Prostate-specific antigen screening and mortality from prostate cancer.
There is no available evidence from randomized trials that early detection of prostate cancer improves health outcomes, but the prostate-specific antigen (PSA) test is commonly used to screen men for prostate cancer. The objective of the study is to see if screening with PSA decreases mortality from prostate cancer. This is a case-control study using one-to-one matching on race, age, and time of availability of exposure to PSA screening. Decedents, 380, from New Jersey Vital Statistics 1997 to 2000 inclusive, 55-79 years of age at diagnosis were matched to living controls without metastatic prostate cancer. Medical records were obtained from all providers, and we abstracted information about PSA tests from 1989 to the time of diagnosis in each index case. Measurements consist of a comparison of screening (yes, no) between cases and controls. Measure of association was the odds ratio. Eligible cases were diagnosed each year from 1989 to 1999 with the median year being 1993. PSA screening was evident in 23.2-29.2% of cases and 21.8-26.1% of controls depending on the screening criteria. The unadjusted, matched odds ratio for dying of prostate cancer if ever screened was 1.09 (95% CI 0.76 to 1.60) for the most restrictive criteria and 1.19 (95% CI, 0.85 to 1.66) for the least restrictive. Adjustment for comorbidity and education level made no significant differences in these values. There were no significant interactions by age or race. PSA screening using an ever/never tabulation for tests from 1989 until 2000 did not protect New Jersey men from prostate cancer mortality.


Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: a systematic review and meta-analysis.
Guidelines recommend intensive blood pressure (BP) lowering in patients at high risk. While placebo-controlled trials have demonstrated 22% reductions in coronary heart disease (CHD) and stroke associated with a 10-mmHg difference in systolic BP, it is unclear if more intensive BP lowering strategies are associated with greater reductions in risk of CHD and stroke. We did a systematic review to assess the effects of intensive BP lowering on vascular, eye, and renal outcomes. We systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and July 2011. We included trials that randomly assigned individuals to different target BP levels. We identified 15 trials including a total of 37,348 participants. On average there was a 7.5/4.5-mmHg BP difference. Intensive BP lowering achieved relative risk (RR) reductions of 11% for major cardiovascular events (95% CI 1%-21%), 13% for myocardial infarction (0%-25%), 24% for stroke (8%-37%), and 11% for end stage kidney disease (3%-18%). Intensive BP lowering regimens also produced a 10% reduction in the risk of albuminuria (4%-16%), and a trend towards benefit for retinopathy (19%, 0%-34%, p = 0.051) in patients with diabetes. There was no clear effect on cardiovascular or noncardiovascular death. Intensive BP lowering was well tolerated; with serious adverse events uncommon and not significantly increased, except for hypotension (RR 4.16, 95% CI 2.25 to 7.70), which occurred infrequently (0.4% per 100 person-years). Intensive BP lowering regimens provided greater vascular protection than standard regimens that was proportional to the achieved difference in systolic BP, but did not have any clear impact on the risk of death or serious adverse events. Further trials are required to more clearly define the risks and benefits of BP targets below those currently recommended, given the benefits suggested by the currently available data.


Dietary restriction reduces the prevalence of osteonecrosis of the caput femoris in spontaneously hypertensive rats.
We investigated the effects of dietary restriction (DR), an experimental intervention known to suppress several strain-specific diseases, on the prevalence of osteonecrosis of the caput femoris in spontaneously hypertensive rats (SHR). At 6 weeks of age, the food intake of DR rats was restricted to 65% of the mean intake of control rats fed ad libitum (AL). Acute osteonecrosis of the caput femoris without reparative tissue response (RTR) was observed at 10 and 15 weeks in both DR and AL groups; no such acute lesion was seen at 20 and 30 weeks. The prevalence of osteonecrosis, osteonecrosis with/without reparative tissue response was significantly reduced in DR rats at 15 and 20 weeks, but not at 10 weeks. DR reduced the body weight by 30% and the length of the femur by 10%. Ossification of the caput femoris, known to be delayed in AL rats compared with Wistar Kyoto rats, was also restored by DR. Our results showed that dietary restriction reduced the prevalence of osteonecrosis and modulated the mechanical factors involved in the lesion. They also indicate that utilization of dietary restriction is a useful research tool for investigating the underlying mechanisms of osteonecrosis of the caput femoris in SHR.


Hydrogen-rich saline is cerebroprotective in a rat model of deep hypothermic circulatory arrest.
Deep hypothermic circulatory arrest (DHCA) has been widely used in the operations involving the aortic arch and brain aneurysm since 1950s; but prolonged DHCA contributes significantly to neurological deficit which remains a major cause of postoperative morbidity and mortality. It has been reported that hydrogen exerts a therapeutic antioxidant activity by selectively reducing hydroxyl radical. In this study, DHCA treated rats developed a significant oxidative stress, inflammatory reaction and apoptosis. The administration of HRS resulted in a significant decrease in the brain injury, together with lower production of IL-1β, TNF-α, 8-OHdG and MDA as well as decreased activity of NOS while increased activity of SOD. The apoptotic index as well as the expressions of caspase-3 in brain tissue was significantly decreased after treatment. HRS administration significantly attenuated the severity of DHCA induced brain injury by mechanisms involving amelioration of oxidative stress, down-regulation of inflammatory factors and reduction of apoptosis.


Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial.
Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes. The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00074581. 1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373-522) cells per μL in patients assigned to the early treatment group and 428 (357-522) cells per μL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197-249) cells per μL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0·73, 95% CI 0·52-1·03; p=0·074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0·64, 0·43-0·96; p=0·031), tuberculosis developed in 17 versus 34 patients, respectively (0·49, 0·28-0·89, p=0·018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24·9 per 100 person-years, 95% CI 22·5-27·5) versus 585 in the delayed treatment group (29·2 per 100 person-years, 26·5-32·1; p=0·025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group. Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment. US National Institute of Allergy and Infectious Diseases.


Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice.
The importance of cholesterol ester synthesis by acyl CoA:cholesterol acyltransferase (ACAT) enzymes in intestinal and hepatic cholesterol metabolism has been unclear. We now demonstrate that ACAT2 is the major ACAT in mouse small intestine and liver, and suggest that ACAT2 deficiency has profound effects on cholesterol metabolism in mice fed a cholesterol-rich diet, including complete resistance to diet-induced hypercholesterolemia and cholesterol gallstone formation. The underlying mechanism involves the lack of cholesterol ester synthesis in the intestine and a resultant reduced capacity to absorb cholesterol. Our results indicate that ACAT2 has an important role in the response to dietary cholesterol, and suggest that ACAT2 inhibition may be a useful strategy for treating hypercholesterolemia or cholesterol gallstones.


Coronary Heart Disease, Diabetes, and Sexuality in Men.
Erectile dysfunction (ED) has been well recognized as a marker of increased cardiovascular risk for more than 15 years, especially in younger men. Early detection of ED represents an opportunity to intervene to decrease the risk of future cardiovascular events and limit the progression of ED severity. Evidence suggests there is a window of opportunity of 3 to 5 years from the onset of ED to subsequent cardiovascular events. This opportunity is usually missed if the onus is placed on the patient to seek care for his sexual problems. Unfortunately, these clear messages have not been incorporated into routine cardiovascular care. The reasons for these disparities within specialties are discussed in this article, in addition to management algorithms. Lifestyle modification is usually recommended as the first-line treatment to correct ED and lessen cardiovascular risk, but evidence suggests that this might be effective only in men without established cardiovascular comorbidities. In men with type 2 diabetes mellitus and established cardiovascular disease, lifestyle modification alone is unlikely to be effective. Cardiovascular medications are often associated with sexual dysfunction but changes in medication are more likely to be beneficial in men with milder recent-onset ED. A balanced view must be taken related to medication adverse events, taking into account optimal management of established cardiovascular disease. Testosterone deficiency has been associated with different metabolic disorders, especially metabolic syndrome and type 2 diabetes mellitus. Testosterone deficiency syndrome has been associated with an independent burden on sexual function globally and increased cardiovascular and all-cause mortality. Testosterone replacement therapy has been shown to improve multiple aspects of sexual function and, in some studies, has been associated with a decrease in mortality, especially in men with type 2 diabetes mellitus. Recent studies have suggested that phosphodiesterase type 5 inhibitors, the first-line medications to treat ED, could decrease cardiovascular and all-cause mortality, through multiple mechanisms, predominantly related to improved endothelial function.


TDQ-30-A New Color Picture-Naming Test for the Diagnostic of Mild Anomia: Validation and Normative Data in Quebec French Adults and Elderly.
A reduction in lexical access is observed in normal aging and a few studies also showed that this ability is affected in individuals with subjective cognitive decline. Lexical access is also affected very early in mild cognitive impairment as well as in major neurocognitive disorders. The detection of word-finding difficulties in the earliest stages of pathological aging is particularly difficult because symptoms are often subtle or mild. Therefore, mild anomia is underdiagnosed, mainly due to the lack of sensitivity of naming tests. In this article, we present the TDQ-30, a new picture-naming test designed to detect mild word-finding deficits in adults and elderly people. The article comprises three studies aiming at the development of the test (Study 1), the establishment of its validity and reliability (Study 2), and finally, the production of normative data for French-speaking adults and elderly people from Quebec (Study 3). The results showed that the TDQ-30 has good convergent validity. Also, the TDQ-30 distinguished the performance of healthy controls from those of participants with mild cognitive impairment, Alzheimer's disease, and post-stroke aphasia. This suggests good discriminant validity. Finally, this study provides normative data computed from a study sample composed of 227 participants aged 50 years and over. The TDQ-30 has the potential to become a valuable picture-naming test for the diagnosis of mild anomia associated with pathological aging.


