Fatal immunopathogenesis by SIV/HIV-1 (SHIV) containing a variant form of the HIV-1SF33 env gene in juvenile and newborn rhesus macaques.
SIV/HIV-1 (SHIV) chimeric clones, constructed by substituting portions of the pathogenic molecular clone SIVmac239 with counterpart portions from HIV-1 clones, provide a means to analyze functions of selected HIV-1 genes in vivo in nonhuman primates. Our studies focused on SHIVSF33, which contains the vpu, tat, rev, and env genes of the cytopathic, T-cell line tropic clone HIV-1sf33 (subtype-B); this clone has a premature stop codon in the vpu gene. In three juvenile macaques inoculated intravenously with SHIVSF33, low-level persistent infection was established; no disease was observed for a period of >2 years. However, at approximately 16 months p.i., one of four SHIVSF33-infected juvenile macaques exhibited an increase in virus load, depletion of CD4(+) T cells in peripheral blood and lymph nodes, and other symptoms of simian AIDS (SAIDS). Virus recovered from this animal in the symptomatic stage was designated SHIVSF33a (A, adapted); this virus displayed multiple amino acid sequence changes throughout the HIV-1 env gene compared with the input SHIVSF33 clone. Additionally, a mutation in all clones from SHIVSF33a restored the open reading frame for the vpu gene. In vitro evaluations in tissue-culture systems revealed that SHIVSF33a replicated to higher levels and exhibited greater cytopathicity than SHIVSF33. Furthermore cloned env genes for SHIVSF33a were more fusogenic in a cell-fusion assay compared with the env gene of the SHIVSF33. Intravenous inoculation of SHIVsf33a into juvenile and newborn macaques resulted in a rapid decline in CD4(+) T cells to very low levels and development of a fatal AIDS-like disease. A cell-free preparation of this pathogenic chimeric virus also established persistent infection when applied to oral mucosal membranes of juvenile macaques and produced a fatal AIDS-like disease. These studies on pathogenic SHIVSF33a establish the basis for further investigations on the role of the HIV-1 env gene in virus adaptation and in mechanism(s) of immunodeficiency in primates; moreover, the chimeric virus SHIVSF33a can play a role in elucidating mucosal membrane transmission and development of antiviral vaccines in newborns as well as juvenile and adult macaques.


Construct Validity of the Gait Deviation Index for People With Incomplete Spinal Cord Injury (GDI-SCI).
The Gait Deviation Index for Spinal Cord Injury (SCI-GDI) was recently proposed as a dimensionless multivariate kinematic measure based on 21 gait features derived from 3-dimensional kinematic data which quantifies gait impairment of adult population with incomplete spinal cord injury (iSCI) relative to the normative gait of a healthy group. Nevertheless, no validity studies of the SCI-GDI have been published to date. To assess the construct validity of the SCI-GDI in adult population following iSCI. Methods. SCI-GDI data were obtained from a sample of 50 healthy volunteers and 35 adults with iSCI. iSCI group was also assessed with the following measures: 10-Meter Walk Test (10MWT) at both self-selected (SS) and maximum speeds, Timed Up and Go Test (TUGT), SS and maximum levels of the Walking Index for Spinal Cord Injury (WISCI) II, mobility items of the Spinal Cord Independence Measure III (SCIM IIIIOMob), Lower Extremity Motor Score (LEMS), and Modified Ashworth Scale (MAS). Spearman's correlation coefficient was used to investigate the relationship with the SCI-GDI. SCI-GDI shows strong correlation with the 10MWT (r ≥ -.716) and good correlation with LEMS (r = .638), TUGT (r = -.582), SS WISCI II levels (r = .521), and SCIM IIIIOMob (r = .501). No significant correlations were found with maximum WISCI II levels and MAS (P > .006). Construct validity of the SCI-GDI was demonstrated with the 10MWT, TUGT, LEMS, SCIM IIIIOMob, and SS WISCI II levels for independently walking adults with iSCI. Future work will include assessing the psychometric characteristics with a more heterogeneous sample, also considering the pediatric population.


Incorporating health workers' perspectives into a WHO guideline on personal protective equipment developed during an Ebola virus disease outbreak.
Background: Ebola virus disease (EVD) health facility transmission can result in infection and death of health workers. The World Health Organization (WHO) supports countries in preparing for and responding to public health emergencies, which often require developing new guidance in short timelines with scarce evidence. The objective of this study was to understand frontline physicians' and nurses' perspectives about personal protective equipment (PPE) use during the 2014-2016 EVD outbreak in West Africa and to incorporate these findings into the development process of a WHO rapid advice guideline. Methods : We surveyed frontline physicians and nurses deployed to West Africa between March and September of 2014. Results: We developed the protocol, obtained ethics approval, delivered the survey, analysed the data and presented the findings as part of the evidence-to-decision tables at the expert panel meeting where the recommendations were formulated within eight weeks. Forty-four physicians and nurses responded to the survey. They generally felt at low or extremely low risk of virus transmission with all types of PPE used. Eye protection reduced the ability to provide care, mainly due to impaired visibility because of fogging. Heat and dehydration were a major issue for 76% of the participants using goggles and for 64% using a hood. Both gowns and coveralls were associated with significant heat stress and dehydration. Most participants (59%) were very confident that they were using PPE correctly. Conclusion : Our study demonstrated that it was possible to incorporate primary data on end-users' preferences into a rapid advice guideline for a public health emergency in difficult field conditions. Health workers perceived a balance between transmission protection and ability to care for patients effectively while wearing PPE. These findings were used by the guideline development expert panel to formulate WHO recommendations on PPE for frontline providers caring for EVD patients in outbreak conditions.


Cognitive Rehabilitation in Alzheimer's Disease: A Controlled Intervention Trial.
Cognitive Rehabilitation for Alzheimer's disease (AD) is an integrative multimodal intervention. It aims to maintain autonomy and quality of life by enhancing the patients' abilities to compensate for decreased cognitive functioning. We evaluated the feasibility of a group-based Cognitive Rehabilitation approach in mild AD dementia and assessed its effect on activities of daily living (ADL). We included 16 patients with AD dementia in a controlled partial-randomized design. We adapted the manual-guided Cognitive Rehabilitation program (CORDIAL) to a group setting. Over the course of three months, one group received the Cognitive Rehabilitation intervention (n = 8), while the other group received a standardized Cognitive Training as an active control condition (n = 8). ADL-competence was measured as primary outcome. The secondary outcome parameters included cognitive abilities related to daily living, functional cognitive state, and non-cognitive domains, e.g., quality of life. For each scale, we assessed the interaction effect 'intervention by time', i.e., from pre-to post-intervention. We found no significant interaction effect of intervention by time on the primary outcome ADL-competence. The interaction effect was significant for quality of life (Cohen's d: -1.43), showing an increase in the intervention group compared with the control group. Our study demonstrates the feasibility of a group-based Cognitive Rehabilitation program for patients with mild AD dementia. The Cognitive Rehabilitation showed no significant effect on ADL, possibly reflecting a lack of transfer between the therapy setting and real life. However, the group setting enhanced communication skills and coping mechanisms. Effects on ADL may not have reached statistical significance due to a limited sample size. Furthermore, future studies might use an extended duration of the intervention and integrate caregivers to a greater extent to increase transfer to activities of daily living.


Dental service provision in Victorian residential aged care facilities.
The Australian population is ageing, and a growing proportion of elderly Australians are now living in residential aged care facilities (RACFs). These residents are at high risk of developing dental diseases, have more teeth present now than at any time in the past 50 years and often have difficulty maintaining adequate oral hygiene. Traditionally, dental service provision has been problematic and sporadic for these residents. A postal survey of a random sample of Victorian general dentists and Directors of Nursing (DONs) of Victorian RACFs was undertaken in 2006 to ascertain the participation of dentists in the provision of dental care and to identify factors impacting on the organization and provision of dental care for residents. The response rate for dentists was 57.3 per cent, and for DONs 64.4 per cent. Half of the dentists reported that they had provided care to residents of aged care facilities in the past 12 months, and they spent an average of one hour per month providing care. Overall, dentists were concerned with their level of undergraduate education and training in various aspects of dentistry for residents of aged care facilities. DONs reported significant difficulty obtaining adequate dental care for their residents. Common problems identified by both dentists and DONs included a preference for dentists to treat residents in their own practice, dentists not willing to go to RACFs and a lack of portable dental equipment for dentists to use. There were low levels of interest and participation from Victorian dentists in providing dental care for residents of aged care facilities. Dentists had a strong preference for treating patients at their own practice, and there were a number of significant barriers that appeared to impact on the provision of dental care in RACFs.


Electromyography activity of vastus lateralis muscle during whole-body vibrations of different frequencies.
The aim of this study was to analyze electromyography (EMG) responses of vastus lateralis muscle to different whole-body vibration frequencies. For this purpose, 16 professional women volleyball players (age, 23.9 +/- 3.6 years; height, 182.5 +/- 11.1 cm; weight, 78.4 +/- 5.6 kg) voluntarily participated in the study. Vibration treatment was administered while standing on a vibrating platform with knees bent at 100 degrees (Nemes Bosco-system, Rome, Italy). EMG root mean square (rms) and was recorded for 60 seconds while standing on the vibrating plate in the following conditions: no vibrations and 30-, 40-, and 50-Hz vibration frequencies in random order. The position was kept for 60 seconds in each treatment condition. EMGrms was collected from the vastus lateralis muscle of the dominant leg. Statistical analysis showed that, in all vibration conditions, average EMGrms activity of vastus lateralis was higher than in the no-vibration condition. The highest EMGrms was found at 30 Hz, suggesting this frequency as the one eliciting the highest reflex response in vastus lateralis muscle during whole-body vibrations in half-squat position. An extension of these studies to a larger population appears worthwhile to further elucidate the responsiveness of the neuromuscular system to whole-body vibrations administered through vibrating platforms and to be able to develop individual treatment protocols.


