The use of gamma irradiation for the sterilization of enamel for intra-oral cariogenicity tests.
The dose of gamma irradiation sufficient to sterilize enamel samples to be used for intra-oral cariogenicity tests (ICT) without alteration to the structure or solubility of the enamel was determined. Each bovine incisor used was cut vertically into eight portions and each portion assigned to one of eight groups. Group 1 was used as control while other groups were subjected to respective doses of gamma irradiation from a cobalt-60 source. Following sterilization, both control and experimental groups were incubated in nutrient broth for 7 days at 37 degrees C under aerobic and anaerobic conditions. Caries-like lesions were subsequently produced in each specimen using acidic buffer solution, and mineral loss quantified using transverse microradiography. Data were analysed statistically. There was no significant difference in mineral loss between the control and experimental groups, but the numerical value of mineral loss was lower in groups irradiated with> 4080 Gy, in addition to full sterilization and enamel discoloration to cream colour observed in these groups. Microbial growth was observed in the control group and in groups irradiated with <4080 Gy but no discoloration. With 4080 Gy full sterilization without discoloration was observed. It was concluded that 4080 Gy of gamma irradiation is optimal for sterilization of enamel samples for use in ICT.


The safety and tolerance of azlocillin.
631 patients treated with azlocillin were evaluated for adverse reactions. Azlocillin doses ranged from 37-714 mg/kg/day (mean 260 mg/kg/day) and duration of treatment ranged from 1 to 276 days (mean 11.1 days). 82% of patients were treated for more than 7 days. 92 (14.6%) experienced systemic and 20 patients (3.2%) experienced local adverse reactions. Hypersensitivity, manifest by drug fever, cutaneous reactions, or eosinophilia occurred in 0.3, 1.8 and 1.1%, respectively. Hypokalemia developed in 0.5% overall and was dose and duration related. Hepatotoxicity occurred in 1.7%, diarrhea in 1.9% and leukopenia in 0.3%. Nephrotoxicity, expressed as elevated serum creatinine, was seen in 0.5%. Bleeding was seen in one group of patients that received cefamandole concomitantly. As these complications were not seen in other patients, these complications are probably due to cefamandole. In comparison with ticarcillin, carbenicillin, piperacillin, and mezlocillin, a similar number and severity of adverse reactions were seen. Although the incidence of certain adverse reactions may be underestimated due to the short duration of therapy, azlocillin appears to be exceptionally safe and well tolerated.


Spectral analysis of the renal sympathetic neurogram during left ventricular assistance.
To assess the effect of left ventricular assistance on cardiac-related sympathetic nerve activity, renal sympathetic nerve activity was analysed using power spectrum and coherence function. Our TH-7B pneumatically driven sac type Ventricular Assist Device (VAD) was used in the acute experiment of 7 adult mongrel dogs. VAD were inserted between the left atrium and the descending aorta as left heart bypass. RSNA was detected by use of the bipolar electrodes attached to the left renal sympathetic nerve. Values of squared coherence between the arterial pulse wave and RSNA were measured at the cardiac rhythm and VAD pumping rhythm. Before the left ventricular assistance, coherence at the cardiac rhythm and the pumping rhythm were 0.62 +/- 0.15, 0.23 +/- 0.18 (mean +/- SD), respectively. With the VAD pumping, these values became 0.09 +/- 0.05, 0.53 +/- 0.20, respectively. These results indicate that arterial pressure wave which was created by the VAD assistance contributed to the post ganglionic sympathetic activity.


A comparison study between lycobetaine-loaded nanoemulsion and liposome using nRGD as therapeutic adjuvant for lung cancer therapy.
To achieve tumor-selective drug delivery, various nanocarriers have been explored using either passive or active targeting strategies. Despite the great number of studies published annually in the field, only nanocarriers using approved excipients reach the clinical stage. In our study, two classic nanoscale formulations, nanoemulsion (NE) and liposome (Lipo) were selected for the encapsulation of lycobetaine (LBT). To improve the lipid solubility of LBT, oleic acid (OA) was used to complex (LBT-OA) with lycobetaine (LBT). Besides, PEGylated lecithin was used to enhance the circulation time. The release behaviors of LBT from non-PEGylated and PEGylated NE and Lipo were compared. PEGylated LBT-OA loaded Lipo (LBT-OA-PEG-Lipo) exhibited a sustained release rate pattern, and in vivo pharmacokinetic profiles showed the extended circulation compared nanoemlusions. Besides, LBT-OA-PEG-Lipo showed an enhanced anti-tumor effect in the mice xenograft lung carcinoma model. Moreover, a multi-target peptide nRGD was co-administered as a therapeutic adjuvant with LBT-OA loaded formulations, which demonstrated improved tumor penetration and enhanced extravasation of formulations. Also, co-administration of nRGD significantly improved the in vivo antitumor efficacy of different formulations, likely due to the depletion of tumor-associated macrophages (TAMs). Thus, LBT-OA-PEG-Lipo+nRGD may represent a promising strategy for cancer chemotherapy against lung carcinoma.


Use of probiotics for the treatment of constipation in Parkinson's disease patients.
The aim of this paper was to assess the effects of milk fermented with the probiotic strain Lactobacillus casei Shirota on constipation in Parkinson's disease patients. Constipation is a common secondary symptom in patients suffering from Parkinson's Disease (PD), generally treated with dietary therapy, soluble fiber supplements and macrogol laxatives without sodium sulfate. There are no studies on the use of probiotics in the treatment of constipation in these patients. The effects of the administration of Lactobacillus casei Shirota on gastrointestinal symptoms have been assessed in two randomized controlled trials on patients suffering from chronic constipation. Forty PD patients suffering from constipation according to Rome III criteria were recruited. We compared the characteristic of intestinal function during two periods with different treatments: in the first week the patients treated constipation only with dietetic therapy; in the following 5 weeks the patients treated constipation not only with dietetic therapy, but also taking a 65 mL fermented milk drink containing 6.5×109 CFU of Lactobacilus casei Shirota daily.They completed a daily diary for 6 weeks, recording details related to their intestinal function. After probiotic intake we observed a statistically significant increase in the number of days per week in which stools were of normal consistency (P<0.01) and significant reductions in the number of days per week in which patients felt bloated (P<0.01), experienced abdominal pain (P<0.01) and sensation of incomplete emptying (P<0.01). This pilot study showed that a regular intake of probiotics can significantly improve stool consistency and bowel habits in Parkinson's disease patients.


Gas plasmas technology: from biomolecule redox research to medical therapy.
Physical plasma is one consequence of gas ionization, i.e. its dissociation of electrons and ions. If operated in ambient air containing oxygen and nitrogen, its high reactivity produces various reactive oxygen and nitrogen species (RONS) simultaneously. Technology leap innovations in the early 2010s facilitated the generation of gas plasmas aimed at clinics and operated at body temperature, enabling their potential use in medicine. In parallel, their high potency as antimicrobial agents was systematically discovered. In combination with first successful clinical trials, this led in 2013 to the clinical approval of first medical gas plasma devices in Europe for promoting the healing of chronic and infected wounds and ulcers in dermatology. While since then, thousands of patients have benefited from medical gas plasma therapy, only the appreciation of the critical role of gas plasma-derived RONS led to unraveling first fragments of the mechanistic basics of gas plasma-mediated biomedical effects. However, drawing the complete picture of effectors and effects is still challenging. This is because gas plasma-produced RONS not only show a great variety of dozens of types but also each of them having distinct spatio-temporal concentration profiles due to their specific half-lives and reactivity with other types of RONS as well as different types of (bio) molecules they can react with. However, this makes gas plasmas fascinating and highly versatile tools for biomolecular redox research, especially considering that the technical capacity of increasing and decreasing individual RONS types holds excellent potential for tailoring gas plasmas toward specific applications and disease therapies.


Endovascular repair of thoracoabdominal aortic aneurysm using the off-the-shelf multibranched t-Branch stent graft.
Endovascular repair has been increasingly used to treat thoracoabdominal aortic aneurysms using patient-specific or off-the-shelf fenestrated and branched stent grafts. Device customization limits the application of patient-specific devices in patients who need urgent or emergency repair because of ruptured or large, rapidly expanding aneurysms. For these patients, an off-the-shelf multibranched stent graft, the t-Branch stent graft (Cook Medical, Bjaeverskov, Denmark) has been developed based on the relative predictability of visceral vessel anatomy, allowing incorporation and intraoperative customization of target vessels with four down-going directional branches. We used the t-Branch stent graft in a 66-year-old woman with a rapidly enlarging type III thoracoabdominal aortic aneurysm. Completion angiography and follow-up computed tomography angiography demonstrated successful exclusion of the aneurysm sac, patent target vessels, and nearly complete sac shrinkage at the 12-month follow-up.


HIV care cost in England: a cross-sectional analysis of antiretroviral treatment and the impact of generic introduction.
Reliable and timely HIV care cost estimates are important for policy option appraisals of HIV treatment and prevention strategies. As HIV clinical management and outcomes have changed, we aimed to update profiles of antiretroviral (ARV) usage pattern, patent/market exclusivity details and management costs in adults (≥ 18 years old) accessing HIV specialist care in England. The data reported quarterly to the HIV and AIDS Reporting System in England was used to identify ARV usage pattern, and were combined with British National Formulary (BNF) prices, non-ARV care costs and patent/market exclusivity information to generate average survival-adjusted lifetime care costs. The cumulative budget impact from 2018 to the year in which all current ARVs were expected to lose market exclusivity was calculated for a hypothetical 85 000 (± 5000) person cohort, which provided an illustration of potential financial savings afforded by bioequivalent generic switches. Price scenarios explored BNF70 (September 2015) prices and generics at 10/20/30/50% of proprietary prices. The analyses took National Health Service (NHS) England's perspective (as the payer), and results are presented in 2016/2017 British pounds. By 2033, most currently available ARVs would lose market exclusivity; that is, generics could be available. Average per person lifetime HIV cost was ~£200 000 (3.5% annual discount) or ~£400 000 (undiscounted), reducing to ~£70 000 (3.5% annual discount; ~£120 000 undiscounted) with the use of generics (assuming that generics cost 10% of proprietary prices). The cumulative budget to cover 85 000 (± 5000) persons for 16 years (2018-2033) was £10.5 (± 0.6) billion, reducing to £3.6 (± 0.2) billion with the use of generics. HIV management costs are high but financial efficiency could be improved by optimizing generic use for treatment and prevention to mitigate the high cost of lifelong HIV treatment. Earlier implementation of generics as they become available offers the potential to maximize the scale of the financial savings.


