Long-distance entanglement-based quantum key distribution experiment using practical detectors.
We report an entanglement-based quantum key distribution experiment that we performed over 100 km of optical fiber using a practical source and detectors. We used a silicon-based photon-pair source that generated high-purity time-bin entangled photons, and high-speed single photon detectors based on InGaAs/InP avalanche photodiodes with the sinusoidal gating technique. To calculate the secure key rate, we employed a security proof that validated the use of practical detectors. As a result, we confirmed the successful generation of sifted keys over 100 km of optical fiber with a key rate of 4.8 bit/s and an error rate of 9.1%, with which we can distill secure keys with a key rate of 0.15 bit/s.


Characteristics and Outcomes of Young Adult Opiate Users Receiving Residential Substance Abuse Treatment.
Opiate use patterns, user characteristics, and treatment response among young adults are of interest due to current high use prevalence and historical low levels of treatment engagement relative to older populations. Prior research in this population suggests that overall, young adults present at treatment with different issues. In this study the authors investigated potential differences between young adult (18-25 years of age) and older adult (26 and older) opiate users and the impact of differences relative to treatment motivation, length and outcomes. Data for this study was drawn from 760 individuals who entered voluntary, private, residential treatment. Study measures included the Addiction Severity Index (ASI), the Treatment Service Review (TSR), and University of Rhode Island Change Assessment (URICA). Interviews were conducted at program intake and 6-month post-discharge. Results indicate that older adults with a history of opiate use present at treatment with higher levels of severity for alcohol, medical, and psychological problems and young adults present at treatment with greater drug use and more legal issues. Significant improvement for both groups was noted at 6 months post treatment; there were also fewer differences between the two age groups of opiate users. Results suggest different strategies within treatment programs may provide benefit in targeting the disparate needs of younger opiate users. Overall, however, results suggest that individualized treatment within a standard, abstinence-based, residential treatment model can be effective across opiate users at different ages and with different issues, levels of severity, and impairment at intake.


Metabolic effects of lifestyle intervention in obese pregnant women. Results from the randomized controlled trial 'Lifestyle in Pregnancy' (LiP).
The Lifestyle in Pregnancy intervention in obese pregnant women resulted in significantly lower gestational weight gain compared with the control group, but without improvement in rates of clinical pregnancy complications. The impact of the lifestyle intervention on metabolic measurements in the study participants is now reported. The Lifestyle in Pregnancy study was a randomized controlled trial among 360 obese women (BMI 30-45 kg/m²) who were allocated in early pregnancy to lifestyle interventions with diet counselling and physical activities or to the control group. Fasting blood samples, including plasma glucose, insulin, lipid profile and capillary blood glucose during a 2-h oral glucose tolerance test were carried out three times throughout pregnancy. Insulin resistance was estimated with the homeostasis model assessment of insulin resistance. Three hundred and four women (84%) were followed until delivery. Women in the intervention group had a significantly lower change in insulin resistance (HOMA-IR) from randomization to 28-30 weeks' gestation compared with control subjects (mean ± SD: 0.7 ± 1.3 vs. 1.0 ± 1.3, P = 0.02). Despite a significantly lower gestational weight gain in the intervention group, there was no difference between the groups with respect to total cholesterol, HDL, LDL or triglycerides. Lifestyle intervention in obese pregnant women resulted in attenuation of the physiologic pregnancy-induced insulin resistance. Despite restricted gestational weight gain, there were no changes in glucose or lipid metabolism between the groups.