High-yield nontoxic gene transfer through conjugation of the CM₁₈-Tat₁₁ chimeric peptide with nanosecond electric pulses.
We report a novel nontoxic, high-yield, gene delivery system based on the synergistic use of nanosecond electric pulses (NPs) and nanomolar doses of the recently introduced CM18-Tat11 chimeric peptide (sequence of KWKLFKKIGAVLKVLTTGYGRKKRRQRRR, residues 1-7 of cecropin-A, 2-12 of melittin, and 47-57 of HIV-1 Tat protein). This combined use makes it possible to drastically reduce the required CM18-Tat11 concentration and confines stable nanopore formation to vesicle membranes followed by DNA release, while no detectable perturbation of the plasma membrane is observed. Two different experimental assays are exploited to quantitatively evaluate the details of NPs and CM18-Tat11 cooperation: (i) cytofluorimetric analysis of the integrity of synthetic 1,2-dioleoyl-sn-glycero-3-phosphocholine giant unilamellar vesicles exposed to CM18-Tat11 and NPs and (ii) the in vitro transfection efficiency of a green fluorescent protein-encoding plasmid conjugated to CM18-Tat11 in the presence of NPs. Data support a model in which NPs induce membrane perturbation in the form of transient pores on all cellular membranes, while the peptide stabilizes membrane defects selectively within endosomes. Interestingly, atomistic molecular dynamics simulations show that the latter activity can be specifically attributed to the CM18 module, while Tat11 remains essential for cargo binding and vector subcellular localization. We argue that this result represents a paradigmatic example that can open the way to other targeted delivery protocols.


[Treatment with psilocybin: applications for patients with psychiatric disorders].
After a cessation of almost 40 years, there is renewed interest into therapeutic applicationsof the serotonergic psychedelic psilocybin for the treatment of patients with various psychiatric disorders. PubMed was searched for clinical trials into "psilocybin" between 2000 and 2020, complemented by handsearching. Articles were also screened for explanatory models and working mechanisms. Psilocybin has been studied in 9 clinical trials: for the treatment of substance use disorders, depression, end-of-life anxiety, demoralization, and obsessive-compulsive disorder. Results show that psilocybin is well tolerated, with only limited side-effects, while even patients with treatment-resistant disorders sometimes show marked, long-term improvements after one or a few sessions. Initial results are encouraging, but there are several limitations. More research is needed to determine which patient populations can benefit, what role setting and the placebo response play, and how these novel treatments can be optimized.


Bilateral thalamic infarction--a rare manifestation of dural venous sinus thrombosis.
Bilateral infarctions of the thalamus account for only a small fraction of ischemic strokes and carry a poor prognosis. These infarcts rarely have a venous etiology. A case secondary to straight sinus thrombosis is presented. Difficulties in considering the diagnosis and its radiological appearances are discussed. A simple imaging pathway including computed tomographic angiography and magnetic resonance imaging including a susceptibility-weighted sequence is presented in order to facilitate determination of the exact etiology in order to optimize therapy accordingly.


Uterine Artery Doppler Velocimetry During Individually Prescribed Exercise in Pregnancy.
To evaluate uterine artery blood flow in response to typical exercise sessions performed in pregnancy in accordance with the current recommendations from the American College of Obstetricians and Gynecologists and the U.S. Department of Health and Human Services. This prospective cross-sectional study measured uterine artery Doppler velocimetry in healthy pregnant women after individually prescribed exercise, including 1) moderate-intensity exercise (40-59% of heart rate reserve) in both nonexercisers and regular exercisers and 2) vigorous-intensity exercise (60-84% of heart rate reserve) in women who regularly engage in exercise. Resting uterine artery Doppler measures were obtained after a 20-minute fetal heart tracing; then the exercise session was performed. Immediately after the exercise session ended, the participants returned to the semirecumbent, leftward tilt position for ultrasound examination. Uterine artery measures were obtained 3.4±0.9 minutes (mean±SD) postexercise. Forty-five healthy pregnant women participated in the study: 30 regular exercisers and 15 nonexercisers. For the moderate-intensity session, mean gestational age was 31.1 and 31.7 weeks for the exercisers and nonexercisers, respectively. Mean uterine artery Doppler indices (pulsatility index, resistance index, systolic/diastolic ratio) did not significantly change with exercise. For the vigorous-intensity session, the average gestational age was 31.5 weeks. After vigorous activity, all mean uterine artery Doppler indices showed reductions postexercise, for example, pulsatility index decreased from 0.63±0.12 to 0.58±0.12 (P=.04). Individually prescribed exercise according to guidelines for pregnant women does not adversely alter uterine artery Doppler values, suggesting that uterine blood flow is not reduced as a result of exercise.


Synucleins in glaucoma: implication of gamma-synuclein in glaucomatous alterations in the optic nerve.
Synucleins are small proteins associated with neurodegenerative diseases and some forms of cancer. They are studied predominantly in the brain; information about their presence and functions in ocular tissues is scarce. Here we describe the localization of three members of the synuclein family in the optic nerve of donors with different types of glaucoma compared with control samples from donors without ocular diseases. We did not find significant differences in the localization of alpha- and beta-synucleins in the optic nerve or retina of glaucoma patients compared with controls, whereas considerable redistribution of gamma-synuclein occurred in the glaucomatous optic nerve compared with control eye without glaucoma. In the optic nerve from control and glaucomatous individuals, nerve bundles are immunopositive for gamma-synuclein; however, a strong gamma-synuclein-immunopositive staining in a subset of glial cells was observed in the lamina and postlamina cribrosa regions of the optic nerve only in glaucoma patients. In the optic nerve of rats with episcleral vein cauterization used as an animal model of glaucoma, the quantity of both gamma-synuclein mRNA and protein was decreased compared with the optic nerves of control animals. Incubation of rat astrocyte culture at elevated hydrostatic pressure reduced the amount of gamma-synuclein but did not affect the quantities of actin and glial fibrillary acidic protein. These data suggest that significant changes in the pattern of expression and/or localization occur in the glaucomatous optic nerve for gamma-synuclein but not for alpha- and beta-members of the synuclein family.


Terrorist on trial: the context of political crime.
When political terrorists stand trial for their violent acts, the political context inevitably plays a major role. This article describes the trial of an Abu Nidal terrorist tried in federal court for skyjacking an Egyptian airliner. The defense portrayed the traumas of the Palestinian people and of the defendant at the hands of the Israelis, offering a not guilty by reason of insanity defense on the basis of posttraumatic stress disorder. Making sense to the jury of how a sane individual could carry out a violent act in which more than 50 innocent men, women, and children died was the task of the author, who served as expert for the U.S. Department of Justice. The paper describes how the subject was socialized to violence in the refugee camps, where he was inspired to be a soldier in the revolution in order to reclaim his family lands. Nationalist-separatist terrorism is particularly intractable because of the generational transmission of hatred and revenge.


Production of trypsins by human gastric cancer cells correlates with their malignant phenotype.
Proteolytic degradation of extracellular matrix is a critical step in tumour invasion and metastasis. To examine the role of trypsin in tumour dissemination, we cloned two variants (S4 and R3 cells) from STKM-1, a trypsinogen 1-producing diffuse gastric cancer cell line. Western blot analysis with antitrypsin antibody showed that 26 and 24 kDa proteins were highly detected in S4 conditioned medium (CM) in comparison to R3 CM. In addition to the 26 and 24 kDa proteins, 25 and 23 kDa bands, which correspond to enterokinase-activated trypsin, were found only in S4 CM. When the CMs of the two clones were treated with enterokinase, the 25 and 23 kDa trypsin activities in S4 CM were effectively increased as compared with R3 CM. When the two clones were inoculated intraperitoneally (i.p.) into nude mice, S4 cells strongly invaded the liver, pancreas and peritoneum and killed the hosts more rapidly than R3 cells: the 50% survival time was 50 days for S4 and 82 days for R3 cells. These results suggest that trypsin production is associated with the invasive growth of STKM-1 gastric cancer cells.


Effects of Resveratrol and Other Polyphenols on the Most Common Brain Age-Related Diseases.
With global increase in elderly population, modern societies must find strategies to reduce the consequences of aging process; thereby decreasing the incidence of age-related neurodegenerative diseases. Oxidative stress and recently inflammation, have been pointed out as the leading causes of brain aging. Thereby, the consumption or administration of antioxidant and anti-inflammatory molecules, such as polyphenols, is a beneficial strategy recommended for preventing brain aging and several brain age-related diseases. Several studies suggest that long term consumption of dietary polyphenols offers protection against development of neurodegenerative diseases. These beneficial effects are in part due to their antioxidant and anti-inflammatory properties, together with their positive role in the modulation of processes involved in the physiopathology of several neurodegenerative diseases (e.g., epigenetic factors, amyloid deposition, cholinesterase inhibition, autophagy, and neurotrophic factors, among others). Altogether, these molecules open the door to the research of new neuroprotective strategies. This review summarizes the latest discoveries in how polyphenols can exert positive effects on brain health in aging, emphasizing those effects on the diseases that most commonly affect the brain during aging: Parkinson's Disease (PD), Alzheimer's disease (AD), dementia and depression. Moreover, within are addressed the epigenetic effects of polyphenols as possible mediators in their positive effects on brain health, and the future challenges of research in this topic Conclusion: In brief, this review presents a report of state-of the art knowledge regarding the positive influences of polyphenols on the most common brain age-related diseases as well as in healthy brain aging.


B-Lymphocytes in plaque and adventitia of coronary arteries in two patients with rheumatoid arthritis and coronary atherosclerosis: preliminary observations.
To describe the subtypes of lymphocytes in coronary arteries of two patients with rheumatoid arthritis (RA) and coronary artery disease (CAD). The Mayo Clinic database was searched for patients with RA and CAD who underwent an autopsy in 2001. Medical records were reviewed, and coronary arteries were examined microscopically. The percentage of B- and T-lymphocytes was determined using histomorphometry on representative sections stained with CD20 and CD3 antibodies, respectively. Two men were diagnosed with RA at ages 52 and 70 years and died at ages 60 and 82 years. One sustained an acute myocardial infarction 2 years prior to the diagnosis of RA and had stable CAD until an arrhythmic death. The other developed congestive heart failure secondary to ischemic heart disease 5 years after RA was diagnosed. Both patients had severe three-vessel CAD with both stable fibrocalcific plaques and acute lesions. B- and T-lymphocytes were identified in the plaque and adventitia of all coronary arteries. The mean percentage of B-lymphocytes was 37% to 52% in the plaque and 78% to 85% in the adventitia, while that of T-lymphocytes was 38% to 51% and 28%, for plaque and adventitia, respectively. In typical CAD, lymphocytic infiltrates are almost exclusively T-cells. In contrast, the two patients with RA and CAD showed prominent infiltrates of B-lymphocytes within plaques and adventitia. Thus, the leukocytic response in atherosclerotic plaques may be altered in patients with autoimmune disorders. This warrants further study.