A randomised controlled trial of the Flinders Program™ of chronic condition management in Vietnam veterans with co-morbid alcohol misuse, and psychiatric and medical conditions.
To evaluate the efficacy of the Flinders Program™ of chronic condition management on alcohol use, psychosocial well-being and quality of life in Vietnam veterans with alcohol misuse. This 9-month wait-list, randomised controlled trial used the Alcohol Use Disorders Identification Test (AUDIT) score ≥ 8 as the entry criterion. Intervention veterans received the Flinders Program plus usual care and controls received usual care. The primary outcome measure was AUDIT score at baseline, 3, 6 and 9 months. Secondary measures included quality of life, alcohol dependence (DSM-IV), anxiety and depression. All measures were repeated at variable trial end dates between 9 and 18 months in the intervention group. Randomisation resulted in 46 intervention and 31 control participants. Intent-to-treat analyses showed AUDIT scores improved significantly from baseline to 9-month follow-up (p = 0.039) in the intervention group compared to control group. The control group had 1.46 times the risk of alcohol dependence than the intervention group at 9 months (p = 0.027). There were no significant differences between groups for secondary measures. Within-group analyses showed that both groups significantly improved in AUDIT (p < 0.001), anxiety and depression (p < 0.01), anger (p < 0.001), and post-traumatic stress (p < 0.01). Improvements in AUDIT (p < 0.001) and alcohol dependence were maintained in the intervention group to 18 months. Use of the Flinders Program in addition to usual care resulted in reduced alcohol use, reduced alcohol dependence, and global clinical improvement in Vietnam veterans with risky alcohol behaviours and chronic mental health problems. The findings demonstrate that the Flinders Program provides a structured framework for delivering self-management support, case management and coordinated care for people with chronic conditions. This clinical approach has the potential to bridge the gap between physical and mental illness service delivery for people with long-term conditions in Australia.


Role of GERD in chronic resistant sinusitis: a prospective, open label, pilot trial.
The objective of this study was to determine whether aggressive medical therapy of gastroesophageal reflux disease (GERD) could improve both subjective and objective features of chronic resistant sinusitis (CRS). Consecutive patients with CRS underwent assessment of GERD and sinus symptoms, esophageal motility testing, dual-channel esophageal pH testing, and laryngoscopy and nasal endoscopy at baseline. The results were compared to those of a group of GERD patients without sinus problems. The CRS patients alone then received omeprazole 20 mg b.i.d. for 3 months with symptom follow-up at monthly intervals. Laryngoscopy and nasal endoscopy were repeated at 3 months. Eleven patients with CRS and 19 GERD patients participated. Eight CRS patients experienced heartburn at least once weekly. Esophageal manometry and pH test results were similar between the two groups. Nine CRS patients had an abnormal pH test. All 11 CRS patients completed the 3-month course of omeprazole. Individual sinus symptoms (nasal congestion, nasal drainage, sinus pressure, facial headache, malaise) and global satisfaction were modestly improved in 25-89% and 91%, respectively, at 12 wk. Resolution of symptoms occurred infrequently. We identified no baseline variable that could predict symptom improvement. Although laryngoscopy and nasal endoscopy were abnormal in most CRS patients at baseline and improved in some after treatment, these changes did not parallel symptom improvement. In this small, prospective, open label study, we demonstrated a high prevalence of GERD in patients with CRS, many of whom experienced modest sinus symptom improvement after using omeprazole b.i.d. for 3 months. These findings warrant further randomized, controlled study in a larger patient population.


Intravital assessment of myelin molecular order with polarimetric multiphoton microscopy.
Myelin plays an essential role in the nervous system and its disruption in diseases such as multiple sclerosis may lead to neuronal death, thus causing irreversible functional impairments. Understanding myelin biology is therefore of fundamental and clinical importance, but no tools currently exist to describe the fine spatial organization of myelin sheaths in vivo. Here we demonstrate intravital quantification of the myelin molecular structure using a microscopy method based on polarization-resolved coherent Raman scattering. Developmental myelination was imaged noninvasively in live zebrafish. Longitudinal imaging of individual axons revealed changes in myelin organization beyond the diffraction limit. Applied to promyelination drug screening, the method uniquely enabled the identification of focal myelin regions with differential architectures. These observations indicate that the study of myelin biology and the identification of therapeutic compounds will largely benefit from a method to quantify the myelin molecular organization in vivo.


GABA concentrations in the human anterior cingulate cortex predict negative BOLD responses in fMRI.
The human anterior cingulate cortex (ACC) is part of the default-mode network that shows predominant negative blood oxygen level-dependent (BOLD) responses in functional magnetic resonance imaging (fMRI). We combined fMRI during emotional processing and resting-state magnetic resonance spectroscopy measurements and observed that the concentration of GABA in the ACC specifically correlated with the amount of negative BOLD responses in the very same region. Our findings show that default-mode network negative BOLD responses during emotions are mediated by GABA.


Myocardial fibrosis progression on cardiac magnetic resonance in hypertrophic cardiomyopathy.
We hypothesised that, in hypertrophic cardiomyopathy (HCM), late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) is progressive and can be predicted by baseline CMR findings and HCM phenotype. In this single-centre cohort study, 71 patients with HCM (59±13 years; 48 men) were prospectively enrolled with clinical, echocardiographic and CMR data. Two consecutive CMR scans were performed with a time interval of 582±174 days. The LGE extent was quantified as a proportion of total LV myocardium (%LGE). LGE was present in 65 patients (91.5%) at the first CMR (CMR-1). In all, LGE extent was significantly increased (p<0.001). A difference in %LGE between the two CMR scans was correlated with the initial %LGE (r=0.44, p<0.001). LGE progression, defined as >4% increase in LGE at the second CMR, was present in 19 patients with non-apical HCM (36.5%), but in only one apical HCM (5.3%). Also, LGE progression rate was significantly higher in non-apical (0.15%/month) versus apical HCM (0.025%/month) (p=0.001). On the multivariate model #1 including only clinical variables (age, history of paroxysmal atrial fibrillation, LV outflow tract obstruction on echocardiography, beta-blocker use, family history of sudden death, family history of HCM, syncope, non-sustained ventricular tachycardia, rate pressure product, and HCM phenotype), only apical HCM phenotype was associated with less LGE progression (p=0.038). On the multivariate model #2 including CMR variables additional to the model #1, %LGE at CMR-1 was the only determinant for LGE progression (p=0.007). When the analysis was limited to patients with preserved EF, results remained unchanged. Myocardial fibrosis in HCM is a progressive phenomenon. Non-apical phenotype and a higher LGE extent at CMR-1 are both associated with greater LGE progression.


"She Would Love That": Identifying Community Needs in a Multisensory Environment.
CareWays Community, a not-for-profit organization that provides community care services within the Illawarra region of Australia, and researchers from the University of Wollongong (Australia) collaborated to conduct research into the requirements and requests of the local community regarding the creation of a multisensory environment (MSE). Guided by the principles of community-based participatory research (CBPR), we sought to gain an understanding of what the community wanted with respect to the design and implementation of a MSE, before its construction at a local community center managed by CareWays. A mixed methods approach was adopted to access as many participants as possible. Participants included both professional and familial caregivers and educators of potential clientele. A total of 24 people participated in either a focus group or a one-on-one telephone interview. Additionally, the Delphi method was used to survey a total of 87 respondents over two rounds to identify the specific equipment preferred for the MSE. Participants expressed both their wishes and concerns regarding the proposed MSE. They wanted a safe, noncategorical environment able to cater to a range of users. They preferred private access, and wanted the MSE to be available for bookings across a wide range of times. Participants wanted the MSE to contain equipment that stimulated all senses, and identified specific items of equipment most preferred. This research enabled the identification of what the local community is seeking in a MSE. The research findings have been incorporated, as far as practicable, into the design and construction of the Careways MSE.


Urban Metabolic Analysis of a Food-Water-Energy System for Sustainable Resources Management.
Urban metabolism analyzes the supply and consumption of nutrition, material, energy, and other resources within cities. Food, water, and energy are critical resources for the human society and have complicated cooperative/competitive influences on each other. The management of interactive resources is essential for supply chain analysis. This research analyzes the food-water-energy system of urban metabolism for sustainable resources management. A system dynamics model is established to investigate the urban metabolism of food, water, and energy resources. This study conducts a case study of Shihmen Reservoir system, hydropower generation, paddy rice irrigation of Taoyuan and Shihmen Irrigation Associations, and water consumption in Taoyuan, New Taipei, and Hsinchu cities. The interactive influence of the food-water-energy nexus is quantified in this study; the uncertainty analysis of food, water, and energy nexus is presented.


Challenges in the design and implementation of the Multicenter Uveitis Steroid Treatment (MUST) Trial--lessons for comparative effectiveness trials.
Randomized clinical trials (RCTs) are an important component of comparative effectiveness (CE) research because they are the optimal design for head-to-head comparisons of different treatment options. To describe decisions made in the design of the Multicenter Uveitis Steroid Treatment (MUST) Trial to ensure that the results would be widely generalizable. Review of design and implementation decisions and their rationale for the trial. The MUST Trial is a multicenter randomized controlled CE trial evaluating a novel local therapy (intraocular fluocinolone acetonide implant) versus the systemic therapy standard of care for noninfectious uveitis. Decisions made in protocol design in order to broaden enrollment included allowing patients with very poor vision and media opacity to enroll and including clinical sites outside the United States. The treatment protocol was designed to follow standard care. The primary outcome, visual acuity, is important to patients and can be evaluated in all eyes with uveitis. Other outcomes include patient-reported visual function, quality of life, and disease and treatment related complications. The trial population is too small for subgroup analyses that are of interest and the trial is being conducted at tertiary medical centers. CE trials require greater emphasis on generalizability than many RCTs but otherwise face similar challenges for design choices as any RCT. The increase in heterogeneity in patients and treatment required to ensure generalizability can be balanced with a rigorous approach to implementation, outcome assessment, and statistical design. This approach requires significant resources that may limit implementation in many RCTs, especially in clinical practice settings.


Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors.
Constitutive WNT activity drives the growth of various human tumors, including nearly all colorectal cancers (CRCs). Despite this prominence in cancer, no WNT inhibitor is currently approved for use in the clinic largely due to the small number of druggable signaling components in the WNT pathway and the substantial toxicity to normal gastrointestinal tissue. We have shown that pyrvinium, which activates casein kinase 1α (CK1α), is a potent inhibitor of WNT signaling. However, its poor bioavailability limited the ability to test this first-in-class WNT inhibitor in vivo. We characterized a novel small-molecule CK1α activator called SSTC3, which has better pharmacokinetic properties than pyrvinium, and found that it inhibited the growth of CRC xenografts in mice. SSTC3 also attenuated the growth of a patient-derived metastatic CRC xenograft, for which few therapies exist. SSTC3 exhibited minimal gastrointestinal toxicity compared to other classes of WNT inhibitors. Consistent with this observation, we showed that the abundance of the SSTC3 target, CK1α, was decreased in WNT-driven tumors relative to normal gastrointestinal tissue, and knocking down CK1α increased cellular sensitivity to SSTC3. Thus, we propose that distinct CK1α abundance provides an enhanced therapeutic index for pharmacological CK1α activators to target WNT-driven tumors.


Speckle myocardial imaging modalities for early detection of myocardial impairment in isolated left ventricular non-compaction.
To examine the hypothesis that speckle myocardial imaging (SMI) modalities, including longitudinal, radial and circumferential systolic (s) and diastolic (d) myocardial velocity imaging, displacement (D), strain rate (SR) and strain (S), as well as left ventricular (LV) rotation/torsion are sensitive for detecting early myocardial dysfunction in isolated LV non-compaction (iLVNC). Twenty patients with iLVNC diagnosed by cardiac magnetic resonance (15) or echocardiography (5) were included. Patients were divided into two groups: ejection fraction (EF)>50% (n=10) and EF<or=50% (n=10). Standard measures of systolic and diastolic function including pulsed wave tissue Doppler Imaging (PWTDI) were obtained. Longitudinal, radial and circumferential SMI, and LV rotation/torsion were compared with values for 20 age/sex-matched controls. EF, PWTDI E', E/E' and all of the SMI modalities were significantly abnormal for patients with EF<or=50% compared with controls. In contrast, EF and PWTDI E', E/E' were not significantly different between controls and patients with iLVNC (EF>50%). However, SMI-derived longitudinal sS, sSR, sD and radial sS, as well as LV rotation/torsion values, were all reduced in iLVNC (EF>50%) compared with controls. Measurements with the highest discriminating power between iLVNC (EF>50%) and controls were longitudinal sS mean of the six apical segments (area under the curve (AUC)=0.94), sS global average (AUC=0.94), LV rotation apical mean (AUC=0.94); LV torsion (AUC=0.93) LV torsion rate (AUC=0.94). LV SMI values are reduced in patients with iLVNC, even those with normal EF and PWTDI. The most accurate SMI modalities to discriminate between patients and controls are longitudinal sS mean of the six apical segments, LV apical rotation or LV torsion rate.


Morphology of the murine optic nerve.
To study the morphology of the murine optic nerve (ON). Eyes of C57/Bl6 and BalbC mice were studied by light and electron microscopy. Microvascular castings of the ON region were prepared by transcardial injection of liquid plastic and studied with a scanning electron microscope. Immunohistochemistry was performed using antibodies against glial fibrillary acidic protein (GFAP), connexin 43, carbonic anhydrase II, and collagen types I and III. The transition between nonmyelinated and myelinated portion of the ON started approximately 0.6 mm behind the globe. A lamina cribrosa was completely absent. Instead, ON axons passed through a scleral hole that was surrounded by a ring of type III and type I collagen fibers. Instead of connective tissue beams within the nerve, layers of elongated astrocytes traversed the ON. All astrocytes stained for GFAP, but not for carbonic anhydrase II. The arterial supply of the nonmyelinated ON derived from branches of the central retinal artery. None of the capillaries derived from choroidal vessels. The mouse ON head differs from that of other species, because it lacks a lamina cribrosa and a choroidal vascular supply. Studies in glaucomatous mice might help to identify the importance of the lamina cribrosa and the choroidal vascular supply for optic nerve damage in glaucoma.


Caspofungin primes the immune response of the larvae of Galleria mellonella and induces a non-specific antimicrobial response.
The echinocandins (e.g. caspofungin) function by inhibiting the synthesis of 1,3-β-glucan in the fungal cell wall. While the potent antifungal activity of caspofungin has been well characterized in mammals, this study investigated the in vivo antifungal effect of caspofungin using larvae of the insect Galleria mellonella. Caspofungin was successful in increasing the survival of larvae that were inoculated with Candida albicans 1 h before the drug was administered, particularly when a concentration of 0.19 μg ml(-1) was used. Pre-injecting larvae with caspofungin also increased their survival when they were inoculated with either Staphylococcus aureus or C. albicans. Caspofungin administration resulted in an increase in the number of circulating immune cells (haemocytes), an increase in the expression of the genes encoding IMPI and transferrin, and an increase in the expression of a number of proteins (identified by liquid chromatography-mass spectrometry) some of which have immune functions. This work indicates that administration of caspofungin can increase the survival of infected G. mellonella larvae, and this is due to the antifungal properties of caspofungin and also to the ability of caspofungin to prime the insect's immune response.


Measurement of DNA synthesis in leucocyte microcultures.
A microculture technique is described in which human peripheral blood leucocytes undergo DNA synthesis in response to specific and non-specific blastogenic factors. A sensitive Millipore filter assay technique is shown to be suitable for determining the incorporation of radioactive thymidine into the DNA of the stimulated cells in these microcultures. With these methods it is possible to measure the DNA synthesis in a 50-mul culture containing an innoculum of only 10(5) leucocytes. This small culture volume, with its low number of leucocytes, therefore makes it possible to perform experiments when either the available leucocytes or blastogenic factors are in limited supply.


CD8(+) T Cells Are Required For Glatiramer Acetate Therapy in Autoimmune Demyelinating Disease.
The exact mechanism of glatiramer acetate (GA, Copaxone®), an FDA-approved immunomodulatory therapy for multiple sclerosis (MS), remains unclear after decades of research. Previously, we have shown that GA therapy of MS induces CD8(+) T cell responses that can potentially suppress pathogenic CD4(+) T cell responses. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we now demonstrate that CD8(+) T cells are necessary in mediating the therapeutic effects of GA. Further, adoptive transfer of GA-induced CD8(+) T cells resulted in amelioration of EAE, establishing a role as a viable immunotherapy in demyelinating disease. Generation of these cells required indoleamine-2,3-dioxygenase (IDO), while suppressive function depended on non-classical MHC class I, IFN-γ, and perforin expression. GA-induced regulatory myeloid cells, previously shown to activate CD4(+) regulatory T cells in an antigen-independent manner, required CD8(+) T cells for disease suppression in vivo. These studies demonstrate an essential role for CD8(+) T cells in GA therapy and identify their potential as an adoptive immunotherapeutic agent.


Understanding the genetic basis of morphological evolution: the role of homeotic genes in the diversification of the arthropod bauplan.
Due to the segmental organization of their body plans, arthropods can be considered the paradigmatic modular organisms. In the past two decades, genetic studies of the homeotic (Hox) genes in Drosophila melanogaster have provided initial insight into the molecular mechanisms that govern the establishment of segmental identity. In this review, we will address the question of the possible role of four Hox genes: labial (lab), proboscipedia (pb), Deformed (Dfd), and Sex combs reduced (Scr) in the morphological evolution of arthropods, particularly with respect to the evolution of the head and head structures in insects. Overall, these preliminary studies illustrate the role that some of the Hox genes expressed in the insect head have played in the morphological evolution of hexapods and likely arthropods in general.


Social tipping points in animal societies.
Animal social groups are complex systems that are likely to exhibit tipping points-which are defined as drastic shifts in the dynamics of systems that arise from small changes in environmental conditions-yet this concept has not been carefully applied to these systems. Here, we summarize the concepts behind tipping points and describe instances in which they are likely to occur in animal societies. We also offer ways in which the study of social tipping points can open up new lines of inquiry in behavioural ecology and generate novel questions, methods, and approaches in animal behaviour and other fields, including community and ecosystem ecology. While some behaviours of living systems are hard to predict, we argue that probing tipping points across animal societies and across tiers of biological organization-populations, communities, ecosystems-may help to reveal principles that transcend traditional disciplinary boundaries.


Sleep, fatigue and burnout among physicians: an American Academy of Sleep Medicine position statement.
Physician burnout is a serious and growing threat to the medical profession and may undermine efforts to maintain a sufficient physician workforce to care for the growing and aging patient population in the United States. Burnout involves a host of complex underlying associations and potential for risk. While prevalence is unknown, recent estimates of physician burnout are quite high, approaching 50% or more, with midcareer physicians at highest risk. Sleep deprivation due to shift-work schedules, high workload, long hours, sleep interruptions, and insufficient recovery sleep have been implicated in the genesis and perpetuation of burnout. Maladaptive attitudes regarding sleep and endurance also may increase the risk for sleep deprivation among attending physicians. While duty-hour restrictions have been instituted to protect sleep opportunity among trainees, virtually no such effort has been made for attending physicians who have completed their training or practicing physicians in nonacademic settings. It is the position of the American Academy of Sleep Medicine that a critical need exists to evaluate the roles of sleep disruption, sleep deprivation, and circadian misalignment in physician well-being and burnout. Such evaluation may pave the way for the development of effective countermeasures that promote healthy sleep, with the goal of reducing burnout and its negative impacts such as a shrinking physician workforce, poor physician health and functional outcomes, lower quality of care, and compromised patient safety.


