Physiological variation and phenotypic plasticity: a response to 'Plasticity in arthropod cryotypes' by Hawes and Bale.
In a recent publication, Hawes and Bale provide an extended discussion of phenotypic plasticity in the context of low temperature responses of animals. They argue that phenotypic plasticity may be partitioned phylogenetically at several levels and go on to explore these levels, and cold hardiness strategies that they term cryotypes, which in their view constitute cryotypic plasticity. Here we argue that this attempt to partition plasticity is misleading, that the term 'genotypic plasticity' is potentially highly confusing and a misnomer for physiological variance, and that the term 'superplasticity' should not be used. We also show that a definition of strategies as cryotypes is not useful and that the hypothesis about the relationship between evolutionary derivation and extent of plasticity in freeze-avoiding vs freeze-tolerant species is not supported by current evidence.


Assessment of HIV-positive in-patients using the International Classification of Functioning, Disability and Health (ICF) at Chris Hani Baragwanath Hospital, Johannesburg.
The International Classification of Functioning, Disability and Health (ICF) short-version checklist was used to assess the impairments, activity limitations and participation restrictions experienced by a sample of HIV-positive in-patients admitted to Chris Hani Baragwanath Hospital in Johannesburg, South Africa. Laboratory tests, observation and review of patients' medical records were used to complete the ICF Checklist. Eighty patients were assessed (23 males and 57 females). Common impairments related to the following functions: digestive, metabolic and endocrine systems (83.9%); sensory (83.5%); haematological, immunological and respiratory systems (82.5%); neuromusculoskeletal movement (73.8%); mental (72.6%); energy and drive (75%); sleep (71%); emotional (62%); and muscle power (75%). Activity limitations were present in the area of mobility (56.4%), major life areas (55.1%), and community, social and civic life (50%). Associations found among impairments, activity limitations and participation restrictions were that patients with sensory problems were five-times more likely to have problems in self-care than people without sensory problems. Patients with impairments in the digestive, genitourinary and neuromusculoskeletal systems experienced problems with general tasks (confidence interval [CI]: 4.05-103.03; p < 0.01). Patients with cardiovascular, haematological, immunological and respiratory system problems were 14-times more likely to have problems with execution of general tasks (odds ratio [OR] 14.06, CI: 2.75-71.94; p = 0.002). Activities of participation restriction, difficulties with general tasks and demands (OR 9.68, CI: 1.20-77.92), interpersonal relationships (OR 3.62, CI: 1.09-12.00), domestic life (OR 3.97, CI: 1.12-14.16), and community, social and civic life (OR 4.13, CI: 1.05-16.20) were closely associated with barriers in obtaining products for personal use and using technology. Understanding the prevalence and associations of disability and function in the course of HIV disease may serve as a baseline for developing appropriate and context-sensitive rehabilitation interventions and management strategies for people living with HIV or AIDS.


Therapeutic Effect of Neurotrophin-3 Treatment in an Injectable Collagen Scaffold Following Rat Spinal Cord Hemisection Injury.
Spinal cord injury (SCI) patients display varying quantities of spinal cord tissue damage with injuries that present as complete, incomplete or compressive. One theory proposed to repair the injured spinal cord and regain motor control is to regenerate axons through the lesion site. This study was designed to quantify the impact of a local injectable in situ forming hydrogel reservoir therapy following rat hemisection SCI. We investigated the effect of hydrogel only treatment following SCI in addition to hydrogels loaded with a neurotrophic factor, Neurotrophin-3 (NT-3), immediately following SCI. Functional recovery, assessed by Basso Beattie Bresnahan (BBB) locomotor test, and local healing mechanisms, including neuronal growth, glial scar formation, inflammation and collagen deposition were investigated one and 6 weeks postsurgery. Delivery of an injectable hydrogel significantly increased functional recovery at four and 6 weeks post injury. In addition, a significant reduction in the inhibitory glial scar and in inflammation was observed at the injury site. Similarly hydrogel + NT-3 delivered directly into the injury site significantly reduced glial scarring and collagen deposition. The hydrogel + NT-3 also resulted in a significant increase in neurons at 6 weeks post injury. This study represents a novel and effective therapy combining growth factor and a biomaterial based therapy following SCI.


Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial.
Numerous observational studies have found supplemental calcium and vitamin D to be associated with reduced risk of common cancers. However, interventional studies to test this effect are lacking. The purpose of this analysis was to determine the efficacy of calcium alone and calcium plus vitamin D in reducing incident cancer risk of all types. This was a 4-y, population-based, double-blind, randomized placebo-controlled trial. The primary outcome was fracture incidence, and the principal secondary outcome was cancer incidence. The subjects were 1179 community-dwelling women randomly selected from the population of healthy postmenopausal women aged >55 y in a 9-county rural area of Nebraska centered at latitude 41.4 degrees N. Subjects were randomly assigned to receive 1400-1500 mg supplemental calcium/d alone (Ca-only), supplemental calcium plus 1100 IU vitamin D3/d (Ca + D), or placebo. When analyzed by intention to treat, cancer incidence was lower in the Ca + D women than in the placebo control subjects (P < 0.03). With the use of logistic regression, the unadjusted relative risks (RR) of incident cancer in the Ca + D and Ca-only groups were 0.402 (P = 0.01) and 0.532 (P = 0.06), respectively. When analysis was confined to cancers diagnosed after the first 12 mo, RR for the Ca + D group fell to 0.232 (CI: 0.09, 0.60; P < 0.005) but did not change significantly for the Ca-only group. In multiple logistic regression models, both treatment and serum 25-hydroxyvitamin D concentrations were significant, independent predictors of cancer risk. Improving calcium and vitamin D nutritional status substantially reduces all-cancer risk in postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00352170.


Mortality from and incidence of pesticide poisoning in South Korea: findings from National Death and Health Utilization Data between 2006 and 2010.
Pesticide poisoning has been recognized as an important public health issue around the world. The objectives of this study were to report nationally representative figures on mortality from and the incidence of pesticide poisoning in South Korea and to describe their epidemiologic characteristics. We calculated the age-standardized rates of mortality from and the incidence of pesticide poisoning in South Korea by gender and region from 2006 through 2010 using registered death data obtained from Statistics Korea and national healthcare utilization data obtained from the National Health Insurance Review and Assessment Service of South Korea. During the study period of 2006 through 2010, a total of 16,161 deaths and 45,291 patients related to pesticide poisoning were identified, marking respective mortality and incidence rates of 5.35 and 15.37 per 100,000 population. Intentional self-poisoning was identified as the major cause of death due to pesticides (85.9%) and accounted for 20.8% of all recorded suicides. The rates of mortality due to and incidence of pesticide poisoning were higher in rural than in urban areas, and this rural-urban discrepancy was more pronounced for mortality than for incidence. Both the rate of mortality due to pesticide poisoning and its incidence rate increased with age and were higher among men than women. This study provides the magnitude and epidemiologic characteristics for mortality from and the incidence of pesticide poisoning at the national level, and strongly suggests the need for further efforts to prevent pesticide self-poisonings, especially in rural areas in South Korea.


Naturally occurring K vitamins inhibit pancreatic cancer cell survival through a caspase-dependent pathway.
Available medical therapies against pancreatic cancer are largely ineffective and have many side-effects. Physiologically, vitamins K1 and K2 (VK) act as co-factors for gamma-carboxylation of prothrombin and other coagulation factors. In previous studies, VK analogs have been found to have potent negative effects on the survival of various cancer cells. We hypothesized that the well-tolerated and naturally occurring VK1 and VK2 may be used to inhibit pancreatic cancer cell survival. Four pancreas cancer cell lines were tested. Two of these (MiaPaCa2 and PL5) were found to be sensitive to VK1 and VK2 (IC50 values < or =150 microM). To address the mechanisms of this effect on cell survival, we performed cell cycle and apoptosis studies using VK2 (the more potent compound). We found that VK induced caspase-dependent apoptosis in over 60% of cells in the sensitive lines at the half maximal inhibitory concentration (IC(50)) range. Further, this induction in apoptosis was antagonized by a caspase inhibitor. Accompanying apoptosis, a dose- and time-dependent induction of extracellular signal-regulated kinase (ERK) phosphorylation occurred when sensitive lines were treated with either VK1 or VK2 at inhibitory doses. Simultaneous co-treatment of cells with a MEK1 inhibitor and VK prevented both the induction of ERK phosphorylation and the apoptosis, showing that the mitogen-activated protein (MAP) kinase pathway is central for VK-mediated apoptosis in pancreatic cancer cells. These data show that naturally-occurring, non-toxic K vitamins can inhibit the survival of some pancreatic cancer cell lines. These novel, safe and clinically-utilized agents initiate a caspase-dependent apoptosis via the MAP kinase pathway and could potentially benefit patients with pancreatic cancer either as a single agent or in combination with chemotherapy for treatment, or for prevention of recurrence of pancreas cancer post resection.


Stimulus-specific adaptation and deviance detection in the rat auditory cortex.
Stimulus-specific adaptation (SSA) is the specific decrease in the response to a frequent ('standard') stimulus, which does not generalize, or generalizes only partially, to another, rare stimulus ('deviant'). Stimulus-specific adaptation could result simply from the depression of the responses to the standard. Alternatively, there may be an increase in the responses to the deviant stimulus due to the violation of expectations set by the standard, indicating the presence of true deviance detection. We studied SSA in the auditory cortex of halothane-anesthetized rats, recording local field potentials and multi-unit activity. We tested the responses to pure tones of one frequency when embedded in sequences that differed from each other in the frequency and probability of the tones composing them. The responses to tones of the same frequency were larger when deviant than when standard, even with inter-stimulus time intervals of almost 2 seconds. Thus, SSA is present and strong in rat auditory cortex. SSA was present even when the frequency difference between deviants and standards was as small as 10%, substantially smaller than the typical width of cortical tuning curves, revealing hyper-resolution in frequency. Strong responses were evoked also by a rare tone presented by itself, and by rare tones presented as part of a sequence of many widely spaced frequencies. On the other hand, when presented within a sequence of narrowly spaced frequencies, the responses to a tone, even when rare, were smaller. A model of SSA that included only adaptation of the responses in narrow frequency channels predicted responses to the deviants that were substantially smaller than the observed ones. Thus, the response to a deviant is at least partially due to the change it represents relative to the regularity set by the standard tone, indicating the presence of true deviance detection in rat auditory cortex.