Vav1 fine tunes p53 control of apoptosis versus proliferation in breast cancer.
Vav1 functions as a signal transducer protein in the hematopoietic system, where it is exclusively expressed. Vav1 was recently implicated in several human cancers, including lung, pancreatic and neuroblasoma. In this study, we analyzed the expression and function of Vav1 in human breast tumors and breast cancer cell lines. Immunohistochemical analysis of primary human breast carcinomas indicated that Vav1 is expressed in 62% of 65 tumors tested and is correlated positively with estrogen receptor expression. Based on published gene profiling of 50 breast cancer cell lines, several Vav1-expressing cell lines were identified. RT-PCR confirmed Vav1 mRNA expression in several of these cell lines, yet no detectable levels of Vav1 protein were observed due to cbl-c proteasomal degradation. We used two of these lines, MCF-7 (Vav1 mRNA negative) and AU565 (Vav1 mRNA positive), to explore the effect of Vav1 expression on breast cell phenotype and function. Vav1 expression had opposite effects on function in these two lines: it reduced proliferation and enhanced cell death in MCF-7 cells but enhanced proliferation in AU565 cells. Consistent with these findings, transcriptome analysis revealed an increase in expression of proliferation-related genes in Vav1-expressing AU565 cells compared to controls, and an increase in apoptosis-related genes in Vav1-expressing MCF-7 cells compared with controls. TUNEL and γ-H2AX foci assays confirmed that expression of Vav1 increased apoptosis in MCF-7 cells but not AU565 cells and shRNA experiments revealed that p53 is required for this pro-apoptotic effect of Vav1 in these cells. These results highlight for the first time the potential role of Vav1 as an oncogenic stress activator in cancer and the p53 dependence of its pro-apoptotic effect in breast cells.


Impact of Sodium-Glucose Cotransporter 2 Inhibitor on Recurrence After Catheter Ablation for Atrial Fibrillation in Patients With Diabetes: A Propensity-Score Matching Study and Meta-Analysis.
The association between sodium-glucose cotransporter 2 inhibitors (SGLT2i) and atrial fibrillation (AF) recurrence after catheter ablation among patients with diabetes and AF remains unclear. Patients with AF undergoing initial catheter ablation with a history of diabetes from the China AF registry were included. Patients using SGLT2i were identified and matched by propensity score with non-SGLT2i patients in a 1:3 ratio. The main outcome was AF recurrence during the 18-month follow-up. A total of 138 patients with diabetes with SGLT2i therapy and 387 without SGLT2i were analyzed. AF recurrence occurred in 37 patients (26.8%) in the SGLT2i group and 152 patients (39.3%) in the non-SGLT2i group during a total of 593.3 person-years follow-up. The SGLT2i group was associated with lower AF recurrence compared with the non-SGLT2i group (hazard ratio, 0.63 [95% CI, 0.44-0.90], P=0.007). A total of 4 studies were analyzed in our meta-analysis demonstrating that SGLT2i was associated with lower AF recurrence after catheter ablation (odds ratio, 0.61 [95% CI, 0.54-0.69]; P<0.001, I2=0.0%). Our prospective study coupled with a meta-analysis demonstrated a lower risk of AF recurrence with the use of SGLT2i among patients with diabetes after AF ablation.


Association of clinical severity with FANCB variant type in Fanconi anemia.
Fanconi anemia (FA) is the most common genetic cause of bone marrow failure and is caused by inherited pathogenic variants in any of 22 genes. Of these, only FANCB is X-linked. We describe a cohort of 19 children with FANCB variants, from 16 families of the International Fanconi Anemia Registry. Those with FANCB deletion or truncation demonstrate earlier-than-average onset of bone marrow failure and more severe congenital abnormalities compared with a large series of FA individuals in published reports. This reflects the indispensable role of FANCB protein in the enzymatic activation of FANCD2 monoubiquitination, an essential step in the repair of DNA interstrand crosslinks. For FANCB missense variants, more variable severity is associated with the extent of residual FANCD2 monoubiquitination activity. We used transcript analysis, genetic complementation, and biochemical reconstitution of FANCD2 monoubiquitination to determine the pathogenicity of each variant. Aberrant splicing and transcript destabilization were associated with 2 missense variants. Individuals carrying missense variants with drastically reduced FANCD2 monoubiquitination in biochemical and/or cell-based assays tended to show earlier onset of hematologic disease and shorter survival. Conversely, variants with near-normal FANCD2 monoubiquitination were associated with more favorable outcome. Our study reveals a genotype-phenotype correlation within the FA-B complementation group of FA, where severity is associated with level of residual FANCD2 monoubiquitination.


Longitudinal trajectories of posttraumatic stress disorder symptoms and binge drinking among adolescent girls: the role of sexual victimization.
Many studies have documented associations among sexual victimization (SV), posttraumatic stress disorder (PTSD) symptoms, and alcohol use; however, few have examined these associations longitudinally among adolescents. The present study evaluated the effect of SV on the longitudinal trajectory of PTSD symptoms and binge drinking (BD) among adolescent girls, a population known to have high rates of SV and alcohol use. Participants (N = 1,808 at wave 1) completed interviews regarding PTSD symptoms, BD, and SV experiences over approximately 3 years. Multilevel modeling revealed decreases in PTSD symptoms over the course of the study; however, compared with nonvictims, adolescents who were sexually victimized reported greater PTSD symptoms at wave 1 and maintained higher levels of PTSD symptoms over the course of the study after controlling for age. SV reported during the study also predicted an acute increase in PTSD symptoms at that occasion. BD increased significantly over the course of the study; however, SV did not predict initial BD or increases over time. SV reported during the study was associated with acute increases in BD at that occasion, although this effect diminished when participants reporting substance-involved rape were excluded. SV was associated with immediate and long-lasting elevations in PTSD symptoms, but not with initial or lasting elevations in BD over time, suggesting that adolescent victims have yet to develop problematic patterns of alcohol use to cope with SV. However, SV was associated with acute increases in PTSD symptoms and BD, suggesting a need for BD interventions to reduce alcohol-related SV.


Health assessments for health governance-concepts and methodologies.
For better supporting the science-governance interface, the potential of health assessments appears underrated. To identify what various types of health assessment have in common; how they differ; which assessment(s) to apply for which purpose; and what needs and options there are for future joint development. This review is based on five types of health assessment: monitoring/surveillance/reporting, assessment of health impact, of health technology, of health systems performance, health-related economic assessment. The approach is exploratory and includes: applying an agreed set of comparative criteria; circulating and supplementing synoptic tables; and interpreting the results. Two of the assessments deal with the question 'Where do we stand?', two others with variants of 'What if' questions. Economic Assessment can take place in combination with any of the others. The assessments involve both overall 'procedures' and a variety of 'methods' which inescapably reflect some subjective assumptions and decisions, e.g. on issue framing. Resources and assistance exist for all these assessments. The paper indicates which type of assessment is appropriate for what purpose. Although scientific soundness of health assessments is not trivial to secure, existing types of health assessment can be interpreted as a useful 'toolkit' for supporting governance. If current traces of 'silo' thinking can be overcome, the attainability of a more unified culture of health assessments increases and such assessments might more widely be recognized as a prime, 'tried and tested' way to voice Public Health knowledge and to support rational governance and policy-making.


Surgical treatment of macrodactyly in older children and adults.
To introduce a surgical technique for the treatment of macrodactyly in older children and adults, to represent the degree of correction obtained by the procedure, and to give the functional results. Two thumbs and 5 fingers of 5 patients aged 12 to 32 years (mean, 17.5 years) with macrodactyly had surgery. The amount of tissue sufficient to reconstruct a normal-sized digit was left attached with the neurovascular bundle on the concave side of the macrodactylic digit and complete excision of whatever remained was performed. This requires usually arthrodesis of the distal interphalangeal joint with bone shortening. The large skin fold created during bone shortening and remaining angulations at the proximal phalanx were corrected during a second procedure. The patients were evaluated for 3 to 9 years (mean, 5.4 years) after the surgery. The length and circumferences of the involved digits and their opposites were measured before surgery and during the last follow-up examination to calculate the differences between the involved and the healthy digits, which were documented. The degree of reduction was quantified and noted. Two-point discrimination tests and active range of motion of the joints were recorded as well. For the thumbs an average 37% of circumference and 15% of length were reduced and for the fingers an average 44% of circumference and 35% of length were reduced. Ranges of motion of the joints of the involved digits were the same or nearly the same as before surgery in all of the cases. Two-point discriminations at the pulp of the involved digits were found to be the same as presurgical values in all digits. The technique is precise and simplifies the planning of the surgery. Although the macrodactylic digits with angulation deformities required a subsequent surgery for corrections patients with marked macrodactyly of the digit without a very wide proximal phalanx and metacarpal gained most from this technique.


Current Immunotherapies for Renal Cell Carcinoma.
Immunotherapy, though not a new modality for cancer treatment, has enjoyed renewed vigor and interest over the last several years. Multiple new targets have been identified, and therapeutic agents are in varying stages of development, with some agents having obtained regulatory approval for administration in the clinic. Renal cell carcinoma is known to potentially respond favorably to immunotherapy, with a small subset of patients achieving durable responses to high dose interleukin-2 therapy. Consequently, renal cell carcinoma is one of the many tumor types in which the efficacy of new agents is being investigated. Here we examine the landscape of current immunotherapeutic options for renal cell carcinoma, including cytokine therapy, immune checkpoint blockade, hematopoietic stem cell transplant, and vaccine therapy. We review approved immune directed therapies as well as new agents undergoing clinical trials in renal cell carcinoma. Immunotherapy has been and remains a promising treatment modality in this tumor type. Hopefully the approval of newer agents will translate into more accessible and efficacious options for patients and oncologists.