Chloroplast genome variation in upland and lowland switchgrass.
Switchgrass (Panicum virgatum L.) exists at multiple ploidies and two phenotypically distinct ecotypes. To facilitate interploidal comparisons and to understand the extent of sequence variation within existing breeding pools, two complete switchgrass chloroplast genomes were sequenced from individuals representative of the upland and lowland ecotypes. The results demonstrated a very high degree of conservation in gene content and order with other sequenced plastid genomes. The lowland ecotype reference sequence (Kanlow Lin1) was 139,677 base pairs while the upland sequence (Summer Lin2) was 139,619 base pairs. Alignments between the lowland reference sequence and short-read sequence data from existing sequence datasets identified as either upland or lowland confirmed known polymorphisms and indicated the presence of other differences. Insertions and deletions principally occurred near stretches of homopolymer simple sequence repeats in intergenic regions while most Single Nucleotide Polymorphisms (SNPs) occurred in intergenic regions and introns within the single copy portions of the genome. The polymorphism rate between upland and lowland switchgrass ecotypes was found to be similar to rates reported between chloroplast genomes of indica and japonica subspecies of rice which were believed to have diverged 0.2-0.4 million years ago.


Assembly of Multifunctional Ni2P/NiS0.66 Heterostructures and Their Superstructure for High Lithium and Sodium Anodic Performance.
The combination of structure designs at the microscopic and macroscopic level can efficiently enable electrode materials with greatly enhanced lithium and sodium storage. In this paper, the construction of Ni2P/NiS0.66 heterostructures and their assembly into a superstructure at the nanoscale were successfully achieved by a facile and effective strategy. In the obtained superstructure, the Ni2P/NiS0.66 heterostructures are homogeneously coated with ultrathin carbon layers (HT-NPS@C) and, at the same time, assembled into a yolk-shell nanosphere. Upon evaluation as the anode materials for Li-ion batteries, the HT-NPS@C delivers a high reversible capacity of 430 mA h g-1 after 200 cycles at 200 mA g-1 and ultrastable cyclability with negligible capacity loss over 500 cycles. Furthermore, the coin-type full cell with the LiNi1/3Co1/3Mn1/3O2 (LNCMO) cathode and HT-NPS@C anode deliver a high specific capacity of 323.5 mA h g-1 after 50 cycles at 0.3 A g-1. Apart from an excellent performance as promising anode materials for LIBs (Li-ion batteries), the Na-ion batteries with HT-NPS@C sphere electrodes also manifest a remarkable electrochemical performance.


Relaxation of adaptive evolution during the HIV-1 infection owing to reduction of CD4+ T cell counts.
The first stages of HIV-1 infection are essential to establish the diversity of virus population within host. It has been suggested that adaptation to host cells and antibody evasion are the leading forces driving HIV evolution at the initial stages of AIDS infection. In order to gain more insights on adaptive HIV-1 evolution, the genetic diversity was evaluated during the infection time in individuals contaminated by the same viral source in an epidemic cluster. Multiple sequences of V3 loop region of the HIV-1 were serially sampled from four individuals: comprising a single blood donor, two blood recipients, and another sexually infected by one of the blood recipients. The diversity of the viral population within each host was analyzed independently in distinct time points during HIV-1 infection. Phylogenetic analysis identified multiple HIV-1 variants transmitted through blood transfusion but the establishing of new infections was initiated by a limited number of viruses. Positive selection (d(N)/d(S)>1) was detected in the viruses within each host in all time points. In the intra-host viruses of the blood donor and of one blood recipient, X4 variants appeared respectively in 1993 and 1989. In both patients X4 variants never reached high frequencies during infection time. The recipient, who X4 variants appeared, developed AIDS but kept narrow and constant immune response against HIV-1 during the infection time. Slowing rates of adaptive evolution and increasing diversity in HIV-1 are consequences of the CD4+ T cells depletion. The dynamic of R5 to X4 shift is not associated with the initial amplitude of humoral immune response or intensity of positive selection.


Antibody protects against lethal infection with the neurally spreading reovirus type 3 (Dearing).
The mammalian reoviruses have provided a valuable model for studying the pathogenesis of viral infections of the central nervous system (CNS). We have used this model to study the effect of antibody on disease produced by the neurally spreading reovirus type 3 (Dearing) (T3). Polyclonal and monoclonal antibodies protect mice from fatal infection with T3 after either footpad or intracerebral virus challenge. Protection occurs with monoclonal antibodies directed against the viral cell attachment protein sigma 1, and with polyclonal antisera without T3 sigma 1 binding activity. In vivo protection occurs with both neutralizing and nonneutralizing monoclonal antibodies. Antibody-mediated protection does not require serum complement and, under specific circumstances, can occur via Fc-independent mechanisms. Antibody can protect mice when transferred up to 5 days after intracerebral challenge and up to 7 days after footpad challenge, times when high titers of virus are present in the CNS. Thus, antibody mediated protection against this neurally spreading virus does not require neutralizing antibody or serum complement and occurs even in the face of established CNS infection.


Development and Assessment of a New Empirical Model for Predicting Full Creep Curves.
This paper details the development and assessment of a new empirical creep model that belongs to the limited ranks of models reproducing full creep curves. The important features of the model are that it is fully standardised and is universally applicable. By standardising, the user no longer chooses functions but rather fits one set of constants only. Testing it on 7 contrasting materials, reproducing 181 creep curves we demonstrate its universality. New model and Theta Projection curves are compared to one another using an assessment tool developed within this paper.


Transcriptional and Post-Transcriptional Modulation of SPI1 and SPI2 Expression by ppGpp, RpoS and DksA in Salmonella enterica sv Typhimurium.
The expression of genes within Salmonella Pathogenicity Islands 1 and 2 (SPI1, SPI2) is required to facilitate invasion and intracellular replication respectively of S. Typhimurium in host cell lines. Control of their expression is complex and occurs via a variety of factors operating at transcriptional and post-transcriptional levels in response to the environmental stimuli found within the host. Several of the factors that modulate SPI1 and SPI2 expression are involved in the redistribution or modification of RNA polymerase (RNAP) specificity. These factors include the bacterial alarmone, ppGpp, the alternative sigma factor, RpoS, and the RNAP accessory protein, DksA. In this report we show not only how these three factors modulate SPI1 and SPI2 expression but also how they contribute to the 'phased' expression of SPI1 and SPI2 during progress through late-log and stationary phase in aerobic rich broth culture conditions. In addition, we demonstrate that the expression of at least one SPI1-encoded protein, SipC is subject to DksA-dependent post-transcriptional control.


Organism complexity anti-correlates with proteomic beta-aggregation propensity.
We introduce a novel approach to estimate differences in the beta-aggregation potential of eukaryotic proteomes. The approach is based on a statistical analysis of the beta-aggregation propensity of polypeptide segments, which is calculated by an equation derived from first principles using the physicochemical properties of the natural amino acids. Our analysis reveals a significant decreasing trend of the overall beta-aggregation tendency with increasing organism complexity and longevity. A comparison with randomized proteomes shows that natural proteomes have a higher degree of polarization in both low and high beta-aggregation prone sequences. The former originates from the requirement of intrinsically disordered proteins, whereas the latter originates from the necessity of proteins with a stable folded structure.


Subcellular Localization of Carotenoid Biosynthesis in Synechocystis sp. PCC 6803.
The biosynthesis pathway of carotenoids in cyanobacteria is partly described. However, the subcellular localization of individual steps is so far unknown. Carotenoid analysis of different membrane subfractions in Synechocystis sp. PCC6803 shows that "light" plasma membranes have a high carotenoid/protein ratio, when compared to "heavier" plasma membranes or thylakoids. The localization of CrtQ and CrtO, two well-defined carotenoid synthesis pathway enzymes in Synechocystis, was studied by epitope tagging and western blots. Both enzymes are locally more abundant in plasma membranes than in thylakoids, implying that the plasma membrane has higher synthesis rates of β-carotene precursor molecules and echinenone.


Hyperpolarization as a mediator of insulin action: increased muscle glucose uptake induced electrically.
Insulin hyperpolarizes. This raises the questions: is hyperpolarization a means by which insulin exerts some of its other effects, and can electrically induced hyperpolarization mimic insulin action on membrane functions? A technique was devised to study the latter question. The technique permits electrical hyperpolarization of a segment of whole muscle. Rat caudofemoralis muscle was threaded into a triple sucrose-gap chamber. Continuous flow of sucrose displaced interstitial fluid of muscle segments in the gaps. In one electrolyte compartment between gaps was placed an anode and in the other a cathode. The muscle segment in the anodal compartment was hyperpolarized continuously for 30 min, probably by about 1.5 mV. Uptake of deoxyglucose was increased in the hyperpolarized muscle segment. This increase, by 39%, was highly significant. It was probably smaller than the twofold increase elicited by insulin (100 mU/ml), but not than the possible effect produced by 10 mU/ml. The effect of hyperpolarization was specific for the D-glucose transport system because uptake of L-glucose was not altered.


lacZ fusions to genes that specify exported proteins: a general technique.
We have devised a general, one-step technique for isolation of strains in which the gene coding for an exported protein is fused to the gene for beta-galactosidase (lacZ). These fusions specify a hybrid protein comprised of an NH2-terminal portion of the exported protein and a large functional COOH-terminal portion of beta-galactosidase. The fusions are constructed with a derivative of the MudII (lac, Ap) phage. To overcome the lethality that is often associated with the expression of such a hybrid gene, we have recombined an early lacZ nonsense mutation onto this phage. With the use of strains that carry a temperature-sensitive nonsense suppressor, expression of the full-length hybrid protein can be controlled by varying the growth temperature. We demonstrated the utility of this technique by isolating a series of fusions to a gene, ompA, coding for a major outer membrane protein. As expected, strains containing these fusions are not viable under conditions that permit synthesis of a functional nonsense suppressor. Accordingly, this method should also be useful for direct selection of export-defective mutants.