Reducing scan angle using adaptive prior knowledge for a limited-angle intrafraction verification (LIVE) system for conformal arc radiotherapy.
The purpose of this study is to develop an adaptive prior knowledge guided image estimation technique to reduce the scan angle needed in the limited-angle intrafraction verification (LIVE) system for 4D-CBCT reconstruction. The LIVE system has been previously developed to reconstruct 4D volumetric images on-the-fly during arc treatment for intrafraction target verification and dose calculation. In this study, we developed an adaptive constrained free-form deformation reconstruction technique in LIVE to further reduce the scanning angle needed to reconstruct the 4D-CBCT images for faster intrafraction verification. This technique uses free form deformation with energy minimization to deform prior images to estimate 4D-CBCT based on kV-MV projections acquired in extremely limited angle (orthogonal 3°) during the treatment. Note that the prior images are adaptively updated using the latest CBCT images reconstructed by LIVE during treatment to utilize the continuity of the respiratory motion. The 4D digital extended-cardiac-torso (XCAT) phantom and a CIRS 008A dynamic thoracic phantom were used to evaluate the effectiveness of this technique. The reconstruction accuracy of the technique was evaluated by calculating both the center-of-mass-shift (COMS) and 3D volume-percentage-difference (VPD) of the tumor in reconstructed images and the true on-board images. The performance of the technique was also assessed with varied breathing signals against scanning angle, lesion size, lesion location, projection sampling interval, and scanning direction. In the XCAT study, using orthogonal-view of 3° kV and portal MV projections, this technique achieved an average tumor COMS/VPD of 0.4 ± 0.1 mm/5.5 ± 2.2%, 0.6 ± 0.3 mm/7.2 ± 2.8%, 0.5 ± 0.2 mm/7.1 ± 2.6%, 0.6 ± 0.2 mm/8.3 ± 2.4%, for baseline drift, amplitude variation, phase shift, and patient breathing signal variation, respectively. In the CIRS phantom study, this technique achieved an average tumor COMS/VPD of 0.7 ± 0.1 mm/7.5 ± 1.3% for a 3 cm lesion and 0.6 ± 0.2 mm/11.4 ± 1.5% for a 2 cm lesion in the baseline drift case. The average tumor COMS/VPD were 0.5 ± 0.2 mm/10.8 ± 1.4%, 0.4 ± 0.3 mm/7.3 ± 2.9%, 0.4 ± 0.2 mm/7.4 ± 2.5%, 0.4 ± 0.2 mm/7.3 ± 2.8% for the four real patient breathing signals, respectively. Results demonstrated that the adaptive prior knowledge guided image estimation technique with LIVE system is robust against scanning angle, lesion size, location and scanning direction. It can estimate on-board images accurately with as little as 6 projections in orthogonal-view 3° angle. In conclusion, adaptive prior knowledge guided image reconstruction technique accurately estimates 4D-CBCT images using extremely-limited angle and projections. This technique greatly improves the efficiency and accuracy of LIVE system for ultrafast 4D intrafraction verification of lung SBRT treatments.


Dually diagnosed patients' benefits of mutual-help groups and the role of social anxiety.
There is debate about whether dually diagnosed patients benefit from mutual-help groups (MHGs), partly because social anxiety may make participation problematic. We examined dually diagnosed patients' participation in MHGs and outcomes at 6, 12, and 24 months post-treatment, and the extent to which social anxiety was associated with participation. We also examined whether MHG participation and social anxiety were related to outcomes, and whether social anxiety moderated associations between participation and outcomes. We found high rates of MHG participation. Among patients who attended at least one meeting, outcomes were positive. Social anxiety was not associated with levels of MHG participation, but more participation was associated with better outcomes. When social anxiety moderated associations between MHG participation and outcomes, patients with more social anxiety benefited more from participation. Treated dually diagnosed patients participate in, and benefit from, MHGs, and participation and benefits are comparable, or even strengthened, among more socially-anxious patients.


Association between appendicectomy in females and subsequent pregnancy rate: a cohort study.
To study whether subsequent pregnancy rate is reduced after appendicectomy. A cohort study was carried out in the General Practice Research Database, a United Kingdom primary care database. University hospital. Female patients who underwent appendicectomy between 1986 and 2009 and appropriate comparators were followed until first pregnancy. None. The association between appendicectomy and subsequent pregnancy was determined by Cox regression models. The analyses included 76,426 appendicectomy patients, with 152,852 comparators from the database. There were 30,030 pregnancies (39.3%) in the appendicectomy cohort and 43,321 (28.3%) in the comparator cohort during a mean (SD) follow-up of 10.5 (6.6) years. Adjusted hazard ratios for subsequent birth rates were 1.54 (95% confidence interval, 1.52-1.56). Appendicectomy was associated with increased subsequent pregnancy rate in this study. This suggests that a history of appendicectomy is not associated with impaired fertility.


Measurement of cerebral blood volume in humans using hyperoxic MRI contrast.
To develop a new method of measuring quantitative regional cerebral blood volume (CBV) using epochs of hyperoxia as an intravenous contrast agent with T2*-weighted MRI. Images were acquired from six subjects (four male, two female, mean age 29 +/- 3.7 years) using a sequence combining pulsed arterial spin labeling interleaved with a gradient echo echo-planar imaging (EPI) blood oxygenation level-dependent (BOLD) sequence at 3T. The hyperoxia paradigm lasted 28 minutes consisting of 4 minutes of normoxia, two 6-minute blocks of hyperoxia separated by 6 minutes of normoxia. During the hyperoxic blocks the subjects were delivered a fractional oxygen concentration of 0.5. The mean CBV was calculated to be 3.77 +/- 1.05 mL/100 g globally, 3.93 +/- 0.90 mL/100 g in gray matter (GM), and 2.52 +/- 0.78 mL/100 g in white matter (WM). The mean GM/WM ratio was thus found to be 1.56. These values are comparable to those obtained in other studies. The hyperoxia technique for measuring CBV may be particularly useful for patient groups where an injected bolus of contrast agent is contraindicated. As more functional studies are employing epochs of inspired gases for calibration purposes, this method is easily incorporated into existing paradigms to produce a noninvasive, repeatable, easily tolerated, and quantitative measurement of regional CBV.


Mechanistic insights from the recent structures of the CRM1 nuclear export complex and its disassembly intermediate.
CRM1 (also known as exportin 1 or Xpo1) is the most versatile nuclear export receptor (exportin) that carries a broad range of proteins and ribonucleoproteins from the nucleus to the cytoplasm through the nuclear pore complex. The majority of the export substrates of CRM1 contain a short peptide sequence, so-called leucine-rich nuclear export signal (NES), which typically harbor four or five characteristically spaced hydrophobic residues. The transport directionality is determined by the small GTPase Ran and Ran-binding proteins that control the binding and dissociation of cargo. Here we review recent structural studies that advanced understanding of how NES is specifically recognized by CRM1 in the nucleus, and how NES is rapidly dissociated from CRM1 in the cytoplasm.


Effect of ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial.
To assess the effects of ruxolitinib on symptom burden and quality of life (QoL) and to evaluate the ability of the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 to measure meaningful changes in myelofibrosis-related symptoms in patients with myelofibrosis. COMFORT-I (Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment-I) is a double-blind, placebo-controlled phase III study evaluating ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis. Exploratory analyses were conducted on the following patient-reported outcomes (PROs) assessments: modified MFSAF v2.0 (individual symptoms and Total Symptom Score [TSS]), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and Patient Global Impression of Change (PGIC). Patients receiving ruxolitinib experienced improvements in individual myelofibrosis-related symptoms, although patients receiving placebo experienced worsening (P < .001). The majority (91%) of ruxolitinib-treated patients designated as ≥ 50% TSS responders (≥ 50% TSS improvement) self-reported their condition as either "Much improved" or "Very much improved" on the PGIC. These patients achieved significant improvements in the EORTC QLQ-C30 functional domains and Global Health Status/QoL versus patients receiving placebo, who experienced worsening on these measures (P ≤ .0135). Ruxolitinib-treated patients with a lesser degree of symptom improvement (< 50% TSS responders) also achieved improvements over placebo on these measures. The degree of spleen volume reduction with ruxolitinib correlated with improvements in TSS, PGIC, PROMIS Fatigue Scale, and EORTC Global Health Status/QoL. Ruxolitinib-treated patients who achieved a ≥ 35% reduction in spleen volume experienced the greatest improvements in these PROs. Ruxolitinib-treated patients achieved clinically meaningful improvements in myelofibrosis-related symptoms and QoL, but patients receiving placebo reported worsening of symptoms and other PROs.


Mechanisms of oxygen demand/supply balance in the right ventricle.
Few studies have investigated factors responsible for the O2 demand/supply balance in the right ventricle. Resting right coronary blood flow is lower than left coronary blood flow, which is consistent with the lesser work of the right ventricle. Because right and left coronary artery perfusion pressures are identical, right coronary conductance is less than left coronary conductance, but the signal relating this conductance to the lower right ventricular O2 demand has not been defined. At rest, the left ventricle extracts approximately 75% of the O2 delivered by coronary blood flow, whereas right ventricular O2 extraction is only ~50%. As a result, resting right coronary venous PO2 is approximately 30 mm Hg, whereas left coronary venous PO2 is approximately 20 mm Hg. Right coronary conductance does not sufficiently restrict flow to force the right ventricle to extract the same percentage of O2 as the left ventricle. Endogenous nitric oxide impacts the right ventricular O2 demand/supply balance by increasing the right coronary blood flow at rest and during acute pulmonary hypertension, systemic hypoxia, norepinephrine infusion, and coronary hypoperfusion. The substantial right ventricular O2 extraction reserve is used preferentially during exercise-induced increases in right ventricular myocardial O2 consumption. An augmented, sympathetic-mediated vasoconstrictor tone blunts metabolically mediated dilator mechanisms during exercise and forces the right ventricle to mobilize its O2 extraction reserve, but this tone does not limit resting right coronary flow. During exercise, right coronary vasodilation does not occur until right coronary venous PO2 decreases to approximately 20 mm Hg. The mechanism responsible for right coronary vasodilation at low PO2 has not been delineated. In the poorly autoregulating right coronary circulation, reduced coronary pressure unloads the coronary hydraulic skeleton and reduces right ventricular systolic stiffness. Thus, normal right ventricular external work and O2 demand/supply balance can be maintained during moderate coronary hypoperfusion.