Newly diagnosed diabetes mellitus as a risk factor for serious liver disease.
The negative impact of diabetes mellitus is well recognized, yet little is known about the effect of this disease on the liver, an organ susceptible to nonalcoholic fatty liver disease related to insulin resistance. We evaluated whether adults with newly diagnosed diabetes were at increased risk of serious liver disease. We used administrative health databases for the province of Ontario (1994-2006) to perform a population-based matched retrospective cohort study. The exposed group comprised 438 069 adults with newly diagnosed diabetes. The unexposed comparison group--those without known diabetes--consisted of 2 059 708 individuals, matched 5:1 to exposed persons, by birth year, sex and local health region. We excluded individuals with pre-existing liver or alcohol-related disease. The primary study outcome was the subsequent development of serious liver disease, namely, liver cirrhosis, liver failure and its sequelae, or receipt of a liver transplant. The incidence rate of serious liver disease was 8.19 per 10 000 person-years among those with newly diagnosed diabetes and 4.17 per 10 000 person-years among those without diabetes. The unadjusted hazard ratio was 1.92 (95% confidence interval [CI] 1.83-2.01). After adjustment for age, income, urban residence, health care utilization and pre-existing hypertension, dyslipidemia, obesity and cardiovascular disease, the hazard ratio was 1.77 (95% CI 1.68-1.86). Adults with newly diagnosed diabetes appeared to be at higher risk of advanced liver disease, also known as diabetic hepatopathy. Whether this reflects nonalcoholic fatty liver disease or direct glycemic injury of the liver remains to be determined.


Downregulation of PTPRH (Sap-1) in colorectal tumors.
Tyrosine phosphorylation is one of the basic mechanisms for signal transduction in the cell. Receptors exhibiting tyrosine kinase activity are widely involved in carcinogenesis and are negatively regulated by receptor protein tyrosine phosphatases (RPTP). Genes encoding different RPTPs are affected by aberrant epigenetic regulation in cancer. PTPRH (SAP-1) has been previously described to be overexpressed in colorectal cancer (CRC) and classified as an oncogenic factor. Previous microarray-based mRNA expression comparison of colorectal adenomas (AD), CRC and normal mucosa samples (NM) demonstrated that PTPRH tumor expression is the most reduced of all RPTP genes. qRT-PCR validation revealed gene downregulation for CRC (7.6-fold-change; P<0.0001) and AD (3.4-fold-change; P<0.0001) compared to NM. This was confirmed by immunohistochemical staining of tumor and NM sections as pronounced decrease of protein expression was observed in CRCs compared to the corresponding normal tissue. DNA methylation of two PTPRH promoter fragments was analyzed by pyrosequencing in a group of CRC, and AD patients as well as NM samples and CRC cell lines. The mean DNA methylation levels of these two regions were significantly higher in CRC than in NM. Both regions were highly methylated in SW480 and HCT116 cell lines contrary to unmethylated HT29 and COLO205. Cell lines with highly methylated promoters notably showed lower PTPRH expression levels, lower RNA II polymerase concentrations and higher levels of H3K27 trimethylation in the promoter and gene body, measured by chromatin immunoprecipitation. Cells were cultured with 5-aza-deoxycitidine and an increase in PTPRH expression was observed in SW480 and HCT116, whereas this was unchanged in the unmethylated cell lines. The results indicate that PTPRH is downregulated in colorectal tumors and its expression is epigenetically regulated via DNA methylation and chromatin modifications.


Experimental demonstration of quantum advantage for one-way communication complexity surpassing best-known classical protocol.
Demonstrating a quantum advantage with currently available experimental systems is of utmost importance in quantum information science. While this remains elusive for quantum computation, the field of communication complexity offers the possibility to already explore and showcase this advantage for useful tasks. Here, we define such a task, the Sampling Matching problem, which is inspired by the Hidden Matching problem and features an exponential gap between quantum and classical protocols in the one-way communication model. Our problem allows by its conception a photonic implementation based on encoding in the phase of coherent states of light, the use of a fixed size linear optic circuit, and single-photon detection. This enables us to demonstrate in a proof-of-principle experiment an advantage in the transmitted information resource over the best known classical protocol, something impossible to reach for the original Hidden Matching problem. Our demonstration has implications in quantum verification and cryptographic settings.


Smart release of antimicrobial ZnO nanoplates from a pH-responsive keratin hydrogel.
A smart antibacterial biomaterial based on a keratin hydrogel with pH-dependent behavior and Zinc Oxide nanoplates as biocide agent has been developed. The pH of a chronic wound is basic due to bacterial metabolism. Originally shrank at acid pH, keratin hydrogels swell upon contact with a bacterial contaminated media leading to the release of the nanoparticles. The material has been thoroughly characterized by infrared spectroscopy, Raman, scanning electron microscope, swelling behavior, Differential scanning calorimetry, Small-angle X-ray scattering, rheology, antimicrobial activity and cytotoxicity. The results show that 5% of Zinc Oxide nanoparticles concentration is the optimum for wound dressing applications.


Lung cancer proteomics, clinical and technological considerations.
The overall survival of lung cancer patients is disappointingly low. This is due to several factors, including the lack of an effective screening strategy to detect tumors at a potentially curable early stage, a marked resistance of lung cancer cells to drug treatment and a still superficial knowledge about the multifactorial cellular networks that are activated or suppressed during cancer progression. Furthermore, the armamentarium of clinicians and researchers in the field does not yet include reliable biomarkers to predict tumor response to treatment and foresee the natural history of the disease. In the present situation, a potential breakthrough is presented by proteomics technologies with the potential to discover relevant biomarkers which can be accurately quantified in multiplexed assays. Proteomics field can also contribute greatly in the understanding of mechanisms in tumor progression and treatment response. In this review we will describe the work that is being done in the field of lung cancer proteomics, focusing on clinically relevant questions that need to be addressed and on the possible applications of novel technologies.


Assessing the chiral switch: approval and use of single-enantiomer drugs, 2001 to 2011.
A "chiral switch" occurs in the pharmaceutical market when a drug made up of 2 enantiomer forms is replaced with a purified single-enantiomer version, often in the context of a patent expiration. We studied the prevalence of chiral switching in the United States over the past decade, including trends in use of, and expenditures on, these products in Medicaid. Retrospective analysis. We used US Adopted Names prefixes (lev/levo/ar/es/dex/dextro) to identify all single-enantiomer drugs approved from 2001 to 2011. From publicly available US Food and Drug Administration (FDA) approval documents, we extracted the characteristics of the pivotal premarket trials for the single enantiomers. Specifically, we evaluated whether the single enantiomer was directly compared with the precursor racemic drug and whether there was evidence of superior efficacy. We used quarterly drug expenditure data from each state Medicaid program to chart trends in use of, and spending on, the single-enantiomer products and their racemic precursors during the study period. From 2001 to 2011, the FDA approved 9 single-enantiomer products: dexlansoprazole, levoleucovorin, levocetirizine, armodafinil, arformoterol, eszopiclone, escitalopram, dexmethylphenidate, and esomeprazole. Of those 9 drugs, 3 had at least 1 pre-approval randomized trial that included the racemic precursor as a direct comparator, but there was no evidence of superiority of the single enantiomer over the racemic at comparable doses. Between 2001 and 2011, US Medicaid programs spent approximately $6.3 billion on these 9 single-enantiomer drugs. Recently approved single-enantiomer drugs showed no evidence of superior efficacy over the older racemic precursors in the pivotal trials leading to their approval, and in a majority of cases, they were not directly compared.


Protein phosphatase-1M and Rho-kinase affect exocytosis from cortical synaptosomes and influence neurotransmission at a glutamatergic giant synapse of the rat auditory system.
Protein phosphatase-1M (PP1M, myosin phosphatase) consists of a PP1 catalytic subunit (PP1c) and the myosin phosphatase target subunit-1 (MYPT1). RhoA-activated kinase (ROK) regulates PP1M via inhibitory phosphorylation of MYPT1. Using multidisciplinary approaches, we have studied the roles of PP1M and ROK in neurotransmission. Electron microscopy demonstrated the presence of MYPT1 and ROK in both pre- and post-synaptic terminals. Tautomycetin (TMC), a PP1-specific inhibitor, decreased the depolarization-induced exocytosis from cortical synaptosomes. trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide dihydrochloride, a ROK-specific inhibitor, had the opposite effect. Mass spectrometry analysis identified several MYPT1-bound synaptosomal proteins, of which interactions of synapsin-I, syntaxin-1, calcineurin-A subunit, and Ca(2+) /calmodulin-dependent kinase II with MYPT1 were confirmed. In intact synaptosomes, TMC increased, whereas Y27632 decreased the phosphorylation levels of MYPT1(Thr696) , myosin-II light chain(Ser19) , synapsin-I(Ser9) , and syntaxin-1(Ser14) , indicating that PP1M and ROK influence their phosphorylation status. Confocal microscopy indicated that MYPT1 and ROK are present in the rat ventral cochlear nucleus both pre- and post-synaptically. Analysis of the neurotransmission in an auditory glutamatergic giant synapse demonstrated that PP1M and ROK affect neurotransmission via both pre- and post-synaptic mechanisms. Our data suggest that both PP1M and ROK influence synaptic transmission, but further studies are needed to give a full account of their mechanism of action.


Characterisation of Plesiomonas shigelloides strains that share type-specific antigen with Shigella flexneri 6 and common group 1 antigen with Shigella flexneri spp. and Shigella dysenteriae 1.
Three strains of Plesiomonas shigelloides isolated from patients with diarrhoea were agglutinated with Shigella flexneri 6 antiserum in slide and tube tests. All the strains were also agglutinated with a monoclonal antibody to the common group 1 antigen shared between S. flexneri serotypes and S. dysenteriae type 1. Further studies with one strain also showed sharing of antigenicity in an enzyme-linked immunosorbent assay. The results suggest that the strains share type-specific antigen with S. flexneri 6 and the common group 1 antigen with S. flexneri serotypes and S. dysenteriae 1. The sharing of antigens may have implications for cross-protection. One strain adhered to HEp-2 cell monolayers. None of the strains contained high mol. wt plasmids and there was no sequence homology with the invasiveness plasmid of Shigella spp. in DNA probe hybridisation. They were susceptible to the commonly used antibiotics. However, they possessed four other virulence-associated properties of Shigella spp. that included Congo-red binding, hydrophobicity, toxicity to HeLa cells and HEp-2 cell invasiveness (although they gave negative results in the Sereny test for invasiveness). These data suggest that the three unique strains might be considered pathogenic. Studies in animal models and human volunteers would be necessary to establish their pathogenic potential.


