Ks, qmax and μmax) for each chemical were determined. In addition, stoichiometric equations for aerobic mineralization of the test chemicals were developed. The theoretically estimated biomass and CO2 yields were similar to those experimentally observed; 35% (s.d ± 8%) of the recovered substrate carbon was converted to biomass, and 65% (s.d ± 8%) was mineralised to CO2. Significant correlations were observed between the experimentally determined specific substrate utilization rates, as represented by qmax and qmax/Ks, at high and low substrate concentrations, respectively, and the first order biodegradation rate constants predicted by a previous QSBR study. Similarly, the correlation between qmax and selected molecular descriptors characterizing the chemicals structure in a previous QSBR study was also significant. These results suggest that QSBR models can be reliable and robust in prioritising chemical half-lives for regulatory screening purposes.


Cumulative Kidney Complication Risk by 50 Years of Type 1 Diabetes: The Effects of Sex, Age, and Calendar Year at Onset.
A common belief is that only a minority of patients with type 1 diabetes (T1D) develop advanced kidney disease and that incidence is higher among men and lower in those diagnosed at a younger age. However, because few patients with T1D survived to older ages until recently, long-term risks have been unclear. We examined the 50-year cumulative kidney complication risk in a childhood-onset T1D cohort diagnosed during 1950-80 (n = 932; mean baseline age 29 years, duration 19 years). Participants comprised 144 who died prior to baseline, 130 followed with periodic surveys, and 658 followed with biennial surveys and a maximum of nine examinations for 25 years. Micro- and macroalbuminuria were defined as an albumin excretion rate of 20-199 and ≥200 μg/min, respectively, and end-stage renal disease (ESRD) was defined as dialysis or kidney transplantation. Cumulative incidence was estimated at 10-year intervals between 20 and 50 years, duration and compared by calendar year of diabetes onset. By 50 years, T1D duration, ESRD affected 60% of the cohort; macroalbuminuria, 72%; and microalbuminuria, 88%. Little evidence existed for declines in cumulative incidence in recent cohorts, except for ESRD (microalbuminuria 3% increase, macroalbuminuria no change; ESRD 45% decrease by 40 years of T1D duration). Onset before age 6 years was associated with the lowest risk; incidence generally did not differ by sex. Some degree of kidney disease in T1D is virtually universal at long durations and not declining, which has major implications for formulating health care and research strategies. ESRD has declined, but continues to affect >25% of the population by 40 years, duration.


[Anemia in the first year of life and its relation to breast-feeding].
Many studies in this field justify the hypothesis that early weaning is one of the causes of anemia in the first year of life. This study seeks to discover the prevalence of iron deficiency anemia and its relation to the duration of breast-feeding among infants aged 0-12 months. A sample of 317 infants of four school health centers in the city of S. Paulo (Brazil) was studied. The information about diet was obtained by interviewing the mothers. The presence of anemia was verified by hemoglobin concentration, using the cianometahemoglobin method, and the criteria recommended by the World Health Organization (WHO) were utilized for the diagnosis. The duration of exclusive breast feeding was calculated by using the life table technique for censored data. The prevalence of anemia was found to be 14.5% for the whole population and 22.6% for infants aged more than 180 days. No association was found between anemia and time of breast-feeding; the median time were the same for both groups, anemic and non-anemic. The results observed are more probably related to the demographic characteristics of the population studied and by no means lessen the importance of exclusive breast feeding in the prevention of anemia.


The consequences of mitochondrial amyloid beta-peptide in Alzheimer's disease.
The Abeta (amyloid-beta peptide) has long been associated with Alzheimer's disease, originally in the form of extracellular plaques. However, in the present paper we review the growing evidence for the role of soluble intracellular Abeta in the disease progression, with particular reference to Abeta found within the mitochondria. Once inside the cell, Abeta is able to interact with a number of targets, including the mitochondrial proteins ABAD (amyloid-binding alcohol dehydrogenase) and CypD (cyclophilin D), which is a component of the mitochondrial permeability transition pore. Interference with the normal functions of these proteins results in disruption of cell homoeostasis and ultimately cell death. The present review explores the possible mechanisms by which cell death occurs, considering the evidence presented on a molecular, cellular and in vivo level.


Mortality of aluminum reduction plant workers, 1950 through 1977.
The mortality experience of 5,406 men (cohort I) employed at one aluminum smelter on Jan. 1, 1950, and 485 men employed at a second plant (cohort II) on Jan. 1, 1951, is reported. For each man, the total number of years of exposure to tars, the number of years since first exposure to tars, and an index of exposure to tars expressed in tar-years were calculated. More than 99% of the men in the first cohort and 98% of the men in the second cohort were traced. Of the 1,539 men in cohort I who were deceased as of December 31, 1977, death certificates were obtained for 1,432 (93%). Of the 92 men in cohort II who were deceased as of December 31, 1977, death certificates were obtained for 80 (87%). The results showed that men in cohort I died of the following causes at approximately the same rate as or less frequently than men of similar age in the Province of Quebec: tuberculosis; circulatory disease; hypertensive heart disease; trauma; leukemia and aleukemia; and malignant neoplasms of the pancreas, genital organs, brain, intestine, and rectum and other abdominal areas. There were no deaths from pneumoconiosis or Alzheimer's disease. Although the observed and expected numbers of deaths in some of the cause-of-death categories were small, men in cohort I died of the following causes more frequently than did men of similar age in the Province of Quebec: respiratory disease; pneumonia and bronchitis; malignant neoplasms (all sites); malignant neoplasms of the stomach and esophagus, bladder, and lung; other malignant neoplasms; Hodgkin's disease; and other hypertensive disease. Mortality from malignant neoplasms of the bladder and lung was meaningfully related to numbers of tar-years and of years of exposure. Exposure-response relationships were less clear for malignant neoplasms of the esophagus and stomach and for other malignancies. Mortality from respiratory disease for men with 21 or more tar-years of exposure was approximately twice that of persons never exposed to tars. The apparent excess of other hypertensive disease was restricted to men never exposed to tars. Malignant neoplasm of the lung was the only cause of death in cohort II that was in excess of that expected at Quebec provincial rates.


Confirmation of food origin claims by fourier transform infrared spectroscopy and chemometrics: extra virgin olive oil from Liguria.
The aim of this study was to explore the potential of Fourier transform infrared spectroscopy and various chemometric tools for confirming the geographic origin of olive oil from Liguria (northern Italy). Authentic extra virgin olive oil samples (n = 913) from three harvests (2004-2007) were collected from Italy, France, Spain, Greece, Cyprus, and Turkeyapproximately one-fourth of all samples originated in Liguria. Attenuated total reflectance spectra were recorded at room temperature; the analytical challenge was to confirm that an oil which claimed to be from Liguria originated there. Derivative and standard normal variate data pretreatments were applied to the recorded spectra, which were subsequently analyzed by a number of multivariate proceduresprincipal component analysis, factorial discriminant analysis, and partial least-squares regression analysis. Prediction models created using samples from all three harvests had sensitivities and selectivities of approximately 0.80.


[Dependence of the duration of inhibition of the hypophyseo-adrenal cortex system on the dose of administered hydrocortisone in rats].
The effect of various doses of hydrocortisone on the functioning of the hypophyseal-adrenocortical system was studied in experiments on rats. The administration of increasing amounts of hydrocortisone (at a single dose of 100 micrograms 300 micrograms/100 g twice a day for 2 days) resulted in a prolonged period of the inhibition of basal and stress factor-induced corticosterone secretion. The stress reaction of the hypophyseal-adrenocortical system changed under the influence of hydrocortisone to a lesser degree than adrenal hormone basal secretion. An increase in the amount of administered hydrocortisone demonstrated a gradual transition from physiological inhibition of the hypophyseal-adrenocortical system to pathologically prolonged inhibition similar to that known in clinical practice.


Migration history and risk of psychosis: results from the multinational EU-GEI study.
Psychosis rates are higher among some migrant groups. We hypothesized that psychosis in migrants is associated with cumulative social disadvantage during different phases of migration. We used data from the EUropean Network of National Schizophrenia Networks studying Gene-Environment Interactions (EU-GEI) case-control study. We defined a set of three indicators of social disadvantage for each phase: pre-migration, migration and post-migration. We examined whether social disadvantage in the pre- and post-migration phases, migration adversities, and mismatch between achievements and expectations differed between first-generation migrants with first-episode psychosis and healthy first-generation migrants, and tested whether this accounted for differences in odds of psychosis in multivariable logistic regression models. In total, 249 cases and 219 controls were assessed. Pre-migration (OR 1.61, 95% CI 1.06-2.44, p = 0.027) and post-migration social disadvantages (OR 1.89, 95% CI 1.02-3.51, p = 0.044), along with expectations/achievements mismatch (OR 1.14, 95% CI 1.03-1.26, p = 0.014) were all significantly associated with psychosis. Migration adversities (OR 1.18, 95% CI 0.672-2.06, p = 0.568) were not significantly related to the outcome. Finally, we found a dose-response effect between the number of adversities across all phases and odds of psychosis (⩾6: OR 14.09, 95% CI 2.06-96.47, p = 0.007). The cumulative effect of social disadvantages before, during and after migration was associated with increased odds of psychosis in migrants, independently of ethnicity or length of stay in the country of arrival. Public health initiatives that address the social disadvantages that many migrants face during the whole migration process and post-migration psychological support may reduce the excess of psychosis in migrants.