Acute toxicity evaluation, antibacterial, antioxidant and immunomodulatory effects of Melastoma malabathricum.
Melastoma malabathricum (MM) is a well-known plant in Malaysian traditional medicine, locally known as senduduk. Its ethanol and aqueous extracts have been used in the present investigation to study the immunomodulatory role on human peripheral blood mononuclear cell (PBMC), and the DPPH, ABTS and FRAP free radical scavenging activities were also measured. Total flavonoids and total phenolic contents were assayed and the antibacterial effect was tested against four species of bacteria; two Gram-positive (Staphylococcus aureus and Streptococcus agalactiae) and two Gram-negative (Escherichia coli and Klebsilla pneumonia). The tests were carried out using the disc diffusion, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) methods. Moreover, the acute toxicity was evaluated in vivo on the ethanol extract of MM to establish its safety when administered orally. In our results, both extracts of MM showed abilities to scavenge DPPH and ABTS free radicals, IC(50) values: (11.599 ± 0.84, 10.573 ± 0.58 µmol/L) and (62.657 ± 0.78, 63.939 ± 0.48 µmol/L) for ethanol and aqueous extracts respectively. Indeed the ethanol extract evidenced high phenolic content (384.33 ± 0.005 mg/g), flavonoids contents (85.8 ± 0.009 mg/g) and ferric reducing antioxidant power (33,590 ± 0.038 mmol/g), with high activity against S. aureus and S. agalactiae (11 ± 0.3 and 12 ± 0.6 mm inhibition zones). Likewise, the percentage of peripheral blood mononuclear cells (PBMC) viability was increased in response to MM, IC(50) values (1.781 ± 1.2 and 6.545 ± 0.93 µg/mL) for ethanol and aqueous extracts, respectively. In addition, our results showed that the MM extract is safe even at a high dose of 5,000 mg/kg and has no oral toxicity. These findings suggest the excellent medicinal bioactivity of MM and explain the popularity of this plant in the folk medicine as a remedy for different illnesses.


Supporting Physical Activity in the Childcare Environment (SPACE): rationale and study protocol for a cluster randomized controlled trial.
Young children are prone to low levels of physical activity in childcare. Researchers have identified that preschoolers tend to be more active outdoors than indoors, with higher activity levels occurring during the first 10 minutes of outdoor playtime. Additionally, interventions incorporating either staff training or the inclusion of play equipment have been effective at increasing children's activity in this setting. As such, the overarching objective of the Supporting Physical Activity in the Childcare Environment (SPACE) intervention is to improve the physical activity levels of preschoolers during childcare hours, utilizing a combination of the above components. The purpose of this manuscript is to provide a detailed account of the protocol, innovative methods, and evaluation plans used in the implementation of the SPACE study; in an effort to support the development of further research in this field. The SPACE study, a cluster randomized controlled trial, involves 22 childcare centres randomly allocated to either the experimental (n = 11) or the control (n = 11) group. Childcare centres receiving the intervention will adopt an 8-week physical activity intervention with the following components: 1. shorter, more frequent bouts of outdoor playtime (4 × 30 min periods rather than 2 × 60 min periods); 2. new portable play equipment (e.g., obstacle course, balls); and, 3. staff training (1 × 4 hr workshop). Actical accelerometers will be used to assess total physical activity with measurements taken at baseline (i.e., week 0), immediately post-intervention (i.e., week 8), and at 6- and 12-month follow-up. As secondary objectives, we aim to evaluate the effectiveness of the intervention on preschoolers': a) sedentary time; b) standardized body mass index scores (percentiles); c) health-related quality of life; and childcare providers' physical activity-related knowledge and self-efficacy to implement physical activity. The SPACE study aims to increase the low levels of physical activity observed within childcare centres. The findings of this work may be useful to policy makers and childcare providers to consider modifications to the current childcare curriculum and associated outdoor play time. ISRCTN70604107 (October 8, 2014).


Synthetic chemerin-derived peptides suppress inflammation through ChemR23.
Chemerin is a chemotactic protein that binds to the G protein-coupled receptor, ChemR23. We demonstrate that murine chemerin possesses potent antiinflammatory properties that are absolutely dependent on proteolytic processing. A series of peptides was designed, and only those identical to specific C-terminal chemerin sequences exerted antiinflammatory effects at picomolar concentrations in vitro. One of these, chemerin15 (C15; A(140)-A(154)), inhibited macrophage (MPhi) activation to a similar extent as proteolyzed chemerin, but exhibited reduced activity as a MPhi chemoattractant. Intraperitoneal administration of C15 (0.32 ng/kg) to mice before zymosan challenge conferred significant protection against zymosan-induced peritonitis, suppressing neutrophil (63%) and monocyte (62%) recruitment with a concomitant reduction in proinflammatory mediator expression. Importantly, C15 was unable to ameliorate zymosan-induced peritonitis in ChemR23(-/-) mice, demonstrating that C15's antiinflammatory effects are entirely ChemR23 dependent. In addition, administration of neutralizing anti-chemerin antibody before zymosan challenge resulted in a significant exacerbation of peritoneal inflammation (up to 170%), suggesting an important endogenous antiinflammatory role for chemerin-derived species. Collectively, these results show that chemerin-derived peptides may represent a novel therapeutic strategy for the treatment of inflammatory diseases through ChemR23.