The need for emergency treatment of transient ischemic attack and minor stroke.
The risk of recurrent stroke following transient ischemic attack or minor stroke has recently been shown to be 5-10% at 1 week and 10-20% at 3 months, depending on study population and methods. This is considerably higher than previously estimated and current clinical guidelines reflect the need for rapid assessment although a wide variation in practice exists. Effective management of patients with transient ischemic attack or minor stroke, therefore, requires identification of individuals at the highest (and lowest) risk and initiation of appropriate secondary prevention. Risk can be stratified at initial presentation by the presence or absence of simple clinical features and following subsequent investigation. For transient ischemic attack patients, older age, diabetes, longer duration of symptoms and weakness or speech disturbance identify patients at highest risk, as does the presence of large artery atherosclerosis (mainly internal carotid artery stenosis) and lesions on diffusion-weighted magnetic resonance imaging. Strong evidence exists for the benefit of some early interventions (carotid endarterectomy and antiplatelet agents), but is circumstantial or awaited for others (statins and antihypertensives). In order for the public health challenge posed by transient ischemic attack and minor stroke to be met, considerable change is required in both public education (to ensure correct recognition of symptoms and swift presentation to medical attention) and the provision of clinical services to ensure the timely initiation of effective treatment.


Surface phonon-polariton enhanced optical forces in silicon carbide nanostructures.
The enhanced optical forces induced by surface phonon-polariton (SPhP) modes are investigated in different silicon carbide (SiC) nanostructures. Specifically, we calculate optical forces using the Maxwell stress tensor for three different geometries: spherical particles, slab waveguides, and rectangular waveguides. We show that SPhP modes in SiC can produce very large forces, more than one order of magnitude larger than the surface plasmon-polariton (SPP) forces in analogous metal nanostructures. The material and geometric basis for these large optical forces are examined in terms of dispersive permittivity, separation distance, and operating wavelength.


In-plane Strain Analysis by Correlating Geometry and Visual Data Through a Gradient-Based Surface Reconstruction.
Abnormalities in tissue can be detected and analyzed by evaluating mechanical properties, such as strain and stiffness. While current sensor systems are effective in measuring longitudinal properties perpendicular to the measurement sensor, identifying in-plane deformation remains a significant challenge. To address this issue, this paper presents a novel method for reconstructing in-plane deformation of observed tissue surfaces using a fringe projection sensor specifically designed for measuring tissue deformations. The method employs the latest techniques from computer vision, such as differentiable rendering, to formulate the in-plane reconstruction as a differentiable optimization problem. This enables the use of gradient-based solvers for an efficient and effective optimization of the problem optimum. Depth information and image information are combined using landmark correspondences between the respective image observations of the undeformed and deformed scenes. By comparing the reconstructed pre- and post-deformation geometry, the in-plane deformation can be revealed through the analysis of relative variations between the corresponding models' geometries. The proposed reconstruction pipeline is validated on an experimental setup, and the potential for intraoperative applications is discussed.


Terminal maturation of megakaryocytes and platelet production by hematopoietic stem cells irradiated with heavy-ion beams.
Hematopoietic processes, especially megakaryocytopoiesis and thrombopoiesis, are highly sensitive to high-linear energy transfer (LET) radiations such as heavy-ion beams that have greater biological effects than low-LET radiation. This study examined the terminal maturation of megakaryocytes and platelet production derived from hematopoietic stem cells irradiated with heavy-ion beams. CD34(+) cells derived from human placental/umbilical cord blood were exposed to monoenergetic carbon-ion beams (LET = 50 keV/µm) and then cultured in a serum-free medium supplemented with thrombopoietin and interleukin-3. There was no significant difference in megakaryocyte-specific markers between nonirradiated control and irradiated cells. Expression of Tie-2, a receptor that acts in early hematopoiesis, showed a significant 1.31-fold increase after 2 Gy irradiation compared to control cells on day 7. There was a significant increase in Tie-2 mRNA expression. In addition, the expression of other mRNAs, such as PECAM1, SELP and CD44, was also significantly increased in cells irradiated with heavy-ion beams. However, the adherent function of platelets derived from the irradiated cells showed no difference from that in the controls. These results clarify that the functions of megakaryocytopoiesis and thrombopoiesis derived from hematopoietic stem/progenitor cells irradiated with heavy-ion beams are similar to those in the unirradiated cells, although heavy-ion beams affect the expression of genes associated with cellular adhesion.


Nf1 Haploinsufficiency Alters Myeloid Lineage Commitment and Function, Leading to Deranged Skeletal Homeostasis.
Although nullizygous loss of NF1 leads to myeloid malignancies, haploinsufficient loss of NF1 (Nf1) has been shown to contribute to osteopenia and osteoporosis which occurs in approximately 50% of neurofibromatosis type 1 (NF1) patients. Bone marrow mononuclear cells of haploinsufficient NF1 patients and Nf1(+/-) mice exhibit increased osteoclastogenesis and accelerated bone turnover; however, the culprit hematopoietic lineages responsible for perpetuating these osteolytic manifestations have yet to be elucidated. Here we demonstrate that conditional inactivation of a single Nf1 allele within the myeloid progenitor cell population (Nf1-LysM) is necessary and sufficient to promote multiple osteoclast gains-in-function, resulting in enhanced osteoclastogenesis and accelerated osteoclast bone lytic activity in response to proresorptive challenge in vivo. Surprisingly, mice conditionally Nf1 heterozygous in mature, terminally differentiated osteoclasts (Nf1-Ctsk) do not exhibit any of these skeletal phenotypes, indicating a critical requirement for Nf1 haploinsufficiency at a more primitive/progenitor stage of myeloid development in perpetuating osteolytic activity. We further identified p21Ras-dependent hyperphosphorylation of Pu.1 within the nucleus of Nf1 haploinsufficient myelomonocytic osteoclast precursors, providing a novel therapeutic target for the potential treatment of NF1 associated osteolytic manifestations.


Folliculotropic mycosis fungoides: an aggressive variant of cutaneous T-cell lymphoma.
To study the clinical features, therapeutic responses, and outcomes in patients with folliculotropic mycosis fungoides (FMF) and to compare our single-center experience of 43 patients with the findings from the Dutch Cutaneous Lymphoma Group. A single-center experience from the Northwestern University Multidisciplinary Cutaneous Lymphoma Group. Forty-three patients with FMF were included in the study and compared with 43 age- and stage-matched patients with classic epidermotropic mycosis fungoides (MF) with similar follow-up time. Folliculotropic mycosis fungoides showed distinct clinical features, with 37 patients having facial involvement (86%) and only 6 having lesions limited to the torso (14%). The morphologic spectrum of lesions is broad and includes erythematous papules and plaques with follicular prominence with or without alopecia; comedonal, acneiform, and cystic lesions; alopecic patches with or without scarring; and nodular and prurigolike lesions. Sixty-five percent of patients had alopecia, which in 71% of cases involved the face. Severe pruritus was seen in 68% of patients. In general, patients responded poorly to skin-directed therapy and in almost all cases required systemic agents to induce even a partial remission, including patients with early-stage disease. Overall survival was poor. Patients with early-stage disease (< or =IIA) had a 10-year survival of 82%, which took a steep drop off to 41% by 15 years. Patients with late-stage disease (> or =IIB) had an outcome similar to those patients in the control group with conventional epidermotropic MF of a similar stage. The morphologic spectrum of clinical presentation for FMF is broad and distinct from those in conventional MF. This is at least partially attributed to the ability of FMF to simulate a variety of inflammatory conditions afflicting the follicular unit. The disease course is aggressive, and many patients, including those with early disease, show a poor outcome particularly between 10 and 15 years after the initial onset of disease. Response to skin-directed therapy is poor even in early-stage disease, and our best results were seen with psoralen plus UV-A (PUVA) therapy with oral bexarotene or PUVA with interferon alfa. These findings corroborate those of the Dutch Cutaneous Lymphoma Group and further validate the classification of FMF as a distinct entity.


Paenibacillus phocaensis sp. nov., isolated from the gut microbiota of a healthy infant.
Paenibacillus phocaensis sp. nov. strain mt24T (= CSUR P2238 = DSM 101777) is a Gram-negative, facultative anaerobic, spore-forming and motile bacilli. This strain was isolated from the stool sample of a healthy infant from Niger. Its genome was estimated to a size of 5 521 415 bp with a 53.54% GC content. It contains 4835 protein-coding genes and 89 RNAs, among which two were 16S rRNA genes. There were also 101 genes (2.09%) identified as ORFans.


Proficiency assessment of gesture analysis in laparoscopy by means of the surgeon's musculo-skeleton model.
This article presents the implementation of surgeon's musculo-skeletal model for gesture analysis in laparoscopy, thereby providing a complete account of the objective metrics needed to evaluate surgical performance and to improve the design of new surgical instruments including robotic instrumentation for surgical procedures. Previous published work has been based exclusively on the kinematics involved whereas, this study is focused on the dynamics and muscle contraction analysis to assess loads on bones and muscle fatigue during simulation of surgical interventions. Nine medical students and 2 fully trained surgeons participated in the experimental sessions using a virtual laparoscopic simulator. Movement was acquired by means of an Optical Localization System and processed by means of the biomechanical software platform ADAMS-LifeMOD. The musculo-skeletal analysis allows calculation of how the muscles are used and their respective mean work during the exercises. Results, relative to biceps and trapezius for left and right arm, clearly demonstrate different proficiencies between surgeons and medical students and highlight differences in using different surgical instruments and assumption of different postures. The model provides data on the evaluation of biomechanical parameters of surgical gesture not only in kinematic terms but also includes analysis of the dynamics of muscle contraction analysis during surgical manipulations.


How did European retirees respond to the COVID-19 pandemic?
We investigate the role of retirement on the adoption of preventive behaviours and on mental health during the first wave of the pandemic. We address the endogeneity of the timing of retirement using variation in early retirement and old-age pension eligibility. We find that those who retired earlier responded to the pandemic by limiting their mobility more, and by adopting stricter preventive behaviours in public. These limitations affected the mental health of singles in retirement.