Metabolic syndrome among individuals with heroin use disorders on methadone therapy: Prevalence, characteristics, and related factors.
Observational studies have reported a high prevalence of obesity and diabetes in subjects on methadone therapy; there are, however, limited data about metabolic syndrome. The aim of the study was to evaluate the prevalence of metabolic syndrome and related factors in individuals with heroin use disorder on methadone therapy. A cross-sectional study in individuals with heroin use disorder on methadone therapy at a drug abuse outpatient center. Medical examinations and laboratory analyses after a 12-hour overnight fast were recorded. Metabolic syndrome was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III (ATP III) criteria. One hundred and twenty-two subjects were included, with a mean age of 46.1 ± 9 years, a median body mass index (BMI) of 25.3 kg/m2 (interquartile range [IQR]: 21.2-28), and 77.9% were men. Median exposure to methadone therapy was 13 years (IQR: 5-20). Overweight and obesity were present in 29.5% and 17.2% of the participants, respectively. Metabolic syndrome components were low high-density lipoprotein (HDL) cholesterol (51.6%), hypertriglyceridemia (36.8%), high blood pressure (36.8%), abdominal obesity (27.0%), and raised blood glucose levels (18.0%). Abdominal obesity was more prevalent in women (52% vs. 20%, P = >0.01) and high blood pressure more prevalent in men (41.1% vs. 22.2%, P = .07). Prevalence of metabolic syndrome was 29.5% (95% confidence interval [CI]: 16.6-31.8). In the multivariate logistic regression analysis, BMI (per 1 kg/m2 increase odds ratio [OR]: 1.49, 95% CI: 1.27-1.76) and exposure time to methadone therapy (per 5 years of treatment increase OR: 1.38, 95% CI: 1.28-1.48) were associated with metabolic syndrome. Overweight and metabolic syndrome are prevalent findings in individuals with heroin use disorder on methadone therapy. Of specific concern is the association of methadone exposure with metabolic syndrome. Preventive measures and clinical routine screening should be recommended to prevent metabolic syndrome in subjects on methadone therapy.


Longitudinal follow-up in acute and transient psychotic disorders and schizophrenia.
We prospectively studied the long-term course of individuals with acute and transient psychotic disorders and a control group with positive schizophrenia matched for age and gender. Follow-up investigations using standardised instruments were performed at three time-points covering 7 years after the index episode or 12 years after the first episode. During follow-up, those with positive schizophrenia experienced a deterioration in their general functioning whereas those with acute and transient psychotic disorders retained their high level of functioning. At the end of the observation period, 12 out of 39 (31%) of those with acute and transient psychotic disorders were functioning well without medication compared with 0 out of 38 with positive schizophrenia.


Systematic literature review on effectiveness of self-management support interventions in patients with chronic conditions and low socio-economic status.
To assess the quality of evidence and determine the effect of patient-related and economic outcomes of self-management support interventions in chronically ill patients with a low socio-economic status. Integrated evidence on self-management support interventions in chronically ill people with low socio-economic status is lacking. Systematic literature review. Cochrane database of trials, PubMed, CINAHL, Web of Science, PsycINFO and Joanna Briggs Institute Library were searched (2000-2013). Randomized controlled trials addressing self-management support interventions for patients with cardiovascular disease, stroke, cancer, diabetes and/or chronic respiratory disease were included. Data extraction and quality assessment were performed by independent researchers using a data extraction form. Studies (n = 27) focused mainly on diabetes. Fourteen studies cited an underlying theoretical basis. Most frequently used self-management support components were lifestyle advice, information provision and symptom management. Problem-solving and goal-setting strategies were frequently integrated. Eleven studies adapted interventions to the needs of patients with a low socio-economic status. No differences were found for interventions developed based on health behaviour theoretical models. Limited evidence was found for self-management support interventions in chronically ill patients with low socio-economic status. Essential characteristics and component(s) of effective self-management support interventions for these patients could not be detected. Rigorous reporting on development and underlying theories in the intervention is recommended.


Assessing Patient-Reported Satisfaction with Appearance and Quality of Life following Rhinoplasty Using the FACE-Q Appraisal Scales.
Patient satisfaction with appearance and improved quality of life are primary outcomes in cosmetic surgery. The purpose of this study was to assess changes in patient satisfaction with facial and nose appearance, and quality of life following rhinoplasty. Patients presenting for rhinoplasty completed the FACE-Q, a new patient-reported outcome instrument composed of scales that measure outcomes in patients undergoing facial cosmetic procedures. The following FACE-Q scales were used: satisfaction with facial appearance overall, satisfaction with nose, psychological well-being, and social function. Fifty-six patients completed the FACE-Q at the time of their preoperative consultation and/or at postoperative follow-up visits. Among all patients presenting for rhinoplasty, FACE-Q scores (range, 0 to 100) increased following the procedure in satisfaction with facial appearance (+26.5; p < 0.01), psychological well-being (+15.7; p < 0.01), and social function (+13.7; p = 0.03). Satisfaction with nose item scores (range, 1 to 4) all increased significantly from before to after rhinoplasty, including in satisfaction with nose appearance in the mirror (+1.4; p < 0.01), size (+1.1; p < 0.01), shape (+1.5; p < 0.01), profile (+1.6; p < 0.01), and in photographs (+1.6; p < 0.01). Similar results were seen among a subgroup of patients who completed the FACE-Q scales both before and after rhinoplasty. In an objective study using a validated patient-reported outcome instrument, improvements in satisfaction with facial and nose appearance and quality of life were demonstrated among rhinoplasty patients. This model supports the successful outcomes possible in rhinoplasty. Therapeutic, IV.


Artificial intelligence in medical consultation systems: a review.
A history of artificial intelligence (AI) in medicine is presented. Pre-1970 medical consultation systems are described briefly. Early prototypes of AI consultation systems are then examined. The shift from predominantly general-problem solving research to domain-specific knowledge-based systems research is discussed. Two phases in the evolution of ideas during the period from 1975-82 are distinguished. From 1975 to 1978, prototype systems were fully developed and subjected to critical testing, while giving rise to generalizations. During the period from 1978 to 1982, the first general system-building frameworks were produced. The reexamination of the foundations of medical consultation systems and the shift to rule-based systems during the period 1982 to 1987 are discussed.


Cycle to cycle variability in a repetitive upper extremity task.
The purpose of this study was to examine the variability in muscle activity at rest and work during a repetitive task. A total of 20 participants performed a bimanual push task using three frequencies (4, 8, 16 pushes/min), three loads (1 kg, 2 kg, 4 kg) and two grip conditions (no grip, 30% maximum). The coefficient of variation (CoV) of muscle activity was determined for the anterior deltoid, biceps brachii, extensor digitorum and flexor digitorum superficialis. Faster push frequencies and heavier loads had lower work-rest ratio CoV and higher mean muscle activity (p < 0.01). Sixteen pushes per minute produced the lowest CoV for the anterior deltoid (p < 0.01), while the 1- kg load produced the lowest CoV for the extensor digitorum and flexor digitorum superficialis (p < 0.01). Changes were driven by the rest phase rather than by the work phase, except for grip decreasing forearm muscle CoV. These findings underscore the importance of variability at rest and indicate that low variability of muscle activity is associated with ergonomic risk factors. Decreased motor variability has been associated with pain and injury. A cyclical push task, evaluated in terms of work and rest phases, found that greater workloads increased variability primarily due to changes in the rest phase. Muscle variability, especially for the rest phase, may provide insight into injury risk.


Radiological protocol in spinal trauma: literature review and Spinal Cord Society position statement.
The Spinal Cord Society constituted a panel tasked with reviewing the literature on the radiological evaluation of spinal trauma with or without spinal cord injury and recommend a protocol. This position statement provides recommendations for the use of each modality, i.e., radiographs (X-rays), computed tomography (CT), magnetic resonance imaging (MRI), as well as vascular imaging, and makes suggestions on identifying or clearing spinal injury in trauma patients. PubMed was searched for the corresponding keywords from January 1, 1980, to August 1, 2017. A MEDLINE search was subsequently undertaken after applying MeSH filters. Appropriate cross-references were retrieved. Out of the 545 articles retrieved, 105 relevant papers that address the present topic were studied and the extracted content was circulated for further discussions. A draft position statement was compiled and circulated among the panel members via e-mail. The draft was modified by incorporating relevant suggestions to reach a consensus. For imaging cervical and thoracolumbar spine trauma patients, CT without contrast is generally considered to be the initial line of imaging and radiographs are required if CT is unavailable or unaffordable. CT screening in polytrauma cases is best done with a multidetector CT by utilizing the reformatted images obtained when scanning the chest, abdomen, and pelvis (CT-CAP). MRI is indicated in cases with neurological involvement and advanced cervical degenerative changes and to determine the extent of soft tissue injury, i.e., disco-ligamentous injuries as well as epidural space compromise. MRI is also usually performed when X-rays and CT are unable to correlate with patient symptomatology. These slides can be retrieved under Electronic Supplementary Material.