Durability of cell line xenograft resection models to interrogate tumor micro-environment targeting agents.
Angiogenesis is a key tumor microenvironment (TME) event underpinning tumor growth and metastasis. Nevertheless, the relatively poor performance of anti-angiogenic therapies in clinical trials compared to pre-clinical studies implies that classical subcutaneous xenograft models have limited predictive potential in this setting. To address this issue, we established orthotopic surgical resection models of breast cancer, which replicate the phenotype of clinical post-resection micro-metastasis. To demonstrate the power and precision of these models, we recapitulated the BETH adjuvant trial (NCT00625898) where the addition of bevacizumab (BVZ) to chemotherapy plus trastuzumab (Trast) failed to provide additional benefit. SCID mice were orthotopically implanted with bioluminescent Her2+ MDA-MB-231 or HCC1954 cells and tumors resected c.5 weeks later. Following resection, mice were treated with 10 mg/kg Trast +5 mg/kg paclitaxel (PAC) IP once weekly for 6 cycles +/- weekly BVZ (5 mg/kg IP). Metastasis was monitored by imaging. Using these models our data confirms that the addition of the anti-angiogenic antibody BVZ to adjuvant Trast + chemotherapy provides no additional benefit compared with Trast + chemotherapy alone. Previous studies using non-resection subcutaneously engrafted xenografts failed to predict this outcome. Our results provide compelling evidence for the utility of cell line xenograft resection models to predict clinical outcome for TME targeting agents.


Multifocal versus monofocal intraocular lenses after cataract extraction.
Good unaided distance visual acuity is now a realistic expectation following cataract surgery and intraocular lens (IOL) implantation. Near vision, however, still requires additional refractive power, usually in the form of reading glasses. Multiple optic (multifocal) IOLs are available which claim to allow good vision at a range of distances. It is unclear whether this benefit outweighs the optical compromises inherent in multifocal IOLs. The objective of this review was to assess the effects of multifocal IOLs, including effects on visual acuity, subjective visual satisfaction, spectacle dependence, glare and contrast sensitivity, compared to standard monofocal lenses in people undergoing cataract surgery. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 2), MEDLINE (January 1946 to March 2012), EMBASE (January 1980 to March 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 6 March 2012. We searched the reference lists of relevant articles and contacted investigators of included studies and manufacturers of multifocal IOLs for information about additional published and unpublished studies. All randomised controlled trials comparing a multifocal IOL of any type with a monofocal IOL as control were included. Both unilateral and bilateral implantation trials were included. Two authors collected data and assessed trial quality. Where possible, we pooled data from the individual studies using a random-effects model, otherwise we tabulated data. Sixteen completed trials (1608 participants) and two ongoing trials were identified. All included trials compared multifocal and monofocal lenses but there was considerable variety in the make and model of lenses implanted. Overall we considered the trials at risk of performance and detection bias because it was difficult to mask patients and outcome assessors. It was also difficult to assess the role of reporting bias. There was moderate quality evidence that similar distance acuity is achieved with both types of lenses (pooled risk ratio (RR) for unaided visual acuity worse than 6/6: 0.98, 95% confidence interval (CI) 0.91 to 1.05). There was also evidence that people with multifocal lenses had better near vision but methodological and statistical heterogeneity meant that we did not calculate a pooled estimate for effect on near vision. Total freedom from use of glasses was achieved more frequently with multifocal than monofocal IOLs. Adverse subjective visual phenomena, particularly haloes, or rings around lights, were more prevalent and more troublesome in participants with the multifocal IOL and there was evidence of reduced contrast sensitivity with the multifocal lenses. Multifocal IOLs are effective at improving near vision relative to monofocal IOLs. Whether that improvement outweighs the adverse effects of multifocal IOLs will vary between patients. Motivation to achieve spectacle independence is likely to be the deciding factor.


In vitro delivery of budesonide from 30 jet nebulizer/compressor combinations using infant and child breathing patterns.
An aerosol of budesonide inhalation suspension is delivered when used with various jet-nebulizer/compressor combinations. The constant introduction of new nebulizer/compressor combinations raises the question of whether the performance of these match the performance of existing devices. The aim of this study was to determine in vitro the inhaled mass and aerosol characteristics of budesonide inhalation suspension from a selection of jet-nebulizer/compressor combinations presently marketed in the United States, Europe, and Japan. The in vitro characterization was performed using standardized and published methods. Each nebulizer was charged with 1 vial (2 mL) of budesonide inhalation suspension 0.25 mg/mL (0.5 mg budesonide) and run until end of aerosol formation. Droplet size and distribution was determined using a cooled impactor at air flow of 15 L/min. The inhaled mass of budesonide (ie, mass on the inhalation filter) was collected using a breathing simulator that mimicked the breathing patterns of an infant and a child. The aerosol was collected on filters placed between the nebulizer mouthpiece and the breathing simulator. Budesonide was quantified via standard high-performance liquid chromatography. The mass median aerodynamic diameter of the aerosol measured with the cooled impactor ranged between 4.8 mum and 9.9 mum, and the geometric standard deviation ranged between 1.7 mum and 2.1 mum. The inhaled mass of budesonide expressed as a percentage of the nebulizer charge ranged from 1% to 9% (infant) and from 4% to 20% (child). The in vitro budesonide mass collected on the inhalation filter and delivery characteristics differed considerably between the 30 nebulizer/compressor combinations. The present in vitro characterization of jet nebulizers can be used as a guidance for selection of jet-nebulizer/compressor combinations for delivery of the budesonide nebulization suspension in the home-care setting. Further investigations of new nebulizer/compressor combinations are warranted.


Efficacy, tolerance and safety of new intragastric air-filled balloon (Heliosphere BAG) for obesity: the experience of 17 cases.
Overweight and obesity lead to serious health consequences, so that many strategies were recommended for preventing or curing this emerging problem. Treatments are various: diet, physical activity, psychotherapy, drugs, and bariatric surgery. Moreover, during these years, the use of intragastric balloon (BIB) to treat obesity increased rapidly, aimed to (1) reduce bariatric surgical risks; (2) reduce general surgical risks; (3) lead to a significant reduction in the prevalence of cardiovascular diseases, diabetes, musculoskeletal disorders and some cancers. Recently, a new device inflated with air to reduce weight has been developed since 2004 (Heliosphere BAG). Between March 2006 and September 2006, in our unit, intragastric air-filled balloon insertion was performed under general anesthesia and endoscopic control. The balloons were removed after 6 months. We evaluated efficacy, tolerance, and safety of this technique. Seventeen patients (eight men, nine women), with a mean age of 43 +/- 10 years (range 18-65), mean basal BMI of 46 +/- 8 (range 35-58) were included, after providing informed consent. Weight and BMI loss were evaluated in all patients. BMI decreased 4 +/- 3 (range +0.33/-11), weight loss was 11 +/- 9 kg (range +1/-29.5; 8.5%). 14/17 patients maintain a BMI > 35 at the time of balloon removal. The difference between initial weight and BMI was statistically significant (p = 0.02 for weight and p < 0.01 for BMI, T Student test). Tolerance was very good, limited only to some dyspeptic symptoms during the first 3 days after insertion. One asymptomatic gastric ulcer was seen at the removal of balloon. Only one severe adverse effect was registered at the time of insertion (acute coronary syndrome in patient with chronic coronary disease). No serious technical problems were noted at balloon insertion. Balloon removal was more difficult and successful in 15/17 cases (one distal migration and one patient led to surgery because of balloon fragmentation). Intragastric air-filled balloon showed a good profile of efficacy and tolerance. Weight loss appeared to be equivalent to other type of balloons. On the other hand, technical problems (especially at the time of removal) probably linked to the device's material, set a low safety profile.


Minimally invasive surgery for inflammatory bowel disease.
Surgical management of inflammatory bowel disease is a challenging endeavor given infectious and inflammatory complications, such as fistula, and abscess, complex often postoperative anatomy, including adhesive disease from previous open operations. Patients with Crohn's disease and ulcerative colitis also bring to the table the burden of their chronic illness with anemia, malnutrition, and immunosuppression, all common and contributing independently as risk factors for increased surgical morbidity in this high-risk population. However, to reduce the physical trauma of surgery, technologic advances and worldwide experience with minimally invasive surgery have allowed laparoscopic management of patients to become standard of care, with significant short- and long-term patient benefits compared with the open approach. In this review, we will describe the current state-of the-art for minimally invasive surgery for inflammatory bowel disease and the caveats inherent with this practice in this complex patient population. Also, we will review the applicability of current and future trends in minimally invasive surgical technique, such as laparoscopic "incisionless," single-incision laparoscopic surgery (SILS), robotic-assisted, and other techniques for the patient with inflammatory bowel disease. There can be no doubt that minimally invasive surgery has been proven to decrease the short- and long-term burden of surgery of these chronic illnesses and represents high-value care for both patient and society.


Prognostic gene expression signature associated with two molecularly distinct subtypes of colorectal cancer.
Despite continual efforts to develop prognostic and predictive models of colorectal cancer by using clinicopathological and genetic parameters, a clinical test that can discriminate between patients with good or poor outcome after treatment has not been established. Thus, the authors aim to uncover subtypes of colorectal cancer that have distinct biological characteristics associated with prognosis and identify potential biomarkers that best reflect the biological and clinical characteristics of subtypes. Unsupervised hierarchical clustering analysis was applied to gene expression data from 177 patients with colorectal cancer to determine a prognostic gene expression signature. Validation of the signature was sought in two independent patient groups. The association between the signature and prognosis of patients was assessed by Kaplan-Meier plots, log-rank tests and the Cox model. The authors identified a gene signature that was associated with overall survival and disease-free survival in 177 patients and validated in two independent cohorts of 213 patients. In multivariate analysis, the signature was an independent risk factor (HR 3.08; 95% CI 1.33 to 7.14; p=0.008 for overall survival). Subset analysis of patients with AJCC (American Joint Committee on Cancer) stage III cancer revealed that the signature can also identify the patients who have better outcome with adjuvant chemotherapy (CTX). Adjuvant chemotherapy significantly affected disease-free survival in patients in subtype B (3-year rate, 71.2% (CTX) vs 41.9% (no CTX); p=0.004). However, such benefit of adjuvant chemotherapy was not significant for patients in subtype A. The gene signature is an independent predictor of response to chemotherapy and clinical outcome in patients with colorectal cancer.