Treatment strategy for main duct intraductal papillary mucinous neoplasms of the pancreas based on the assessment of recurrence in the remnant pancreas after resection: a retrospective review.
To clarify the recurrence pattern after resection of main duct intraductal papillary mucinous neoplasms (MD-IPMNs) using molecular analyses and determine the most adequate treatment strategy. The most appropriate resection line for MD-IPMNs remains an unresolved issue. Medical records of 56 patients with pancreatectomy were retrospectively reviewed. Histological subtypes and Kras/GNAS mutations were assessed in patients with recurrence in the remnant pancreas. Forty-nine patients underwent partial pancreatectomy and 7 underwent total pancreatectomy. Thirty-six patients (64%) had malignant MD-IPMNs. Recurrence was observed in 7 of 49 patients (14%), including 6 with malignant IPMNs and 1 with pancreatic ductal adenocarcinoma, all of whom underwent remnant pancreatectomy. The cumulative disease-specific survival rate of patients with pancreatic recurrence was greater than that of patients with extrapancreatic recurrence (P < 0.001). Although the pancreatic margin status at the initial operation did not affect the pancreatic recurrence rate, all 4 recurrent IPMNs examined had histological subtypes and Kras/GNAS mutations identical to those of the initial lesions. Four patients experienced recurrence in the remnant pancreas or systemic recurrence after resection of high-grade dysplasia of MD-IPMN. Three of the 56 patients had concomitant pancreatic ductal adenocarcinomas and MD-IPMNs. One-step total pancreatectomy can be avoided, and remnant total pancreatectomy would lead to favorable outcomes even in patients with pancreatic recurrence, some cases of which seem to involve residual lesions. Postoperative surveillance of high-grade dysplasia should be performed as if malignant, and close attention should be paid to the occurrence of concomitant pancreatic ductal adenocarcinomas in patients with MD-IPMNs.


Clinical Outcomes of Arteriovenous Access in Incident Hemodialysis Patients with Medicare Coverage, 2012-2014.
Chronic hemodialysis requires a mode of vascular access through an arteriovenous fistula (AVF), a prosthetic arteriovenous graft (AVG), or a central venous catheter (CVC). AVF is recommended over AVG or CVC due to increased patency and decreased intervention rates for those that mature. AVG are preferred over CVC due to decreased infection and mortality risk. The aims of this study were to evaluate the lifespan of AVF and AVG in maturation, sustained access use, and abandonment. The United States Renal Data System (USRDS), Medicare claims, and CROWNWeb were used to identify access placements. Patients with a first end-stage renal disease (ESRD) service from January 1, 2012 to June 30, 2014 with continuous coverage with Medicare as primary payer and ≥1 AVF or AVG placed after ESRD onset were included. Maturation was defined as the first use of the access for hemodialysis recorded in CROWNWeb. Sustained access use was defined as 3 consecutive months of use without catheter placement or replacement. Accesses that were never used at any time post-placement were considered abandoned. The cohort included 38,035 AVF placements and 12,789 AVG placements. Sixty-nine percent of AVF and 72% of AVG matured. Fifty-two percent of AVF and 51% of AVG achieved sustained access use. One quarter of AVF and 14% of AVG were abandoned without use as recorded in CROWNWeb. Although considered the gold standard for vascular access, only half of AVF and AVG placements achieved sustained access use. The USRDS database has inherent limitations but provides useful clinical insight into maturation, sustained use, and abandonment.


Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition.
Prostate cancer is the most prevalent cancer in males, and treatment options are limited for advanced forms of the disease. Loss of the PTEN and TP53 tumor suppressor genes is commonly observed in prostate cancer, whereas their compound loss is often observed in advanced prostate cancer. Here, we show that PARP inhibition triggers a p53-dependent cellular senescence in a PTEN-deficient setting in the prostate. Surprisingly, we also find that PARP-induced cellular senescence is morphed into an apoptotic response upon compound loss of PTEN and p53. We further show that superactivation of the prosurvival PI3K-AKT signaling pathway limits the efficacy of a PARP single-agent treatment, and that PARP and PI3K inhibitors effectively synergize to suppress tumorigenesis in human prostate cancer cell lines and in a Pten/Trp53-deficient mouse model of advanced prostate cancer. Our findings, therefore, identify a combinatorial treatment with PARP and PI3K inhibitors as an effective option for PTEN-deficient prostate cancer. The paucity of therapeutic options in advanced prostate cancer displays an urgent need for the preclinical assessment of novel therapeutic strategies. We identified differential therapeutic vulnerabilities that emerge upon the loss of both PTEN and p53, and observed that combined inhibition of PARP and PI3K provides increased efficacy in hormone-insensitive advanced prostate cancer.


Renal-cell carcinoma risk estimates based on participants in the prostate, lung, colorectal, and ovarian cancer screening trial and national lung screening trial.
Current knowledge regarding risk of renal-cell carcinoma (RCC) is based on meta-analyses of case-control studies. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and National Lung Screening Trial (NLST) provide robust prospective databases with clinical information and rates of cancer development. PLCO and NLST were used to identify risk factors for RCC. Data were extracted from PLCO and NLST to stratify risk of RCC by sex, race, age at inclusion, obesity, and smoking status. Incidence rates between groups were compared using the chi-square test. We excluded urothelial carcinomas. Overall, 701/154,118 and 190/53,242 RCCs were detected in PLCO and NLST, respectively. Incidence rates were higher in men (PLCO: 0.56 vs. 0.28/1000 person y, NLST: 0.73 vs. 0.35/1000 person y; both with P<0.0001). In the PLCO, male sex, age>60 years, obesity, and intensity of smoking were associated with higher risk of developing RCC. In the NLST, sex and morbid obesity increased the risk for RCC but age, ethnicity, and smoking intensity were not predictors. There was no effect of screening for other cancers on detection of RCC. High-grade (grades ≥3) RCCs were diagnosed in 145 (20.7%) and 60 (31.6%) in the PLCO and NLST. In PLCO, age (60-64y), male sex, obesity, and current smokers with>50 pack years were at increased risk for high-grade RCC. In NLST, only male sex was an independent predictor of high-grade RCC. Age over 60 years, male sex, smoking intensity, and obesity affect the risk of RCC. Identification of a high-risk population may allow a pilot study of rational screening for RCC.


Perceived discrimination and health-related quality-of-life: gender differences among older African Americans.
Emerging data suggest that African-American women may fare worse than African-American men in health-related quality-of-life (HRQOL). Perceived discrimination is an important contributor to poor health overall among African Americans, but few studies examined the intersecting effects of perceived discrimination and gender in explaining HRQOL disparities. We investigated gender differences in HRQOL and tested whether perceived discrimination accounted for these differences. We examined data from the Chicago Health and Aging Project in which 5652 African-American adults aged 65 and older completed structured questionnaires about demographic and socioeconomic characteristics, HRQOL, perceived discrimination, and health-related variables. Logistic regression models were used to identify associations between perceived discrimination and gender differences in poor HRQOL outcomes (defined as 14+ unhealthy days in overall, physical, or mental health over the past 30 days) when controlling for the other variables. More women reported poor overall HRQOL than men (24 vs. 16% respectively). Higher perceived discrimination was significantly associated with worse overall HRQOL (OR 1.11; 95% CI 1.08, 1.15), with stronger effects for women in overall and mental HRQOL. These gender disparities remained significant until controlling for potentially confounding variables. Perceived discrimination did not account for gender differences in poor physical HRQOL. Perceived discrimination is associated with poor HRQOL in older African Americans, with this association appearing stronger in women than men for mental HRQOL. These findings warrant further investigation of effects of perceived discrimination in gender disparities in overall health, and such research can inform and guide efforts for reducing these disparities.


Oxysterols and multiple sclerosis: Physiopathology, evolutive biomarkers and therapeutic strategy.
Multiple sclerosis is an autoimmune disease that affects the central nervous system. Dysfunction of the immune system leads to lesions that cause motor, sensory, cognitive, visual and/or sphincter disturbances. In the long term, these disorders can progress towards an irreversible handicap. The diagnosis takes time because there are no specific criteria to diagnose multiple sclerosis. To realize the diagnosis, a combination of clinical, biological, and radiological arguments is therefore required. Hence, there is a need to identify multiple sclerosis biomarkers. Some biomarkers target immunity through the detection of oligoclonal bands, the measurement of the IgG index and cytokines. During the physiopathological process, the blood-brain barrier can be broken, and this event can be identified by measuring metalloproteinase activity and diffusion of gadolinium in the brain by magnetic resonance imaging. Markers of demyelination and of astrocyte and microglial activity may also be of interest as well as markers of neuronal damage and mitochondrial status. The measurement of different lipids in the plasma and cerebrospinal fluid can also provide suitable information. These different lipids include fatty acids, fatty acid peroxidation products, phospholipids as well as oxidized derivatives of cholesterol (oxysterols). Oxysterols could constitute new biomarkers providing information on the form of multiple sclerosis, the outcome of the disease and the answer to treatment.