Multiple traumatic limb loss: a comparison of Vietnam veterans to OIF/OEF servicemembers.
Multiple-limb loss due to war-theater injuries results in a unique group of servicemembers requiring intensive rehabilitation and diverse prosthetic devices. This article compares the Vietnam and the Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) groups with war-theater-associated multiple-limb loss to document significant changes in health status, prosthetic-device use, and long-term prognosis. During 2007 and 2008, a national survey queried 73 Vietnam veterans and 61 OIF/OEF servicemembers sustaining multiple-limb loss. Average years since limb loss are 39 for Vietnam veterans and 3 for OIF/OEF servicemembers. Self-rated health status was excellent or very good in 38.9% of the Vietnam group and 60.7% of the OIF/OEF group (p = 0.01). More of the OIF/OEF group than the Vietnam group reported performing high-impact aerobic activities, 18% versus 3% (p = 0.005). The OIF/OEF group currently uses more diverse prosthetic-device types than the Vietnam group. Based on Vietnam veterans' 39-year experience, the long-term prognosis for OIF/OEF servicemembers with multiple-limb loss is an active, fulfilling life. The healthcare team caring for these patients should carefully address proper prosthesis fit and maintenance of good health and function.


Can all healthy adults use the current evidential breath alcohol analysers? An investigation using a large spirometry database.
People failing to give a specimen of breath at a police station are assumed to be deliberately obstructive and are charged with Failure to Provide under the Road Traffic Act 1988. However, spirometry records of 281,210 healthy individuals from UK BioBank showed that a significant minority cannot use existing evidential breath analysis machines. Women were three times more likely to be unable to use them than men (1.64% vs 0.54%) with the risk rising with age six-fold from those in their 40s (0.43%) to 2.7% in their 70s, with women more affected (0.65% to 3.8%). Short stature was a further risk factor: 2.6% of men and 3.8% of women below the 2nd percentile of height could not use the current machines, with almost one in ten elderly, short women unable to do so, while smokers aged 50+ were twice as likely as non-smokers of the same age to be unable to provide breath specimens.


Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010.
Although stroke is the second leading cause of death worldwide, no comprehensive and comparable assessment of incidence, prevalence, mortality, disability, and epidemiological trends has been estimated for most regions. We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) to estimate the global and regional burden of stroke during 1990-2010. We searched Medline, Embase, LILACS, Scopus, PubMed, Science Direct, Global Health Database, the WHO library, and WHO regional databases from 1990 to 2012 to identify relevant studies published between 1990 and 2010.We applied the GBD 2010 analytical technique (DisMod-MR), based on disease-specific, pre-specified associations between incidence, prevalence, and mortality, to calculate regional and country-specific estimates of stroke incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) lost by age group (<75 years, ≥ 75 years, and in total)and country income level (high-income, and low-income and middle-income) for 1990, 2005, and 2010. We included 119 studies (58 from high-income countries and 61 from low-income and middle-income countries). From 1990 to 2010, the age-standardised incidence of stroke significantly decreased by 12% (95% CI 6-17)in high-income countries, and increased by 12% (-3 to 22) in low-income and middle-income countries, albeit nonsignificantly. Mortality rates decreased significantly in both high income (37%, 31-41) and low-income and middle income countries (20%, 15-30). In 2010, the absolute numbers of people with fi rst stroke (16・9 million), stroke survivors (33 million), stroke-related deaths (5・9 million), and DALYs lost (102 million) were high and had significantly increased since 1990 (68%, 84%, 26%, and 12% increase, respectively), with most of the burden (68・6% incident strokes, 52・2% prevalent strokes, 70・9% stroke deaths, and 77・7% DALYs lost) in low-income and middle-income countries. In 2010, 5・2 million (31%) strokes were in children (aged <20 years old) and young and middle-aged adults(20-64 years), to which children and young and middle-aged adults from low-income and middle-income countries contributed almost 74 000 (89%) and 4・0 million (78%), respectively, of the burden. Additionally, we noted significant geographical differences of between three and ten times in stroke burden between GBD regions and countries. More than 62% of new strokes, 69・8% of prevalent strokes, 45・5% of deaths from stroke, and 71・7% of DALYs lost because of stroke were in people younger than 75 years. Although age-standardised rates of stroke mortality have decreased worldwide in the past two decades,the absolute number of people who have a stroke every year, stroke survivors, related deaths, and the overall global burden of stroke (DALYs lost) are great and increasing. Further study is needed to improve understanding of stroke determinants and burden worldwide, and to establish causes of disparities and changes in trends in stroke burden between countries of different income levels. Bill & Melinda Gates Foundation.


Scalable High-Affinity Stabilization of Magnetic Iron Oxide Nanostructures by a Biocompatible Antifouling Homopolymer.
Iron oxide nanostructures have been widely developed for biomedical applications because of their magnetic properties and biocompatibility. In clinical applications, stabilization of these nanostructures against aggregation and nonspecific interactions is typically achieved using weakly anchored polysaccharides, with better-defined and more strongly anchored synthetic polymers not commercially adopted because of their complexity of synthesis and use. Here, we show for the first time stabilization and biocompatibilization of iron oxide nanoparticles by a synthetic homopolymer with strong surface anchoring and a history of clinical use in other applications, poly(2-methacryloyloxyethyl phosphorylcholine) [poly(MPC)]. For the commercially important case of spherical particles, binding of poly(MPC) to iron oxide surfaces and highly effective individualization of magnetite nanoparticles (20 nm) are demonstrated. Next-generation high-aspect-ratio nanowires (both magnetite/maghemite and core-shell iron/iron oxide) are, furthermore, stabilized by poly(MPC) coating, with the nanowire cytotoxicity at large concentrations significantly reduced. The synthesis approach exploited to incorporate functionality into the poly(MPC) chain is demonstrated by random copolymerization with an alkyne-containing monomer for click chemistry. Taking these results together, poly(MPC) homopolymers and random copolymers offer a significant improvement over current iron oxide nanoformulations, combining straightforward synthesis, strong surface anchoring, and well-defined molecular weight.


Chinese Materia Medica in Treating Depression: The Role of Intestinal Microenvironment.
Depression is a highly heterogeneous mental illness. Drug treatment is currently the main therapeutic strategy used in the clinic, but its efficacy is limited by the modulation of a single target, slow onset, and side effects. The gut-brain axis is of increasing interest because intestinal microenvironment disorders increase susceptibility to depression. In turn, depression affects intestinal microenvironment homeostasis by altering intestinal tissue structure, flora abundance and metabolism, hormone secretion, neurotransmitter transmission, and immune balance. Depression falls into the category of "stagnation syndrome" according to Traditional Chinese Medicine (TCM), which further specifies that "the heart governs the spirit and is exterior-interior with the small intestine". However, the exact mechanisms of the means by which the disordered intestinal microenvironment affects depression are still unclear. Here, we present an overview of how the Chinese materia medica (CMM) protects against depression by repairing intestinal microenvironment homeostasis. We review the past five years of research progress in classical antidepressant TCM formulae and single CMMs on regulating the intestinal microenvironment for the treatment of depression. We then analyze and clarify the multitarget functions of CMM in repairing intestinal homeostasis and aim to provide a new theoretical basis for CMM clinical application in the treatment of depression.


Lung allograft rejection in the rat. V. Inhaled stimuli aggravate the rejection response.
Responses to inhaled stimuli in lung allografts might intensify the rejection response against the grafts. Therefore, we investigated the rejection of lung allografts in rats exposed to various degrees of stimuli via the airways. A group of these rats was selectively decontaminated to eliminate infection of the graft. Stimuli provided were intrabronchially injected purified protein derivative in sensitized rats and dust inhaled from sawdust used as bedding in the cages. Both intrabronchially injected purified protein derivative and stimuli inhaled from sawdust were found to aggravate lung allograft rejection, thus shortening mean graft survival from 32 to 11 days. Selective decontamination did prolong lung graft survival (p less than 0.05) because it lowered the overall immune reactivity of the recipient rats. For clinical lung transplantation, these observations suggest that patients should be selectively decontaminated and protected against inhalation of exogenous stimuli during a rejection episode.