[Effect of Escherichia coli mutations affecting the transcription termination rho on the development of T-even phages].
The functionally active transcription termination factor rho is necessary for the T-even phages development. The inactivation of the factor by thermosensitive E. coli gene rho mutations results in blocking phage development. It should be noted that phages T2 and T4 require different levels of this factor's activity. The synthesis of some early proteins diminishes during factor rho inactivation and a number of proteins typical for a later stage are observed early in infection. Under the conditions of the factor rho being inactivated the synthesis of a number of proteins is weakened late in infection and the capside proteins maturation is impaired. Alongside with this the factor rho inactivation results in a sharp decrease of phage DNA replication in infected cells. The obtained data suggests that in the absense of functionally active factor rho all the proteins necessary for phage DNA replication are formed. Besides, this factor is directly involved in the process of T-even phages DNA replication. One may conclude that the inability of T-even phages to develop in mutant cells rho is to a greater extent due to the impairment in phage DNA replication than to its transcription. The possible role of the factor rho in the process of DNA replication is discussed.


Free-air CO2 enrichment (FACE) enhances biomass production in a short-rotation poplar plantation.
This paper investigates the possible contribution of Short Rotation Cultures (SRC) to carbon sequestration in both current and elevated atmospheric CO2 concentrations ([CO2]). A dense poplar plantation (1 x 1 m) was exposed to a [CO2] of 550 ppm in Central Italy using the free-air CO2 enrichment (FACE) technique. Three species of Populus were examined, namely P. alba L., P. nigra L. and P. x euramericana Dode (Guinier). Aboveground woody biomass of trees exposed to elevated [CO2] for three growing seasons increased by 15 to 27%, depending on species. As a result, light-use efficiency increased. Aboveground biomass allocation was unaffected, and belowground biomass also increased under elevated [CO2] conditions, by 22 to 38%. Populus nigra, with total biomass equal to 62.02 and 72.03 Mg ha-1 in ambient and elevated [CO2], respectively, was the most productive species, although its productivity was stimulated least by atmospheric CO2 enrichment. There was greater depletion of inorganic nitrogen from the soil after three growing seasons in elevated [CO2], but no effect of [CO2] on stem wood density, which differed significantly only among species.


Future Clinical Trials in DIPG: Bringing Epigenetics to the Clinic.
In spite of major recent advances in diffuse intrinsic pontine glioma (DIPG) molecular characterization, this body of knowledge has not yet translated into better treatments. To date, more than 250 clinical trials evaluating radiotherapy along with conventional cytotoxic chemotherapy as well as newer biologic agents have failed to improve the dismal outcome when compared to palliative radiation alone. The biology of DIPG remained unknown until recently when the neurosurgical expertise along with the recognition by the scientific and clinical community of the importance of tissue sampling at diagnosis; ideally, in the context of a clinical trial and by trained neurosurgical teams to maximize patient safety. These pre-treatment tumor samples, and others coming from tissue obtained post-mortem, have yielded new insights into DIPG molecular pathogenesis. We now know that DIPG comprises a heterogeneous disease with variable molecular phenotypes, different from adult high-grade glioma, other non-pontine pediatric high-grade gliomas, and even between pontine gliomas. The discovery of histone H3.3 or H3.1 mutations has been an important step forward in understanding tumor formation, maintenance, and progression. Pharmacologic reversal of DIPG histone demethylation therefore offers an important potential intervention strategy for the treatment of DIPG. To date, clinical trials of newly diagnosed or progressive DIPG with epigenetic (histone) modifiers have been unsuccessful. Whether this failure represents limited activity of the agents used, their CNS penetration, redundant pathways within the tumor, or the possibility that histone mutations are necessary only to initiate DIPGs but not maintain their growth, suggest that a great deal still needs to be elucidated in both the underlying biology of these pathways and the drugs designed to target them. In this review, we will discuss the role of both epigenetic and genetic mutations within DIPG and the development of treatment strategies directed against the unique abnormalities present in this disease.


Enhancing parent-child interaction with a prenatal couple intervention.
To determine the effect of a prenatal couple group intervention on parent-child interaction postbirth. Quasiexperimental study. A nonrandomized convenience sample of treatment group (TG) couples (n = 35) who attended an additional prenatal three-class series was compared to a control group (CG) from childbirth education classes on measures of videotaped parent-child interaction using the NCATS tool. The intervention class series was based on individual and couple changes in meaning/identity, roles, and relationship/interaction during the transition to parenthood. It addressed mother/father roles, infant communication abilities, and patterns of the first 3 months of life in a mutually enjoyable, possibility-focused way. T-tests and ANCOVA on NCATS scores between groups showed higher TG scores for mothers in sensitivity to cues, for fathers in social-emotional growth fostering, and for couple mean scores in social-emotional growth fostering, couple mean response to child distress, caregiver total, and caregiver-child total. Higher contingency scores were also found in the TG group. Fewer TG mothers and fathers fell below NCATS lower cutoff scores. Interventions that enhance mutual parent-child interaction through increased sensitivity to cues and responsiveness to infant needs or signals are important avenues for facilitating secure attachment, father and mother involvement, optimal development, and prevention of child abuse and neglect. The positive approach to this intervention invites couples to see themselves as developing with their infants over time, and to view their infants in new ways that will help develop satisfying, self-reinforcing patterns of interaction.


Improvement in genetic evaluation of female fertility in dairy cattle using multiple-trait models including milk production traits.
This study investigated the improvement in genetic evaluation of fertility traits by using production traits as secondary traits (MILK = 305-d milk yield, FAT = 305-d fat yield, and PROT = 305-d protein yield). Data including 471,742 records from first lactations of Denmark Holstein cows, covering the years of inseminations during first lactations from 1995 to 2004, were analyzed. Six fertility traits (i.e., interval in days from calving to first insemination, calving interval, days open, interval in days from first to last insemination, numbers of inseminations per conception, and nonreturn rate within 56 d after first service) were analyzed using single- and multiple-trait sire models including 1 or 3 production traits. Model stability was evaluated by correlation between EBV from 2 sub-data sets (DATA(A) and DATA(B)). Model predictive ability was assessed by the correlation between EBV from training data (DATA(A) or DATA(B)) and daughter performance (yield deviation, defined as average of daughter-records adjusted for nongenetic effects) from test data (DATA(B) or DATA(A)) in a cross-validation procedure, and correlation between EBV obtained from the whole data set (DATA(T)) and from a reduced data set (DATA(C1), which only contained the first crop daughters) for proven bulls. In addition, the superiority of the models was evaluated by expected reliability of EBV, calculated from the prediction error variance of EBV. Based on these criteria, the models combining milk production traits showed better model stability and predictive ability than single-trait models for all the fertility traits, except for nonreturn rate within 56 d after first service. The stability and predictive ability for the model including MILK or PROT were similar to the model including all 3 milk production traits and better than the model including FAT. In addition, it was found that single-trait models underestimated genetic trend of fertility traits. These results suggested that genetic evaluation of fertility traits would be improved using a multiple-trait model including MILK or PROT.


Anomalous Thermal Conductivity and Magnetic Torque Response in the Honeycomb Magnet α-RuCl_{3}.
We report on the unusual behavior of the in-plane thermal conductivity κ and torque τ response in the Kitaev-Heisenberg material α-RuCl_{3}. κ shows a striking enhancement with linear growth beyond H=7 T, where magnetic order disappears, while τ for both of the in-plane symmetry directions shows an anomaly at the same field. The temperature and field dependence of κ are far more complex than conventional phonon and magnon contributions, and require us to invoke the presence of unconventional spin excitations whose properties are characteristic of a field-induced spin-liquid phase related to the enigmatic physics of the Kitaev model in an applied magnetic field.


Laser trabeculoplasty for open-angle glaucoma: a report by the american academy of ophthalmology.
To provide an evidence-based summary of the outcomes, repeatability, and safety of laser trabeculoplasty for open-angle glaucoma. A search of the peer-reviewed literature in the PubMed and the Cochrane Library databases was conducted in June 2008 and was last repeated in March 2010 with no date or language restrictions. The search yielded 637 unique citations, of which 145 were considered to be of possible clinical relevance for further review and were included in the evidence analysis. Level I evidence indicates an acceptable long-term efficacy of initial argon laser trabeculoplasty for open-angle glaucoma compared with initial medical treatment. Among the remaining studies, level II evidence supports the efficacy of selective laser trabeculoplasty for lowering intraocular pressure for patients with open-angle glaucoma. Level III evidence supports the efficacy of repeat use of laser trabeculoplasty. Laser trabeculoplasty is successful in lowering intraocular pressure for patients with open-angle glaucoma. At this time, there is no literature establishing the superiority of any particular form of laser trabeculoplasty. The theories of action of laser trabeculoplasty are not elucidated fully. Further research into the differences among the lasers used in trabeculoplasty, the repeatability of the procedure, and techniques of treatment is necessary. Proprietary or commercial disclosure may be found after the references.


Proinflammatory Caspase A Activation and an Antiviral State Are Induced by a Zebrafish Perforin after Possible Cellular and Functional Diversification from a Myeloid Ancestor.
In mammals, perforins play a central role in the granule-dependent cell death induced by natural killer T cells and cytotoxic T lymphocytes, and participate both in the defense against virus-infected and neoplastic cells and in the recognition of nonself molecules by the immune system. Little is known about fish perforin genes. We examined the zebrafish with the aim of increasing our knowledge about the role of perforins. We characterized 6 perforin genes in the zebrafish genome, and we studied them at the evolutionary level in combination with expression patterns in several tissues and cell populations, during both larval development and in the course of a viral infection. Our results suggest the specialization of different cell types in the production of perforins. Moreover, functional diversification during the evolution of these molecules could be inferred from this study. In particular, one of the genes, prf19b, which is mainly produced by myeloid cells, seemed to be involved in antiviral defense, conferring protection after an in vivo infection.