Delivery of LLKKK18 loaded into self-assembling hyaluronic acid nanogel for tuberculosis treatment.
Tuberculosis (TB), a disease caused by the human pathogen Mycobacterium tuberculosis, recently joined HIV/AIDS on the top rank of deadliest infectious diseases. Low patient compliance due to the expensive, long-lasting and multi-drug standard therapies often results in treatment failure and emergence of multi-drug resistant strains. In this scope, antimicrobial peptides (AMPs) arise as promising candidates for TB treatment. Here we describe the ability of the exogenous AMP LLKKK18 to efficiently kill mycobacteria. The peptide's potential was boosted by loading into self-assembling Hyaluronic Acid (HA) nanogels. These provide increased stability, reduced cytotoxicity and degradability, while potentiating peptide targeting to main sites of infection. The nanogels were effectively internalized by macrophages and the peptide presence and co-localization with mycobacteria within host cells was confirmed. This resulted in a significant reduction of the mycobacterial load in macrophages infected in vitro with the opportunistic M. avium or the pathogenic M. tuberculosis, an effect accompanied by lowered pro-inflammatory cytokine levels (IL-6 and TNF-α). Remarkably, intra-tracheal administration of peptide-loaded nanogels significantly reduced infection levels in mice infected with M. avium or M. tuberculosis, after just 5 or 10 every other day administrations. Considering the reported low probability of resistance acquisition, these findings suggest a great potential of LLKKK18-loaded nanogels for TB therapeutics.


TLR9 polymorphisms in African populations: no association with severe malaria, but evidence of cis-variants acting on gene expression.
During malaria infection the Toll-like receptor 9 (TLR9) is activated through induction with plasmodium DNA or another malaria motif not yet identified. Although TLR9 activation by malaria parasites is well reported, the implication to the susceptibility to severe malaria is not clear. The aim of this study was to assess the contribution of genetic variation at TLR9 to severe malaria. This study explores the contribution of TLR9 genetic variants to severe malaria using two approaches. First, an association study of four common single nucleotide polymorphisms was performed on both family- and population-based studies from Malawian and Gambian populations (n>6000 individual). Subsequently, it was assessed whether TLR9 expression is affected by cis-acting variants and if these variants could be mapped. For this work, an allele specific expression (ASE) assay on a panel of HapMap cell lines was carried out. No convincing association was found with polymorphisms in TLR9 for malaria severity, in either Gambian or Malawian populations, using both case-control and family based study designs. Using an allele specific expression assay it was observed that TLR9 expression is affected by cis-acting variants, these results were replicated in a second experiment using biological replicates. By using the largest cohorts analysed to date, as well as a standardized phenotype definition and study design, no association of TLR9 genetic variants with severe malaria was found. This analysis considered all common variants in the region, but it is remains possible that there are rare variants with association signals. This report also shows that TLR9 expression is potentially modulated through cis-regulatory variants, which may lead to differential inflammatory responses to infection between individuals.


Oligoclonal repertoire of the CD8 alpha alpha and the CD8 alpha beta TCR-alpha/beta murine intestinal intraepithelial T lymphocytes: evidence for the random emergence of T cells.
The epithelium of the small intestine in normal euthymic mice contains a large number of intraepithelial lymphocytes (IEL), some of which bear a T cell receptor alpha/beta (TCR-alpha/beta). About half of these TCR-alpha/beta IEL display the CD8 alpha alpha phenotype and the remaining have the CD8 alpha beta or the CD4 phenotypes. To examine whether TCR-alpha/beta IEL have a TCR-beta chain repertoire as diverse as that of TCR-alpha/beta lymph node lymphocytes (LNL), we used a recently described PCR technique that allows a global analysis of the TCR-beta chain repertoire. Within any given mouse, the repertoires expressed in both CD8 alpha alpha and CD8 alpha beta TCR-alpha/beta IEL populations are oligoclonal and nonoverlapping between the two subsets. The clones are largely conserved through the length of the small intestine of the same individual. However, genetically identical individuals raised under indistinguishable environmental conditions display distinct oligoclonal repertoires. Those findings indicate that few cells of CD8 alpha alpha or of the CD8 alpha beta phenotype are responsible for the repopulation of the intestinal epithelium.


The vesicle transport protein Vac1p is required for virulence of Candida albicans.
The putative vesicle transport protein Vac1p of the human pathogenic yeast Candida albicans plays an important role in virulence. To determine the cellular functions of Vac1p, a null mutant was generated by sequential disruption of both alleles. The vac1 null mutant strain showed defective endosomal vesicle transport, demonstrating a role of Vac1p in protein transport to the vacuole. Vac1p also contributes to resistance to metal ions, as the null mutant strain was hypersensitive to Cu(2+), Zn(2+) and Ni(2+). In addition, the loss of Vac1p affected several virulence factors of C. albicans. In particular, the vac1 null mutant strain showed defective hyphal growth, even when hyphal formation was induced via different pathways. Furthermore, Vac1p affects chlamydospore formation, adherence to human vaginal epithelial cells, and the secretion of aspartyl proteinases (Saps). Avirulence in a mouse model of systemic infection of the vac1 null mutant strongly suggests that Vac1p of C. albicans is essential for pathogenicity. In summary, the Vac1p protein is required for several cellular pathways, in particular those that control virulence and pathogenicity. Consequently, Vac1p is a novel and interesting target for antifungal drugs.


Isolation of Salmonella enterica subspecies enterica serovar Paratyphi B dT+, or Salmonella Java, from Indonesia and alteration of the d-tartrate fermentation phenotype by disrupting the ORF STM 3356.
Salmonella enterica subspecies enterica serovar Paratyphi B [O1,4,(5),12 : Hb : 1,2] can cause either an enteric fever (paratyphoid fever) or self-limiting gastroenteritis in humans. The d-tartrate non-fermenting variant S. enterica subsp. enterica serovar Paratyphi B dT- (S. Paratyphi B) is the causative agent of paratyphoid fever, and the d-tartrate fermenting variant S. enterica subsp. enterica serovar Paratyphi B dT+ (S. Paratyphi B dT+; formerly called Salmonella Java) causes gastroenteritis. S. Java is currently recognized as an emerging problem worldwide. Twelve dT+ S. Java isolates were collected in Indonesia between 2000 and 2002. One-third of them contained Salmonella genomic island 1 (SGI1), which gives the multidrug-resistant phenotype to the bacteria. In this study, a PCR-based method to detect a single nucleotide difference responsible for the inability to ferment d-tartrate, reported elsewhere, was validated. The d-tartrate fermenting phenotype of S. Java was converted to the non-fermenting phenotype by the disruption of the ORF STM 3356, and the d-tartrate non-fermenting phenotype of the ORF STM 3356-disrupted strain and the dT- reference strain was changed to the dT+ phenotype by complementing ORF STM 3356 in trans. The results show that the dT+ phenotype requires a functional product encoded by STM 3356, and support the use of the PCR-based discrimination method for S. Paratyphi B and S. Java as the standard differentiation method.


Segmenting the human genome based on states of neutral genetic divergence.
Many studies have demonstrated that divergence levels generated by different mutation types vary and covary across the human genome. To improve our still-incomplete understanding of the mechanistic basis of this phenomenon, we analyze several mutation types simultaneously, anchoring their variation to specific regions of the genome. Using hidden Markov models on insertion, deletion, nucleotide substitution, and microsatellite divergence estimates inferred from human-orangutan alignments of neutrally evolving genomic sequences, we segment the human genome into regions corresponding to different divergence states--each uniquely characterized by specific combinations of divergence levels. We then parsed the mutagenic contributions of various biochemical processes associating divergence states with a broad range of genomic landscape features. We find that high divergence states inhabit guanine- and cytosine (GC)-rich, highly recombining subtelomeric regions; low divergence states cover inner parts of autosomes; chromosome X forms its own state with lowest divergence; and a state of elevated microsatellite mutability is interspersed across the genome. These general trends are mirrored in human diversity data from the 1000 Genomes Project, and departures from them highlight the evolutionary history of primate chromosomes. We also find that genes and noncoding functional marks [annotations from the Encyclopedia of DNA Elements (ENCODE)] are concentrated in high divergence states. Our results provide a powerful tool for biomedical data analysis: segmentations can be used to screen personal genome variants--including those associated with cancer and other diseases--and to improve computational predictions of noncoding functional elements.


The HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: Possible relevance for treatment-resistant depression.
Major depression is a highly complex disabling psychiatric disorder affecting millions of people worldwide. Despite the availability of several classes of antidepressants, a substantial percentage of patients are unresponsive to these medications. A better understanding of the neurobiology of depression and the mechanisms underlying antidepressant response is thus critically needed. We previously reported that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) exhibit a depressive-like phenotype and a blunted antidepressant response to the selective serotonin reuptake inhibitor fluoxetine. In this study, we similarly show that Crtc1(-/-) mice are resistant to the antidepressant effect of chronic desipramine in a behavioral despair paradigm. Supporting the blunted response to this tricyclic antidepressant, we found that desipramine does not significantly increase the expression of Bdnf and Nr4a1-3 in the hippocampus and prefrontal cortex of Crtc1(-/-) mice. Epigenetic regulation of neuroplasticity gene expression has been associated with depression and antidepressant response, and histone deacetylase (HDAC) inhibitors have been shown to have antidepressant-like properties. Here, we show that unlike conventional antidepressants, chronic systemic administration of the HDAC inhibitor SAHA partially rescues the depressive-like behavior of Crtc1(-/-) mice. This behavioral effect is accompanied by an increased expression of Bdnf, but not Nr4a1-3, in the prefrontal cortex of these mice, suggesting that this epigenetic intervention restores the expression of a subset of genes by acting downstream of CRTC1. These findings suggest that CRTC1 alterations may be associated with treatment-resistant depression, and support the interesting possibility that targeting HDACs may be a useful therapeutic strategy in antidepressant development.