Investigation of the Accuracy of 18 Marketed Blood Glucose Monitors.
Cleared blood glucose monitors (BGMs) for personal use may not always deliver levels of accuracy currently specified by international and U.S. regulatory bodies. This study's objective was to assess the accuracy of 18 such systems cleared by the U.S. Food and Drug Administration representing approximately 90% of commercially available systems used from 2013 to 2015. A total of 1,035 subjects were recruited to have a capillary blood glucose (BG) level measured on six different systems and a reference capillary sample prepared for plasma testing at a reference laboratory. Products were obtained from consumer outlets and tested in three triple-blinded studies. Each of the three participating clinical sites tested a different set of six systems for each of the three studies in a round-robin. In each study, on average, a BGM was tested on 115 subjects. A compliant BG result was defined as within 15% of a reference plasma value (for BG ≥100 mg/dL [5.55 mmol/L]) or within 15 mg/dL (0.83 mmol/L) (for BG <100 mg/dL [5.55 mmol/L]). The proportion of compliant readings in each study was compared against a predetermined accuracy standard similar to, but more lenient than, current regulatory standards. Other metrics of accuracy included the overall compliance proportion; the proportion of extreme outlier readings differing from the reference value by >20%; modified Bland-Altman analysis including average bias, coefficient of variation, and 95% limits of agreement; and proportion of readings with no clinical risk as determined by the Surveillance Error Grid. The different accuracy metrics produced almost identical BGM rankings. Six of the 18 systems met the predetermined accuracy standard in all three studies, 5 systems met it in two studies, and 3 met it in one study. Four BGMs did not meet the accuracy standard in any of the three studies. Cleared BGMs do not always meet the level of analytical accuracy currently required for regulatory clearance. This information could assist patients, professionals, and payers in choosing products and regulators in evaluating postclearance performance.


Cowpox virus infection in natural field vole Microtus agrestis populations: delayed density dependence and individual risk.
1. Little is known about the dynamics of pathogen (microparasite) infection in wildlife populations, and less still about sources of variation in the risk of infection. Here we present the first detailed analysis of such variation. 2. Cowpox virus is an endemic sublethal pathogen circulating in populations of wild rodents. Cowpox prevalence was monitored longitudinally for 2 years, in populations of field voles exhibiting multiannual cycles of density in Kielder Forest, UK. 3. The probability that available susceptible animals seroconverted in a given trap session was significantly positively related to host density with a 3-month time lag. 4. Males were significantly more likely to seroconvert than females. 5. Despite most infection being found in young animals (because transmission rates were generally high) mature individuals were more likely to seroconvert than immature ones, suggesting that behavioural or physiological changes associated with maturity contribute to variation in infection risk. 6. Hence, these analyses confirm that there is a delayed numerical response of cowpox infection to vole density, supporting the hypothesis that endemic pathogens may play some part in shaping vole cycles.