Evaluation of rate-responsive pacemakers by transesophageal Holter monitoring of spontaneous atrial rate.
One of the most important problems in rate responsive (RR) pacing is the clinical experimental evaluation of the reliability of various sensors. In particular, it is difficult to test their sensitivity and specificity during daily activity of the patients. Atrial rate, when present and normal, is the most physiological marker of metabolic requirements, but sometimes it is impossible to analyze the P wave in ventricular paced rhythm during routinely performed tests (e.g., ergometric test and 24-hour Holter monitoring). During various physical activities, we monitored atrial electrograms on an esophageal lead on the first channel of a standard Holter tape recorder; on the second channel a surface ECG lead was recorded. We selected 10 patients with high grade heart block and normal sinus node function paced in RR-VVI mode. RR pacing was obtained using various sensors (body activity, blood temperature, spike-T interval, minute ventilation). The good quality of recording allowed an easy evaluation of atrial and ventricular rates. In four cases an appropriate increase in heart rate was documented; sensitivity threshold and/or rate response slope were reprogrammed when indicated. The pacing rate of one patient did not parallel the atrial rate during walking only. In three cases, we observed a delay in the ventricular rate increase, with ventricular rate decreasing at peak exercise despite further atrial rate increase. In the last two patients, we observed inappropriate pacing response; pacing rate increased later and to a lower level than the atrial one. This new method is applied easily and appears reliable to evaluate the response of RR pacemakers to individual metabolic needs.(ABSTRACT TRUNCATED AT 250 WORDS)


Selectivity of hyaluronic acid binding for spermatozoa with normal Tygerberg strict morphology.
During spermiogenesis, a plasma membrane remodelling step facilitates formation of sperm zona pellucida and hyaluronic acid (HA) binding sites. Enrichment of Tygerberg normal spermatozoa in HA-bound versus semen sperm fractions was postulated. Semen was placed on the uncoated A side and HA-coated B side of a semen chamber. After 15 min, the HA binding score (proportion of HA-bound motile spermatozoa) was assessed on the B side, and unbound spermatozoa were removed by gentle rinsing. Following Diff-Quick staining, sperm morphology of A and B sides was evaluated by three blinded investigators at Yale and Tygerberg. The proportion of Tygerberg normal spermatozoa was higher in HA-bound versus semen spermatozoa (n = 63 subjects) with a 3.04-fold improvement (95% confidence limits: 1.9-4.7) in 37 teratozoospermic men, comparable with a 4.2-fold enrichment in zona pellucida-bound spermatozoa reported earlier by the Tygerberg group. The morphology scores of three investigators were different but related, indicating that the variations reflect individual-to-individual differences in the perception of shape normality. The selection power of HA and zona pellucida for normal spermatozoa are similar. The sperm biomarkers of creatine phosphokinase (reflecting retained cytoplasm in arrested maturity spermatozoa) and chaperone protein HspA2 (heat shock protein) were proportional with sperm HA binding. As HA binding reflects sperm maturity and function, the combination of Tygerberg morphology and HA binding is likely to improve male infertility management.


Realizing a high OER activity in new single-atom catalysts formed by introducing TMNx (x = 3 and 4) units into carbon nanotubes using high-throughput calculations.
Exploring highly efficient electrocatalysts for the oxygen evolution reaction (OER) is of great significance for hydrogen production through water splitting. By means of high-throughput density functional theory (DFT) calculations, we investigated the OER catalytic activity of a series of one-dimensional carbon nanotube (CNT)-based systems containing TMN4 or TMN3 functional units. Through the screening of 3d/4d/5d transition metals (TMs) from Group IVB to Group VIII, eight newly obtained TMNx@CNT (x = 3 and 4) systems were found to exhibit excellent OER activity, with very low overpotentials in the range 0.29-0.51 V, where the Co, Rh, Ir, Ti, Fe, and Ru atoms could be used as active sites. It was found that under the framework of TMN3@CNTs, the pre-adsorption of some species from water dissociation on the relevant TM sites (TM = Ti, Fe, and Ru) could lead to a high OER catalytic activity, which was different from the general situation where OER reactions directly occur on the clean surfaces of the remaining systems with Co/Rh/Ir metal centers. Moreover, the catalytic mechanisms were analyzed in detail. This work can be conducive to obtaining low-cost and high-performance OER single-atom electrocatalysts based on excellent CNT nanomaterials.


Breakfast intake is associated with nutritional status, Mediterranean diet adherence, serum iron and fasting glucose: the CYFamilies study.
To assess the association of breakfast intake with Mediterranean diet adherence, physical activity levels, obesity, selected cardiovascular risk markers and Fe status. Cross-sectional study. BMI, body fat percentage and waist circumference were assessed. Physical activity was assessed using a pedometer and diet quality was evaluated by applying the KIDMED index. Blood tests to assess blood lipids, high-sensitivity C-reactive protein, fasting glucose, serum Fe and ferritin, as well as Hb, were performed. Primary-school children of the Troodos mountainous area in Cyprus. Eighty-three Cypriot children (mean age 9·2 (sd 1·7) years). Compared with breakfast skippers, regular breakfast eaters were 40 % more likely to have a KIDMED score higher by one point on average (OR=1·41; 95 % CI 1·08, 1·84) after accounting for obesity levels and other confounders. Breakfast skippers, on the other hand, were by about 14 % more likely to have a body fat percentage value higher by one unit, as well as higher values for both BMI and waist circumference. The relationship was significantly strengthened when combining body fat percentage and waist circumference into a composite variable (OR=0·20; 95 % CI 0·06, 0·69). Fasting glucose was inversely correlated to breakfast intake in descriptive analyses, whereas serum Fe was positively correlated to breakfast intake after considering age, gender and diet quality. The latter relationship disappeared, however, after considering physical activity levels. Cypriot children who take breakfast regularly exhibit a higher adherence to the Mediterranean diet and have higher serum Fe concentrations and lower BMI, waist circumference, body fat percentage and fasting glucose levels, compared with children who skip breakfast. Public health professionals, educators and parents should prioritize on actions that will motivate children to regularly eat breakfast.


Structural basis for the interaction of lipopolysaccharide with outer membrane protein H (OprH) from Pseudomonas aeruginosa.
Pseudomonas aeruginosa is a major nosocomial pathogen that infects cystic fibrosis and immunocompromised patients. The impermeability of the P. aeruginosa outer membrane contributes substantially to the notorious antibiotic resistance of this human pathogen. This impermeability is partially imparted by the outer membrane protein H (OprH). Here we have solved the structure of OprH in a lipid environment by solution NMR. The structure reveals an eight-stranded β-barrel protein with four extracellular loops of unequal size. Fast time-scale dynamics measurements show that the extracellular loops are disordered and unstructured. It was previously suggested that the function of OprH is to provide increased stability to the outer membranes of P. aeruginosa by directly interacting with lipopolysaccharide (LPS) molecules. Using in vivo and in vitro biochemical assays, we show that OprH indeed interacts with LPS in P. aeruginosa outer membranes. Based upon NMR chemical shift perturbations observed upon the addition of LPS to OprH in lipid micelles, we conclude that the interaction is predominantly electrostatic and localized to charged regions near both rims of the barrel, but also through two conspicuous tyrosines in the middle of the bilayer. These results provide the first molecular structure of OprH and offer evidence for multiple interactions between OprH and LPS that likely contribute to the antibiotic resistance of P. aeruginosa.


[Sporotrichosis and dematiaceous fungal skin infections].
Sporotrichosis is a chronic infectious granuloma of skin. The detection of fungal elements in pathological examination and the isolation of Sporothrix schenckii from the lesion are requisite for diagnosis. The sporotrichin test is useful as an auxiliary examination, but a false-negative reaction might occur in some cases. Oral potassium iodide is first choice of treatment, because of its modest cost and usefulness, although gastrointestinal disorder is a frequent side effect. Itraconazole should be the second selection, and then terbinafine. Local thermotherapy is also effective as an additional therapy. Dematiaceous fungal skin infections are divided into two groups by their parasitic form, chromoblastomycosis and phaeohyphomycosis. Chromoblastomycosis is also called chromomycosis in Japan. It is most important for clinical diagnosis to detect dark brown spores in the scale of chromoblastomycosis and dark brown hyphae in the pus of phaeohyphomycosis by microscopic examination. Both morphological and molecular biological approaches are recommended for identification of fungi. In treatment, the drug appropriate in each case should be selected, and the combination of surgical excision, local thermotherapy, laser therapy or cryotherapy must be considered.


Trefoil factor 3 mediation of oncogenicity and chemoresistance in hepatocellular carcinoma is AKT-BCL-2 dependent.
The efficacious treatment of hepatocellular carcinoma (HCC) remains a challenge, partially being attributed to intrinsic chemoresistance. Previous reports have observed increased TFF3 expression in HCC. Herein, we investigated the functional role of TFF3 in progression of HCC, and in both intrinsic and acquired chemoresistance. TFF3 expression was observed to be upregulated in HCC and associated with poor clinicopathological features and worse patient survival outcome. Functionally, forced expression of TFF3 in HCC cell lines increased cell proliferation, cell survival, anchorage-independent and 3D matrigel growth, cell invasion and migration, and in vivo tumor growth. In contrast, depleted expression of TFF3 decreased the oncogenicity of HCC cells as indicated by the above parameters. Furthermore, forced expression of TFF3 decreased doxorubicin sensitivity of HCC cells, which was attributed to increased doxorubicin efflux and cancer stem cell-like behavior of Hep3B cells. In contrast, depletion of TFF3 increased doxorubicin sensitivity and decreased cancer stem cell-like behavior of Hep3B cells. Correspondingly, TFF3 expression was markedly increased in Hep3B cells with acquired doxorubicin resistance, while the depletion of TFF3 resulted in re-sensitization of the Hep3B cells to doxorubicin. The increased doxorubicin efflux and enhanced cancer stem cell-like behavior of the doxorubicin-resistant Hep3B cells was observed to be dependent on TFF3 expression. In addition, we determined that TFF3-stimulated oncogenicity and chemoresistance in HCC cells was mediated by AKT-dependent expression of BCL-2. Hence, therapeutic inhibition of TFF3 should be considered to hinder HCC progression and overcome intrinsic and acquired chemoresistance in HCC.