LncRNA FOXC2-AS1 regulated proliferation and apoptosis of vascular smooth muscle cell through targeting miR-1253/FOXF1 axis in atherosclerosis.
Atherosclerosis (AS) is the most dangerous factor for human death, which is responsible for coronary heart disease. Growing evidence has showed that long non-coding RNAs (lncRNAs) are involved in the development of AS. In this study, we mainly aimed at investigating the roles of FOXC2-AS1 in AS patients. RT-PCR was performed to detect the expressions of FOXC2-AS1 and miR-1253 in serum samples of AS patients (n=35) and healthy volunteer (n=35). The correlation between FOXC2-AS1 and miR-1253 was further analyzed. Human vascular smooth muscle cells (VSMCs) were respectively treated with ox-LDL, IL-6, CRP, TNF-α and IL-8 to explore the affecting factors. P-FOXC2-AS1 was constructed and transfected into VSMCs. Cell proliferation abilities were measured by CCK-8 assay. Cell apoptotic rates were measured by flow cytometry (FACS) analysis. Western blot (WB) was performed to detect protein levels of FOXF1, Bcl-2, Bax and Cleaved Caspase3. Finally, luciferase gene reporter assay was performed to prove the relationships between FOXC2-AS1 and miR-1253, miR-1253 and FOXF1. We found that FOXC2-AS1 was significantly upregulated in AS patients, which could be induced by ox-LDL and IL-6 in VSMCs. MiR-1253 was decreased in AS patients, which was negatively correlated with FOXC2-AS1. Furthermore, FOXC2-AS1 overexpression promoted proliferation and inhibited apoptosis in VSMCs. Luciferase gene reporter assay showed that FOXC2-AS1 could bind to miR-1253 in VSMCs and 293 cells. Moreover, miR-1253 overexpression inhibited proliferation and promoted apoptosis of VSMCs. Luciferase reporter assay proved that miR-1253 could target at FOXF1 in VSMCs and 293 cells, which was reported to be associated with cell proliferation and apoptosis in some cancers. Additionally, miR-1253 mimic or GSK343, a FOXF1 inhibitor, was respectively transfected into VSMCs with p-FOXC2-AS1. Results showed that the promoted cell proliferation and inhibited cell apoptosis were reversed as well, confirming that FOXC2-AS1 promoted cell proliferation and inhibited apoptosis via miR-1253/FOXF1 signaling axis in AS patients. According to the results, we found that FOXC2-AS1 was upregulated in AS patients; furthermore, FOXC2-AS1 overexpression promoted cell proliferation and inhibited cell apoptosis via targeting miR-1253/FOXF1 signaling axis. Our results elucidated a potential mechanism underlying the role of FOXC2-AS1, which might be used as a promising marker and a potential target for AS patients.


Person-centered approaches in the study of personality disorders.
Existing categorical models of personality disorder diagnoses capture heterogeneous populations in terms of symptom presentation and etiological influences on personality pathology. Though several well-validated alternative dimensional trait models (i.e., variable-centered approaches) of personality disorders have been developed, person-centered approaches can provide important additional information on both the phenotypic expression and etiology of personality pathology. We discuss the utility and necessary attributes of person-centered or subtype models of personality disorders and briefly review statistical approaches and other methodological considerations, drawing specific examples from the psychopathy literature. We conclude by advocating a utilitarian approach whereby person-centered and variable-centered methods complement each other to better understand personality disorders. (PsycINFO Database Record


The Australasian Society for Infectious Diseases and Refugee Health Network of Australia recommendations for health assessment for people from refugee-like backgrounds: an abridged outline.
In 2009, the Australasian Society of Infectious Diseases published guidelines on the post-arrival health assessment of recently arrived refugees. Since then, the number of refugees and asylum seekers reaching Australia has increased substantially (17 555 refugees in 2015-16) and the countries of origin have changed. These groups are likely to have had poor access to health care pre-arrival and, consequently, are at risk of a range of chronic and infectious diseases. We established an advisory group that included infectious diseases physicians, general practitioners, public health specialists, paediatricians and refugee health nurses to update the 2009 guidelines.Main recommendations: All people from refugee-like backgrounds, including children, should be offered a tailored comprehensive health assessment and management plan, ideally within 1 month of arrival in Australia. This can be offered at any time if initial contact with a GP or clinic is delayed. Recommended screening depends on history, examination and previous investigations, and is tailored based on age, gender, countries of origin and transit and risk profile. The full version of the guidelines is available at http://www.asid.net.au/documents/item/1225.Changes in management as a result of this guideline: These guidelines apply to all people from refugee-like backgrounds, including asylum seekers. They provide more information about non-communicable diseases and consider Asia and the Middle East as regions of origin as well as Africa. Key changes include an emphasis on person-centred care; risk-based rather than universal screening for hepatitis C virus, malaria, schistosomiasis and sexually transmissible infections; updated immunisation guidelines; and new recommendations for other problems, such as nutritional deficiencies, women's health and mental health.


Nanoscale heat transfer--from computation to experiment.
Heat transfer can differ distinctly at the nanoscale from that at the macroscale. Recent advancement in computational and experimental techniques has enabled a large number of interesting observations and understanding of heat transfer processes at the nanoscale. In this review, we will first discuss recent advances in computational and experimental methods used in nanoscale thermal transport studies, followed by reviews of novel thermal transport phenomena at the nanoscale observed in both computational and experimental studies, and discussion on current understanding of these novel phenomena. Our perspectives on challenges and opportunities on computational and experimental methods are also presented.


Functional Connectivity Analysis of Visually Evoked ERPs for Mild Cognitive Impairment: Pilot Study.
Mild cognitive impairment (MCI) is considered the early stage of Alzheimer's disease, characterized as mild memory loss. A novel method of functional connectivity (FC) analysis can be used to detect MCI before memory is significantly impaired allowing for preventative measures to be taken. FC examines interactions between EEG channels to grant insight on underlying neural networks and analyze the effects of MCI. Applying FC method of weighted phase lag index (wPLI) to P300 ERPs provided insight on the link between the pathology of Alzheimer's disease and cognitive loss. wPLI was analyzed per frequency band (θ, α, μ, β) and by channel combination groups (intra-hemispheric short, intra-hemispheric long, inter-hemispheric short, inter-hemispheric long, transverse). MCI was found to have a statistically significant lower ΔwPLIP300 compared to normal controls in the μ intra-hemispheric short (p = 0.0286), μ intra-hemispheric long (p = 0.0477), μ inter-hemispheric short (p = 0.0018) and the α intra-hemispheric short (p = 0.0423). Results indicate a possible deficiency in the dorsal visual processing pathway among MCI subjects as well as an unbalanced coordination between the two hemispheres.


Arthropathy, ankylosing spondylitis, and clubbing of fingers in ulcerative colitis.
In a retrospective study of 399 patients with ulcerative colitis, 27 patients had colitic arthritis, 17 had ankylosing spondylitis, and 20 had clubbing of the fingers. Colitic arthritis and ankylosing spondylitis were not related to severity, extent of involvement, or duration of colitis. A significant association between colitic arthropathy and other complications of ulcerative colitis, such as pseudopolyposis, perianal disease, eye lesions, skin eruptions, aphthous ulceration, and liver disease has been demonstrated. The outcome of the first referred attack of colitis in the presence of colitic arthritis and ankylosing spondylitis remained uninfluenced. Clubbing of fingers was related to severity, extent of involvement, and length of the history of colitis. A significant association between clubbing of the fingers and carcinoma of the colon, pseudopolyposis, toxic dilatation, and arthropathy has been shown. The frequency of surgical intervention in patients with clubbing was higher but the overall mortality was not significantly different from the patients without clubbing.


[Prognosis of an acute pancreatitis and its postop course].
Dynamical investigation of clinical and laboratory indexes in 108 patients, in whom 155 operative interventions were performed for destructive pancreatitis, was done. The statistically trustworthy difference in the indexes obtained in the patients was established after performance of the first operation and in those who were reoperated on.


Overcoming the phage replication threshold: a mathematical model with implications for phage therapy.
Prior observations of phage-host systems in vitro have led to the conclusion that susceptible host cell populations must reach a critical density before phage replication can occur. Such a replication threshold density would have broad implications for the therapeutic use of phage. In this report, we demonstrate experimentally that no such replication threshold exists and explain the previous data used to support the existence of the threshold in terms of a classical model of the kinetics of colloidal particle interactions in solution. This result leads us to conclude that the frequently used measure of multiplicity of infection (MOI), computed as the ratio of the number of phage to the number of cells, is generally inappropriate for situations in which cell concentrations are less than 10(7)/ml. In its place, we propose an alternative measure, MOI(actual), that takes into account the cell concentration and adsorption time. Properties of this function are elucidated that explain the demonstrated usefulness of MOI at high cell densities, as well as some unexpected consequences at low concentrations. In addition, the concept of MOI(actual) allows us to write simple formulas for computing practical quantities, such as the number of phage sufficient to infect 99.99% of host cells at arbitrary concentrations.


In vivo cardiovascular effects of the new atypical neuroleptic sertindole.
The goal of this open clinical study was to perform a detailed investigation of the cardiovascular effects of the novel atypical neuroleptic sertindole. Thirty initially untreated schizophrenic inpatients (diagnosed according to DSM-III-R) underwent a total of 103 serial recordings of standardized autonomic tests during a sertindole dose titration programme (4-16 mg/d). The autonomic test battery included: (1) conventional ECGs with 12 channels, (2) computer-assisted analysis of the 5-min resting heart rate variability (HRV); (3) HRV during standard autonomic reflex tests (deep breathing test, 30:15 ratio); and (4) blood pressure measurement under resting conditions and during orthostatic stress (Schellong test). Reference values for the HRV study were obtained from healthy controls ( n =80). The most important findings were: (1) sertindole significantly increased the resting heart rate; (2) sertindole induced a significant and probably dose-dependent prolongation of the frequency-corrected QT-times, while mean PQ-conduction times remained unchanged; (3) sertindole had no significant effects on autonomic parasympathetic tone, both in the resting study and following the autonomic reflex tests; and (4) sertindole at doses between 4 and 16 mg/d did not significantly influence blood pressure either under resting conditions or during orthostatic stress. The implications of these findings for the cardiovascular safety and tolerance of sertindole are discussed comprehensively, while considering the pathophysiologically relevant mechanisms underlying the appearance of life-threatening cardiac arrhythmias and sudden cardiac death. ( Int J Psych Clin Pract 2001; 5:33-40).