STIs and blood borne viruses - risk factors for individuals with mental illness.
Individuals with mental illness have poorer sexual health compared to the general population and experience a number of barriers to accessing health care. This population demonstrates elevated rates of sexually transmitted infections (STIs) and blood borne viruses (BBVs), as well as higher rates of associated risky behaviours. To review factors associated with increased risk for STI/BBV infection among individuals with mental health problems, and to discuss the potential implications for general practice management. There are multiple factors associated with risk for STI/BBV infection among people with mental health problems. An awareness of relevant risk factors is necessary for providing a timely and comprehensive approach. Relevant strategies include sexual health and STI/BBV screening, education/counselling, diagnosis, treatment, skills training and appropriate referral. General practitioners play an important role in ensuring the sexual health needs of those with mental heath issues are adequately addressed.


Microbial synergy in experimental intra-abdominal abscess.
Intra-abdominal sepsis was studied in Wistar rats by using four microbial species: Escherichia coli, enterococci, Bacteroides fragilis, and Fusobacterium varium. These organisms were implanted into the peritoneal cavity singly and in all possible dual combinations. Results were evaluated by mortality rates and the incidence of intra-abdominal abscesses on autopsy following sacrifice after 7 days. Mortality was restricted to recipients of E. coli, thus implicating coliforms in the acute lethality associated with this experimental model. Intra-abdominal abscesses were produced in 61 of 95 (94%) animals that received the combination of an anaerobe and a facultative organism. Abscesses failed to form with any single strain or with E. coli plus enterococci, and they were detected in one 1 of 19 animals receiving B. fragilis plus F. varium. These results suggest that intra-abdominal abscess formation is related to synergy between anaerobes and facultative bacteria.


Does sleep relate to next-day cannabis use during treatment? Findings from an adolescent and young adult motivational enhancement and cognitive behavioral therapy plus topiramate intervention.
Interventions for youth cannabis use have limited efficacy. Sleep is likely to affect treatment response, as sleep difficulties are cross-sectionally associated with use and common during treatment. This analysis examined how sleep duration and subjective trouble sleeping related to next-day cannabis use among youth during cannabis treatment. Participants (N=64) received a psychosocial intervention plus topiramate versus placebo while completing a 6-week ecological momentary assessment study. Time-varying effect modeling (TVEM) examined within- and between-person associations between sleep and cannabis use and how the strength of within-person associations varied over the course of treatment. TVEM resvealed that, between-participants, youth with longer average sleep duration used cannabis less often controlling for baseline cannabis use, topiramate, and weekend status. Daily within-person fluctuations in sleep duration and trouble were not associated with use. Findings suggest regularly shorter sleep may impede treatment outcomes. Adolescents who regularly have insufficient sleep durations likely need additional intervention to improve sleep difficulties in tandem with cannabis use reduction.


Association of Income Inequality With Pediatric Hospitalizations for Ambulatory Care-Sensitive Conditions.
The level of income inequality (ie, the variation in median household income among households within a geographic area), in addition to family-level income, is associated with worsened health outcomes in children. To determine the influence of income inequality on pediatric hospitalization rates for ambulatory care-sensitive conditions (ACSCs) and whether income inequality affects use of resources per hospitalization for ACSCs. This retrospective, cross-sectional analysis used the 2014 State Inpatient Databases of the Healthcare Cost and Utilization Project of 14 states to evaluate all hospital discharges for patients aged 0 to 17 years (hereafter referred to as children) from January 1 through December 31, 2014. Using the 2014 American Community Survey (US Census), income inequality (Gini index; range, 0 [perfect equality] to 1.00 [perfect inequality]), median household income, and total population of children aged 0 to 17 years for each zip code in the 14 states were measured. The Gini index for zip codes was divided into quartiles for low, low-middle, high-middle, and high income inequality. Rate, length of stay, and charges for pediatric hospitalizations for ACSCs. A total of 79 275 hospitalizations for ACSCs occurred among the 21 737 661 children living in the 8375 zip codes in the 14 included states. After adjustment for median household income and state of residence, ACSC hospitalization rates per 10 000 children increased significantly as income inequality increased from low (27.2; 95% CI, 26.5-27.9) to low-middle (27.9; 95% CI, 27.4-28.5), high-middle (29.2; 95% CI, 28.6-29.7), and high (31.8; 95% CI, 31.2-32.3) categories (P < .001). A significant, clinically unimportant longer length of stay was found for high inequality (2.5 days; 95% CI, 2.4-2.5 days) compared with low inequality (2.4 days; 95% CI, 2.4-2.5 days; P < .001) zip codes and between charges ($765 difference among groups; P < .001). Children living in areas of high income inequality have higher rates of hospitalizations for ACSCs. Consideration of income inequality, in addition to income level, may provide a better understanding of the complex relationship between socioeconomic status and pediatric health outcomes for ACSCs. Efforts aimed at reducing rates of hospitalizations for ACSCs should consider focusing on areas with high income inequality.


Neural correlates of topographic mental exploration: the impact of route versus survey perspective learning.
There are two major sources of information to build a topographic representation of an environment, namely actual navigation within the environment (route perspective) and map learning (survey perspective). The aim of the present work was to use positron emission tomography (PET) to compare the neural substrate of the topographic representation built from these two modes. One group of subjects performed a mental exploration task in an environment learned from actual navigation (mental navigation task). Another group of subjects performed exploration in the same environment learned from a map (mental map task). A right hippocampal activation common to both mental navigation and mental map tasks was evidenced and may correspond the neural substrate of a "dual-perspective" representation. The parahippocampal gyrus was additionally activated bilaterally during mental navigation only. These results suggest that the right hippocampus involvement would be sufficient when the representation incorporates essentially survey information while the bilateral parahippocampal gyrus would be involved when the environment incorporates route information and includes "object" landmarks. The activation of a parietofrontal network composed of the intraparietal sulcus, the superior frontal sulcus, the middle frontal gyrus, and the pre-SMA was observed in common for both mental navigation and mental map and is likely to reflect the spatial mental imagery components of the tasks.


Sperm cryopreservation in an Australian skink (Eulamprus quoyii).
Assisted reproductive technologies for population and genetic management for threatened herpetofauna have grown substantially in the past decade. Here we describe experiments to optimise sperm cryopreservation in a model squamate, the eastern water skink Eulamprus quoyii . Small, concentrated volumes of highly motile spermatozoa were reliably collected from adult male E. quoyii by non-lethal ventral massage. Samples were used to: (1) test whether protein-rich diluents, namely Beltsville poultry semen extender (BPSE) and TES and Tris (TEST) yolk buffer (TYB), improve post-thaw quality metrics compared with Dulbecco's phosphate-buffered saline (DPBS); and (2) compare the efficacy of these diluents in combination with either 1.35M glycerol or 1.35M dimethyl sulfoxide (DMSO) at two freezing rates, fast (approximately -20°C min-1 ) versus slow (-6°C min-1 ). Glycerol and DMSO performed equally well in preserving spermatozoa under slow freezing rates. Under these conditions, the use of the complex diluents BPSE and TYB significantly improved post-thaw total motility compared with DPBS. Complex interactions occurred between cryodiluent type, cryoprotectant and freezing rate when testing fast versus slow freezing rates among treatment groups. Under slow freezing rates, DMSO was better at preserving membrane integrity and motility, regardless of diluent type, but successful fast freezing required complex diluents to support motility and membrane integrity, which has implications for implementation in a field setting.


Blood culture accuracy: discards from central venous catheters in pediatric oncology patients in the emergency department.
Lack of specific guidelines regarding collection of blood for culture from central venous catheters (CVCs) has led to inconsistencies in policies among hospitals. Currently, no specific professional or regulatory recommendations exist in relation to using, reinfusing, or discarding blood drawn from CVCs before drawing blood for a culture. Repeated wasting of blood may harm immunocompromised pediatric oncology patients. The purpose of this comparative study was to determine whether differences exist between blood cultures obtained from the first 5 mL of blood drawn from a CVC line when compared with the second 5 mL drawn. During 2009-2011, 62 pediatric oncology patients with CVCs and orders for blood cultures to determine potential sepsis were enrolled during ED visits. Trained study nurses aseptically drew blood and injected the normally discarded first 5 mL and the second specimen (usual care) into separate culture bottles. Specimens were processed in the microbiology laboratory per hospital policy. Positive cultures were evaluated to assess agreement between specimen results and to determine that the identified pathogen was not a contaminant. Out of 186 blood culture pairs, 4.8% demonstrated positive results. In all positive-positive matches, the normal discard specimen contained the same organism as the usual care specimen. In 4 matches, the normally discarded specimen demonstrated notably earlier time to positivity (4 to 31 hours) compared with the usual care specimen, which resulted in earlier initiation of definitive antibiotics. These findings support the accuracy of the specimen that is normally discarded and suggest the need to reconsider its use for blood culture testing.


The emerging roles of leptin and ghrelin in cardiovascular physiology and pathophysiology.
Leptin and ghrelin are novel peptide hormones which are counter-regulatory in the central control of appetite. More recently, it has become clear that these hormones have a range of effects on the cardiovascular system. Leptin increases sympathetic activity, producing a pressor effect when acting on the central nervous system. However, leptin produces vasodilation by an endothelium-dependent mechanism peripherally. Ghrelin decreases sympathetic activity and has a depressor effect when acting on the central nervous system. Peripherally, ghrelin produces vasodilation by an endothelium-independent mechanism. Ghrelin improves left ventricular function and cardiac cachexia in heart failure. Leptin may contribute to cardiac cachexia, and to obesity-related cardiomyopathy by a variety of mechanisms. Leptin has pro-inflammatory, proliferative and calcification promoting effects in the vasculature. Ghrelin has recently been shown to be anti-inflammatory in the vasculature. Leptin may also produce a pro-thrombotic state through stimulation of platelet aggregation and inhibition of coagulation and fibrinolysis. The evidence for and against these effects as well as their pathophysiological significance in obesity hypertension, heart failure, atherosclerosis and thrombosis are discussed.