Liquid-crystalline phase transitions in lipid droplets are related to cellular states and specific organelle association.
Lipid droplets (LDs) are ubiquitous organelles comprising a central hub for cellular lipid metabolism and trafficking. This role is tightly associated with their interactions with several cellular organelles. Here, we provide a systematic and quantitative structural description of LDs in their native state in HeLa cells enabled by cellular cryoelectron microscopy. LDs consist of a hydrophobic neutral lipid mixture of triacylglycerols (TAG) and cholesteryl esters (CE), surrounded by a single monolayer of phospholipids. We show that under normal culture conditions, LDs are amorphous and that they transition into a smectic liquid-crystalline phase surrounding an amorphous core at physiological temperature under certain cell-cycle stages or metabolic scenarios. Following determination of the crystal lattice spacing of 3.5 nm and of a phase transition temperature below 43 °C, we attributed the liquid-crystalline phase to CE. We suggest that under mitotic arrest and starvation, relative CE levels increase, presumably due to the consumption of TAG metabolites for membrane synthesis and mitochondrial respiration, respectively, supported by direct visualization of LD-mitochondrial membrane contact sites. We hypothesize that the structural phase transition may have a major impact on the accessibility of lipids in LDs to enzymes or lipid transporters. These may become restricted in the smectic phase, affecting the exchange rate of lipids with surrounding membranes and lead to a different surface occupancy of LD-associated proteins. Therefore, the composition and the resulting internal structure of LDs is expected to play a key role in their function as hubs of cellular lipid flux.


Reversible Cerebral Vasoconstriction Syndrome: A Common Occurrence but Rare Diagnosis.
Reversible cerebral vasoconstriction syndrome (RCVS) is an under-diagnosed condition that results from reversible segmental and multifocal vasoconstriction of cerebral arteries. It can present with a variety of symptoms including sudden "thunder clap" headaches, neurologic deficits, photophobia, phonophobia, nausea, vomiting, and can mimic life-threatening conditions such as a ruptured intracranial aneurysm, primary angiitis of the central nervous system, and cervical artery dissection. The pathology of this condition is still not fully understood and the etiologies vary, making treatment difficult. Our objective is to draw attention to an under-diagnosed condition with common presenting symptoms. We present a 60-year-old male with sudden onset of severe headache, left-sided numbness and weakness, blurred vision, ataxia, nausea, and dyspnea. CT and MRI brain showed no evidence of infarct or hemorrhage. CT angiography (CTA) of the head and neck showed a narrow caliber basilar artery. With the patient's clinical presentation and imaging findings, RCVS was suspected and the patient was started on a calcium channel blocker and glucocorticoids. A repeat CTA of the head and neck was performed after initiation of therapy and showed dilation of the basilar artery. Treatment with verapamil and prednisone was continued and the patient's symptoms gradually improved. He was discharged to skilled nursing for continued physical therapy. RCVS is a little-understood, under-diagnosed condition that needs to be considered in patients presenting with headaches and neurologic deficits. Additionally, more research needs to be done to truly understand the etiology of this condition.


Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis.
Imbalance in the autonomic nervous system (ANS) has been observed in many established chronic autoimmune diseases, including rheumatoid arthritis (RA), which is a prototypic immune-mediated inflammatory disease (IMID). We recently discovered that autonomic dysfunction precedes and predicts arthritis development in subjects at risk of developing seropositive RA. In addition, RA patients with relatively high vagus nerve tone (higher parasympathetic parameters, measured by heart rate variability) respond better to antirheumatic therapies. Together, these data suggest that the ANS may control inflammation in humans. This notion is supported by experimental studies in animal models of RA. We have found that stimulation of the so-called cholinergic anti-inflammatory pathway by efferent electrical vagus nerve stimulation (VNS) or pharmacological activation of the alpha7 subunit of nicotinic acetylcholine receptors (α7nAChR) improves clinical signs and symptoms of arthritis, reduces cytokine production and protects against progressive joint destruction. Conversely, increased arthritis activity was observed in alpha7nAChR knockout mice. These studies together with previous work in animal models of sepsis and other forms of inflammation provided the rationale for an experimental clinical trial in patients with RA. We could for the first time show that an implantable vagus nerve stimulator inhibits peripheral blood cytokine production in humans. VNS significantly inhibited TNF and IL-6 production and improved RA disease severity, even in some patients with therapy-resistant disease. This work strongly supports further studies using a bioelectronic approach to treat RA and other IMIDs.


Needle thoracostomy: implications of computed tomography chest wall thickness.
To determine the length of catheter required to perform a needle thoracostomy, as determined by chest wall thickness, to treat the majority of patients presenting to the emergency department (ED) with a potential tension pneumothorax. A convenience sample of 111 computed tomography (CT) scans of the chest in trauma and medical resuscitation patients at a military Level 1 trauma center in San Antonio, Texas, was pooled, and the chest wall thickness was measured at the second intercostal space, midclavicular line, to the nearest 0.1 cm. The mean chest wall thickness in the patients studied averaged 4.24 cm (95% confidence interval [CI] = 3.97 to 4.52). Nearly one fourth (25) of the study patients had a chest wall thicker than 5 cm. Women, on average, have thicker chest walls than men (4.90 for women; 4.16 for men; p = 0.022). In this study, a catheter length of 5 cm would reliably penetrate the pleural space of only 75% of patients. A longer catheter should be considered, especially in women.


EUR-1008 pancreatic enzyme replacement is safe and effective in patients with cystic fibrosis and pancreatic insufficiency.
EUR-1008 (Zenpep [pancrelipase]) is a new, enteric-coated, porcine-derived pancreatic enzyme product (PEP) developed for the treatment of cystic fibrosis (CF) patients with malabsorption associated with exocrine pancreatic insufficiency (EPI). Unlike currently marketed PEPs, EUR-1008 contains the label-claimed lipase content. Safety and efficacy were assessed in younger (<7 years) and older (> or =7 years) CF patients with EPI. Two multicenter studies were conducted: a randomized, double-blind, placebo-controlled, crossover trial in patients > or =7 years of age (N=34) and a supplemental, open-label study in children <7 years of age (N=19). Use of any medications altering gastric pH/motility was prohibited during the studies. Outcome measures in the randomized trial included changes in the coefficient of fat absorption (CFA), coefficient of nitrogen absorption (CNA), and signs/symptoms of malabsorption for EUR-1008 vs. placebo. Outcome measures in the supplemental study included safety and response (defined as no steatorrhea and no overt signs/symptoms of malabsorption) to EUR-1008 vs. previous enzyme treatment. In the randomized trial, EUR-1008 treatment compared to placebo resulted in a significantly higher mean CFA (88.3% vs. 62.8%, respectively) and CNA (87.2% vs. 65.7%, respectively) (both p<0.001) and reduced the incidence of malabsorption signs and symptoms in 32 evaluable patients. In the supplemental study, 11 of 19 patients met the criteria for responder with EUR-1008 at the end of the study vs. 10 of 19 patients at screening (previous PEP), and improvements in clinical symptoms were reported with EUR-1008 treatment. EUR-1008 was safe and well tolerated, and no serious drug-related AEs were reported in either study. EUR-1008 was safe, well tolerated, and effective in CF patients of all ages with EPI-associated malabsorption in two clinical trials. Treatment led to clinically and statistically significant improvements in CFA and CNA in the randomized study, and control of malabsorption and clinical symptoms in both studies.


Some infant ventilators do not limit peak inspiratory pressure reliably during active expiration.
In order to minimize barotrauma in newborn infants with respiratory failure, peak inspiratory pressures should not exceed those required for adequate gas exchange. We examined whether four commonly used pressure-limited, constant flow ventilators limit pressure reliably during simulated active expiration against the inspiratory stroke of the ventilator. Three machines of each type were tested at 13 different expiratory flow rates (2 to 14 L/min). Flow-dependent pressure overshoot above a dialed pressure limit of 20 cm H2O was observed in all machines. However, the magnitude differed significantly between ventilators from different manufacturers (p = .0009). Pressure overshoot above 20 cm H2O was consistently lowest in the Healthdyne (0.8 cm H2O at 2 L/min, 3.6 cm H2O at 14 L/min) and highest in the Bourns BP200 (3.0 cm H2O at 2 L/min, 15.4 cm H2O at 14 L/min). We conclude that peak inspiratory pressure overshoots on pressure-limited ventilators occur during asynchronous expiration. This shortcoming may contribute to barotrauma in newborn infants who "fight" positive-pressure ventilation.


Efficacy of Secretagogues in Patients With Irritable Bowel Syndrome With Constipation: Systematic Review and Network Meta-analysis.
Several secretagogues have been approved for the treatment of irritable bowel syndrome with constipation (IBS-C). However, their relative efficacy is unclear because there have been no head-to-head randomized controlled trials. We conducted a network meta-analysis to compare their efficacies in patients with IBS-C. We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane Central Register of Controlled Trials through June 2018 to identify randomized controlled trials assessing the efficacy of secretagogues in adults with IBS-C. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random-effects model. Efficacy and safety of secretagogues were reported as a pooled relative risk with 95% confidence interval to summarize the effect of each comparison tested, and treatments were ranked according to their P score. We identified 15 eligible randomized controlled trials of secretagogues that included 8462 patients. Linaclotide, lubiprostone, plecanatide, and tenapanor were superior to placebo for the treatment of IBS-C. Linaclotide (290 μg once daily) was ranked first in efficacy based on the end point recommended by the Food and Drug Administration for trials in IBS-C, the primary end point used in each trial, abdominal pain, and complete spontaneous bowel movements. Tenapanor (50 mg twice daily) was ranked first for decreasing bloating. Total numbers of adverse events were significantly larger with linaclotide (290 and 500 μg once daily) and plecanatide (3 mg once daily) compared with placebo. However, plecanatide 6 mg once daily ranked first for safety. Diarrhea was significantly more common with all drugs, except lubiprostone (8 μg twice daily). Nausea was significantly more common in patients who received lubiprostone. In a network analysis of randomized controlled trials of secretagogues for IBS-C, we found all drugs to be superior to placebo. Efficacy was similar among individual drugs and dosages for most end points. However, data were extracted at the 12-week time point, so the long-term relative efficacy of these drugs is unknown.