Influence of School-Based Smoking Prevention Education on Reducing Gap in Exposure to Anti-Tobacco Media Message among Korean Adolescents.
Korean adolescents at high risk for smoking are less exposed to anti-tobacco media messages. This study examines whether school-based smoking prevention education is related to media exposure and whether it can contribute to reducing the gap in exposure to anti-tobacco media messages between smoking vulnerable and non-vulnerable groups. A nationally representative dataset, the 2018 Korea youth risk behavior web-based survey, comprising 59,410 students from grades 7-12, was analyzed. Logistic regression models were designed to evaluate the association between school-based smoking prevention education and media messages exposure. Within-group differences in exposure levels based on sociodemographic characteristics were compared depending on participation or nonparticipation in school-based smoking prevention education. Experience of smoking prevention education within a year was significantly associated with exposure to anti-tobacco media messages. Among Korean adolescents who participated in smoking prevention education compared to those who did not, the media messages exposure rate was more than 20% higher, and the exposure gap within the subgroups by sociodemographic characteristics was narrower. Participation in school-based smoking prevention education was significantly related to media messages exposure. This relationship can be used to improve the overall media messages exposure rate and to reduce the differences in exposure rate based on sociodemographic traits.


[Experience with sevelamer in peritoneal dialysis].
Sevelamer is a non-absorbable phosphorus chelator that is not a source of aluminium, calcium or base. The clinical experience with sevelamer in peritoneal dialysis and in daily clinical practice is scarce. The aim of this study is to evaluate the results of therapy of hyperphosphoremia with sevelamer on serum phosphorus and phosphorus chelators requirements, in a peritoneal dialysis clinical practice. Sevalamer 400 mg was prescribed to peritoneal dialysis patients with hyperphosphoremia who were treated with aluminium hydroxide or with calcium salts in the absence of hypocalcemia. Fourteen patients completed 12 months of therapy. The initial sevelamer dose was 2,280 +/- 760 mg/day, and was increased to 2,760 +/- 1,160 mg/day at 12 months. At 12 months no patient was on aluminium salts and calcium salts had been significantly reduced. Phosphoremia (5.9 +/- 0.6 to 5.0 +/- 1.4 mg/dL, p = 0.049), calcium-phosphorus product (59.8 +/- 5.8 to 48.6 +/- 12.5 mg2/dL2, p = 0.01) and serum cholesterol (191 +/- 29 to 167 +/- 33 mg/dL, p = 0.02) decreased at 12 months. No significant changes were observed in serum triglycerides, total CO2 or PTH. Serum alkaline phosphatase increased at 6 months, but values returned to normal at 12 months. No changes were observed in serum gamma-glutamyl-transpeptidase. Five patients were started on 1.25 (OH)2 vitamin D therapy. In peritoneal dialysis patients, sevelamer allows a satisfactory control of serum phosphorus levels and calcium-phosphorus product, while decreasing the amount of aluminium and calcium salts prescribed.


Hypoxia induces phenotypic plasticity and therapy resistance in melanoma via the tyrosine kinase receptors ROR1 and ROR2.
An emerging concept in melanoma biology is that of dynamic, adaptive phenotype switching, where cells switch from a highly proliferative, poorly invasive phenotype to a highly invasive, less proliferative one. This switch may hold significant implications not just for metastasis, but also for therapy resistance. We demonstrate that phenotype switching and subsequent resistance can be guided by changes in expression of receptors involved in the noncanonical Wnt5A signaling pathway, ROR1 and ROR2. ROR1 and ROR2 are inversely expressed in melanomas and negatively regulate each other. Furthermore, hypoxia initiates a shift of ROR1-positive melanomas to a more invasive, ROR2-positive phenotype. Notably, this receptor switch induces a 10-fold decrease in sensitivity to BRAF inhibitors. In patients with melanoma treated with the BRAF inhibitor vemurafenib, Wnt5A expression correlates with clinical response and therapy resistance. These data highlight the fact that mechanisms that guide metastatic progression may be linked to those that mediate therapy resistance. These data show for the fi rst time that a single signaling pathway, the Wnt signaling pathway, can effectively guide the phenotypic plasticity of tumor cells, when primed to do so by a hypoxic microenvironment. Importantly, this increased Wnt5A signaling can give rise to a subpopulation of highly invasive cells that are intrinsically less sensitive to novel therapies for melanoma, and targeting the Wnt5A/ROR2 axis could improve the efficacy and duration of response for patients with melanoma on vemurafenib.


High quality, high throughput, and low-cost simultaneous video recording of 60 animals in operant chambers using PiRATeMC.
The development of Raspberry Pi-based recording devices for video analyses of drug self-administration studies has shown to be promising in terms of affordability, customizability, and capacity to extract in-depth behavioral patterns. Yet, most video recording systems are limited to a few cameras making them incompatible with large-scale studies. We expanded the PiRATeMC (Pi-based Remote Acquisition Technology for Motion Capture) recording system by increasing its scale, modifying its code, and adding equipment to accommodate large-scale video acquisition, accompanied by data on the throughput capabilities, video fidelity, synchronicity of devices, and comparisons between the Raspberry Pi 3B+ and 4B models. Using PiRATeMC default recording parameters resulted in minimal storage (∼350MB/h), high throughput (< ∼120 seconds/Pi), high video fidelity, and synchronicity within ∼0.02 seconds, affording the ability to simultaneously record 60 animals in individual self-administration chambers at a fraction of current commercial costs. No consequential differences were found between Raspberry Pi 3B+ and 4B models. This system allows greater acquisition of video data simultaneously than other video recording systems by an order of magnitude with less storage needs and lower costs. Additionally, we report in-depth quantitative assessments of throughput, fidelity, and synchronicity, displaying real-time system capabilities. The system presented is able to be fully installed in a month's time by a single technician and provides a scalable, low cost, and quality-assured procedure with a high-degree of customization and synchronicity between recording devices, capable of recording a large number of subjects with high turnover in a variety of species and settings.


Expression and Characterization of Serotype 2 Streptococcus suis Arginine Deiminase.
Arginine deiminase (ArcA) has been speculated to facilitate the intracellular survival of Streptococcus suis under acidic conditions. However, the physical and biological properties and function of SS2-ArcA have not yet been elucidated. Recombinant SS2-ArcA (rSS2-ArcA) was expressed and purified using Ni-NTA affinity chromatography. Under various pH and temperature conditions, the enzymatic properties of purified rSS2-ArcA and crude native SS2-ArcA were determined. The SS2-arcA-deduced amino acid sequence contained a conserved catalytic triad (Cys399-His273-Glu218). The optimum temperature and pH of 47-kDa rSS2-ArcA and crude native SS2-ArcA were 42°C and pH 7.2. The rSS2-ArcA and crude native SS2-ArcA were stable for 3 h at 4 and 25°C, respectively. The pH stability and dependency tests suggested that rSS2-ArcA and crude native SS2-ArcA were functionally active in acidic conditions. The L-arginine substrate binding affinity (Km) values of rSS2-ArcA (specific activity 16.00 U/mg) and crude native SS2-ArcA (specific activity 0.23 U/mg) were 0.058 and 0.157 mM, respectively. rSS2-ArcA exhibited a weak binding affinity with the common ArcA inhibitors L-canavanine and L-NIO. Furthermore, the partial inactivation of SS2-ArcA significantly impaired the viability and growth of SS2 at pH 4.0, 6.0, and 7.5. This study profoundly demonstrated the involvement of ArcA enzymatic activity in S. suis survival under acidic conditions.


Antiplasmodial activities of homogentisic acid derivative protein kinase inhibitors isolated from a Vanuatu marine sponge Pseudoceratina sp.
As part of our search for new antimalarial drugs in South Pacific marine sponges, we have looked for inhibitors of Pfnek-1, a specific protein kinase of Plasmodium falciparum. On the basis of promising activity in a preliminary screening, the ethanolic crude extract of a new species of Pseudoceratina collected in Vanuatu was selected for further investigation. A bioassay-guided fractionation led to the isolation of a derivative of homogentisic acid [methyl (2,4-dibromo-3,6-dihydroxyphenyl)acetate, 4a] which inhibited Pfnek-1 with an IC(50) around 1.8 muM. This product was moderately active in vitro against a FcB1 P. falciparum strain (IC(50) = 12 muM). From the same sponge, we isolated three known compounds [11,19-dideoxyfistularin-3 (1), 11-deoxyfistularin-3 (2) and dibromo-verongiaquinol (3)] which were inactive against Pfnek-1. Synthesis and biological evaluation of some derivatives of 4a are reported.