Role of surface antibody in hepatitis B reactivation in patients with resolved infection and hematologic malignancy: A meta-analysis.
Patients with resolved hepatitis B virus (HBV) infection who are treated for hematological malignancies remain at risk for HBV reactivation. Because of conflicting studies about whether the antibody to hepatitis B surface antigen (anti-HBs) protects against reactivation in patients with resolved infection (hepatitis B surface antigen negative) receiving chemotherapy for hematological malignancies, we conducted a meta-analysis to determine if anti-HBs reduces HBV reactivation risk. We sought English-language studies through March 1, 2016, in Medline and other sources that examined reactivation in patients with resolved HBV infection receiving chemotherapy for hematologic malignancies. The absolute risks and odds ratio (OR) of reactivation with versus without anti-HBs were estimated in random-effects model meta-analyses. In 20 studies involving 1,672 patients not receiving antiviral prophylaxis, the reactivation risk was 14% (95% confidence interval [CI] 9.4%-19%) in 388 patients who had antibodies to hepatitis B core antigen only versus 5.0% (95% CI 3.0%-7.0%) in 1,284 patients who also had anti-HBs. Anti-HBs reduced reactivation risk with a pooled OR of 0.21 (95% CI 0.14-0.32) versus patients with antibody to hepatitis B core antigen only. Similar results were found when limiting the analysis to rituximab chemotherapy (OR = 0.19, 95% CI 0.11-0.32) and lymphoma (OR = 0.18, 95% CI 0.11-0.28). In patients with resolved HBV receiving chemotherapy for hematological malignancies without antiviral prophylaxis, anti-HBs positivity is associated with a decreased risk of reactivation; HBV screening in this patient population should include the routine use of anti-HBs, and those who are anti-HBs-negative should receive antiviral prophylaxis. Future studies should examine the effect of anti-HBs serum titers, the potential role for booster vaccinations, and antiviral prophylaxis prior to chemotherapy in this patient population. (Hepatology 2017;66:379-388).


Monitoring the toxicity of antiretroviral therapy in resource limited settings: a prospective clinical trial cohort in Thailand.
One of the many challenges which come together with the implementation of antiretroviral therapy (ART) in settings with limited resources is the monitoring of toxicity. This monitoring increases costs of ART and strains resources. We therefore investigated the necessity for laboratory toxicity monitoring of ART in Thailand. DESIGN, METHODS AND PARTICIPANTS: A prospective Thai cohort of 417 HIV-infected patients were enrolled in randomized clinical trials investigating ART. Time-dependent occurrence of grade III/IV abnormal laboratory values as defined by the AIDS Clinical Trial Group was analysed. During a median observation period of 3.7 years (2.4-4.3) 142 grade III/IV toxicities occurred in 101 (24.2%) patients. Hepatic toxicity (n = 33, 7.9%), hypercholesterolaemia (n = 57, 13.7%), hypertriglyceridaemia (n = 26, 6.2%), anaemia (n = 16, 3.8%) and low platelet counts (n = 8, 1.9%) were frequently observed. Anaemia and low platelets occurred early and during the first 2 years of ART. Hepatic toxicity was seen early and throughout the observation period. Hypertriglyceridaemia and hypercholesterolaemia occurred throughout the observation period, and increased over time. Hypercreatininaemia and hyperglycaemia occurred once after 120 and 132 weeks. ART was changed or interrupted for grade III/IV hepatic toxicity, anaemia and hyperglycaemia only. The incidence rate for grade III/IV toxicity was between 5.56 (95% CI, 6.76-18.02) for low platelet counts and 41.18 (31.77-53.39) per 1000 patient years for hypercholesterolaemia. Antiretrovirals used were zidovudine, stavudine, lamivudine, zalcitabine, didanosine, efavirenz, saquinavir, ritonavir and indinavir. Grade III/IV toxicity is frequently observed in Thai patients treated with ART. The simple and inexpensive monitoring of ALT and haemoglobin could prevent most serious short-term toxicity. Long-term toxicity can be addressed with a yearly monitoring of triglycerides, cholesterol, glucose and creatinine if nephrotoxic drugs are used.


Trouble for trials - The worrying state of the research nurse workforce.
Clinical research nurses (CRNs) are a specialty of Registered Nurses that are highly trained to support the breadth of clinical trial operations and manage participant care in community settings new to research. CRNs are uniquely equipped with a scope of practice that permits product administration, participant assessments, and data management. As clinical trials and their management expand beyond traditional, site-based operations models to decentralized or remote models, the need becomes great to ensure adequate staffing of experienced research professionals, such as CRNs. However, the 2020 National Nursing Workforce Survey reported consecutive contractions in the number of CRNs practicing in the U.S in both 2017 and 2020 surveys when compared to previous reports in 2013 and 2015. The Society of Clinical Research Associates 2020 Salary Survey further described much of the current CRN workforce as nearing or at retirement age, raising concern for additional reductions. This workforce contraction tangents one of the highest volumes of clinical trial starts in modern history, prompting concern for adequate staffing of CRNs to facilitate continued examination of novel therapies and devices. Complex investigative products and evolving safety profiles coupled with an increased focus on community participant enrollment requires CRN involvement in heightened safety monitoring and interdisciplinary communication among clinical providers and research collaborators. This paper examines the contributory factors of the CRN workforce contraction and response efforts at professional and organizational system levels.


Bardet-Biedl syndrome with end-stage kidney disease in a four-year-old Romanian boy: a case report.
Bardet-Biedl syndrome is a significant genetic cause of chronic kidney disease in children. Kidney abnormalities are a major cause of morbidity and mortality in Bardet-Biedl syndrome, but the onset of end-stage renal disease at an early age and continuous ambulatory peritoneal dialysis, however, are not commonly mentioned in the literature. We present the case of a four-year-old Romanian boy who presented to our department with 'febrile seizures'. After an initial evaluation, we diagnosed our patient as having hypertension, severe anemia and end-stage renal disease. He met the major and minor criteria for the diagnosis of Bardet-Biedl syndrome and underwent continuous ambulatory peritoneal dialysis. Close follow-up for renal involvement in patients with Bardet-Biedl syndrome and Alström syndrome from an early age is highly recommended to prevent end-stage renal disease and so renal replacement therapy can be started immediately.


Molecular characterisation of clinical and environmental isolates of Mycobacterium kansasii isolates from South African gold mines.
Mycobacterium kansasii (M. kansasii) is a major cause of non-tuberculous mycobacterial pulmonary disease in the South African gold-mining workforce, but the source of infection and molecular epidemiology are unknown. This study investigated the presence of M. kansasii in gold and coal mine and associated hostel water supplies and compared the genetic diversity of clinical and environmental isolates of M. kansasii. Five M. kansasii and ten other potentially pathogenic mycobacteria were cultured mainly from showerhead biofilms. Polymerase chain reaction-restriction analysis of the hsp65 gene on 196 clinical and environmental M. kansasii isolates revealed 160 subtype I, eight subtype II and six subtype IV strains. Twenty-two isolates did not show the typical M. kansasii restriction patterns, suggesting that these isolates may represent new subtypes of M. kansasii. In contrast to the clonal population structure found amongst the subtype I isolates from studies in other countries, DNA fingerprinting of 114 clinical and three environmental subtype I isolates demonstrated genetic diversity amongst the isolates. This study demonstrated that showerheads are possible sources of M. kansasii and other pathogenic non-tuberculous mycobacterial infection in a gold-mining region, that subtype I is the major clinical isolate of M. kansasii strain and that this subtype exhibits genetic diversity.


Airway purinergic responses in healthy, atopic nonasthmatic, and atopic asthmatic subjects exposed to ozone.
Ozone exposure triggers airway inflammatory responses that may be influenced by biologically active purine metabolites. To examine the relationships between airway purine metabolites and established inflammatory markers of ozone exposure, and to determine if these relationships are altered in individuals with atopy or asthma. Mass spectrometry was utilized to measure concentrations of purine metabolites (adenosine monophosphate [AMP], adenosine, hypoxanthine, uric acid) and non-purine metabolites (taurine, urea, phenylalanine, tyrosine) in induced sputum obtained from 31 subjects with normal lung function (13 healthy controls, eight atopic nonasthmatics, and 10 atopic asthmatic [AA]) before and 4 h after ozone exposure. At baseline, the purines AMP and hypoxanthine correlated with multiple inflammatory markers including neutrophil counts and the cytokines interleukin (IL)-6, IL-8, tumor necrosis factor alpha (TNF-α), and IL-1β (r ranged from 0.41 to 0.66, all P < 0.05). Following ozone exposure, these purines remained correlated with IL-6, IL-8, and TNF-α (r = 0.37-0.68). However, AMP and hypoxanthine increased significantly post ozone exposure in atopic nonasthmatics but not in AA. In contrast, the non-purine metabolite taurine correlated with baseline neutrophil counts (r = 0.56) and IL-6 (r = 0.53) and was elevated post-exposure in both atopic cohorts. The purine metabolites AMP and hypoxanthine are correlated with multiple inflammatory markers at baseline and after ozone exposure. However, changes in these purine metabolites after ozone appear to differ from other inflammatory markers, with less response in AA relative to atopic nonasthmatics. Purine metabolites may play a role in the signaling responses to ozone, but these responses may be altered in subjects with asthma.


Value of Public Health Funding in Preventing Hospital Bloodstream Infections in the United States.
To estimate the association of 1 activity of the Prevention and Public Health Fund with hospital bloodstream infections and calculate the return on investment (ROI). The activity was funded for 1 year (2013). A difference-in-differences specification evaluated hospital standardized infection ratios (SIRs) before funding allocation (years 2011 and 2012) and after funding allocation (years 2013 and 2014) in the 15 US states that received the funding compared with hospital SIRs in states that did not receive the funding. We estimated the association of the funded public health activity with SIRs for bloodstream infections. We calculated the ROI by dividing cost offsets from infections averted by the amount invested. The funding was associated with a 33% (P < .05) reduction in SIRs and an ROI of $1.10 to $11.20 per $1 invested in the year of funding allocation (2013). In 2014, after the funding stopped, significant reductions were no longer evident. This activity was associated with a reduction in bloodstream infections large enough to recoup the investment. Public health funding of carefully targeted areas may improve health and reduce health care costs.


Fiber-taper coupling to Whispering-Gallery modes of fluidic resonators embedded in a liquid medium.
We demonstrate efficient coupling to the optical Whispering- Gallery (WG) modes of a fluidic resonator consisting of a droplet embedded in a liquid medium. Unlike previous experiments the droplet is not levitated in an optical or electrostatic trap and free space coupling is replaced by phase-matched, waveguide coupling using a fiber-taper. We have observed critical coupling to fundamental WG modes of a 600 mum diameter water droplet at 980 nm. The experimental challenges towards making, stabilizing and coupling to the droplet resonators are addressed in this paper.