Intergenerational Transmission of Overweight and Obesity from Parents to Their Adolescent Offspring - The HUNT Study.
The main aim of this study was to examine weight associations between parents and offspring at two time points: 1995-97 and 2006-08, taking into account body mass index (BMI) and waist circumference. The study included 8425 parent-offspring trios who participated in the population based Health Study of Nord Trøndelag (the HUNT Study), Norway, at either the HUNT2 (1995-97) or the HUNT3 (2006-08) survey. We used linear mixed effects models with siblings clustered within mothers to analyze the associations between 1) parental grouped BMI and offspring BMI z-scores and 2) parental grouped waist circumference and offspring waist circumference z-scores. Adolescent and adult overweight and obesity were higher in 2006-08 than in 1995-97, with the greatest increase observed in waist circumference. Both mother's and father's BMI and waist circumference were strongly associated with corresponding measures in offspring. Compared with both parents being normal weight (BMI <25 kg/m2), having two overweight or obese parents (BMI ≥25 kg/m2) was associated with a higher offspring BMI z-score of 0.76 (95% CI; 0.65, 0.87) and 0.64 (95% CI; 0.48, 0.80) in daughters, and 0.76 (95% CI; 0.65, 0.87) and 0.69 (95% CI; 0.53, 0.80) in sons, in 1995-97 and 2006-08 respectively. Offspring with one parent being overweight/obese had BMI z-scores of approximately half of offspring with two parents categorized as overweight/obese. The results of the waist circumference based analyses did not differ substantially from the BMI based analyses. Parental overweight was strongly positively associated with offspring weight both in 1995-97 and 2006-08 where both parents being overweight/obese gave the largest effect. This seemingly stable association, strongly address the importance of public health initiatives towards preventing obesity in parents of both sexes to decrease further obesity expansion in offspring.


The effects of Artemisia deserti ethanolic extract on pathology and function of rat kidney.
Medicinal plants played an important role in human health. The kidney is a major organ for elimination the additional materials of body. Some of metabolic waste products are excreted through the kidneys, give us useful information about kidney health. Therefore, the aim of this research was to study the effects of A. deserti flowering tips extract on kidney. Three groups of animal were studied. Wistar rats were divided into three groups. Group 1 was injected with saline, group 2 and 3 were injected with extract, 100 mg/kg and 200 mg/kg, respectively. The animals were anesthetized, blood samples were collected 2 days after the last injection, then urea, uric acid and creatinine levels were assayed. Also, the kidney histology was studied. No significant changes in urea and uric acid were observed. But, creatinine concentration was changed significantly in group 3 compared to other groups. The extract caused histologic changes in the kidney, including, glomerular atrophy, congestion of inflammatory cells and degeneration of the renal tubules. The results showed that A. deserti extract was able to damage the kidney tissue. However, the reason for these histopathological changes remains to be clarified.


Disposition of penicillin G sodium following intravenous and oral administration to Equidae.
The present study was designed to determine and compare the plasma disposition and pharmacokinetics of penicillin G sodium following intravenous (i.v.) administration to horses, ponies and donkeys. The plasma disposition and pharmacokinetics of penicillin G was similar in horses, ponies and donkeys (elimination half-lives--39.0, 27.3 and 31.5 min, respectively) and a dosage interval of 6-8 h would be suitable to treat infections caused by susceptible bacteria. Although penicillin G was absorbed rapidly following nasogastric administration, the systemic availability was low (0.12-0.34%), therefore oral administration would be unsuitable for systemic antimicrobial therapy in the equine. The elimination of penicillin G into the gastrointestinal tract following i.v. administration and the absorption of penicillin G from the gastrointestinal tract following oral administration were studied in two ponies with cannulated caecal fistulas. A low concentration of penicillin G (< or = 0.6 micrograms ml-1) was measured in caecal liquor following i.v. administration, however the risk of development of antimicrobial-associated colitis would be high following oral administration of penicillin G since high concentrations of drug (4.96-157.12 micrograms ml-1) were measured in caecal liquor.