Effects of automatic/controlled access processes on semantic memory in Alzheimer's disease.
This study examines the impact of automatic/controlled access processes on the semantic network in 30 patients with Alzheimer's disease (AD). The AD group was compared with a control group using a battery of neuropsychological tests, a variation of Hodges's semantic testing battery, designed to assess semantic knowledge. The AD group had markedly lower scores than the normal group on each semantic test, but with a different degree of deterioration depending on the nature of the processes (controlled/automatic) in accessing the semantic network. AD patients had poorer performances on the explicit semantic tasks mainly involving controlled-process access (e.g., the WAIS Similarities Subtest) than those involving mainly automatic-process access (e.g., the Verbal Automatism test). Analyses of confidence intervals allowed a gradient of impaired performances in increasing order to be elaborated: a) the Verbal Automatism test, b) the WAIS Vocabulary Subtest, c) the WAIS Information Subtest, d) the Letter Fluency Task, e) Naming as a Response to Definition, f) the Category Fluency Task, g) the WAIS Similarities Subtest, and h) the Oral Denomination 80 Test. The results of our study suggest that explicit semantic tasks needing passive or automatic processes to access semantic memory would be better preserved in AD.


Two Novel er1 Alleles Conferring Powdery Mildew (Erysiphe pisi) Resistance Identified in a Worldwide Collection of Pea (Pisum sativum L.) Germplasms.
Powdery mildew caused by Erysiphe pisi DC. severely affects pea crops worldwide. The use of resistant cultivars containing the er1 gene is the most effective way to control this disease. The objectives of this study were to reveal er1 alleles contained in 55 E. pisi-resistant pea germplasms and to develop the functional markers of novel alleles. Sequences of 10 homologous PsMLO1 cDNA clones from each germplasm accession were used to determine their er1 alleles. The frame shift mutations and various alternative splicing patterns were observed during transcription of the er1 gene. Two novel er1 alleles, er1-8 and er1-9, were discovered in the germplasm accessions G0004839 and G0004400, respectively, and four known er1 alleles were identified in 53 other accessions. One mutation in G0004839 was characterized by a 3-bp (GTG) deletion of the wild-type PsMLO1 cDNA, resulting in a missing valine at position 447 of the PsMLO1 protein sequence. Another mutation in G0004400 was caused by a 1-bp (T) deletion of the wild-type PsMLO1 cDNA sequence, resulting in a serine to leucine change of the PsMLO1 protein sequence. The er1-8 and er1-9 alleles were verified using resistance inheritance analysis and genetic mapping with respectively derived F2 and F2:3 populations. Finally, co-dominant functional markers specific to er1-8 and er1-9 were developed and validated in populations and pea germplasms. These results improve our understanding of E. pisi resistance in pea germplasms worldwide and provide powerful tools for marker-assisted selection in pea breeding.


Venus clouds: a dirty hydrochloric Acid model.
The spectral and polarization data for Venus are consistent with micrometer-sized aerosol cloud particles of hydrochloric acid with soluble and insoluble iron compounds, whose source could be volcanic or crustal dust. The yellow color of the clouds could be due to absorption bands in the near ultraviolet involving ferric iron and chlorine complexes. The ultraviolet features could arise from variations in the concentrations of iron and hydrochloric acid in the cloud particles.


Grey and white matter differences in Chronic Fatigue Syndrome - A voxel-based morphometry study.
Investigate global and regional grey and white matter volumes in patients with Chronic Fatigue Syndrome (CFS) using magnetic resonance imaging (MRI) and recent voxel-based morphometry (VBM) methods. Forty-two patients with CFS and thirty healthy volunteers were scanned on a 3-Tesla MRI scanner. Anatomical MRI scans were segmented, normalized and submitted to a VBM analysis using randomisation methods. Group differences were identified in overall segment volumes and voxel-wise in spatially normalized grey matter (GM) and white matter (WM) segments. Accounting for total intracranial volume, patients had larger GM volume and lower WM volume. The voxel-wise analysis showed increased GM volume in several structures including the amygdala and insula in the patient group. Reductions in WM volume in the patient group were seen primarily in the midbrain, pons and right temporal lobe. Elevated GM volume in CFS is seen in areas related to processing of interoceptive signals and stress. Reduced WM volume in the patient group partially supports earlier findings of WM abnormalities in regions of the midbrain and brainstem.


Powering microbes with electricity: direct electron transfer from electrodes to microbes.
The discovery of electrotrophs, microorganisms that can directly accept electrons from electrodes for the reduction of terminal electron acceptors, has spurred the investigation of a wide range of potential applications. To date, only a handful of pure cultures have been shown to be capable of electrotrophy, but this process has also been inferred in many studies with undefined consortia. Potential electron acceptors include: carbon dioxide, nitrate, metals, chlorinated compounds, organic acids, protons and oxygen. Direct electron transfer from electrodes to cells has many advantages over indirect electrical stimulation of microbial metabolism via electron shuttles or hydrogen production. Supplying electrons with electrodes for the bioremediation of chlorinated compounds, nitrate or toxic metals may be preferable to adding organic electron donors or hydrogen to the subsurface or bioreactors. The most transformative application of electrotrophy may be microbial electrosynthesis in which carbon dioxide and water are converted to multi-carbon organic compounds that are released extracellularly. Coupling photovoltaic technology with microbial electrosynthesis represents a novel photosynthesis strategy that avoids many of the drawbacks of biomass-based strategies for the production of transportation fuels and other organic chemicals. The mechanisms for direct electron transfer from electrodes to microorganisms warrant further investigation in order to optimize envisioned applications.


Anticancer drug discovery using chemical genomics.
Cancer is the leading cause of death in United States and World wide. Drug discovery and development for cancer therapeutics takes several years before a patient is benefited from a new drug. The average time length from start to finish is approximately 15 years. This time length includes 4-5 years of basic research, discovery, preclinical development and validation studies. Next, it takes approximately 7-10 years for a drug to go through human clinical trials. This time length is too long and need to be shortened to benefit patients quickly from new technologies and product development ideas. Furthermore, with the recent explosion of genomics and proteomics information, it is now becoming difficult to make rapid and logical decisions on hundreds of potential drug targets available. Thus, there is immediate need to develop and integrate tools and technologies that will not only reduce the time length but also the risk of late clinical drug failure. Chemical Genomics is an emerging field in which tools and technologies from biology and chemistry are utilized in a parallel and cyclic fashion very early in the development process. In addition chemical genomics proposes to integrate latest developments in tools and technologies from a variety of modern fields such as combinatorial chemistry, informatics, synthesis chemistries, cell based assays, microarrays, genomics and proteomics tools to accelerate drug discovery and development. Thus, in cancer therapeutics the aim of chemical genomics is not only to reduce the time length of pre-clinical development but also the risk of late clinical failure by making smart decisions early in the process.


Comparison of alemtuzumab vs. antithymocyte globulin induction therapy in primary non-sensitized renal transplant patients treated with rapid steroid withdrawal.
Alemtuzumab and rabbit antithymocyte globulin (rATG) are commonly used for induction therapy in renal transplantation. This retrospective, single-center, cohort study evaluated cumulative incidence of one-yr biopsy-proven acute rejection (BPAR) among 200 consecutive primary non-sensitized kidney transplant recipients who received either alemtuzumab (n = 100) or rATG (n = 100) induction followed by rapid steroid taper, tacrolimus, and mycophenolate mofetil. Protocol biopsies, plasma and urine BK virus PCR, serum creatinine and iothalamate glomerular filtration rate (iGFR), were obtained at 1, 4, and 12 months from transplantation. The one-yr BPAR rates were similar between the alemtuzumab and rATG groups; however, rejection Banff IA and higher was more common in the alemtuzumab arm (18% vs. 5%, p = 0.047). After adjusting for confounding variables, alemtuzumab was still associated with Banff IA and higher rejection (adjusted OR: 3.7, CI: 1.2-10.5, p = 0.02). Despite similar rates of BK viremia, more patients in the alemtuzumab arm developed BK nephropathy (16% vs. 3%, p = 0.046). One-year iGFR (53.4 ± 20.2 vs. 71.9 ± 27.2 mL/min/1.73 m(2), p = 0.002) and three-yr graft survival (89.5% vs. 95%, p = 0.05) were lower in the alemtuzumab group. In low immunological risk kidney transplant recipients on steroid-free immunosuppression, alemtuzumab was associated with more severe rejection and BK nephropathy compared to rATG.