Recent advances in neuroendocrine imaging.
Imaging is a critical component of both neuroendocrine lesion identification and anatomic delineation for treatment planning. Cross-sectional and isotopic-based physiologic imaging techniques have, to date, been the radiological modalities of choice. This review focuses on recent advances in imaging that are related to the evaluation of neuroendocrine abnormalities, in particular advances in MRI. Magnetic-resonance perfusion examination of tissue characteristics in the pituitary, adrenal and thyroid glands indicates that, in many cases, adenomas of these glands have distinguishable hemodynamic characteristics relative to the parenchyma of the gland as a whole and to other lesions. Moreover, perfusion metrics might provide a basis for evaluating response to therapy (in the pituitary) and delineation of lesions in the adrenal and thyroid glands. Anisotropy-based imaging techniques show promise in providing direct, relevant information about pituitary tumor involvement of the adjacent cavernous sinuses. The most recent methodological advances in the imaging of neuroendocrine disorder involves the continued development and application of MRI, in particular using pulse sequences, which provide a greater insight into the internal structure and physiology of the tissues interrogated, relative to standard sequences.


On Bion's Concept of Truth in an Extra-Moral Sense.
The paper explores the concept of truth in Bion's theory and in the post-Bionian context of the analytic field. Truth is addressed on three levels: epistemological, metapsychological, and clinical. Bion criticizes positivism in psychoanalysis, and the same vertex when it appears in psychoanalysis itself, stating that the search for truth at all costs is similar to the arrogance and stupidity of the psychotic part of the personality. He revolutionizes the analytic concept of truth by orienting it to the function of the emotional linking between analyst and patient rather than to content. Post-Bionian analytic theory further develops these concepts. In a field or radically intersubjective perspective, the author emphasizes the shift from an "I/you" perspective to a "we" perspective. The treatment is less about the abstract search for supposed truths and more about the truth being expressed in the process of emotional and affective attunement.


Predicting incidence of long-term care insurance certification in Japan with the Kihon Checklist for frailty screening tool: analysis of local government survey data.
Predicting incidence of long-term care insurance (LTCI) certification in the short term is of increasing importance in Japan. The present study examined whether the Kihon Checklist (KCL) can be used to predict incidence of LTCI certification (care level 1 or higher) in the short term among older Japanese persons. In 2015, the local government in Tokyo, Japan, distributed the KCL to all individuals older than 65 years who had not been certified as having a disability or who had already been certified as requiring support level 1-2 according to LTCI system. We also collected LTCI certification data within the 3 months after collecting the KCL data. The data of 17,785 respondents were analyzed. First, we selected KCL items strongly associated with incidence of LTCI certification, using stepwise forward-selection multiple logistic regression. Second, we conducted receiver operating characteristic (ROC) analyses for three conditions (1: Selected KCL items, 2: The main 20 KCL items (nos. 1-20), 3: All 25 KCL items). Third, we estimated specificity and sensitivity for each condition. During a 3-month follow-up, 81 (0.5%) individuals required new LTCI certification. Eight KCL items were selected by multiple logistic regression as predictive of certification. The area under the ROC curve in the three conditions was 0.92-0.93, and specificity and sensitivity for all conditions were greater than 80%. Three KCL conditions predicted short-term incidence of LTCI certification. This suggests that KCL items may be used to screen for the risk of incident LTCI certification.


Characterization of tumor cell lines derived from murine gammaherpesvirus-68-infected mice.
Cell lines were derived from mice with murine gammaherpesvirus-68 (MHV-68)-associated lymphoproliferative disease. Four were of an ambiguous phenotype and were MHV-68 negative. One, S11, was a B lymphocyte that contained MHV-68 genomes in both linear and episomal forms and released virus. The line was clonable and grew into tumors in nude mice. This is the first naturally occurring MHV-68-positive B-cell line to be generated, and it will be an invaluable tool for the study of MHV-68 latency.


Inside-out Ca(2+) signalling prompted by STIM1 conformational switch.
Store-operated Ca(2+) entry mediated by STIM1 and ORAI1 constitutes one of the major Ca(2+) entry routes in mammalian cells. The molecular choreography of STIM1-ORAI1 coupling is initiated by endoplasmic reticulum (ER) Ca(2+) store depletion with subsequent oligomerization of the STIM1 ER-luminal domain, followed by its redistribution towards the plasma membrane to gate ORAI1 channels. The mechanistic underpinnings of this inside-out Ca(2+) signalling were largely undefined. By taking advantage of a unique gain-of-function mutation within the STIM1 transmembrane domain (STIM1-TM), here we show that local rearrangement, rather than alteration in the oligomeric state of STIM1-TM, prompts conformational changes in the cytosolic juxtamembrane coiled-coil region. Importantly, we further identify critical residues within the cytoplasmic domain of STIM1 (STIM1-CT) that entail autoinhibition. On the basis of these findings, we propose a model in which STIM1-TM reorganization switches STIM1-CT into an extended conformation, thereby projecting the ORAI-activating domain to gate ORAI1 channels.


Optogenetic stimulation of accumbens shell or shell projections to lateral hypothalamus produce differential effects on the motivation for cocaine.
Previous studies suggest that pharmacological or molecular activation of the nucleus accumbens shell (AcbSh) facilitates extinction of cocaine-seeking behavior. However, overexpression of CREB, which increases excitability of AcbSh neurons, enhances cocaine-seeking behavior while producing depression-like behavior in tests of mood. These discrepancies may reflect activity in differential AcbSh outputs, including those to the lateral hypothalamus (LH), a target region known to influence addictive behavior and mood. Presently, it is unknown whether there is a causal link between altered activity in the AcbSh-LH pathway and changes in the motivation for cocaine. In this study, we used an optogenetics approach to either globally stimulate AcbSh neurons or to selectively stimulate AcbSh terminal projections in the LH, in rats self-administering cocaine. We found that stimulation of the AcbSh-LH pathway enhanced the motivation to self-administer cocaine in progressive ratio testing, and led to long-lasting facilitation of cocaine-seeking behavior during extinction tests conducted after withdrawal from cocaine self-administration. In contrast, global AcbSh stimulation reduced extinction responding. We compared these opposing motivational effects with effects on mood using the forced swim test, where both global AcbSh neuron and selective AcbSh-LH terminal stimulation facilitated depression-like behavioral despair. Together, these findings suggest that the AcbSh neurons convey complex, pathway-specific modulation of addiction and depression-like behavior, and that these motivation and mood phenomenon are dissociable.


Minimum detectable activity when background is counted longer than the sample.
This note discusses the use of blank or background counting data that are measured for times that differ from times used for the sample counts. The correct formula for the minimum detectable activity, under this condition, is given as follows: MDA = [3 + 3.29 square root of Rbtg(1 + tg/tb)]/epsilon tg, where Rb denotes background count rate, tb and tg denote background and gross count times, and epsilon denotes counting efficiency. Counting backgrounds for a long time reduces decision levels, uncertainties, and minimum detectable activities. These benefits are fully available only when there is no other source of variability than random fluctuations in count rates.


[Transmissible spongiform encephalopathies (TSE): old diseases with new explosive force].
In view of the first 64 BSE cases (date: 11.5.01) in German cattle herds an overview on TSE and their similarities and differences regarding clinic, pathogenesis and pathology is given. The mechanism of the unconventional agent, an infectious protein (prion), is explained based on the prion model of Stanley Prusiner. The knowledge on transmission, incubation time, host specificity as well as resistance and immunity drawn from experimentally infected animals is discussed. Thus, after oral infection prions are transported by lymphocytes from the stomach-intestinal tract to the spleen. The way to the CNS is still unknown. The presumption for crossing the species barrier is twofold: first the prions of different species have to be biochemically homologous and a genetical disposition has to exist. This is the case for BSE and the new variant of Creutzfeldt-Jakob-Disease (vCJD). There is evidence that in Great Britain so far 97 (date: 30.3.01) young people acquired vCJD due to consumption of food that contained bovine risk material. Regarding the infectious prion dosis brain, spinal cord and lymphoid tissues are regarded to be most dangerous. The principle of the BSE-test, its evidence as well as steps for prevention and control of BSE are presented.


Improving Employee Well-Being and Effectiveness: Systematic Review and Meta-Analysis of Web-Based Psychological Interventions Delivered in the Workplace.
Stress, depression, and anxiety among working populations can result in reduced work performance and increased absenteeism. Although there is evidence that these common mental health problems are preventable and treatable in the workplace, uptake of psychological treatments among the working population is low. One way to address this may be the delivery of occupational digital mental health interventions. While there is convincing evidence for delivering digital psychological interventions within a health and community context, there is no systematic review or meta-analysis of these interventions in an occupational setting. The aim of this study was to identify the effectiveness of occupational digital mental health interventions in enhancing employee psychological well-being and increasing work effectiveness and to identify intervention features associated with the highest rates of engagement and adherence. A systematic review of the literature was conducted using Cochrane guidelines. Papers published from January 2000 to May 2016 were searched in the PsychINFO, MEDLINE, PubMed, Science Direct, and the Cochrane databases, as well as the databases of the researchers and relevant websites. Unpublished data was sought using the Conference Proceedings Citation Index and the Clinical Trials and International Standard Randomized Controlled Trial Number (ISRCTN) research registers. A meta-analysis was conducted by applying a random-effects model to assess the pooled effect size for psychological well-being and the work effectiveness outcomes. A positive deviance approach was used to identify those intervention features associated with the highest rates of engagement and adherence. In total, 21 randomized controlled trials (RCTs) met the search criteria. Occupational digital mental health interventions had a statistically significant effect post intervention on both psychological well-being (g=0.37, 95% CI 0.23-0.50) and work effectiveness (g=0.25, 95% CI 0.09-0.41) compared with the control condition. No statistically significant differences were found on either outcome between studies using cognitive behavioral therapy (CBT) approaches (as defined by the authors) compared with other psychological approaches, offering guidance compared with self-guidance, or recruiting from a targeted workplace population compared with a universal workplace population. In-depth analysis of the interventions identified by the positive deviance approach suggests that interventions that offer guidance are delivered over a shorter time frame (6 to 7 weeks), utilize secondary modalities for delivering the interventions and engaging users (ie, emails and text messages [short message service, SMS]), and use elements of persuasive technology (ie, self-monitoring and tailoring), which may achieve greater engagement and adherence. This review provides evidence that occupational digital mental health interventions can improve workers' psychological well-being and increase work effectiveness. It identifies intervention characteristics that may increase engagement. Recommendations are made for future research, practice, and intervention development.