Neurosurgical Coverage for Emergency and Trauma Call.
Traditionally, neurosurgeons have responded to calls to treat new patients or address emergent, acute neurosurgical pathology in the hospitals they staff as part of their duty to the medical profession and community. Due to increasing financial pressures placed upon neurosurgical practice from hospitals and regulatory mandates, remuneration for neurosurgeon availability to serve on trauma call has become more frequent and is increasingly seen as essential. In this study, we present the first peer-review published survey of neurosurgical emergency and trauma call coverage patterns, scope, schedules, compensation, liability exposure, and call cessation. We surveyed all practicing neurosurgeon members of the American Association of Neurological Surgeons and Congress of Neurological Surgeons with a 24% response rate. The vast majority of respondents (86%), through their practice, provide 24/7/365 trauma coverage at their primary hospital site. About a third (29%) of respondents have been sued by a patient seen in the emergency department. Twenty percent of respondents anticipate retiring within the next 2 yr. Understanding trauma call coverage, remuneration, and the barriers to taking call provide needed transparency to neurosurgeons who are providing emergency, life-saving services for patients across the country. An understanding of supply and demand forces governing call coverage also assists the field in necessary workforce planning and innovation in providing access to needed, timely acute neurosurgical care.


Time-varying processes involved in smoking lapse in a randomized trial of smoking cessation therapies.
Researchers have increasingly begun to gather ecological momentary assessment (EMA) data on smoking, but new statistical methods are necessary to fully unlock information from such data. In this paper, we use a new technique, the logistic time-varying effect model (logistic TVEM), to examine the odds of smoking in the 2 weeks after a quit attempt. Data are from a subsample of participants from a randomized, placebo-controlled trial of smoking cessation pharmacotherapies who achieved initial abstinence (N = 1,106, 58% female). Participants completed up to 4 EMA assessments per day during the 2 weeks after their quit day. Predictors include baseline nicotine dependence, EMA measures of craving and negative affect, and whether an individual was assigned to a placebo, monotherapy, or combination therapy condition. Time-varying effects of these predictors were estimated using logistic TVEM. Cravings were a significant predictor of smoking throughout the entire 2 weeks postquit, whereas the effect of baseline dependence became nonsignificant by the second week, and the effect of negative affect increased over time. Individuals in the monotherapy and combination therapy conditions had decreased odds of smoking compared with placebo in the first week postquit, but these differences were nonsignificant in the second week. Findings suggest that pharmacotherapies are more effective compared with placebo earlier in a quit attempt, when the effect of baseline nicotine dependence on smoking is stronger, whereas the effect of craving and negative affect increased over time. Future cessation therapies may be more successful by providing additional support in the second week after quit attempt.


Smoking cessation alters intestinal microbiota: insights from quantitative investigations on human fecal samples using FISH.
There has been a dramatic increase in investigations on the potential mechanistic role of the intestinal microbiota in various diseases and factors modulating intestinal microbial composition. We recently reported on intestinal microbial shifts after smoking cessation in humans. In this study, we aimed to conduct further microbial analyses and verify our previous results obtained by pyrosequencing using a direct quantitative microbial approach. Stool samples of healthy smoking human subjects undergoing controlled smoking cessation during a 9-week observational period were analyzed and compared with 2 control groups, ongoing smoking and nonsmoking subjects. Fluorescence in situ hybridization was applied to quantify specific bacterial groups. Intestinal microbiota composition was substantially altered after smoking cessation as characterized by an increase in key representatives from the phyla of Firmicutes (Clostridium coccoides, Eubacterium rectale, and Clostridium leptum subgroup) and Actinobacteria (HGC bacteria and Bifidobacteria) as well as a decrease in Bacteroidetes (Prevotella spp. and Bacteroides spp.) and Proteobacteria (β- and γ-subgroup of Proteobacteria). As determined by fluorescence in situ hybridization, an independent direct quantitative microbial approach, we could confirm that intestinal microbiota composition in humans is influenced by smoking. The characteristics of observed microbial shifts suggest a potential mechanistic association to alterations in body weight subsequent to smoking cessation. More importantly, regarding previously described microbial hallmarks of dysbiosis in inflammatory bowel diseases, a variety of observed microbial alterations after smoking cessation deserve further consideration in view of the divergent effect of smoking on the clinical course of Crohn's disease and ulcerative colitis.