The Relationship Between Body Mass Index and Fluoroscopy Time During Intraarticular Hip Injection: A Multicenter Cohort Study.
Higher body mass index (BMI) is associated with difficulty in obtaining imaging studies. While there is a small body of literature regarding the relationship between fluoroscopy time and BMI during injections for pain management, this has not been studied for intraarticular (IA) hip injections. Further, in academic training centers, trainee involvement may affect this relationship. To determine the relationship between BMI and fluoroscopy time during IA hip injections, both with and without involvement of a trainee. Multicenter retrospective cohort study. Three academic, outpatient musculoskeletal and pain medicine centers. Patients who underwent fluoroscopically guided IA hip injections with encounter data regarding fluoroscopy time during the procedure and BMI were included. Mean and standard deviation fluoroscopy time were recorded. Comparisons were made between BMI categories of normal (18.5 - 24.9 kg/m2), overweight (25.0 - 29.9 kg/m2), and obese (greater than or equal to30.0 kg/m2). Statistical significance was set at P = 0.01 due to multiple comparisons. A total of 559 IA hip injections are represented in this cohort. Patients had a mean age of 58 (standard deviation [SD] 14) years and 63% were women. There was no significant difference in fluoroscopy time when comparing BMI categories (P = 0.02). However, when trainees were not involved in the injection, fluoroscopy times were significantly shorter with decreasing BMI category, with normal weight patients requiring the shortest fluoroscopy times (P = 0.01). This study evaluated total fluoroscopy time, not radiation dose exposure per injection, which provides more direct and precise information with regard to provider and patient radiation exposure and overall safety. Future study of the impact of BMI on radiation dose during fluoroscopically guided IA hip injections is needed. Fluoroscopy times during IA hip injections increase with higher BMI categories in a statistically significant manner when performed by experienced clinicians but this relationship is not observed when injections are performed with a trainee in a teaching institution. This finding appears to be related to longer fluoroscopy time required to complete an IA hip injection in patients with lower BMI when a trainee is involved. Hip, injections, obesity, overweight, body mass index, fluoroscopy, radiation, pain.


Perioperative anesthetic risk of noncardiac surgery in hypertrophic obstructive cardiomyopathy.
To determine their perioperative risk, we reviewed the records of 35 patients with hypertrophic cardiomyopathy diagnosed by cardiac ultrasound and/or catheterization who underwent general (52) or spinal (four) anesthesia--a total of 56 major surgical procedures. There were no operative or related perioperative deaths and no significant ventricular tachyarrhythmias. Intraoperative or postoperative complications included: myocardial infarction with heart failure in one patient who also had coronary artery disease and was one of three patients who had spinal anesthesia, arrhythmia requiring therapy in eight, and angina during supraventricular tachycardia in one. We conclude that the risk of general anesthesia and major noncardiac surgery is low in patients with hypertrophic obstructive cardiomyopathy. Spinal anesthesia, which decreases systemic vascular resistance and increases capacitance, may be relatively contraindicated. Concomitant coronary artery disease may increase the risk.


Clinical Characteristics of Patients with Myocarditis following COVID-19 mRNA Vaccination: A Systematic Review and Meta-Analysis.
COVID-19 mRNA vaccinations have recently been implicated in causing myocarditis. Therefore, the primary aim of this systematic review and meta-analysis was to investigate the clinical characteristics of patients with myocarditis following mRNA vaccination. The secondary aims were to report common imaging and laboratory findings, as well as treatment regimes, in these patients. A literature search was performed from December 2019 to June 2022. Eligible studies reported patients older than 18 years vaccinated with mRNA, a diagnosis of myocarditis, and subsequent outcomes. Pooled mean or proportion were analyzed using a random-effects model. Seventy-five unique studies (patient n = 188, 89.4% male, mean age 18-67 years) were included. Eighty-six patients had Moderna vaccines while one hundred and two patients had Pfizer-BioNTech vaccines. The most common presenting symptoms were chest pain (34.5%), fever (17.1%), myalgia (12.4%), and chills (12.1%). The most common radiologic findings were ST-related changes on an electrocardiogram (58.7%) and hypokinesia on cardiac magnetic resonance imaging or echocardiography (50.7%). Laboratory findings included elevated Troponin I levels (81.7%) and elevated C-reactive protein (71.5%). Seven patients were admitted to the intensive care unit. The most common treatment modality was non-steroid anti-inflammatory drugs (36.6%) followed by colchicine (28.5%). This meta-analysis presents novel evidence to suggest possible myocarditis post mRNA vaccination in certain individuals, especially young male patients. Clinical practice must therefore take appropriate pre-cautionary measures when administrating COVID-19 mRNA vaccinations.


Molecular Pathways of Interferon-Stimulated Gene 15: Implications in Cancer.
Human interferon-stimulated gene 15 (ISG15) is a 15-kDa ubiquitin-like protein that can be detected as either free ISG15 or covalently associated with its target proteins through a process termed ISGylation. Interestingly, extracellular free ISG15 has been proposed as a cytokinelike protein, whereas ISGylation is a posttranslational modification. ISG15 is a small protein with implications in some biological processes and pathologies that include cancer. This review highlights the findings of both free ISG15 and protein ISGylation involved in several molecular pathways, emerging as central elements in some cancer types.


[Antimicrobial sensitivity of the environmental microbiota in the intensive care units of a peruvian hospital].
The objective was to detect Gram-negative bacilli and Gram-positive cocci isolated from the environmental microbiota of the Intensive Care Unit (ICU) departments of Neonatology, Pediatrics, and Transplants (kidney, liver, and general) in a Lima hospital and determine their antimicrobial sensitivity. Eighty samples were obtained from inanimate surfaces using a wet swab. A total of 61 bacterial strains were identified, including Staphylococcus epidermis (46.0%), Alcaligenes sp. (21.3%), Pseudomonas aeruginosa (16.4%), Acinetobacter sp. (13.1%), Staphylococcus aureus (1.6%), and Staphylococcus haemolyticus (1.6%). Acinetobacter sp. and P. aeruginosa showed a heightened sensitivity to the antibiotics assessed, while Alcaligenes sp. and S. epidermidis presented the highest antimicrobial resistance. It is recommended that sustained asepsis and monitoring methods be used in ICUs.


Reversion of B cell commitment upon loss of Pax5 expression.
The transcription factor Pax5 is essential for initiating B cell lineage commitment, but its role in maintaining commitment is unknown. Using conditional Pax5 inactivation in committed pro-B cells, we demonstrate that Pax5 is required not only to initiate its B lymphoid transcription program, but also to maintain it in early B cell development. As a consequence of Pax5 inactivation, previously committed pro-B cells regained the capacity to differentiate into macrophages in vitro and to reconstitute T cell development in vivo in RAG2-/- mice. Hence, Pax5 expression is continuously required to maintain B cell lineage commitment, because its loss converts committed pro-B cells into hematopoietic progenitors with multilineage potential.


The 2014 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension.
Herein, updated evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in Canadian adults are detailed. For 2014, 3 existing recommendations were modified and 2 new recommendations were added. The following recommendations were modified: (1) the recommended sodium intake threshold was changed from ≤ 1500 mg (3.75 g of salt) to approximately 2000 mg (5 g of salt) per day; (2) a pharmacotherapy treatment initiation systolic blood pressure threshold of ≥ 160 mm Hg was added in very elderly (age ≥ 80 years) patients who do not have diabetes or target organ damage (systolic blood pressure target in this population remains at < 150 mm Hg); and (3) the target population recommended to receive low-dose acetylsalicylic acid therapy for primary prevention was narrowed from all patients with controlled hypertension to only those ≥ 50 years of age. The 2 new recommendations are: (1) advice to be cautious when lowering systolic blood pressure to target levels in patients with established coronary artery disease if diastolic blood pressure is ≤ 60 mm Hg because of concerns that myocardial ischemia might be exacerbated; and (2) the addition of glycated hemoglobin (A1c) in the diagnostic work-up of patients with newly diagnosed hypertension. The rationale for these recommendation changes is discussed. In addition, emerging data on blood pressure targets in stroke patients are discussed; these data did not lead to recommendation changes at this time. The Canadian Hypertension Education Program recommendations will continue to be updated annually.


Bayesian semiparametric regression models for evaluating pathway effects on continuous and binary clinical outcomes.
Many statistical methods for microarray data analysis consider one gene at a time, and they may miss subtle changes at the single gene level. This limitation may be overcome by considering a set of genes simultaneously where the gene sets are derived from prior biological knowledge. Limited work has been carried out in the regression setting to study the effects of clinical covariates and expression levels of genes in a pathway either on a continuous or on a binary clinical outcome. Hence, we propose a Bayesian approach for identifying pathways related to both types of outcomes. We compare our Bayesian approaches with a likelihood-based approach that was developed by relating a least squares kernel machine for nonparametric pathway effect with a restricted maximum likelihood for variance components. Unlike the likelihood-based approach, the Bayesian approach allows us to directly estimate all parameters and pathway effects. It can incorporate prior knowledge into Bayesian hierarchical model formulation and makes inference by using the posterior samples without asymptotic theory. We consider several kernels (Gaussian, polynomial, and neural network kernels) to characterize gene expression effects in a pathway on clinical outcomes. Our simulation results suggest that the Bayesian approach has more accurate coverage probability than the likelihood-based approach, and this is especially so when the sample size is small compared with the number of genes being studied in a pathway. We demonstrate the usefulness of our approaches through its applications to a type II diabetes mellitus data set. Our approaches can also be applied to other settings where a large number of strongly correlated predictors are present.