The Role of Awareness of Age-Related Change in the Longitudinal Association between Pain and Physical Activity.
We examined how physical pain impacts the developmental construct of Awareness of Age-Related Change (AARC-gains and AARC-losses) and, in turn, how AARC mediates and moderates the association between pain and subsequent physical activity. We used longitudinal data from 434 participants of the UK PROTECT Study (mean age = 65.5 years; SD = 6.94 years). We found that pain in 2019 predicted higher AARC-losses (β = .07; p = .036) and less physical activity (β = -.13; p-value = .001) in 2020. Additionally, we found that AARC-losses partially mediated, but did not moderate, the association of pain in 2019 and physical activity in 2020. AARC-losses may explain physical inactivity in middle-aged and older adults experiencing pain. Incorporating developmental constructs such as AARC into theories and empirical studies on pain and pain management may be necessary to more fully capture people's responses to pain.


Manubrium-limited ministernotomy versus conventional sternotomy for aortic valve replacement (MAVRIC): study protocol for a randomised controlled trial.
Aortic valve replacement is one of the most common cardiac surgical procedures performed worldwide. Conventional aortic valve replacement surgery is performed via a median sternotomy; the sternum is divided completely from the sternal notch to the xiphisternum. Minimally invasive aortic valve replacement, using a new technique called manubrium-limited ministernotomy, divides only the manubrium from the sternal notch to 1 cm below the manubrio-sternal junction. More than one third of patients undergoing conventional sternotomy develop clinically significant bleeding requiring post-operative red blood cell transfusion. Case series data suggest a potentially clinically significant difference in red blood cell transfusion requirements between the two techniques. Given the implications for National Health Service resources and patient outcomes, a definitive trial is needed. This is a single-centre, single-blind, randomised controlled trial comparing aortic valve replacement surgery using manubrium-limited ministernotomy (intervention) and conventional median sternotomy (usual care). Two hundred and seventy patients will be randomised in a 1:1 ratio between the intervention and control arms, stratified by baseline logistic EuroSCORE and haemoglobin value. Patients will be followed for 12 weeks from discharge following their index operation. The primary outcome is the proportion of patients who receive a red blood cell transfusion post-operatively within 7 days of surgery. Secondary outcomes include red blood cell and blood product transfusions, blood loss, re-operation rates, sternal wound pain, quality of life, markers of inflammatory response, hospital discharge, health care utilisation, cost and cost effectiveness and adverse events. This is the first trial to examine aortic valve replacement via manubrium-limited ministernotomy versus conventional sternotomy when comparing red blood cell transfusion rates following surgery. Surgical trials present significant challenges; strengths of this trial include a rigorous research design, standardised surgery performed by experienced consultant cardiothoracic surgeons, an agreed anaesthetic regimen, patient blinding and consultant-led patient recruitment. The MAVRIC trial will demonstrate that complex surgical trials can be delivered to exemplary standards and provide the community with the knowledge required to inform future care for patients requiring aortic valve replacement surgery. International Standard Randomised Controlled Trial Number (ISRCTN) ISRCTN29567910 . Registered on 3 February 2014.


Mechanisms of urinary K+ and H+ excretion: primary structure and functional expression of a novel H,K-ATPase.
The kidney plays an essential role in regulating potassium and acid balance. A major site for these regulations is in the collecting tubule. In the present study, we report the primary sequence of a novel alpha subunit of the P-ATPase gene family, which we isolated from the urinary bladder epithelium of the toad Bufo marinus, the amphibian equivalent of the mammalian collecting tubule. The cDNA encodes a protein of 1,042 amino acids which shares approximately 67% identity with the alpha 1 subunit of the ouabain-inhibitable Na,K-ATPase and approximately 69% identity with the alpha subunit of the SCH28080-inhibitable gastric H,K-ATPase. When coexpressed in Xenopus oocytes with a beta subunit isolated from the same cDNA library, the ATPase is able to transport rubidium (a potassium surrogate) inward, and hydrogen outward, leading to alkalization of the intracellular compartment and acidification of the external medium. The novel ATPase has a unique pharmacological profile showing intermediate sensitivity to both ouabain and SCH28080. Our findings indicate that the bladder ATPase is a member of a new ion motive P-ATPase subfamily. The bladder ATPase is expressed in the urinary tract but not in the stomach or the colon. This H,K-ATPase may be one of the molecules involved in H+ and K+ homeostasis, mediating the transport of these ions across urinary epithelia and therefore regulating their urinary excretion.


[Research on current situation of standardization of Chinese medicine and acupuncture in Oceania].
The development status of standardization of Chinese medicine and acupuncture in Australia and New Zealand is respectively introduced from 3 levels-national standard, regional standard and association standard. A national registration standard for Chinese medicine has been implemented since July 1, 2012 in Australia. The Oceania Federation of Chinese Medicine and Acupuncture Societies was also founded in capital of New Zealand. Four characteristics are revealed from researches and analyses: people's needs and the relevant system are the foundations of national standards of Chinese medicine; legislation on Chinese medicine is the guarantee for setting and implementing national standards, where necessity, scientificity, vitality, diversity and breakthroughs are embodied; registration standards are the key in international standardization of Chinese medicine; and international organizations are major force in promoting standardization of Chinese medicine and acupunc ture.


Atypical teratoid/rhabdoid tumor presenting with subarachnoid and intraventricular hemorrhage.
Sellar masses comprise 14-18% of all intracranial tumors. Pituitary adenomas account for 85% of these lesions, while 15% of sellar masses stem from other etiologies. Intratumoral hemorrhage (apoplexy), while not exceptionally common, can be discovered at presentation. While the hemorrhage pattern is typically contained within the tumor, an extension of bleeding beyond the sella has been reported. A 55-year-old female presented with an anterior interhemispheric subarachnoid hemorrhage and extensive intraventricular hemorrhage (IVH). Initially, the IVH was thought to be due to a ruptured aneurysm. After further workup, a hemorrhagic sellar mass was diagnosed. The patient underwent transsphenoidal resection of a pituitary adenoma. The patient returned to the emergency department6 weeks later with an atypical rapidly expanding sellar mass. After tumor debulking, the pathology revealed an atypical teratoid/rhabdoid tumor (ATRT). Here, we reviewed this and other such cases of sellar ATRT. The early diagnosis of sellar ATRT with lack of integrase interactor 1 expression and elevated Ki67 proliferation indices can prompt more aggressive attempted gross total resection, chemotherapy, and radiation treatments.


[Jaffe color test-based microtechnique for determination of milk lactose].
The picric acid reaction (Jaffe test) that is widely used in clinical biochemical practice to determine creatinine has proven to be suitable for the assay of lactose in milk samples. The reaction conditions (picric acid concentration, sample heating time, etc.) were examined to optimize this method. The specificity of this color test was also studied. Other reducing sugars, as well as glucose-6-phosphate and glycerol yielded a picric acid reaction. The level of lactose in the test milk samples (n = 14) ranged from 0.120 to 0.148 mmol/l.


Laser-induced breakdown spectroscopy is a reliable method for urinary stone analysis.
We compared laser-induced breakdown spectroscopy (LIBS) with the traditionally used and recommended X-ray diffraction technique (XRD) for urinary stone analysis. In total, 65 patients with urinary calculi were enrolled in this prospective study. Stones were obtained after surgical or extracorporeal shockwave lithotripsy procedures. All stones were divided into two equal pieces. One sample was analyzed by XRD and the other by LIBS. The results were compared by the kappa (κ) and Spearman's correlation coefficient (rho) tests. Using LIBS, 95 components were identified from 65 stones, while XRD identified 88 components. LIBS identified 40 stones with a single pure component, 20 stones with two different components, and 5 stones with three components. XRD demonstrated 42 stones with a single component, 22 stones with two different components, and only 1 stone with three different components. There was a strong relationship in the detection of stone types between LIBS and XRD for stones components (Spearman rho, 0.866; p<0.001). There was excellent agreement between the two techniques among 38 patients with pure stones (κ index, 0.910; Spearman rho, 0.916; p<0.001). Our study indicates that LIBS is a valid and reliable technique for determining urinary stone composition. Moreover, it is a simple, low-cost, and nondestructive technique. LIBS can be safely used in routine daily practice if our results are supported by studies with larger numbers of patients.


Psychometric Properties of Carver and White's (1994) BIS/BAS Scales in a Large Sample of Offenders.
Contemporary motivational theories of psychopathy (Lykken, 1995) employ constructs from Gray's Reinforcement Sensitivity Theory (RST; Gray, 1982), behavioral inhibition system (BIS) and behavioral activation system (BAS) functioning, to explain etiologic differences in psychopathy subtypes. Carver and White's (1994) BIS/BAS scales are the most widely used measures of these constructs, yet there is a dearth of research on how these measures perform with offenders. Using a sample of 1,515 offenders, we found evidence that five, rather than the usual four factors, underpin the BIS/BAS scales. Importantly, BIS items that tap into anxiety and fear sensitivity, respectively, split to form separate factors, yielding a structure that is more consistent with the revised (Gray & McNaughton, 2000) than with the earlier version of RST. Implications for the use of the BIS/BAS scales to study psychopathy in offenders are discussed.


The structure of the complex between a branched pentasaccharide and Thermobacillus xylanilyticus GH-51 arabinofuranosidase reveals xylan-binding determinants and induced fit.
The crystal structure of the family GH-51 alpha- l-arabinofuranosidase from Thermobacillus xylanilyticus has been solved as a seleno-methionyl derivative. In addition, the structure of an inactive mutant Glu176Gln is presented in complex with a branched pentasaccharide, a fragment of its natural substrate xylan. The overall structure shows the two characteristic GH-51 domains: a catalytic domain that is folded into a (beta/alpha) 8-barrel and a C-terminal domain that displays jelly roll architecture. The pentasaccharide is bound in a groove on the surface of the enzyme, with the mono arabinosyl branch entering a tight pocket harboring the catalytic dyad. Detailed analyses of both structures and comparisons with the two previously determined structures from Geobacillus stearothermophilus and Clostridium thermocellum reveal important details unique to the Thermobacillus xylanilyticus enzyme. In the absence of substrate, the enzyme adopts an open conformation. In the substrate-bound form, the long loop connecting beta-strand 2 to alpha-helix 2 closes the active site and interacts with the substrate through residues His98 and Trp99. The results of kinetic and fluorescence titration studies using mutants underline the importance of this loop, and support the notion of an interaction between Trp99 and the bound substrate. We suggest that the changes in loop conformation are an integral part of the T. xylanilyticus alpha- l-arabinofuranosidase reaction mechanism, and ensure efficient binding and release of substrate.