Meta-analysis showing the beneficial effect of α-blockers on ureteric stent discomfort.
What's known on the subject? and What does the study add? Ureteric stents cause significant discomfort and this is probably related to ureteric smooth muscle spasm and trigonal irritation. Alpha-adrenoceptor antagonists reduce smooth muscle activity and are already widely used in medical expulsive therapy to aid passage of ureteric calculi. This meta-analysis incorporating five randomized controlled trials provides evidence that alpha-adrenoceptor antagonists reduce stent-related pain and storage symptoms as assessed by the Ureteric Stent Symptoms Questionnaire (USSQ). • To evaluate the efficacy of α-blockers with respect to improving stent-related symptoms. • Ureteric stents remain a source of marked discomfort and their placement is often required after certain ureteroscopic procedures or in the acute setting. This analysis identifies and reviews the several studies that have investigated the role of α-blockers after stent placement. • Pubmed/Medline, EMBASE, CINAHL and Cochrane Library databases were scrutinized using standard MeSH headings. • Randomized or controlled trials comparing α-blockers with control or standard therapy were included. • In all studies, patients completed the Ureteral Stent Symptom Questionnaire (USSQ). • The study data were independently reviewed by two assessors. • In total, five studies of varying quality were identified, including 461 patients receiving either tamsulosin or alfuzosin, or control. • On meta-analysis, all five studies showed a reduction in USSQ urinary symptom score and body pain scores. There was mean reduction of 8.4 (95% CI, 5.6-11.1) in the urinary symptom score and 7.2 (95% CI, 2.5-11.8) in the body pain score. • In three studies, the numbers of patients experiencing stent related pain were stated: 45% (51/114) of patients receiving an α-blocker experienced painful episodes within the follow-up period defined for that study compared to 76% (88/116) in the control groups, which is equivalent to a relative risk of pain of 0.59 (95% confidence interval, 0.47-0.71). • There were also reductions in other aspects of the USSQ, such as the general health score and sexual matters score, although these were not statistically significant or uniformly reported. • There is evidence that α-blockers provide an improvement in discomfort after placement of a ureteric stent.


The Poggendorff illusion affects manual pointing as well as perceptual judgements.
Pointing movements made to a target defined by the imaginary intersection of a pointer with a distant landing line were examined in healthy human observers in order to determine whether such motor responses are susceptible to the Poggendorff effect. In this well-known geometric illusion observers make systematic extrapolation errors when the pointer abuts a second line (the inducer). The kinematics of extrapolation movements, in which no explicit target was present, where similar to those made in response to a rapid-onset (explicit) dot target. The results unambiguously demonstrate that motor (pointing) responses are susceptible to the illusion. In fact, raw motor biases were greater than for perceptual responses: in the absence of an inducer (and hence also the acute angle of the Poggendorff stimulus) perceptual responses were near-veridical, whilst motor responses retained a bias. Therefore, the full Poggendorff stimulus contained two biases: one mediated by the acute angle formed between the oblique pointer and the inducing line (the classic Poggendorff effect), which affected both motor and perceptual responses equally, and another bias, which was independent of the inducer and primarily affected motor responses. We conjecture that this additional motor bias is associated with an undershoot in the unknown direction of movement and provide evidence to justify this claim. In conclusion, both manual pointing and perceptual judgements are susceptible to the well-known Poggendorff effect, supporting the notion of a unitary representation of space for action and perception or else an early locus for the effect, prior to the divergence of processing streams.


Vibrational spectroscopic studies and DFT calculations on NaCH3CO2(aq) and CH3COOH(aq).
Aqueous solutions of sodium acetate, NaCH3CO2, and acetic acid, CH3COOH, were studied using Raman and infrared spectroscopy. The spectra were recorded over a large concentration range, in the terahertz region and up to 4000 cm(-1). In the isotropic Raman spectrum in R-format, a polarized band at 189 cm(-1) was assigned to the ν1Na-O stretch of the hydrated Na(+)-ion and a shoulder at 245 cm(-1) to the restricted translation band, νsO-H···O* of the hydrated acetate ion, CH3CO2(-)(aq). The CH3CO2(-)(aq) and the hydrated acetic acid, CH3COOH(aq), possess pseudo Cs symmetry. Geometrical parameters for the species in the gas phase and for CH3CO2(-)(aq) and CH3COOH(aq) are reported. Characteristic bands for CH3CO2(-)(aq) and CH3COOH(aq) were assigned under the guidance of the DFT vibrational frequency calculations and discussed in detail. In aqueous NaCH3CO2 solutions, at high concentrations, no contact ion pairs could be detected, but instead solvent separated ion pairs were found. In LiCH3CO2(aq), however, contact ion pairs are formed which is indicated by the appearance of a shoulder at 939 cm(-1) and the shift of the symmetric stretching mode of the -CO2(-) group to higher wavenumbers.


What is safe enough - asthma in pregnancy - a review of current literature and recommendations.
Although asthma is one of the most serious diseases causing complications during pregnancy, half of the women discontinue therapy thus diminishing the control of the disease, mostly due to the inadequate education and fear of adverse events. Sadly, this is sometimes encouraged by insufficiently educated physicians. Since the incidence and the prevalence of asthma is increasing, it is important to arouse the importance of proper asthma therapy during pregnancy. Inadequate therapy, as well as interrupting or discontinuing therapy, may result in adverse perinatal outcomes for both mother and child. The main goal of asthma control during pregnancy is control of symptoms and prevention of exacerbations, same as in every asthmatic, but even more important. Maintaining optimal lung function, as well as regular daily activities, ensures maintenance of optimal fetal oxygenation. The therapy should be adapted depending on the frequency and severity of daily and nocturnal symptoms, demand for reliever therapy, by the limitations in everyday activities and the frequency of emergency asthma-related hospitalizations. Pre-conceptual education and therapy are very important and should be supported by an asthma action plan adjusted for the period of pregnancy. It is very important to note that most of the drugs used before pregnancy can be safely continued during pregnancy. Pharmacological and non-pharmacological therapy should be used in parallel. Pregnant women should be informed about the nature of the disease, therapy used during pregnancy, possible complications, avoidance of triggers, proper administration of therapy and, most important, why should the therapy be continued throughout the pregnancy on individual basis. Although drug treatment should be based on using drugs with less harm risk, if control of severe symptoms is needed to be achieved in order to protect both mother and child, any anti-asthmatic drug would have the beneficial benefit/harm ratio. There is no solid evidence that asthma treatment during pregnancy causes adverse outcomes for the mother and child but for many, especially new drugs, there is not enough data gathered. On the other hand, harmfulness of uncontrolled asthma during pregnancy is well documented so every effort should be put on preserving good control of asthma during pregnancy.


A rigorous experimental framework for detecting protein oligomerization using bioluminescence resonance energy transfer.
Bioluminescence resonance energy transfer (BRET), which relies on nonradiative energy transfer between luciferase-coupled donors and GFP-coupled acceptors, is emerging as a useful tool for analyzing the quaternary structures of cell-surface molecules. Conventional BRET analyses are generally done at maximal expression levels and single acceptor/donor ratios. We show that under these conditions substantial energy transfer arises from random interactions within the membrane. The dependence of BRET efficiency on acceptor/donor ratio at fixed surface density, or expression level at a defined acceptor/donor ratio, can nevertheless be used to correctly distinguish between well-characterized monomeric and oligomeric proteins, including a very weak dimer. The pitfalls associated with the nonrigorous treatment of BRET data are illustrated for the case of G protein-coupled receptors (GPCRs) proposed to form homophilic and/or mixed oligomers on the basis of previous, conventional BRET experiments.


Regulation of Insulin Receptor Pathway and Glucose Metabolism by CD36 Signaling.
During reduced energy intake, skeletal muscle maintains homeostasis by rapidly suppressing insulin-stimulated glucose utilization. Loss of this adaptation is observed with deficiency of the fatty acid transporter CD36. A similar loss is also characteristic of the insulin-resistant state where CD36 is dysfunctional. To elucidate what links CD36 to muscle glucose utilization, we examined whether CD36 signaling might influence insulin action. First, we show that CD36 deletion specific to skeletal muscle reduces expression of insulin signaling and glucose metabolism genes. It decreases muscle ceramides but impairs glucose disposal during a meal. Second, depletion of CD36 suppresses insulin signaling in primary-derived human myotubes, and the mechanism is shown to involve functional CD36 interaction with the insulin receptor (IR). CD36 promotes tyrosine phosphorylation of IR by the Fyn kinase and enhances IR recruitment of P85 and downstream signaling. Third, pretreatment for 15 min with saturated fatty acids suppresses CD36-Fyn enhancement of IR phosphorylation, whereas unsaturated fatty acids are neutral or stimulatory. These findings define mechanisms important for muscle glucose metabolism and optimal insulin responsiveness. Potential human relevance is suggested by genome-wide analysis and RNA sequencing data that associate genetically determined low muscle CD36 expression to incidence of type 2 diabetes.


Appropriate patient selection at abdominal dual-energy CT using 80 kV: relationship between patient size, image noise, and image quality.
To determine the computed tomographic (CT) detector configuration, patient size, and image noise limitations that will result in acceptable image quality of 80-kV images obtained at abdominal dual-energy CT. The Institutional Review Board approved this HIPAA-compliant retrospective study from archival material from patients consenting to the use of medical records for research purposes. A retrospective review of contrast material-enhanced abdominal dual-energy CT scans in 116 consecutive patients was performed. Three gastrointestinal radiologists noted detector configuration and graded image quality and artifacts at specified levels-midliver, midpancreas, midkidneys, and terminal ileum-by using two five-point scales. In addition, an organ-specific enhancement-to-noise ratio and background noise were measured in each patient. Patient size was measured by using the longest linear dimension at the level of interest, weight, lean body weight, body mass index, and body surface area. Detector configuration, patient sizes, and image noise levels that resulted in unacceptable image quality and artifact rankings (score of 4 or higher) were determined by using multivariate logistic regression. A 14 × 1.2-mm detector configuration resulted in fewer images with unacceptable quality than did the 64 × 0.6-mm configuration at all anatomic levels (P = .004, .01, and .02 for liver, pancreas, and kidneys, respectively). Image acceptability for the kidneys and ileum was significantly greater than that for the liver for all readers and detector configurations (P < .001). For the 14 × 1.2-mm detector configuration, patient longest linear dimensions yielding acceptable image quality across readers ranged from 34.9 to 35.8 cm at the four anatomic levels. An 80-kV abdominal CT can be performed with appropriate diagnostic quality in a substantial percentage of the population, but it is not recommended beyond the described patient size for each anatomic level. The 14 × 1.2-mm detector configuration should be preferred.