Clathrin-coated vesicular transport of secretory proteins during the formation of ACTH-containing secretory granules in AtT20 cells.
We have studied by electron microscopy and immunocytochemistry the formation of secretory granules containing adrenocorticotropic hormone (ACTH) in murine pituitary cells of the AtT20 line. The first compartment in which condensed secretory protein appears is a complex reticular network at the extreme trans side of the Golgi stacks beyond the TPPase-positive cisternae. Condensed secretory protein accumulates in dilated regions of this trans Golgi network. Examination of en face and serial sections revealed that "condensing vacuoles" are in fact dilations of the trans Golgi network and not detached vacuoles. Only after presumptive secretory granules have reached an advanced stage of morphological maturation do they detach from the trans Golgi network. Frequently both the dilations of the trans Golgi network containing condensing secretory protein and the detached immature granules in the peri-Golgi region have surface coats which were identified as clathrin by immunocytochemistry. Moreover both are the site of budding (or fusion) of coated vesicles, some of which contain condensed secretory protein. The mature granules below the plasma membrane do not, however, have surface coats. Immunoperoxidase labeling with an antiserum specific for ACTH and its precursor polypeptide confirmed that many of the coated vesicles associated with the trans Golgi network contain ACTH. The involvement of the trans Golgi network and coated vesicles in the formation of secretory granules is discussed.


Smokeless tobacco, viruses and oral cancer.
Oral Squamous Cell Carcinoma (OSCC) is the most common epithelial malignancy in the oral cavity. OSCCs and their variants constitute over 90% of oral malignancies, and the disease is associated with poor prognosis. OSCC is a complex malignancy where environmental factors, viral infections, and genetic alterations most likely interact, and thus give rise to the malignant condition. The International Agency for Research on Cancer (IARC) in 2007 concluded: "there is sufficient evidence in humans to establish smokeless tobacco as carcinogenic, i.e. smokeless tobacco causes cancer of the oral cavity and pancreas". ST products contain a large array of carcinogens, although the number found is actually smaller than in cigarette smoke. Worldwide, ST products have many different names depending on the region where it is produced. However, there are two main types of ST, chewing tobacco and snuff. It is estimated that approximately 150 million people in the world use ST. Herein, we review available literature regarding smokeless tobacco and oral Carcinogenesis. We also discuss the role of viral infections in combination with ST in OSCC development.


Adeno-associated virus and development of cervical neoplasia.
Evidence from several sources has suggested that adeno-associated virus (AAV) infection might protect against cervical cancer, in part, by interfering with human papillomavirus (HPV)-induced tumorigenesis. Detection of AAV type 2 (AAV-2) DNA in cervical tissues has been reported. However, there have been few in vivo studies of women with cervical HPV infection or neoplasia, and these have reported inconsistent results. Therefore, we used polymerase chain reaction (PCR) assays targeted to the AAV-2 rep and cap genes to test tissue specimens from women in an epidemiological study of cervical neoplasia in Jamaica. We tested 105 women with low-grade cervical intraepithelial neoplasia (CIN-1), 92 women with CIN-3/carcinoma in situ or invasive cancer (CIN-3/CA), and 94 normal subjects. PCR amplification of human beta-globin DNA was found in almost all cervical specimens, indicating that these materials were adequate for PCR testing. The prevalence of HPV DNA, determined by HPV L1 consensus primer PCR was, as expected, strongly associated with presence and grade of neoplasia. Each of the AAV PCR assays detected as few as 10 copies of the virus genome. However, none of the 291 cervical specimens from Jamaican subjects tested positive for AAV DNA. Negative AAV PCR results were also obtained in tests of cervical samples from 79 university students in the United States. Exposure to AAV was assessed further by serology. Using a whole virus AAV-2 sandwich enzyme-linked immunosorbent assay, we found no relationship between AAV antibodies and presence or grade of neoplasia in either the Jamaican study subjects or women enrolled in a U.S. cervical cancer case (n = 74) -control (n = 77) study. Overall, the data provide no evidence that AAV infection plays a role in cervical tumorigenesis or that AAV commonly infects cervical epithelial cells.