Enantioselective [3 + 2] Cycloaddition Reaction of Ethynylethylene Carbonates with Malononitrile Enabled by Organo/Metal Cooperative Catalysis.
The first catalytic asymmetric decarboxylative [3 + 2] cycloaddition reaction of ethynylethylene carbonates with malononitrile has been developed successfully by an organo/copper cooperative system. This strategy led to a series of optically active polysubstituted dihydrofurans in good yields with high levels of enantioselectivities (up to 99% yield, 97% ee). The presence of the terminal alkynyl and the cyano group in the dihydrofuran products provides a wide scope for further structural transformations. More importantly, this organo/metal cooperative catalytic system will broaden the substrate scope and enable fundamentally new reactions.


Association of somatic burden of disease with age and neuropsychological measures in attenuated mucopolysaccharidosis types I, II and VI.
The mucopolysaccharidoses (MPSs) are a group of rare genetic lysosomal disorders with progressive multisystem involvement. An MPS-specific physical symptom scale was developed and introduced a Physical Symptom Score (PSS) to quantify the somatic disease burden across MPS I, II and VI. Somatic burden of disease in patients with attenuated MPS I, II and VI as measured by the PSS will be positively associated with age and negatively associated with neuropsychological functions [i.e. full scale intelligence quotient (FSIQ) and attention]. Forty-eight patients with attenuated MPS I (n = 24), II (n = 14), and VI (n = 10) aged 6 to 32 years on enzyme replacement therapy who were enrolled in "Longitudinal Studies of Brain Structure and Functions in MPS Disorders" across seven centers. Somatic disease burden was measured by the PSS. Neuropsychological functions were measured by the Wechsler Abbreviated Scale of Intelligence (WASI) and Test of Variables of Attention (TOVA). PSS was positively associated with age in attenuated MPS I (P < 0.001), MPS II (P < 0.01) and MPS VI (P < 0.05). There was a negative association of PSS with FSIQ in attenuated MPS I (P < 0.001) and in MPS VI (P < 0.001) but not with MPS II. Although attention scores were below average in all groups, a significant negative association between PSS and one measures of sustained attention (TOVA d prime) was found only in MPS VI. Physical Symptom Score increased with age in attenuated MPS I, II and VI, reflecting progressive somatic burden of disease despite treatment with enzyme replacement therapy. Furthermore, the association of increased somatic disease burden with decreased neurocognitive ability suggests that both measures reflect disease severity and are not independent.


Functional significance of skeletal muscle adiponectin production, changes in animal models of obesity and diabetes, and regulation by rosiglitazone treatment.
Endocrine effects of adipose-derived adiponectin on skeletal muscle have been shown to account, at least in part, for the anti-diabetic effects of this adipokine. Recently, the concept of myokines has gained credence, and the potential for skeletal muscle to produce adiponectin has been suggested. Here we demonstrated an increased level of adiponectin mRNA and protein expression as well as protein secretion in response to rosiglitazone treatment in L6 muscle cells. This correlated with the ability of rosiglitazone to enhance insulin sensitivity for stimulation of protein kinase B (Akt) phosphorylation and glucose transport; rosiglitazone also corrected high-glucose-induced insulin resistance in L6 cells. Overexpression of adiponectin confirmed the functional significance of local production of adiponectin in muscle cells via elevated glucose uptake and increased insulin sensitivity. In obese diabetic db/db mice, there was a change in the adiponectin expression profile in soleus and extensor digitorum longus (EDL) muscle with less high molecular weight (HMW) and more medium (MMW)/low (LMW) molecular weight species detected. Induction of obesity and insulin resistance in rats by feeding a high-fat high-sucrose diet also led to decreased muscle HMW adiponectin content that could be corrected by rosiglitazone treatment. In summary, we show the ability of skeletal muscle cells to produce adiponectin, which can mediate autocrine metabolic effects, thus establishing adiponectin as a bona fide myokine. We also demonstrate that skeletal muscle adiponectin production is altered in animal models of obesity and diabetes and that these changes can be corrected by rosiglitazone.


Cytochrome P4503A is the major source of N-vinylprotoporphyrin IX formation after administration of 3-[2-(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone to untreated and dexamethasone-pretreated rats.
The sydnone, 3-[2-(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone (TTMS), which has previously been shown to cause mechanism-based inactivation of rat hepatic cytochrome P450 (P450) 1A and 3A, was shown to cause in vitro mechanism-based inactivation of rat P450s 2B1, 2C6, and 2C11, but not of P4502A1/2. Administration of TTMS to rats is known to cause degradation of rat hepatic P450 by heme N-alkylation yielding N-vinylprotoporphyrin IX (N-vinylPP). Pretreatment of rats with beta-naphthoflavone (beta NF) failed to increase hepatic N-vinylPP after TTMS administration. Because beta NF causes a marked increase in hepatic levels of P4501A, we conclude that P4501A of rat liver is not a quantitatively important source of N-vinylPP from TTMS. The increased formation of N-vinylPP in phenobarbital (PB)- and dexamethasone (DEX)-pretreated rats suggested that an inducible P450 isozyme (e.g. P4502B1/2, P4503A, or both) is/are an important contributor to N-vinylPP formation from TTMS. When troleandomycin (TAO) (a selective inhibitor of P4503A) was coadministered with TTMS, N-vinylPP formation was reduced to 25% of control in DEX-pretreated rats and to 34% of control in untreated (UT) rats, showing that P4503A was quantitatively the major source of N-vinylPP formation in UT- and DEX-pretreated rats. No significant differences were found in the formation of the ring A-substituted (NA), ring B-substituted (NB), ring C-substituted (NC), and ring D-substituted (ND) regioisomers of N-vinylPP among UT, beta NF-, PB-, or DEX-pretreated rats. Regioisomer data, in addition to data obtained with TAO, indicate that a single inducible form of P450, namely P4503A, is responsible for the bulk of N-vinylPP formation in UT and DEX-pretreated rat liver after TTMS administration.


Endovascular treatment for unruptured intracranial aneurysms in elderly patients: single-center report.
The optimal management of patients with unruptured intracranial aneurysms remains controversial in elderly populations. The aim of this study was to evaluate technical results and clinical outcomes in a single center of consecutive elderly patients with unruptured intracranial aneurysms treated with endovascular embolization. Between May 2003 and February 2010, 96 patients older than 70 years (men, 16 patients; women, 80 patients; mean age, 73 years) with 122 saccular unruptured intracranial aneurysms were treated in our hospital with an endovascular approach. The endovascular procedures and technique, angiographic follow-up, and complications were evaluated. Successful embolizations without complications were completed in 95.9%. Five patients had procedure-related events, including thromboembolism in 1 patient, aneurysm perforation during the procedure in 1, and 3 postoperative transient minor symptoms (headache, otalgia, and trigeminal pain) in 3. The degree of occlusion of the treated aneurysm was complete in 46.7%; there was a small neck remnant in 40.9% and residual filling in 12.2%. Imaging (MR angiography) follow-up was performed in 68.7% of the patients. The mean follow-up duration was 19.4 months (range, 5-57 months). Fifty-five patients (93.9%) showed no interval change of the residual neck. Four (6%) demonstrated recanalizations, all of which were successfully recoiled. Endovascular treatment of unruptured intracranial aneurysms in patients older than 70 years of age appears to be safe. Favorable outcomes with low morbidities may replace surgery or conservative treatment as an active management alternative.


Quality of life among immigrants in Swedish immigration detention centres: a cross-sectional questionnaire study.
Detention of immigrants negatively affects their health and well-being. Quality of life (QOL) is a broad concept incorporating the self-evaluation of one's own health and well-being that can provide an understanding of the health and well-being of immigrant detainees. The aim of this study was to estimate QOL among immigrant detainees in Sweden and to assess its relationship with the services provided in detention centres and with the duration of detention. All immigrants in all five existing Swedish detention centres (N=193) were invited to participate in the study (n=127). In this cross-sectional study, QOL was measured using the WHOQOL-BREF questionnaire, which was administered by the first author. The questionnaire contained four additional questions measuring participants' satisfaction with the services provided in detention. Associations between QOL domain scores and service satisfaction scores were assessed using regression analysis. The Spearman's rank correlation coefficient was calculated to measure the degree of association between the duration of detention and QOL scores. The mean QOL domain scores (out of 100) were 47.0, 57.5, 41.9, and 60.5 for the environmental, physical, psychological, and social domains, respectively. The level of support detainees received from detention staff was significantly positively associated with detainees' physical (βadjusted 3.93, confidence interval [CI] 0.06-7.80) and psychological (βadjusted 5.72, CI 1.77-9.66) domain scores. There was also significant positive association between detainees' satisfaction with the care they received from detention staff and the domain scores. The general health score in the WHOQOL-BREF was significantly associated with the detainees' ability to understand the Swedish or English languages. Although not statistically significant, a longer duration of detention was negatively correlated with QOL scores. Immigrant detainees report low QOL. Services provided at the centres, especially the support received from detention staff, is positively associated with their QOL. A review of detention guidelines addressing language barriers, staff training, and duration of detention is highly recommended.


Extracellular vesicles--vehicles that spread cancer genes.
Once regarded as cellular 'debris' extracellular vesicles (EVs) emerge as one of the most intriguing entities in cancer pathogenesis. Intercellular trafficking of EVs challenges the notion of cancer cell autonomy, and highlights the multicellular nature of such fundamental processes as stem cell niche formation, tumour stroma generation, angiogenesis, inflammation or immunity. Recent studies reveal that intercellular exchange mediated by EVs runs deeper than expected, and includes molecules causative for cancer progression, such as oncogenes (epidermal growth factor receptor, Ras), and tumour suppressors (PTEN). The uptake of oncogenic EVs (oncosomes) by various cells may profoundly change their biology, signalling patterns and gene expression, and in some cases cause their overt tumorigenic conversion. Moreover, EVs circulating in blood and present in body fluids provide an unprecedented access to the molecular circuitry driving cancer cells, and new technologies are being developed to exploit this property as a source of unique cancer biomarkers.