Ketamine Restores Thalamic-Prefrontal Cortex Functional Connectivity in a Mouse Model of Neurodevelopmental Disorder-Associated 2p16.3 Deletion.
2p16.3 deletions, involving heterozygous NEUREXIN1 (NRXN1) deletion, dramatically increase the risk of developing neurodevelopmental disorders, including autism and schizophrenia. We have little understanding of how NRXN1 heterozygosity increases the risk of developing these disorders, particularly in terms of the impact on brain and neurotransmitter system function and brain network connectivity. Thus, here we characterize cerebral metabolism and functional brain network connectivity in Nrxn1α heterozygous mice (Nrxn1α+/- mice), and assess the impact of ketamine and dextro-amphetamine on cerebral metabolism in these animals. We show that heterozygous Nrxn1α deletion alters cerebral metabolism in neural systems implicated in autism and schizophrenia including the thalamus, mesolimbic system, and select cortical regions. Nrxn1α heterozygosity also reduces the efficiency of functional brain networks, through lost thalamic "rich club" and prefrontal cortex (PFC) hub connectivity and through reduced thalamic-PFC and thalamic "rich club" regional interconnectivity. Subanesthetic ketamine administration normalizes the thalamic hypermetabolism and partially normalizes thalamic disconnectivity present in Nrxn1α+/- mice, while cerebral metabolic responses to dextro-amphetamine are unaltered. The data provide new insight into the systems-level impact of heterozygous Nrxn1α deletion and how this increases the risk of developing neurodevelopmental disorders. The data also suggest that the thalamic dysfunction induced by heterozygous Nrxn1α deletion may be NMDA receptor-dependent.


Early Conversion From Twice-Daily Tacrolimus to Prolonged-Release Tacrolimus in Liver Transplantation: A Single-Center Experience.
BACKGROUND Prolonged-release tacrolimus (Tac QD) is widely used in organ transplantation. However, the conversion from twice-daily tacrolimus (Tac BID) to Tac QD in Japan is usually done in stable patients months or years after liver transplantation. The aim of this study was to assess the early conversion of Tac QD during liver transplant hospital stay. MATERIAL AND METHODS Eighteen liver transplants (excluding pediatric) were performed during 2014-2015. All cases except 2 early-expired patients were enrolled. Our standard immunosuppression is oral Tac BID and steroid taper, and we add mycophenolate mofetil if indicated. Conversion criteria from Tac BID to Tac QD were: 1) relatively stable liver function with stable trough level by oral Tac BID, and 2) good general condition (no or well-controlled complications). We did not fix the exact conversion date because each patient's recovery was different. Dose conversion rate from Tac BID to Tac QD was set at 1:1. RESULTS The median number of conversion days after liver transplant was 27 days. Sixty-two percent of patients were converted within 4 weeks after liver transplant, and 56% were discharged from the hospital within 2 weeks after conversion. The comparison of the last week of Tac BID and the first week of Tac QD revealed that the mean tacrolimus trough level declined by 30.4%, resulting in the 26.2% tacrolimus dose increase during the first 2 weeks after conversion. Adverse events after conversion were limited, and all patients show normal liver function to date. CONCLUSIONS Early Tac QD conversion is safe and feasible, but its long-term effects need further investigation.


Rousette Bat Dendritic Cells Overcome Marburg Virus-Mediated Antiviral Responses by Upregulation of Interferon-Related Genes While Downregulating Proinflammatory Disease Mediators.
Dysregulated and maladaptive immune responses are at the forefront of human diseases caused by infection with zoonotic viral hemorrhagic fever viruses. Elucidating mechanisms of how the natural animal reservoirs of these viruses coexist with these agents without overt disease, while permitting sufficient replication to allow for transmission and maintenance in a population, is important for understanding the viral ecology and spillover to humans. The Egyptian rousette bat (ERB) has been identified as a reservoir for Marburg virus (MARV), a filovirus and the etiological agent of the highly lethal Marburg virus disease. Little is known regarding how these bats immunologically respond to MARV infection. In humans, macrophages and dendritic cells (DCs) are primary targets of infection, and their dysregulation is thought to play a central role in filovirus diseases, by disturbing their normal functions as innate sensors and adaptive immune response facilitators while serving as amplification and dissemination agents for the virus. The infection status and responses to MARV in bat myeloid-lineage cells are uncharacterized and likely represent an important modulator of the bat's immune response to MARV infection. Here, we generate DCs from the bone marrow of rousette bats. Infection with a bat isolate of MARV resulted in a low level of transcription in these cells and significantly downregulated DC maturation and adaptive immune-stimulatory pathways while simultaneously upregulating interferon-related pathogen-sensing pathways. This study provides a first insight into how the bat immune response is directed toward preventing aberrant inflammatory responses while mounting an antiviral response to defend against MARV infection.IMPORTANCE Marburg viruses (MARVs) cause severe human disease resulting from aberrant immune responses. Dendritic cells (DCs) are primary targets of infection and are dysregulated by MARV. Dysregulation of DCs facilitates MARV replication and virus dissemination and influences downstream immune responses that result in immunopathology. Egyptian rousette bats (ERBs) are natural reservoirs of MARV, and infection results in virus replication and shedding, with asymptomatic control of the virus within weeks. The mechanisms that bats employ to appropriately respond to infection while avoiding disease are unknown. Because DC infection and modulation are important early events in human disease, we measured the transcriptional responses of ERB DCs to MARV. The significance of this work is in identifying cell type-specific coevolved responses between ERBs and MARV, which gives insight into how bat reservoirs are able to harbor MARV and permit viral replication, allowing transmission and maintenance in the population while simultaneously preventing immunopathogenesis.


Reducing Lateral Femoral Cutaneous Nerve Palsy in Obese Patients in the Beach Chair Position: Effect of a Standardized Positioning and Padding Protocol.
To report on the effectiveness of a standardized patient positioning and padding protocol in reducing lateral femoral cutaneous nerve (LFCN) palsy in obese patients who have undergone shoulder surgery in the beach chair position. We retrospectively reviewed the medical records of 400 consecutive patients with a body mass index (BMI) of ≥30 kg/m who underwent either open or arthroscopic shoulder surgery in the beach chair position by a single surgeon. Before June 2013, all patients were placed in standard beach chair positioning with no extra padding. After June 2013, patients had foam padding placed over their thighs underneath a wide safety strap and underneath the abdominal pannus. Flexion at the waist was minimized, and reverse Trendelenburg was used to position the shoulder appropriately. Patient demographic and surgical data, including age, sex, weight, BMI, presence of diabetes, procedure duration, American Society of Anesthesiologists (ASA) grade, and anesthesia type (general, regional, regional/general) were recorded. Symptoms of LFCN palsy were specifically elicited postoperatively in a prospective fashion and identified clinically by focal pain, numbness, and/or tingling over the anterolateral thigh. The median age was 58.0 years, and the study consisted of 142 male (36%) and 258 female (64%) subjects. Five cases (3.6%) of LFCN palsy occurred with conventional beach chair positioning, and a single case (0.4%) occurred with the standardized positioning and padding technique (P = 0.02). Median age, sex, presence of diabetes, median BMI, surgery type, and surgical time were not significantly different between the patients who did and did not develop LFCN palsy. All cases resolved completely within 6 months. The occurrence of LFCN palsy following shoulder surgery in the beach chair position remains uncommon, even among obese patients. Use of a standardized positioning and padding protocol for obese patients in the beach chair position reduced the prevalence of LFCN palsy. Level III (prognostic).


Are PrEP services in France reaching all those exposed to HIV who want to take PrEP? MSM respondents who are eligible but not using PrEP (EMIS 2017).
Pre-exposure prophylaxis (PrEP) is fully reimbursed by the French health insurance system since 2016. However, uptake of PrEP is slower than expected and little is known about men who have sex with men (MSM) who are eligible for PrEP according to French guidelines, but not using it. This study aims to (1) assess and describe MSM that are eligible to PrEP but not using it, and (2) identify potential individual and structural barriers of PrEP uptake among eligible MSM who are aware and intend to take PrEP. Data from EMIS-2017, a cross-sectional internet survey among gay, bisexual, and other MSM, were used. Among 7965 respondents without diagnosed HIV, 9.2% were PrEP users. Among 7231 non-PrEP users, 35.2% were eligible to PrEP and 15.2% were eligible, aware and intended to take PrEP. Eligible MSM who are not using PrEP are mostly younger, students, less "out", living in small cities, using condoms more frequently but still with low self-efficacy regarding safe sex and more distant from preventive health care and information than PrEP users. Despite free PrEP availability in France, results suggest that PrEP is not fully accessible and that there is a need to increase PrEP demand and decentralize PrEP delivery.


Physics-based visualization of dense natural clouds. I. Three-dimensional discrete ordinates radiative transfer.
A technique is developed to model radiative transfer in three-dimensional natural clouds with a standard discrete ordinates finite-element method modified to evaluate cell-surface-averaged radiances. A log-least-squares-based scale transformation is used to improve the discrete phase-function model. We handle dense media by assuming constant diffuse radiances over input faces to cubic cells, allowing analytical forms for transmittance factors. Transmission equations are combined with diffuse volumetric single-scattering calculations to support evaluations of cell energy balance. Energy not accounted for volumetrically is treated with surface-based effects. Results produced show accurate flux computations at over 30 optical depths per modeled cell. Comparisons with nonuniform cloud Monte Carlo calculations show less than 1% rms error and correlations greater than 0.999 for cases in which cloud-density fluctuations are resolved.