W(h)ither human cardiac and body magnetic resonance at ultrahigh fields? technical advances, practical considerations, applications, and clinical opportunities.
The objective of this study was to document and review advances and groundbreaking progress in cardiac and body MR at ultrahigh fields (UHF, B0 ≥ 7.0 T) with the goal to attract talent, clinical adopters, collaborations and resources to the biomedical and diagnostic imaging communities. This review surveys traits, advantages and challenges of cardiac and body MR at 7.0 T. The considerations run the gamut from technical advances to clinical opportunities. Key concepts, emerging technologies, practical considerations, frontier applications and future directions of UHF body and cardiac MR are provided. Examples of UHF cardiac and body imaging strategies are demonstrated. Their added value over the kindred counterparts at lower fields is explored along with an outline of research promises. The achievements of cardiac and body UHF-MR are powerful motivators and enablers, since extra speed, signal and imaging capabilities may be invested to overcome the fundamental constraints that continue to hamper traditional cardiac and body MR applications. If practical obstacles, concomitant physics effects and technical impediments can be overcome in equal measure, sophisticated cardiac and body UHF-MR will help to open the door to new MRI and MRS approaches for basic research and clinical science, with the lessons learned at 7.0 T being transferred into broad clinical use including diagnostics and therapy guiding at lower fields. Copyright © 2015 John Wiley & Sons, Ltd.


International Depository Authority and its Role in Microorganism's Deposition.
After the World Trade Organization's agreement on Trade Related Aspect of Intellectual Property Right, patents have come into major play. Patenting of work related to live organisms that have medical, agricultural and other uses is always a tedious, complicated and controversial job. In view of this an agreement called as Budapest Treaty was passed in 1977 for deposition of microorganisms in culture collection centers for patent purpose. To make a culture collection center an IDA the culture center has to follow rules and regulations made in Budapest Treaty. Today several culture collection centers are working as International Depository Authority (IDA) in India and abroad that are storing microorganisms for patent purpose. India has two IDA units; one is Microbial Culture Collection in National Centre for Cell Science Pune, India, and second one is Microbial Type Culture Collection and Gene Bank at Institute of Microbial Technology Chandigarh, India. IDA units are important for valuable sample depositions, supply of cultures, characterization of samples and conservation of biological materials.


A SYSTEM OF "DEFINITIVE UNITS" PROPOSED FOR UNIVERSAL USE.
It is proposed that physicists discard the CGS and Heaviside units, which are responsible for much confusion and needless mental effort, and employ exclusively a single system of "definitive units." The units suggested include the international meter, the international kilogram, the second, the mechanical watt, the international mercury ohm and they conform with the other international units as closely as is compatible with self-consistency. The system is not only definite and absolute, but also comprehensive, readily visualized and, in large part, already employed under well-established names. The system was proposed in 1901 by Giorgi and in 1904 by Robertson but received scant attention on account of the artificial prestige of the CGS system. A single universal system of units should be the ultimate goal, and the "definitive units" are chosen with a view to their adoption not only by all scientists but also by the butcher, the baker and the candlestick-maker. The definitive system of units makes it perfectly feasible to employ a single system much more generally than has ever been the case in the past; the natural ultimate goal is the universal use of these units for all purposes. In the attempt to extend the application of metric units in the United States the meter-stere-kilogram, rather than the meter-liter-gram, should form the basis for legislation, in order to give definitive units their proper legalized status and to secure to the full the advantages of a comprehensive system consistently interrelated with the legalized international electrical units. The gradual discarding of CGS and other redundant units would inevitably follow. Even in the absence of official recognition of definitive units, individuals may advantageously employ the system. This would cause confusion neither to authors nor readers, since these units, in the main, have already acquired vital existence through world-wide, daily use under familiar, well-established names.


The search for very low loss fiber-optic materials.
Today's fiber-optic communications systems are fused-silica-based fibers for which signals require reamplification every 30 kilometers. Repeaterless long-haul (transcontinental and transoceanic) links can only be envisaged if a new fiber material with intrinsic power losses significantly lower than those of silica can be identified and developed. This article reviews the development of silica-based systems, details the physical mechanisms which produce signal attenuation in fiber materials in general, and identifies that class of materials from which ultralow loss glasses are most likely to be developed in the future.


Staphylococcus aureus Downregulates IP-10 Production and Prevents Th1 Cell Recruitment.
Staphylococcal superantigens cause toxic shock syndrome, which is characterized by massive T cell activation and a predominant Th1 profile of cytokine production. However, superantigen-producing Staphylococcus aureus strains are often part of the human nasal microbiome, and this carrier state has often been associated with some type 2 immune responses such as chronic sinusitis with polyps and atopic dermatitis. We have previously reported that the S. aureus cell wall downregulates the human T cell response to superantigens through a TLR2-dependent, IL-10-mediated mechanism. In this study, we show that S. aureus also regulates the profile of superantigen-induced T cell recruitment. The staphylococcal superantigen SEE induced the production of Th1 cell-recruiting chemokines, including IP-10, through an IFN-γ-dependent mechanism. Such an induction was suppressed by the concomitant presence of S. aureus The downregulation of IP-10 by S. aureus was mediated by components of its cell wall, but was not due to peptidoglycan-induced IL-10 production. Instead, S. aureus triggered activation of MAPKs p38 and ERK, as well as inhibition of STAT1 signaling in monocytes, altogether contributing to the downregulation of IP-10 and other Th1 cell-recruiting chemokines (e.g., CXCL9 and CXCL11). These effects translated into inhibition of superantigen-induced Th1 cell recruitment. Taken together, our data may explain why colonization of superantigen-producing S. aureus can induce, under some circumstances, mucosal type 2 immune responses.


Oral history, subjectivity, and environmental reality: occupational health histories in twentieth-century Scotland.
This essay uses oral histories of dust disease in twentieth-century Scotland to illustrate the ways in which such history can illuminate how the working environment and work cultures affect workers' bodies and how workers come to terms with the ill-health caused by their employment. It emphasizes the agency of the interpreter but argues further that oral histories of dust disease in twentieth-century Scotland are simultaneously influenced by, and evidence for, material conditions. The essay explores the notion that the bodies, not just the voices of interviewees, are material testament to health-corroding work practices, cultures, and habitat. The focus is the problems caused by the inhalation of coal and asbestos dust.


[Musical relaxation therapy on the cerebral arteriosclerosis].
The transcranial Doppler and psychological measurement methods were used to evaluate the effect of musical relaxation therapy on the cerebral arteriosclerosis. The results showed that the musical relaxation therapy could improve the cerebral blood flow (physiological), offset the Type A behavior and eliminate the emotional disturbance (psychological), and that its effect was better than that of the control patients. The mechanism of the effect may be related to the 1/f sound wave (physical), abdominal respiration with long expiration and involuntary inspiration (physiological) and the hinting effects of the inducing phrases (psychological).


Experimental validation of a novel method of dose accumulation for the rectum.
Dose-surface maps (DSMs) are an increasingly popular tool to evaluate spatial dose-outcome relationships for the rectum. Recently, DSM addition has been proposed as an alternative method of dose accumulation from deformable registration-based techniques. In this study, we performed the first experimental investigation of the accuracy at which DSM accumulation can capture the total dose delivered to a rectum's surface in the presence of inter-fraction motion. A custom PVC rectum phantom capable of representing typical rectum inter-fraction motion and filling variations was constructed for this project. The phantom allowed for the placement of EBT3 film sheets on the representative rectum surface to measure rectum surface dose. A multi-fraction prostate VMAT treatment was designed and delivered to the phantom in a water tank for a variety of inter-fraction motion scenarios. DSMs for each fraction were calculated in two ways using CBCT images acquired during delivery and summed to produce accumulated DSMs. Accumulated DSMs were then compared to film measurements using gamma analysis (3%/2 mm criteria). Similarity of isodose clusters between films and DSMs was also investigated. Baseline agreement between film measurements and accumulated DSMs for a stationary rectum was 95.6%. Agreement between film and accumulated DSMs in the presence of different types of inter.-fraction motion was ≥92%, and isodose cluster mean distance to agreement was within 1.5 mm for most scenarios. Overall, DSM accumulation performed the best when using DSMs that accounted for changes in rectum path orientation. Dose accumulation performed with DSMs was found to accurately replicate total delivered dose to a rectum phantom in the presence of inter-fraction motion.


Association of treatment with carvedilol vs metoprolol succinate and mortality in patients with heart failure.
The β-blockers carvedilol and metoprolol succinate both reduce mortality in patients with heart failure (HF), but the comparative clinical effectiveness of these drugs is unknown. To investigate whether carvedilol is associated with improved survival compared with metoprolol succinate. Cohort study of patients with incident HF with reduced left ventricular ejection fraction (LVEF) (≤40%) who received carvedilol (n = 6026) or metoprolol succinate (n = 5638) using data from a Danish national HF registry linked with health care and administrative databases. All-cause mortality (primary outcome) and cardiovascular mortality (secondary outcome) were analyzed using Cox regression with adjustment for a propensity score, derived from a range of clinical, socioeconomic, and demographic characteristics. The mean (SD) age of the patients was 69.3 (9.1) years, 71% were men, and 51% were hospitalized at index HF diagnosis. During a median (interquartile range) 2.4 (1.0-3.0) years of follow-up, 875 carvedilol users and 754 metoprolol users died; the cumulative incidence of mortality was 18.3% and 18.8%, respectively. The adjusted hazard ratio for carvedilol users vs metoprolol users was 0.99 (95% CI, 0.88 to 1.11), corresponding to an absolute risk difference of -0.07 (95% CI, -0.84 to 0.77) deaths per 100 person-years. Estimates were consistent across subgroup analyses by sex, age, levels of LVEF, New York Heart Association classification, and history of ischemic heart disease. A higher proportion of carvedilol users achieved the recommended daily target dose (50 mg; 3124 [52%]) than did metoprolol users (200 mg; 689 [12%]); among patients who reached the target dose, the adjusted hazard ratio was 0.97 (95% CI, 0.72-1.30). A robustness analysis with 1:1 propensity score matching confirmed the primary findings (hazard ratio, 0.97 [95% CI, 0.84-1.13]). The adjusted hazard ratio for cardiovascular mortality was 1.05 (95% CI, 0.88-1.26). These findings from real-world clinical practice indicate that the effectiveness of carvedilol and metoprolol succinate in patients with HF is similar.