Baroreflex dysfunction induced by microgravity: potential relevance to postflight orthostatic intolerance.
Microgravity imposes adaptive changes in the human body. This review focuses on the changes in baroreflex function produced by actual spaceflight, or by experimental models that simulate microgravity, e.g., bed rest. We will analyze separately studies involving baroreflexes arising from carotid sinus and aortic arch afferents ("high-pressure baroreceptors"), and cardiopulmonary afferents ("low-pressure receptors"). Studies from unrelated laboratories using different techniques have concluded that actual or simulated exposure to microgravity reduces baroreflex function arising from carotid sinus afferents ("carotic-cardiac baroreflex"). The techniques used to study the carotid-cardiac baroreflex, using neck suction and compression to simulate changes in blood pressure, have been extensively validated. In contrast, it is more difficult to selectively study aortic arch or cardiopulmonary baroreceptors. Nonetheless, studies that have examined these baroreceptors suggest that microgravity produces the opposite effect, ie, an increase in the gain of aortic arch and cardiopulmonary baroreflexes. Furthermore, most studies have focus on instantaneous changes in heart rate, which almost exclusively examines the vagal limb of the baroreflex. In comparison, there is limited information about the effect of microgravity on sympathetic function. A substantial proportion of subjects exposed to microgravity develop transient orthostatic intolerance. It has been proposed that alterations in baroreflex function play a role in the orthostatic intolerance induced by microgravity. The evidence in favor and against this hypothesis is reviewed.


Money makes the world go 'round: A qualitative examination of the role funding plays in large-scale implementation and sustainment of youth evidence-based practice.
Funding is posited to affect evidence-based practice implementation, yet the complex interplay between financial matters and successful implementation is understudied. This study examined stakeholder perspectives on the impact of funding in evidence-based practice implementation. All participants were key stakeholders (e.g., clinicians, case managers, agency leaders; N = 41) involved in a trauma-focused cognitive-behavioral therapy implementation effort using a community-based learning collaborative model within the community's child welfare system. Semistructured interviews were conducted and qualitatively analyzed as part of a program evaluation of the implementation effort. Funding emerged as a key theme influencing implementation within this program evaluation from the perspective of all stakeholders. Thirty-four participants (83%) independently raised funding as an important factor affecting implementation outcomes across seven specific themes: (a) the impact of privatization, (b) turfism, (c) money as a primary implementation facilitator, (d) implementation costs impacting participation, (e) burden associated with funding evaluation efforts, (f) need for reimbursement practices to align with the use of trauma-informed treatment, and (g) a sense of shared mission to serve clients above money. Recommendations for addressing these challenges are provided. Future research should examine funding qualitatively and quantitatively across diverse communities and funding systems to improve understanding of the impact of funding on implementation and, ultimately, care provided to clients. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


A new polyaniline-catalase-glutaraldehyde-modified biosensor for hydrogen peroxide detection.
A new biosensor based on catalase enzyme immobilized on electrochemically constructed polyaniline (PANI) film modified with glutaraldehyde has been developed for the determination of hydrogen peroxide (H2O2) in milk samples. Assembly processes of polyaniline and immobilization of the enzyme were monitored with the help of electrochemical impedance spectroscopy. Amperometric measurements have been performed at cathodic peak (-0.3 V vs. Ag/AgCI) which was attributed to reduction of PANI. Hydrogen peroxide was determined by using amperometric method at -0.3 V. The biosensor responses were correlated linearly with the hydrogen peroxide concentrations between 5.0 × 10-6 and 1.0 × 10-4 M by amperometric method. Detection limit of the biosensor is 2.18 × 10-6 M for H2O2. In the optimization studies of the biosensor, some parameters such as optimum pH, temperature, concentration of aniline, amount of enzyme, and number of scans during electropolymerization were investigated.


New on-orbit geometric interior parameters self-calibration approach based on three-view stereoscopic images from high-resolution multi-TDI-CCD optical satellites.
To increase the field of view (FOV), combining multiple time-delayed and integrated charge-coupled devices (TDI-CCD) into the camera and the pushbroom imaging modality are traditionally used with high-resolution optical satellites. It is becoming increasingly labor- and cost-intensive to build and maintain a calibration field with high resolution and broad coverage. This paper introduces a simple and feasible on-orbit geometric self-calibration approach for high-resolution multi-TDI-CCD optical satellites based on three-view stereoscopic images. With the aid of the a priori geometric constraint of tie points in the triple-overlap regions of stereoscopic images, as well as tie points between adjacent single TDI-CCD images (STIs), high accuracy calibration of all TDI-CCD detectors can be achieved using a small number of absolute ground control points (GCPs) covering the selected primary STI. This method greatly reduces the demand on the calibration field and thus is more time-, effort- and cost-effective. Experimental results indicated that the proposed self-calibration approach is effective for increasing the relative internal accuracy without the limitations associated with using a traditional reference calibration field, which could have great significance for future super-high-resolution optical satellites.


Microparticles Carrying Sonic Hedgehog Are Increased in Humans with Peripheral Artery Disease.
Sonic hedgehog (Shh) is a prototypical angiogenic agent with a crucial role in the regulation of angiogenesis. Experimental studies have shown that Shh is upregulated in response to ischemia. Also, Shh may be found on the surface of circulating microparticles (MPs) and MPs bearing Shh (Shh + MPs) have shown the ability to contribute to reparative neovascularization after ischemic injury in mice. The goal of this study was to test the hypothesis that, in humans with peripheral artery disease (PAD), there is increased number of circulating Shh + MPs. This was done by assessing the number of Shh + MPs in plasma of patients with PAD and control subjects without PAD. We found significantly higher number of Shh + MPs in plasma of subjects with PAD, compared to controls, while the global number of MPs-produced either by endothelial cells, platelets, leukocytes, and erythrocytes-was not different between PAD patients and controls. We also found a significant association between the number of Shh + MPs and the number of collateral vessels in the ischemic limbs of PAD patients. Interestingly, the concentration of Shh protein unbound to MPs-which was measured in MP-depleted plasma-was not different between subjects with PAD and the controls, indicating that, in the setting of PAD, the call for Shh recapitulation does not lead to secretion of protein into the blood but to binding of the protein to the membrane of MPs. These findings provide novel information on Shh signaling during ischemia in humans, with potentially important biological and clinical implications.


Light scattering in the C57BL/6 mouse lens.
To characterize inherent light scattering in the C57BL/6 mouse lens. Lenses from 20 6-week-old female C57BL/6 mice were extracted from freshly enucleated globes and microsurgically cleaned of remnants of the ciliary body. Lens light scattering was measured quantitatively with a light dissemination meter (LDM). Morphological properties of the mouse lenses were documented using grid- and dark-field illumination photography. Analysis of variance was performed to establish variance for animals, variance between left and right eyes and variance for measurements. Average inherent light scattering in the C57BL/6 mouse lens is 0.16 +/- 0.02 tEDC (transformed equivalent diazepam concentration). The mean size of a mouse lens at 6 weeks is 1.9 mm in diameter. Two lenses featured pre-existing cortical lens opacities. Variance for animals was assessed to be 7.9 10(- 4) tEDC(2), variance for measurements was 1.6 10(- 4) tEDC(2), and variance between left and right eyes was 8.8 10(- 4) tEDC(2). The tolerance limit for non-pathological light scattering was determined to 0.26 tEDC. No significant difference in light scattering between left and right mouse lenses was found. The minimum number of C57BL/6 mice required for detection of a 10% experimentally induced change in light scattering intensity was estimated to be 50 for independent group experiments and 25 for paired design experiments. The C57BL/6 mouse is a suitable animal in which to conduct experiments on light scattering or cataractogenesis with high precision at reasonable sample sizes. Before including C57BL/6 mice into a study on cataractogenesis, pre-existing lens opacities such as congenital cataract must be excluded.


Genetic modulation of Shigella flexneri 2a lipopolysaccharide O antigen modal chain length reveals that it has been optimized for virulence.
The lipopolysaccharide (LPS) molecules of Shigella flexneri 2a have O antigen (Oag) polysaccharides with two modal chain length distributions. The chromosomal wzz(SF) gene results in short (S) type Oag chains [11-17 Oag repeat units (RUs)], and the pHS-2 plasmid-located wzz(pHS2) gene results in very long (VL) type Oag chains (>90 Oag RUs). S. flexneri wzz(SF) mutants are unable to form plaques on HeLa cell monolayers and F-actin comet tails, indicating that IcsA/VirG function in actin-based motility (ABM) is defective. An S. flexneri wzz(SF) wzz(pHS2) double mutant had LPS with relatively short, random length Oag chains and, paradoxically, was able to form plaques and F-actin comet tails. The influence of Oag modal chain length distribution on virulence and related properties was investigated using complementation with different wzz genes. Wzz(O139) from Vibrio cholerae O139 and Wzz(ST) from Salmonella enterica serovar Typhimurium were fully functional in Shigella flexneri, resulting in LPS with either very short (VS) type Oag chains (2-7 Oag RUs) or long (L) type Oag chains (19-35 RUs), respectively. In the absence of VL-type Oag chains, the VS-, S- and L-type Oag chains were permissive for plaque and F-actin comet tail formation. However, in the presence of LPS with VL-type Oag chains, the VS- and S-type Oag chains but not the L-type Oag chains were permissive for plaque and F-actin comet tail formation. These data, and the results of a previous investigation, show that IcsA function in ABM requires LPS Oag chains with at least two but less than 18 RUs when VL-type Oag chains are co-expressed on the cell surface. However, in the absence of the VL-type Oag chains, LPS Oag chains with at least two but less than 90 RUs are able to support IcsA function in ABM. Indirect immunofluorescence staining of IcsA on the cell surface of the S. flexneri strains did not correlate with the observed effect of Oag chain length on plaque and F-actin comet tail formation. However, when intracellular bacteria lacking VL-type Oag chains were examined, an inverse correlation between Oag modal chain length and detection of IcsA was observed, i.e. staining decreased with increased modal length. It is hypothesized that Oag chains can mask IcsA and interfere with its function in ABM, and a model is presented to explain how LPS Oag and IcsA may interact. It is suggested that S. flexneri 2a has evolved to synthesize LPS with two Oag modal chain lengths, as S-type Oag chains allow IcsA to function in ABM in the presence of VL-type Oag chains that confer resistance to serum.