Ecological and Evolutionary Stabilities of Biotrophism, Necrotrophism, and Saprotrophism.
Fungi have multiple trophic behaviors, including biotrophism (parasitism on living hosts), necrotrophism (parasitism through killing host tissues), and saprotrophism (feeding on decaying organic matter). Historical classifications of plant pathogens are based on many different axes, including their trophic dependence on living and dead plants, their pathogenicity and mutualistic relationship to host plants, and their transmission pathways and infection mechanisms. Such diverse classifications sometimes conflict with each other. Clarifying the delineations among these groups would promote synthesis of fungal biology with current ecological and evolutionary concepts. To ask when biotrophic, necrotrophic, or saprotrophic fungi are maintained and favored by selection, we constructed an epidemiological model that describes the transitions between four states of host plants: susceptible living plant (S), infected living plant (I), uninfected dead plant (D), and infected dead plant, or plant residue (R). States S and D represent two kinds of resource-living and dead plant tissues-for fungal inocula (I and R). We obtained values for the basic reproductive number (R0), which defines the persistence criteria of fungi. On the basis of our results, we propose four types of ecological groups, corresponding to the patterns of dependence on nutrient resources: (1) parasitism-dependent fungi, characterized by their critical dependence on living plants; (2) saprotrophism-dependent fungi, characterized by their critical dependence on dead plants; (3) facultatively dependent fungi, which are neither parasitism nor saprotrophism dependent; and (4) doubly dependent fungi, which are neither wholly parasitism dependent nor wholly saprotrophism dependent. This grouping can be used to suggest principles for effective pest control. Our model also reveals simple conditions for the evolution of fungal trophic behaviors. We found that, in the absence of a trade-off between virulence and other life-history parameters, milder fungal virulence in living plants is always selected for if plant-fungus population dynamics are stable. However, with sufficiently strong necrotrophic transmission, the host population densities show sustained cycles, which promote the evolution of higher virulence. Epidemiological synthesis of diverse trophism in plant-fungi relationship in our model thus opens the way to discuss the evolution of fungal lifestyles as a function of ecological conditions.


Effects of phosphate deficiency and sugars on expression of rab18 in Arabidopsis: hexokinase-dependent and okadaic acid-sensitive transduction of the sugar signal.
The lack of phosphorus in the nutrient medium increased the expression of rab18, an abscisic acid (ABA)-responsive gene, in leaves of Arabidopsis thaliana. The expression of this gene was also upregulated after feeding the excised leaves with D-mannose and sucrose for both wild-type (wt) and aba1 (ABA-deficient) mutant plants. For aba1 mutants, both the phosphate deficiency and sugar effects on rab18 were weaker than in wt plants, suggesting possible involvement of both ABA-dependent and ABA-independent components in signalling. Transgenic Arabidopsis plants with increased hexokinase (HXK) expression had a much higher sucrose-dependent level of rab18 mRNA, implying the HXK involvement in sensing/transmitting the sugar signal. Sucrose-related induction of rab18 was completely inhibited by okadaic acid (OKA), suggesting the involvement of specific protein phosphatase(s) in transduction of the sugar signal. The results suggest that rab18 is regulated via interaction of a plethora of signals, including ABA, sugar and phosphate deficiency, and that the sugar effect is transmitted via a HXK-pathway, involving OKA-sensitive component(s). The findings prompt caution in linking the expression of rab18 solely to ABA signalling.


In-Depth Characterization of Bioactive Extracts from Posidonia oceanica Waste Biomass.
Posidonia oceanica waste biomass has been valorised to produce extracts by means of different methodologies and their bioactive properties have been evaluated. Water-based extracts were produced using ultrasound-assisted and hot water methods and classified according to their ethanol-affinity (E1: ethanol soluble; E2: non-soluble). Moreover, a conventional protocol with organic solvents was applied, yielding E3 extracts. Compositional and structural characterization confirmed that while E1 and E3 extracts were mainly composed of minerals and lipids, respectively, E2 extracts were a mixture of minerals, proteins and carbohydrates. All the extracts showed remarkably high antioxidant capacity, which was not only related to phenolic compounds but also to the presence of proteins and polysaccharides. All E2 and E3 extracts inhibited the growth of several foodborne fungi, while only E3 extracts decreased substantially the infectivity of feline calicivirus and murine norovirus. These results show the potential of P. oceanica waste biomass for the production of bioactive extracts.


Human cytomegalovirus glycoproteins gB and gH/gL mediate epithelial cell-cell fusion when expressed either in cis or in trans.
Herpesviruses use a cascade of interactions with different cell surface molecules to gain entry into cells. In many cases, this involves binding to abundant glycosaminoglycans or integrins followed by interactions with more limited cell surface proteins, leading to fusion with cellular membranes. Human cytomegalovirus (HCMV) has the ability to infect a wide variety of human cell types in vivo. However, very little is known about which HCMV glycoproteins mediate entry into various cell types, including relevant epithelial and endothelial cells. For other herpesviruses, studies of cell-cell fusion induced by viral proteins have provided substantial information about late stages of entry. In this report, we describe the fusion of epithelial, endothelial, microglial, and fibroblast cells in which HCMV gB and gH/gL were expressed from nonreplicating adenovirus vectors. Fusion frequently involved the majority of cells, and gB and gH/gL were both necessary and sufficient for fusion, whereas no fusion occurred when either glycoprotein was omitted. Coexpression of UL128, UL130, and UL131 did not enhance fusion. We concluded that the HCMV core fusion machinery consists of gB and gH/gL. Coimmunoprecipitation indicated that HCMV gB and gH/gL can interact. Importantly, expression of gB and gH/gL in trans (gB-expressing cells mixed with other gH/gL-expressing cells) resulted in substantial fusion. We believe that this is the first description of a multicomponent viral fusion machine that can be split between cells. If gB and gH/gL must interact for fusion, then these molecules must reach across the space between apposing cells. Expression of gB and gH/gL in trans with different cell types revealed surface molecules that are required for fusion on HCMV-permissive cells but not on nonpermissive cells.


Ribavirin restores IFNα responsiveness in HCV-infected livers by epigenetic remodelling at interferon stimulated genes.
Caveats in the understanding of ribavirin (RBV) mechanisms of action has somehow prevented the development of better analogues able to further improve its therapeutic contribution in interferon (IFN)-based and direct antiviral agent-based regimens for chronic HCV or other indications. Here, we describe a new mechanism by which RBV modulates IFN-stimulated genes (ISGs) and contributes to restore hepatic immune responsiveness. RBV effect on ISG expression was monitored in vitro and in vivo, that is, in non-transformed hepatocytes and in the liver of RBV mono-treated patients, respectively. Modulation of histone modifications and recruitment of histone-modifying enzymes at target promoters was analysed by chromatin immunoprecipitation in RBV-treated primary human hepatocytes and in patients' liver biopsies. RBV decreases the mRNA levels of several abnormally preactivated ISGs in patients with HCV, who are non-responders to IFN therapy. RBV increases G9a histone methyltransferase recruitment and histone-H3 lysine-9 dimethylation/trimethylation at selected ISG promoters in vitro and in vivo. G9a pharmacological blockade abolishes RBV-induced ISG downregulation and severely impairs RBV ability to potentiate IFN antiviral action and induction of ISGs following HCV infection of primary human hepatocytes. RBV-induced epigenetic changes, leading to decreased ISG expression, restore an IFN-responsive hepatic environment in patients with HCV, which may also prove useful in IFN-free regimens.


Is there any fundamental difference between ionic, covalent, and others types of bond? A canonical perspective on the question.
The concept of chemical bonding is normally presented and simplified through two models: the covalent bond and the ionic bond. Expansion of the ideal covalent and ionic models leads chemists to the concepts of electronegativity and polarizability, and thus to the classification of polar and non-polar bonds. In addition, the intermolecular interactions are normally viewed as physical phenomena without direct correlation to the chemical bond in any simplistic model. Contrary to these traditional concepts of chemical bonding, recently developed canonical approaches demonstrate a unified perspective on the nature of binding in pairwise interatomic interactions. This new canonical model, which is a force-based approach with a basis in fundamental molecular quantum mechanics, confirms much earlier assertions that in fact there are no fundamental distinctions among covalent bonds, ionic bonds, and intermolecular interactions including the hydrogen bond, the halogen bond, and van der Waals interactions.


Do airway secretions play an underappreciated role in acute respiratory distress syndrome?
We review the evidence that airway secretions may have an underappreciated role in acute respiratory distress syndrome, contributing to physiologic disarrangements, ventilator dependence and perhaps to injury generation. As common manipulations of ventilator settings, position and fluid status have the potential to influence these problems, explorations into the secretion dynamics of acute lung injury may be fertile ground for developing therapeutic advances. Principles that govern the interaction of airflow and airway fluids suggest that mobile fluids and secretions are pumped by well-selected ventilatory patterns toward the airway opening. Conversely, other selections may inhibit these fluids from clearance or encourage their translocation between lung regions. Recent laboratory work demonstrates that choices for tidal volume and positive end-expiratory pressure may localize or disperse proteinaceous lung edema or bacteria. Gravitational factors may interact with ventilatory pattern for benefit or harm. Capability of ventilation and positioning to mobilize secretions implies the potential for clearance or containment of inflammatory mediators and infection. Ventilatory and positional prescriptions could be designed to meet one of either conflicting targets. Additional experimental and clinical investigations are required before adopting these proposed therapeutic principles into practice.