C-H bond functionalization by dual catalysis: merging of high-valent cobalt and photoredox catalysis.
The merger of transition metal catalysis and photocatalysis has emerged as a versatile platform that opened the gateway to diverse low-energy pathways for several synthetic transformations. However, amidst the first-row transition metals, directed C-H bond functionalization mediated by high-valent cobalt catalysis has advanced with rising momentum owing to its unique reactivity and the ability to participate in both one- and two-electron transfer reactions. However, the use of expensive, privileged Cp* ligands or use of stoichiometric silver(I) or manganese(III) is unavoidable. Despite significant advances in their respective fields, the combination of these two "green" approaches to further the vested interest of the scientific research community towards the development of ecofriendly and sustainable protocols is noticeably limited. Thus, the methodology based on high-cobalt-photoredox dual-catalytic strategy has high dormant potential and is worthy to explore. Herein, we highlight the recent advances in the high-valent cobalt-catalyzed sustainable catalytic approach by harnessing light energy for oxidative C-H bond functionalization. With this, we hope to inspire the development of unexplored cobalt-photoredox-catalyzed reactions with improved efficiency and selectivity.


A script for initiating molecular biology studies with non-conventional yeasts based on Saccharomycopsis schoenii.
Non-conventional yeasts (NCYs), i.e. all yeasts other than Saccharomyces cerevisiae, are emerging as novel production strains and gain more and more attention to exploit their unique properties. Yet, these yeasts can hardly compete against the advanced methodology and genetic tool kit available for exploiting and engineering S. cerevisiae. Currently, for many NCYs one has to start from scratch to initiate molecular genetic manipulations, which is often time consuming and not straight-forward. More so because utilization of S. cerevisiae tools based on short-flank mediated homologous recombination or plasmid biology are not readily applicable in NCYs. Here we present a script with discrete steps that will lead to the development of a basic and expandable molecular toolkit for ascomycetous NCYs and will allow genetic engineering of novel platform strains. For toolkit development the highly efficient in vivo recombination efficiency of S. cerevisiae is utilized in the generation and initial testing of tools. The basic toolkit includes promoters, reporter genes, selectable markers based on dominant antibiotic resistance genes and the generation of long-flanking homology disruption cassettes. The advantage of having pretested molecular tools that function in a heterologous host facilitate NCY strain manipulations. We demonstrate the usefulness of this script on Saccharomycopsis schoenii, a predator yeast with useful properties in fermentation and fungal biocontrol.


[Methotrexate as inducer of proinflammatory cytokines by epithelial cells].
Methotrexate (MTX), a drug commonly used in childhood cancer, has also been indicated as a cytotoxic agent of the oral mucosa, which can trigger the inflammatory process and increase the vascularity of epithelial tissues during the early stages of oral mucositis. The aim of this study was to determine the production of proinflammatory cytokines IL-1beta, IL-6 y TNF-alpha in epithelial cell cultures treated with MTX. Epithelial cells of human larynx, obtained from the cell line Hep-2, were cultured with different doses of MTX during different incubation times. The drug cytotoxicity was analyzed by means of the colorimetric test, which is based on the metabolic reduction of the bromide of 3-(4, 5-dimetiltiazol-2-ilo)-2,5-difeniltetrazol (MTT); and the proinflammatory cytokines production by the test enzyme-linked immunosorbent assay (ELISA). Cultures of HEp-2 cells showed increased production of proinflammatory cytokines at 72 hours with 0.32 microM of MTX. These results suggest that depending on the dose and exposure time, MTX alters the physiology of human epithelial cells, which may play an important role during the phases of initiation and development of oral mucositis.


Surgical management of epilepsy due to cerebral cavernomas using neuronavigation and intraoperative MR imaging.
Cure from seizures due to cavernomas might be surgically achieved dependent on both, the complete removal of the cavernoma as well as its surrounding hemosiderin rim. High field intraoperative MRI imaging (iopMRI) and neuronavigation might play a crucial role to achieve both goals. We retrospectively investigated the long-term results and impact of intraoperative 1·5T MRI (iopMRI) and neuronavigation on the completeness of surgical removal of a cavernous malformation (CM) and its perilesional hemosiderin rim as well as reduction of surgical morbidity. 26 patients (14 female, 12 male, mean age 39·1 years, range: 17-63 years) with CM related epilepsy were identified. Eighteen patients suffered from drug resistant epilepsy (69·2%). Mean duration of epilepsy was 11·9 years in subjects with drug resistant epilepsy (n = 18) and 0·3 years in subjects presenting with first-time seizures (n = 8). We performed 24 lesionectomies and two lesionectomies combined with extended temporal resections. Seven lesions were located extratemporally. Complete CM removal was documented by postsurgical MRI in all patients. As direct consequence of iopMRI, refined surgery was necessary in 11·5% of patients to achieve complete cavernoma removal and in another 11·5% for complete resection of additional adjacent epileptogenic cortex. Removal of the hemosiderin rim was confirmed by iopMRI in 92% of patients. Two patients suffered from mild (7·7%) and one from moderate (3·8%) visual field deficits. Complete seizure control (Engel class 1A) was achieved in 80·8% of patients with a mean follow-up period of 47·7 months. We report excellent long-term seizure control with minimal surgical morbidity after complete resection of CM using our multimodal approach.


Mapping the oculomotor system.
Over the last three decades and together with Bernard Cohen, Volker Henn, Ulrich Büttner, and Anja Horn, it has been possible to morphologically identify several functional cell groups in the oculomotor system: the medium-sized horizontal excitatory and inhibitory burst neurons (EBNs, IBNs) in the paramedian pontine reticular formation (PPRF), the more sparsely scattered vertical EBNs in the rostral interstitial nucleus of the MLF (RIMLF), and the typically elongated omnipause neurons (OPNs) in nucleus raphé interpositus--all essential for the generation of saccades. In contrast, the role of the central mesencephalic reticular formation (cMRF) in saccades is more complex, as is the morphological outlining of its borders. A detailed study of the extraocular motoneurons showed that they can be divided into two separate types: those for singly innervated (twitch) muscle fibres (SIFs) and those for multiply innervated (non-twitch) muscle fibres (MIFs). The two motoneuron types receive different premotor afferents, proving that MIF and SIF motoneurons have different functions. The cell groups were outlined by different tract tracing methods including rabies virus. The localization and histochemical characterization of all these functional cell groups in monkey formed the basis for the identification of the homologous groups in the human brainstem. Taken together these studies provide a neuroanatomical background for understanding clinical eye movement disorders.


The topographical regulation of embryonic stem cell differentiation.
The potential use of pluripotent stem cells for tissue repair or replacement is now well recognized. While the ability of embryonic stem (ES) cells to differentiate into all cells of the body is undisputed, their use is currently restricted by our limited knowledge of the mechanisms controlling their differentiation. This review discusses recent work by ourselves and others investigating the intercellular signalling events that occur within aggregates of mouse ES cells. The work illustrates that the processes of ES cell differentiation, epithelialization and programmed cell death are dependent upon their location within the aggregates and coordinated by the extracellular matrix. Establishment of the mechanisms involved in these events is not only of use for the manipulation of ES cells themselves, but it also throws light on the ways in which differentiation is coordinated during embryogenesis.


A phase I trial to determine the safety, pharmacokinetics, and pharmacodynamics of intercalated BMS-690514 with paclitaxel/carboplatin (PC) in advanced or metastatic solid malignancies.
A phase I dose escalation study was performed to determine the maximum tolerated dose (MTD) of intercalated dosing of BMS-690514, a reversible oral panHER/VEGF receptor inhibitor, combined with paclitaxel/carboplatin (PC) in advanced solid tumors. Secondary endpoints included safety, pharmacokinetics (PK), exploratory pharmacodynamics (PD), and preliminary efficacy. Patients received fixed doses of P (200 mg/m(2)) and C (AUC 6 mg/mL min) q21 days with intercalated BMS-690514 (Days 4-19) starting at 100 mg/day and increasing by 50 mg/day using a 3 + 3 dose escalation design until the MTD was reached. Twenty additional patients were enrolled in the expansion cohort at the recommended phase II dose (RP2D). The MTD was reached at 150 mg/day. DLTs included grade 3 thrombosis at 100 mg (1 patient) and grade 3 diarrhea at 150 mg (1 patient) and 200 mg (2 patients). Serious adverse events (AEs) occurring in 20/37 patients included neutropenia (n = 5), diarrhea (n = 4), pulmonary embolism (n = 3), and simultaneous dehydration, acute renal failure, and febrile neutropenia (n = 2). BMS-690514-related AEs included diarrhea (97 %), acneiform rash (60 %), fatigue (43 %), nausea (30 %), and anorexia (30 %). There were no treatment-related deaths. Sequential intermittent administration of PC did not affect the PK of BMS-690514. Of the 32 patients evaluable for efficacy, there were 12 partial responses including five patients with non-small-cell lung cancer and 12 patients with stable disease. The MTD of intercalated BMS-609514 combined with PC was 150 mg/day. This approach was tolerable with manageable toxicities and antitumor activity in a variety of solid tumor types.