Expression of Fc receptors is suppressed in alveolar macrophages from patients with sarcoidosis.
To study the expression of Fc receptors in human alveolar macrophages (AM), the cells were collected from 12 healthy controls and 22 patients with sarcoidosis and the activity involved in binding to 125I-soluble immune complexes (IC) was investigated. The binding of 125I-IC was significantly suppressed in cells from the patients. A Scatchard plot analysis revealed that this suppression was due to a reduction in the number of Fc receptors on the surface membrane and not the result of a decrease in the binding affinity of the receptors. Rosette formation was observed by incubating AM with antibody-coated ox red blood cells. The presence of rosette forming cells was about 70% in the AM from healthy controls, while, a rate of only 50% was seen in those with sarcoidosis. These results indicate that the decrease of the 125I-IC binding in the AM from patients with sarcoidosis is to some extent the result of an increase in the population of the Fc receptor negative macrophages.


The conundrum of species delimitation: a genomic perspective on a mitogenetically super-variable butterfly.
The Palaearctic butterfly Melitaea didyma stands out as one of the most striking cases of intraspecific genetic differentiation detected in Lepidoptera: 11 partially sympatric mitochondrial lineages have been reported, displaying levels of divergence of up to 7.4%. To better understand the evolutionary processes underlying the diversity observed in mtDNA, we compared mtDNA and genome-wide SNP data using double-digest restriction site-associated DNA sequencing (ddRADseq) results from 93 specimens of M. didyma ranging from Morocco to eastern Kazakhstan. We found that, between ddRADseq and mtDNA results, there is a match only in populations that probably remained allopatric for long periods of time. Other mtDNA lineages may have resulted from introgression events and were probably affected by Wolbachia infection. The five main ddRADseq clades supported by STRUCTURE were parapatric or allopatric and showed high pairwise FST values, but some were also estimated to display various levels of gene flow. Melitaea didyma represents one of the first cases of deep mtDNA splits among European butterflies assessed by a genome-wide DNA analysis and reveals that the interpretation of patterns remains challenging even when a high amount of genomic data is available. These findings actualize the ongoing debate of species delimitation in allopatry, an issue probably of relevance to a significant proportion of global biodiversity.


The Compass-like locus, exclusive to the Ambulacrarians, encodes a chromatin insulator binding protein in the sea urchin embryo.
Chromatin insulators are eukaryotic genome elements that upon binding of specific proteins display barrier and/or enhancer-blocking activity. Although several insulators have been described throughout various metazoans, much less is known about proteins that mediate their functions. This article deals with the identification and functional characterization in Paracentrotus lividus of COMPASS-like (CMPl), a novel echinoderm insulator binding protein. Phylogenetic analysis shows that the CMPl factor, encoded by the alternative spliced Cmp/Cmpl transcript, is the founder of a novel ambulacrarian-specific family of Homeodomain proteins containing the Compass domain. Specific association of CMPl with the boxB cis-element of the sns5 chromatin insulator is demonstrated by using a yeast one-hybrid system, and further corroborated by ChIP-qPCR and trans-activation assays in developing sea urchin embryos. The sns5 insulator lies within the early histone gene cluster, basically between the H2A enhancer and H1 promoter. To assess the functional role of CMPl within this locus, we challenged the activity of CMPl by two distinct experimental strategies. First we expressed in the developing embryo a chimeric protein, containing the DNA-binding domain of CMPl, which efficiently compete with the endogenous CMPl for the binding to the boxB sequence. Second, to titrate the embryonic CMPl protein, we microinjected an affinity-purified CMPl antibody. In both the experimental assays we congruently observed the loss of the enhancer-blocking function of sns5, as indicated by the specific increase of the H1 expression level. Furthermore, microinjection of the CMPl antiserum in combination with a synthetic mRNA encoding a forced repressor of the H2A enhancer-bound MBF1 factor restores the normal H1 mRNA abundance. Altogether, these results strongly support the conclusion that the recruitment of CMPl on sns5 is required for buffering the H1 promoter from the H2A enhancer activity, and this, in turn, accounts for the different level of accumulation of early linker and nucleosomal transcripts.


Occasional cigarette smoking chronically affects arterial function.
Cigarette smoking is associated with impaired arterial function as measured by reduced vasodilation in response to reactive hyperemia. However, previous studies did not account for potential differences in shear stimuli. The purpose of this study was to use young, occasional smokers to ethically evaluate the effects of acute and chronic smoking on shear rate-diameter dose-response slopes. Young (20 to 26-y-old) nonsmokers (n = 9) and occasional (<1 pack/week) smokers were tested (n = 9). Smokers were tested after abstaining for 2 or more d and then immediately after smoking two cigarettes. Shear rate was manipulated using five upstream ischemic durations (0.5, 1, 2, 5 and 10 min). Radial artery blood velocities and diameters were assessed using Doppler ultrasound. Hierarchical linear modeling (HLM) was used to estimate change in diameter using repeated measures of shear rate nested within each subject. The shear rate-diameter slope was reduced by 35.9% in occasional smokers compared with nonsmoking controls (beta = 2.78(10-4) versus 1.78(10-4), p = 0.004). Acute smoking further attenuated the shear rate-diameter slope (i.e., arterial function) by 23.8% (beta = 1.79(10-4) versus 1.36(10-4), p = 0.037). These results suggest that repeated bouts of occasional cigarette smoking can chronically attenuate arterial function in otherwise healthy, young persons.


Temporal Trends and Factors Associated With Cardiac Rehabilitation Participation Among Medicare Beneficiaries With Heart Failure.
The purpose of this study was to assess temporal trends and factors associated with cardiac rehabilitation (CR) enrollment and participation among Medicare beneficiaries after the 2014 Medicare coverage expansion. CR improves exercise capacity, quality of life, and clinical outcomes in heart failure (HF) with reduced ejection fraction (HFrEF). In 2014, Medicare coverage for CR was expanded to include chronic HFrEF. Among Medicare beneficiaries from quarter (Q) 1 2014 to Q2 2016, 11,696 patients from 14,258 hospitalizations with primary discharge diagnosis of HF were identified. Patients with HF with preserved ejection fraction were excluded. Quarterly CR participation rates among hospitalized HF patients within 6 months of discharge were identified through outpatient administrative claims. The predictors of CR participation were assessed with the use of a multivariable logistic regression model that included patient- and hospital-level characteristics. A secondary analysis to assess participation rates of CR after outpatient encounters for HF was performed. Overall, only 611 (4.3%) and 349 (2.2%) eligible patients participated CR after primary hospitalization or outpatient visit for HF, respectively. There was a modest, statistically significant increase in CR participation after HF admissions (2.8% in Q1 2014; 5.0% in Q2 2016; p < 0.001) without significant increase after outpatient visits for HF (2.6% to 3.8%; p = 0.21). Younger age, male sex, nonblack race, previous cardiovascular procedures, and hospitalization at hospitals with available CR facilities were all independently associated with CR participation. CR participation among eligible Medicare beneficiaries with HFrEF was low with minimal increase since 2014 Medicare coverage decision. Sex, race, and institution-dependent variables were independent predictors of CR participation.


Interferon-λ3 polymorphisms in pegylated-interferon-α plus ribavirin therapy for genotype-2 chronic hepatitis C.
To evaluate interferon-λ3 (IFNL3) polymorphisms in response-guided pegylated interferon-α plus ribavirin (Peg-IFNα/RBV) therapy for genotype 2 (G2) chronic hepatitis C. Between January 2006 and June 2012, a total of 180 patients with chronic infections of G2 hepatitis C virus (HCV) were treated with response-guided Peg-IFNα/RBV therapy. The treatment duration was 24 wk for patients who achieved rapid virologic response (RVR), and 36 or 48 wk for patients who did not. Then, the impact of the IFNL3 single nucleotide polymorphism genotype (TT/non-TT at rs8099917) on treatment outcomes was evaluated in the 180 patients, and between patients infected with either HCV sub-genotype 2a or 2b. Of the 180 patients evaluated, 111 achieved RVR, while the remaining 69 patients did not. In RVR patients, the sustained virologic response (SVR) rate was 96.4%, and the IFNL3 genotype did not influence the SVR rate (96.6% vs 95.8% in IFNL3 genotype TT vs non-TT). However, in non-RVR patients, the SVR rate decreased to 72.5% (P < 0.0001), and this rate was significantly different between the IFNL3 genotype TT and non-TT groups (80.0% vs 42.9%, P = 0.0146). Multivariate regression analysis in non-RVR patients identified the IFNL3 genotype TT as the only baseline-significant factor associated with SVR (OR = 5.39, 95%CI: 1.29-22.62; P = 0.0189). In analysis according to HCV sub-genotype, no significant difference in the SVR rate was found between HCV sub-genotypes 2a and 2b. In response-guided Peg-IFNα/RBV combination therapy for chronically HCV G2-infected patients, the impact of the IFNL3 genotype on SVR was limited to non-RVR patients.


Three-dimensional structure of the amino-terminal domain of syntaxin 6, a SNAP-25 C homolog.
Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins are required for intracellular membrane fusion, and are differentially localized throughout the cell. SNAREs on vesicle and target membranes contain "SNARE motifs" which interact to form a four-helix bundle that contributes to the fusion of two membranes. SNARE motif sequences fall into four classes, homologous to the neuronal proteins syntaxin 1a, VAMP 2, and the N- and C-terminal SNARE motifs of SNAP-25 (S25N and S25C), and it is thought that one member from each class interacts to form a SNARE complex. Many SNAREs also feature N-terminal domains believed to function in regulating SNARE complex assembly or other aspects of vesicle transport. Syntaxin 6 is a SNARE found primarily in endosomal transport vesicles and whose SNARE motif shows significant homology to both syntaxin 1a and S25C. The crystal structure of the syntaxin 6 N-terminal domain reveals strong structural similarity with the N-terminal domains of syntaxin family members syntaxin 1a, Sso1p, and Vam3p, despite a very low level of sequence similarity. The syntaxin 6 SNARE motif can substitute for S25C in in vitro binding experiments, supporting the classification of syntaxin 6 as an S25C family member. Secondary structure prediction of SNARE proteins shows that the N-terminal domains of many syntaxin, S25N, and S25C family members are likely to be similar to one another, but are distinct from those of VAMP family members, indicating that syntaxin, S25N, and S25C SNAREs may have shared a common ancestor.