Metastasis-inducing S100A4 protein is associated with the disease activity of rheumatoid arthritis.
To evaluate the association between metastasis-inducing protein S100A4 and disease activity in patients with RA, and to demonstrate the effect of TNF-alpha blocking therapy on plasma levels of S100A4 in these patients. Plasma levels of the S100A4 protein were analysed in 40 anti-TNF-alpha naive patients with active RA. Of the 40 patients, 25 were treated with adalimumab and monitored over time. The conformational form of S100A4 was analysed using size-exclusion gel chromatography. TNF-alpha mRNA expression and protein synthesis were analysed by RT-PCR and ELISA, respectively. Baseline levels of S100A4 were significantly correlated with disease activity in RA patients (r = 0.41; P < 0.01). After 12 weeks of treatment with adalimumab, there was an obvious shift in the conformations of S100A4 from the multimeric to the dimeric forms, whereas the total levels of the S100A4 protein remained unchanged. This suggests that the bioactive (multimer) S100A4 may decline in response to successful treatment with adalimumab. In addition, we showed significant up-regulation of TNF-alpha mRNA (P < 0.01), and protein release to the cell culture medium of monocytes stimulated with the S100A4 multimer compared with those treated with the dimer and to the unstimulated monocytes (P < 0.001). This is the first study to show that the levels of the S100A4 protein are correlated with RA disease activity. Furthermore, only the bioactive form, but not the total amount of S100A4, decreases after successful TNF-alpha blocking therapy in patients with RA. These data support an important role for the S100A4 multimer in the pathogenesis of RA.


Individual, environmental, and meteorological predictors of daily personal ultraviolet radiation exposure measurements in a United States cohort study.
Individual exposure to ultraviolet radiation (UVR) is challenging to measure, particularly for diseases with substantial latency periods between first exposure and diagnosis of outcome, such as cancer. To guide the choice of surrogates for long-term UVR exposure in epidemiologic studies, we assessed how well stable sun-related individual characteristics and environmental/meteorological factors predicted daily personal UVR exposure measurements. We evaluated 123 United States Radiologic Technologists subjects who wore personal UVR dosimeters for 8 hours daily for up to 7 days (N = 837 days). Potential predictors of personal UVR derived from a self-administered questionnaire, and public databases that provided daily estimates of ambient UVR and weather conditions. Factors potentially related to personal UVR exposure were tested individually and in a model including all significant variables. The strongest predictors of daily personal UVR exposure in the full model were ambient UVR, latitude, daily rainfall, and skin reaction to prolonged sunlight (R(2) = 0.30). In a model containing only environmental and meteorological variables, ambient UVR, latitude, and daily rainfall were the strongest predictors of daily personal UVR exposure (R(2) = 0.25). In the absence of feasible measures of individual longitudinal sun exposure history, stable personal characteristics, ambient UVR, and weather parameters may help estimate long-term personal UVR exposure.


Cytoplasmic Ubiquitin-Specific Protease 19 (USP19) Modulates Aggregation of Polyglutamine-Expanded Ataxin-3 and Huntingtin through the HSP90 Chaperone.
Ubiquitin-specific protease 19 (USP19) is one of the deubiquitinating enzymes (DUBs) involved in regulating the ubiquitination status of substrate proteins. There are two major isoforms of USP19 with distinct C-termini; the USP19_a isoform has a transmembrane domain for anchoring to the endoplasmic reticulum, while USP19_b contains an EEVD motif. Here, we report that the cytoplasmic isoform USP19_b up-regulates the protein levels of the polyglutamine (polyQ)-containing proteins, ataxin-3 (Atx3) and huntingtin (Htt), and thus promotes aggregation of their polyQ-expanded species in cell models. Our data demonstrate that USP19_b may orchestrate the stability, aggregation and degradation of the polyQ-expanded proteins through the heat shock protein 90 (HSP90) chaperone system. USP19_b directly interacts with HSP90 through its N-terminal CS (CHORD and SGT1)/P23 domains. In conjunction with HSP90, the cytoplasmic USP19 may play a key role in triage decision for the disease-related polyQ-expanded substrates, suggesting a function of USP19 in quality control of misfolded proteins by regulating their protein levels.


Identification of genotype 3 hepatitis E virus (HEV) in serum and fecal samples from pigs in Thailand and Mexico, where genotype 1 and 2 HEV strains are prevalent in the respective human populations.
Hepatitis E virus (HEV), the causative agent of hepatitis E, is an important public health concern in many developing countries. Increasing evidence indicates that hepatitis E is a zoonotic disease. There exist four major genotypes of HEV, and HEV isolates identified in samples from pigs belong to either genotype 3 or 4. Genotype 1 and 2 HEVs are found exclusively in humans. To determine whether genotype 1 and 2 HEVs also exist in pigs, a universal reverse transcription-PCR assay that is capable of detecting all four HEV genotypes was used to test for the presence of HEV RNA in serum and/or fecal samples from pigs in Thailand, where genotype 1 human HEV is prevalent, and from pigs in Mexico, where genotype 2 human HEV was epidemic. In Thailand, swine HEV RNA was detected in sera from 10/26 pigs of 2 to 4 months of age but not in sera from 50 pigs of other ages. In Mexico, swine HEV RNA was detected in 8/125 sera and 28/92 fecal samples from 2- to 4-month-old pigs. Antibodies to swine HEV were also detected in about 81% of the Mexican pigs. A total of 44 swine HEV isolates were sequenced for the open reading frame 2 gene region. Sequence analyses revealed that all swine HEV isolates identified in samples from pigs in Thailand and Mexico belong to genotype 3. Phylogenetic analyses revealed that minor branches associated with geographic origin exist among the swine HEV isolates. The results indicated that genotype 1 or 2 swine HEV does not exist in pigs from countries where the respective human HEV genotype 1 or 2 is prevalent. It is likely that only genotype 3 and 4 HEV strains have zoonotic potential.


Occupational therapy workforce needs: a model for demand-based studies.
To provide a model for assessing occupational therapy workforce needs by using a demand-based approach to determine current workforce status in the Northwest region. Regional information may have implications for addressing national occupational therapy service needs. A questionnaire was sent to a proportional random sample of 234 facilities that hire occupational therapy practitioners. Data were collected in July-August 2003 using structured mailing and follow-up procedures. Response rate was 79%. Twenty-four percent reported occupational therapy vacancies and 11% occupational therapy assistant vacancies; 48% predicted an increase in occupational therapy positions in the next 2 years and 41% an increase in occupational therapy assistant positions. Sixty-three percent of respondents reported difficulty in hiring. This study identifies an occupational therapy workforce shortage in the Northwest. Management of a shortage is critical, for even short-term adjustments could lead to permanent changes in service provision. This study demonstrates the importance of current information on the status of the national workforce and serves as a model for future studies.


Looking away from a moving target does not disrupt the way in which the movement toward the target is guided.
People usually follow a moving object with their gaze if they intend to interact with it. What would happen if they did not? We recorded eye and finger movements while participants moved a cursor toward a moving target. An unpredictable delay in updating the position of the cursor on the basis of that of the invisible finger made it essential to use visual information to guide the finger's ongoing movement. Decreasing the contrast between the cursor and the background from trial to trial made it difficult to see the cursor without looking at it. In separate experiments, either participants were free to hit the target anywhere along its trajectory or they had to move along a specified path. In the two experiments, participants tracked the cursor rather than the target with their gaze on 13% and 32% of the trials, respectively. They hit fewer targets when the contrast was low or a path was imposed. Not looking at the target did not disrupt the visual guidance that was required to deal with the delays that we imposed. Our results suggest that peripheral vision can be used to guide one item to another, irrespective of which item one is looking at.


Prevalence trend and correlates of HHV-8 infection in HIV-infected patients.
To assess the circulation of human herpesvirus (HHV)-8 infection over the years, two seroprevalence surveys were conducted, which tested sera from HIV-infected individuals recruited 10 years apart (206 individuals from 1986 to 1988 and 177 individuals from 1997 to 1998). For all patients, antibodies to hepatitis C virus (HCV), hepatitis B virus (HBV), and HHV-8 lytic and latent antigens were evaluated.HHV-8 seroprevalence was higher among individuals recruited in the 1990s (31.6% for anti-lytic, 8.5% for anti-latent antibodies) compared with similar findings in those seen in the late 1980s (14.6% and 3.4% for anti-lytic and anti-latent antibodies, respectively), with a twofold increase of the risk of HHV-8 infection. However, the increase was observed only among injecting drug users, whereas seroprevalence tended to slightly increase among those infected by sexual contact. At univariate analysis, time of recruitment and being homosexual men were factors associated with HHV-8 infection, an association that remained after adjusting for age. HBV infection was significantly associated with HHV-8 infection (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.3-3.6), whereas those infected with HCV had a lower probability of having HHV-8 antibodies (OR, 0.3; 95% CI, 0.20-0.6). After controlling for age and gender, time of recruitment remained independently associated with HHV-8 infection among injecting drug users. In conclusion, HHV-8 seroprevalence appears to be increased during 10 years among HIV-infected injection drug users but not among homosexual men, who remain those at the highest risk of infection.


Characterisation of selected drugs with nitrogen-containing saturated ring structures by use of electrospray ionisation with ion-trap mass spectrometry.
The electrospray ionisation-ion-trap mass spectrometry (ESI-MS(n)) of selected drugs with nitrogen-containing saturated ring structures has been investigated. Sequential product-ion fragmentation experiments (MS(n)) have been performed to elucidate degradation pathways for the [M+H](+) ions and their predominant fragment ions. These MS(n) experiments result in characteristic fragmentations in which functional groups are generally cleaved from the ring systems as neutral molecules such as H(2)O, amines, alkenes, esters, carboxylic acids, etc. When such a nitrogen-containing drug molecule also contains a functional group, such as an ester, that on liberation as a neutral molecule has a significantly lower -Delta H(f) degrees value than that of the corresponding amine then the former is preferentially liberated. Furthermore, when an aromatic entity is present in these drug molecules together with the nitrogen-containing saturated ring structure fragmentation of the latter ring occurs with the former, predictably, being resistant to fragmentation. The structures of fragment ions proposed for ESI-MS(n) can be supported by electrospray ionisation-quadrupole time-of-flight mass spectrometry (ESI-QTOFMS). The data presented in this paper therefore provide useful information on the structure of these heterocyclic compounds which could be used to characterise unknown drug compounds isolated from natural sources, for example.