Does KRAS testing in metastatic colorectal cancer impact overall survival? A comparative effectiveness study in a population-based sample.
Epidermal growth factor receptor (EGFR) inhibitors are approved for treating metastatic colorectal cancer (CRC); KRAS mutation testing is recommended prior to treatment. We conducted a non-inferiority analysis to examine whether KRAS testing has impacted survival in CRC patients. We included 1186 metastatic CRC cases from seven health plans. A cutpoint of July, 2008, was used to define two KRAS testing time period groups: "pre-testing" (n = 760 cases) and "post-testing" (n = 426 cases). Overall survival (OS) was estimated, and the difference in median OS between the groups was calculated. The lower bound of the one-sided 95% confidence interval (CI) for the difference in survival was used to test the null hypothesis of post-testing inferiority. Multivariable Cox regression models were constructed to adjust for covariates. The median unadjusted OS was 15.4 months (95% CI: 14.0-17.5) and 12.8 months (95% CI: 10.0-15.2) in the pre- and post-testing groups, respectively. The OS difference was -2.6 months with one-sided 95% lower confidence bound of -5.13 months, which was less than the non-inferiority margin (-5.0 months, unadjusted p = 0.06), leading to a failure to reject inferiority of OS in the post-testing period. In contrast, in the adjusted analysis, OS non-inferiority was identified in the post-testing period (p = 0.001). Sensitivity analyses using cutpoints before and after July, 2008, also met the criteria for non-inferiority. Implementation of KRAS testing did not influence CRC OS. Our data support the use of KRAS testing to guide administration of EGFR inhibitors for treatment of metastatic CRC without diminished OS.


Paraduodenal pancreatitis: benign and malignant mimics at MRI.
Paraduodenal pancreatitis, also known as groove pancreatitis, is a rare form of chronic pancreatitis that masquerades as pancreatic adenocarcinoma affecting the pancreaticoduodenal groove, a potential space between the head of the pancreas, duodenum, and common bile duct. Two forms of groove pancreatitis have been described. The segmental form involves the pancreatic head with development of scar tissue within the groove, whereas the pure form affects the groove only, sparing the pancreatic head. Imaging findings of groove pancreatitis often overlap with primary duodenal, ampullary, or pancreatic neoplasms, which often results in a diagnostic challenge. In addition, paraduodenal pancreatitis can be mistaken for cystic pancreatic lesions, especially when there is involvement of the duodenal wall. Preoperative recognition of this entity is very important in order to avoid unnecessary procedures, although surgery, such as pancreaticoduodenectomy, may still be required to relieve obstructive symptoms. In this article, the pathophysiology and magnetic resonance imaging characteristics of paraduodenal pancreatitis and important benign and malignant mimics are discussed.


Surface topography regulates wnt signaling through control of primary cilia structure in mesenchymal stem cells.
The primary cilium regulates cellular signalling including influencing wnt sensitivity by sequestering β-catenin within the ciliary compartment. Topographic regulation of intracellular actin-myosin tension can control stem cell fate of which wnt is an important mediator. We hypothesized that topography influences mesenchymal stem cell (MSC) wnt signaling through the regulation of primary cilia structure and function. MSCs cultured on grooves expressed elongated primary cilia, through reduced actin organization. siRNA inhibition of anterograde intraflagellar transport (IFT88) reduced cilia length and increased active nuclear β-catenin. Conversely, increased primary cilia assembly in MSCs cultured on the grooves was associated with decreased levels of nuclear active β-catenin, axin-2 induction and proliferation, in response to wnt3a. This negative regulation, on grooved topography, was reversed by siRNA to IFT88. This indicates that subtle regulation of IFT and associated cilia structure, tunes the wnt response controlling stem cell differentiation.


Phosphoinositides and cell proliferation.
Certain growth factors act by stimulating the hydrolysis of inositol lipids to yield putative second messengers such as diacylglycerol (DG) and inositol trisphosphate (IP3). One function of the former is to stimulate C-kinase, which may act by switching on a sodium/hydrogen exchanger to induce the increase in pH that appears to have a permissive effect on DNA synthesis. Studies on Swiss 3T3 cells have revealed that growth factors stimulate an increase in two separate isomers of IP3. In addition to inositol 1,4,5-trisphosphate there was a large increase in inositol 1,3,4-trisphosphate. While the former functions to elevate intracellular calcium, which has been implicated in the control of growth of many different cell types, the function of the latter is unknown. Since the 1,3,4 isomer turns over very slowly, it may control long-term events and thus could play a role in cell growth. There are other growth factors such as insulin and epidermal growth factor (EGF), which apparently do not work through the inositol lipids but they may initiate ionic events similar to those just described for calcium-mobilizing receptors. The bifurcating signal pathway based on IP3/Ca2+ and DG/C-kinase provides an interesting framework within which to consider the mode of action of oncogenes.


Could resistant starch supplementation improve inflammatory and oxidative stress biomarkers and uremic toxins levels in hemodialysis patients? A pilot randomized controlled trial.
An imbalance of gut microbiota is considered a new cardiovascular risk factor for chronic kidney disease (CKD) patients, since it is directly associated with increased uremic toxin production, inflammation and oxidative stress. Strategies such as prebiotic supplementation have been suggested to mitigate these complications. We hypothesized that prebiotic-resistant starch could ameliorate uremic toxins levels, oxidative stress, and inflammatory states in hemodialysis (HD) patients. This pilot study evaluated 31 HD patients assigned to either resistant starch (16 g of resistant starch Hi-Maize® 260) or placebo (manioc flour) supplementation, which they received for 4 weeks on alternate days through cookies on dialysis days and powder in a sachet on non-dialysis days. Levels of interleukin (IL)-6, high-sensitive C-reactive protein, thiobarbituric acid reactive substances plasma (TBARS), protein carbonylation, indoxyl sulfate (IS) and p-cresyl sulfate were measured. Anthropometric and biochemical parameters, as well as, food intake were also evaluated. As expected, resistant starch group increased fiber intake (p > 0.01), in addition the prebiotic supplementation reduced IL-6 (p = 0.01), TBARS (p > 0.01), and IS (p > 0.01) plasma levels. No significant differences were evident in the placebo group. Prebiotic-resistant starch supplementation seems to be a promising nutritional strategy to improve inflammation, oxidative stress and to reduce IS plasma levels in CKD patients on HD.


Patients in 24-hour home care striving for control and safety.
This article concerns Swedish patients receiving 24-hour home care from health care assistants (HC assistants) employed by the municipality. Home care is a complex interactive process involving the patient, family, HC assistants as well as professional care providers. Previous studies exploring patient perspectives on home care have been based mainly on patient interviews. In contrast, the present study took a broad perspective on patients' experiences and thoughts by combining field observations on care situations with patient and HC assistant interviews. The aim of the study presented in this article was to promote a new and broadened understanding of patients receiving 24-hour home care by constructing a theoretical model to illuminate their main concern. Field observations and semi-structured interviews were conducted with four patients receiving 24-hour home care and their HC assistants. Grounded theory methodology was used. The core process identified was Grasping the lifeline, which describes compensatory processes through which patients strived for control and safe care when experiencing a number of exposed states due to inadequate home care. Patients tried to take control by selecting their own HC assistants and sought safe hands by instructing untrained HC assistants in care procedures. When navigating the care system, the patients maintained contacts with professional care providers and coordinated their own care. When necessary, a devoted HC assistant could take over the navigating role. The results are illuminated in a theoretical model. The results accentuate the importance to patients of participating in their own care, especially in the selection of HC assistants. The model illustrates some challenging areas for improvement within the organisation of 24-hour home care, such as personnel continuity and competence, collaboration, and routines for acute care. Furthermore, it may be used as a basis for reflection during the planning of care for individual patients within home care.


Autosomal dominant cerebellar ataxia type I: a review of the phenotypic and genotypic characteristics.
Type I autosomal dominant cerebellar ataxia (ADCA) is a type of spinocerebellar ataxia (SCA) characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA). Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical examination, genetic molecular testing, and exclusion of other diseases. Differential diagnosis is broad and includes secondary ataxias caused by drug or toxic effects, nutritional deficiencies, endocrinopathies, infections and post-infection states, structural abnormalities, paraneoplastic conditions and certain neurodegenerative disorders. Given the autosomal dominant pattern of inheritance, genetic counseling is essential and best performed in specialized genetic clinics. There are currently no known effective treatments to modify disease progression. Care is therefore supportive. Occupational and physical therapy for gait dysfunction and speech therapy for dysarthria is essential. Prognosis is variable depending on the type of ADCA and even among kindreds.


Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40.
CD40 signaling modulates the immune response at least in part by activation of nuclear factor kappaB (NFkappaB). It has been shown that two distinct domains in the CD40 cytoplasmic tail (cyt), namely cyt-N and cyt-C, independently activate NFkappaB. Although four members of the tumor necrosis factor receptor-associated factor (TRAF) family, including TRAF2, TRAF3, TRAF5, and TRAF6, bind to the CD40 cyt, how each TRAF protein contributes to the NFkappaB activation by CD40 is not clear. Here we report that TRAF2, TRAF3, and TRAF5 bind cyt-C, whereas TRAF6 binds cyt-N. cyt-N is conserved poorly between human and mouse CD40, while cyt-C is highly conserved. However, single aa substitution of Glu-235 in cyt-N of human CD40 with Ala abolishes the binding of TRAF6 to cyt-N and NFkappaB activation by cyt-N. Conservation of this Glu between mouse and human CD40 strongly suggests that TRAF6 could link cyt-N to signals essential for CD40-mediated immune response. Furthermore, NFkappaB activation by cyt-C is inhibited by a kinase-negative form of NFkappaB-inducing kinase more efficiently than that by cyt-N, consistent with the result that NFkappaB activation by TRAF2 and TRAF5 is inhibited by a kinase-negative form of NFkappaB-inducing kinase more efficiently than that by TRAF6. These results indicate that NFkappaB activating signals emanating from cyt-N and cyt-C are mediated by the different members of the TRAF family and could be regulated in a distinct manner.


Crystal structures of prethrombin-2 reveal alternative conformations under identical solution conditions and the mechanism of zymogen activation.
Prethrombin-2 is the immediate zymogen precursor of the clotting enzyme thrombin, which is generated upon cleavage at R15 and separation of the A chain and catalytic B chain. The X-ray structure of prethrombin-2 determined in the free form at 1.9 Å resolution shows the 215-217 segment collapsed into the active site and occluding 49% of the volume available for substrate binding. Remarkably, some of the crystals harvested from the same crystallization well, under identical solution conditions, diffract to 2.2 Å resolution in the same space group but produce a structure in which the 215-217 segment moves >5 Å and occludes 24% of the volume available for substrate binding. The two alternative conformations of prethrombin-2 have the side chain of W215 relocating >9 Å within the active site and are relevant to the allosteric E*-E equilibrium of the mature enzyme. Another unanticipated feature of prethrombin-2 bears on the mechanism of prothrombin activation. R15 is found buried within the protein in ionic interactions with E14e, D14l, and E18, thereby making its exposure to solvent necessary for proteolytic attack and conversion to thrombin. On the basis of this structural observation, we constructed the E14eA/D14lA/E18A triple mutant to reduce the level of electrostatic coupling with R15 and promote zymogen activation. The mutation causes prethrombin-2 to spontaneously convert to thrombin, without the need for the snake venom ecarin or the physiological prothrombinase complex.


Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages.
Excessive lipid accumulation in macrophages plays an important role in the development of atherosclerosis. Recently, we discovered an adipocyte-specific plasma protein, adiponectin, that is decreased in patients with coronary artery disease. We previously demonstrated that adiponectin acts as a modulator for proinflammatory stimuli and inhibits monocyte adhesion to endothelial cells. The present study investigated the effects of adiponectin on lipid accumulation in human monocyte-derived macrophages. Human monocytes were differentiated into macrophages by incubation in human type AB serum for 7 days, and the effects of adiponectin were investigated at different time intervals. Treatment with physiological concentrations of adiponectin reduced intracellular cholesteryl ester content, as determined using the enzymatic, fluorometric method. The adiponectin-treated macrophages contained fewer lipid droplets stained by oil red O. Adiponectin suppressed the expression of the class A macrophage scavenger receptor (MSR) at both mRNA and protein levels by Northern and immunoblot analyses, respectively, without affecting the expression of CD36, which was quantified by flow cytometry. Adiponectin reduced the class A MSR promoter activity, as measured by luciferase reporter assay. Adiponectin treatment dose-dependently decreased class A MSR ligand binding and uptake activities. The mRNA level of lipoprotein lipase as a marker of macrophage differentiation was decreased by adiponectin treatment, but that of apolipoprotein E was not altered. Adiponectin was detected around macrophages in the human injured aorta by immunohistochemistry. The adipocyte-derived plasma protein adiponectin suppressed macrophage-to-foam cell transformation, suggesting that adiponectin may act as a modulator for macrophage-to-foam cell transformation.


Recent developments in asthma education.
Asthma education is a key component of the National Heart, Lung, and Blood Institute (NHLBI) asthma guidelines. Although the benefits and importance of asthma patient education are well documented, there are still many open questions regarding how to best provide asthma education. The following review highlights recent developments in this topic. Recent innovations have applied asthma education in a variety of settings. Ensuring that health professionals within a community provide consistent educational messages about asthma can create synergy and leverage limited healthcare resources to improve outcomes. In addition, children seem to have greater responsibility for self-management of asthma at younger ages. Further work is needed to understand how clinicians can best educate and give parents anticipatory guidance about how to best teach and transfer asthma self-management skills to young children. By developing teaching and mastering self-management skills at an early age, children may be able to carry such skills into adulthood. Finally, given the prevalence of healthcare disparities, there is a continued need for rigorously evaluated programs that are culturally appropriate and effective.


Smartphone-Based Psychotherapeutic Micro-Interventions to Improve Mood in a Real-World Setting.
Using mobile communication technology as new personalized approach to treat mental disorders or to more generally improve quality of life is highly promising. Knowledge about intervention components that target key psychopathological processes in terms of transdiagnostic psychotherapy approaches is urgently needed. We explored the use of smartphone-based micro-interventions based on psychotherapeutic techniques, guided by short video-clips, to elicit mood changes. As part of a larger neurofeedback study, all subjects-after being randomly assigned to an experimental or control neurofeedback condition-underwent daily smartphone-based micro-interventions for 13 consecutive days. They were free to choose out of provided techniques, including viscerosensory attention, emotional imagery, facial expression, and contemplative repetition. Changes in mood were assessed in real world using the Multidimensional Mood State Questionnaire (scales: good-bad, GB; awake-tired, AT; and calm-nervous, CN). Twenty-seven men participated on at least 11 days and were thus included in the analyses. Altogether, they underwent 335, generally well-tolerated, micro-intervention sessions, with viscerosensory attention (178 sessions, 53.13%) and contemplative repetition (68 sessions, 20.30%) being the most frequently applied techniques. Mixed models indicated that subjects showed better mood [GB: b = 0.464, 95%confidence interval (CI) [0.068, 0.860], t (613.3) = 2.298, p = 0.022] and became more awake [AT: b = 0.514, 95%CI [0.103, 0.925], t (612.4) = 2.456, p = 0.014] and calmer [CN: b = 0.685, 95%CI [0.360, 1.010], t (612.3) = 4.137, p < 0.001] from pre- to post-micro-intervention. These mood improvements from pre- to post-micro-intervention were associated with changes in mood from the 1st day until the last day with regard to GB mood (r = 0.614, 95%CI [0.297, 0.809], p < 0.001), but not AT mood (r = 0.279, 95%CI [-0.122, 0.602], p = 0.167) and CN mood (r = 0.277, 95%CI [0.124, 0.601], p = 0.170). Our findings provide evidence for the applicability of smartphone-based micro-interventions eliciting short-term mood changes, based on techniques used in psychotherapeutic approaches, such as mindfulness-based psychotherapy, transcendental meditation, and other contemplative therapies. The results encourage exploring these techniques' capability to improve mood in randomized controlled studies and patients. Smartphone-based micro-interventions are promising to modify mood in real-world settings, complementing other psychotherapeutic interventions, in line with the precision medicine approach. The here presented data were collected within a randomized trial, registered at ClinicalTrials.gov (Identifier: NCT01921088) https://clinicaltrials.gov/ct2/show/NCT01921088.


Bat white-nose syndrome: an emerging fungal pathogen?
White-nose syndrome (WNS) is a condition associated with an unprecedented bat mortality event in the northeastern United States. Since the winter of 2006*2007, bat declines exceeding 75% have been observed at surveyed hibernacula. Affected bats often present with visually striking white fungal growth on their muzzles, ears, and/or wing membranes. Direct microscopy and culture analyses demonstrated that the skin of WNS-affected bats is colonized by a psychrophilic fungus that is phylogenetically related to Geomyces spp. but with a conidial morphology distinct from characterized members of this genus. This report characterizes the cutaneous fungal infection associated with WNS.


Is surgical intervention still indicated in recurrent aortic arch obstruction?
Introduction of balloon dilatation has become the standard treatment for recurrent aortic arch obstruction and has changed the therapeutic approach to patients with this disorder. Whether all patients with recurrent aortic arch obstruction are candidates for balloon dilatation remains unanswered. In addition, only few reports have tried to compare the results between patients undergoing balloon dilatation or redo operations. Since 1983, 97 patients underwent reintervention for recurrent aortic arch obstruction (42 dilations and 55 reoperations). Eight had immediate unsuccessful dilatation and were shifted to the surgical group (n = 63). The median age at reintervention was 21.7 months (10 days-45 years), and the median delay was 13.6 months (7 days-17 years). Anatomy of the aortic arch oriented the surgical approach to treat arch hypoplasia. It could be performed through a left thoracotomy in 52 patients, with extended end-to-end anastomosis in 34 patients, subclavian flap repair in 9 patients, conduit insertion in 6 patients, and patch enlargement in 3 patients. More recently, an anterior approach with cardiopulmonary bypass without circulatory arrest was applied to enlarge the patch in all the aortic arches. There was one early death in the surgical intervention group and 2 late deaths in the dilation group. Major complications and recurrence were higher in the dilated group (4 vs 0, P <.01, and 14 vs 5, P <.0004, respectively). At a mean follow-up of 11.8 +/- 4.1 years in the surgical intervention group and 7.5 +/- 2.5 years in the dilated group, systemic hypertension was normalized in all but 5 patients in the surgical intervention group and 6 patients in the dilated group. Reoperation for recurrent aortic arch obstruction can be performed safely, with low rates of mortality and morbidity. This approach should be considered versus balloon angioplasty, especially in patients older than 4 years and in the presence of aortic arch hypoplasia.


Ethanolamine utilization in Salmonella typhimurium.
Ethanolamine can serve as the sole source of carbon and nitrogen for Salmonella typhimurium if vitamin B12 is present to serve as a cofactor. The pathway for ethanolamine utilization has been investigated in order to understand its regulation and determine whether the pathway is important to the selective forces that have maintained the ability to synthesize B12 in S. typhimurium. We isolated mutants that are defective in ethanolamine utilization (eut mutants). These mutants defined a cluster of genes located between purC and cysA at 50 min on the Salmonella chromosome. A genetic map of the eut region was constructed. Included in the map are mutations which affect ethanolamine ammonia lyase, the first degradative enzyme, and mutations which affect the second enzyme in the pathway, acetaldehyde dehydrogenase. Transcriptional regulation of the eut genes was studied by using eut-lac operon fusions created by insertion of Mu d lac. Transcription is induced by the simultaneous presence of ethanolamine and B12 in the growth medium. The eut genes constitute a single unit of transcription. One class of mutations located at the promoter-distal end of the eut operon prevent induction of transcription.


The architecture of an empirical genotype-phenotype map.
Recent advances in high-throughput technologies are bringing the study of empirical genotype-phenotype (GP) maps to the fore. Here, we use data from protein-binding microarrays to study an empirical GP map of transcription factor (TF) -binding preferences. In this map, each genotype is a DNA sequence. The phenotype of this DNA sequence is its ability to bind one or more TFs. We study this GP map using genotype networks, in which nodes represent genotypes with the same phenotype, and edges connect nodes if their genotypes differ by a single small mutation. We describe the structure and arrangement of genotype networks within the space of all possible binding sites for 525 TFs from three eukaryotic species encompassing three kingdoms of life (animal, plant, and fungi). We thus provide a high-resolution depiction of the architecture of an empirical GP map. Among a number of findings, we show that these genotype networks are "small-world" and assortative, and that they ubiquitously overlap and interface with one another. We also use polymorphism data from Arabidopsis thaliana to show how genotype network structure influences the evolution of TF-binding sites in vivo. We discuss our findings in the context of regulatory evolution.