Rationale for the clinical use of adipose-derived mesenchymal stem cells for COVID-19 patients.
In late 2019, a novel coronavirus (SARS-CoV-2) emerged in Wuhan, capital city of Hubei province in China. Cases of SARS-CoV-2 infection quickly grew by several thousand per day. Less than 100 days later, the World Health Organization declared that the rapidly spreading viral outbreak had become a global pandemic. Coronavirus disease 2019 (COVID-19) is typically associated with fever and respiratory symptoms. It often progresses to severe respiratory distress and multi-organ failure which carry a high mortality rate. Older patients or those with medical comorbidities are at greater risk for severe disease. Inflammation, pulmonary edema and an over-reactive immune response can lead to hypoxia, respiratory distress and lung damage. Mesenchymal stromal/stem cells (MSCs) possess potent and broad-ranging immunomodulatory activities. Multiple in vivo studies in animal models and ex vivo human lung models have demonstrated the MSC's impressive capacity to inhibit lung damage, reduce inflammation, dampen immune responses and aid with alveolar fluid clearance. Additionally, MSCs produce molecules that are antimicrobial and reduce pain. Upon administration by the intravenous route, the cells travel directly to the lungs where the majority are sequestered, a great benefit for the treatment of pulmonary disease. The in vivo safety of local and intravenous administration of MSCs has been demonstrated in multiple human clinical trials, including studies of acute respiratory distress syndrome (ARDS). Recently, the application of MSCs in the context of ongoing COVID-19 disease and other viral respiratory illnesses has demonstrated reduced patient mortality and, in some cases, improved long-term pulmonary function. Adipose-derived stem cells (ASC), an abundant type of MSC, are proposed as a therapeutic option for the treatment of COVID-19 in order to reduce morbidity and mortality. Additionally, when proven to be safe and effective, ASC treatments may reduce the demand on critical hospital resources. The ongoing COVID-19 outbreak has resulted in significant healthcare and socioeconomic burdens across the globe. There is a desperate need for safe and effective treatments. Cellular based therapies hold great promise for the treatment of COVID-19. This literature summary reviews the scientific rationale and need for clinical studies of adipose-derived stem cells and other types of mesenchymal stem cells in the treatment of patients who suffer with COVID-19.


Cost and utilisation of community services for people with HIV infection in London.
This study aimed to describe the use and costs of community services for HIV-infected people by disease stage, sex and transmission category (homosexual, heterosexual, injecting drug use) by use of a prospective cohort study in which people were followed up for six months. There were two major components; gathering quantitative information on service utilisation from people with HIV infection using two interviewer-administered questionnaires and six self-completed monthly diaries; and estimating the costs of the services provided. People were recruited from two London clinics: the Jefferiss Wing Genito-urinary Medicine (GUM) clinic at St. Mary's Hospital, Paddington, and the Patrick Clements GUM clinic at the Central Middlesex Hospital, Harlesden. Costing data was obtained from providers of community services throughout Greater London. The main outcome measures were contacts per person-year, and costs per person-year, for all community services stratified by service sector. The people studied each made, on average, 139 community service contacts per year at a cost of 2,806 pounds; there was little difference in average utilisation between the three transmission categories. There were differences in both the utilisation of services and costs within the formal and informal sectors for subjects from different disease stages. Although the average number of contacts per person-year were similar for women and men, the total cost of community services was higher for women than for men, reflecting the differences in types of services used. The results indicated a high proportion of total care costs for people with HIV and AIDS is incurred through community-based social care.(ABSTRACT TRUNCATED AT 250 WORDS)


Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study.
Most patients with neuromyelitis optica (NMO) and many with NMO spectrum disorder have autoantibodies against aquaporin-4 (AQP4-Abs), but recently, myelin-oligodendrocyte glycoprotein antibodies (MOG-Abs) have been found in some patients. Here, we showed that patients with NMO/NMOSD with MOG-Abs demonstrate differences when compared with patients with AQP4-Abs. To characterize the features of patients with NMO/NMOSD with MOG-Abs and compare them with patients with AQP4-Ab-positive NMO/NMOSD. This observational study was conducted at a single UK specialist center for NMO. Patients with a first demyelinating event between January 1, 2010, and April 1, 2013, seen within the Oxford NMO service and who tested positive for MOG-Abs or AQP4-Abs were included in the study. Cell-based assays using C-terminal-truncated human MOG and full-length M23-AQP4 were used to test patient serum samples for AQP4-Abs and MOG-Abs. Demographic, clinical, and disability data, and magnetic resonance imaging findings. Twenty AQP4-Ab-positive patients and 9 MOG-Ab-positive patients were identified. Most patients in both groups were white. Ninety percent of AQP4-Ab-positive patients but only 44% MOG-Ab-positive patients were females (P = .02) with a trend toward older age at disease onset in AQP4-Ab-positive patients (44.9 vs 32.3 years; P = .05). MOG-Ab-positive patients more frequently presented with simultaneous/sequential optic neuritis and myelitis (44% vs 0%; P = .005). Onset episode severity did not differ between the 2 groups, but patients with MOG-Abs had better outcomes from the onset episode, with better recovery Expanded Disability Status Scale scores and a lower risk for visual and motor disability. Myelin-oligodendrocyte glycoprotein antibody-positive patients were more likely to have conus involvement on spinal magnetic resonance imaging (75% vs 17%; P = .02) and involvement of deep gray nuclei on brain magnetic resonance imaging (P = .03). Cerebrospinal fluid characteristics were similar in the 2 groups. A higher proportion of AQP4-Ab-positive patients relapsed (40% vs 0%; P = .03) despite similar follow-up durations. Despite the fact that patients with MOG-Abs can fulfill the diagnostic criteria for NMO, there are differences when compared with those with AQP4-Abs. These include a higher proportion of males, younger age, and greater likelihood of involvement of the conus and deep gray matter structures on imaging. Additionally, patients with MOG-Abs had more favorable outcomes. Patients with AQP4-Ab-negative NMO/NMOSD should be tested for MOG-Abs.


The Wilms tumor gene, Wt1, is required for Sox9 expression and maintenance of tubular architecture in the developing testis.
Mutation of the transcription factor and tumor suppressor gene WT1 results in a range of genitourinary anomalies in humans, including 46,XY gonadal dysgenesis, indicating that WT1 plays a critical role in sex determination. However, because knockout of Wt1 in mice results in apoptosis of the genital ridge, it is unknown whether WT1 is required for testis development after the initial steps of sex determination. To address this question, we generated a mouse strain carrying a Wt1 conditional knockout allele and ablated Wt1 function specifically in Sertoli cells by embryonic day 14.5, several days after testis determination. Wt1 knockout resulted in disruption of developing seminiferous tubules and subsequent progressive loss of Sertoli cells and germ cells such that postnatal mutant testes were almost completely devoid of these cell types and were severely hypoplastic. Thus, Wt1 is essential for the maintenance of Sertoli cells and seminiferous tubules in the developing testes. Of particular note, expression of the testis-determining gene Sox9 in mutant Sertoli cells was turned off at embryonic day 14.5 after Wt1 ablation, suggesting that WT1 regulates Sox9, either directly or indirectly, after Sry expression ceases. Our data, along with previous work demonstrating the role of Wt1 at early stages of gonadal development, thus indicate that Wt1 is essential at multiple steps in testicular development.


Structural determinants of integrin β-subunit specificity for latent TGF-β.
Eight integrin α-β heterodimers recognize ligands with an Arg-Gly-Asp (RGD) motif. However, the structural mechanism by which integrins differentiate among extracellular proteins with RGD motifs is not understood. Here, crystal structures, mutations and peptide-affinity measurements show that αVβ6 binds with high affinity to a RGDLXXL/I motif within the prodomains of TGF-β1 and TGF-β3. The LXXL/I motif forms an amphipathic α-helix that binds in a hydrophobic pocket in the β6 subunit. Elucidation of the basis for ligand binding specificity by the integrin β subunit reveals contributions by three different βI-domain loops, which we designate specificity-determining loops (SDLs) 1, 2 and 3. Variation in a pair of single key residues in SDL1 and SDL3 correlates with the variation of the entire β subunit in integrin evolution, thus suggesting a paradigmatic role in overall β-subunit function.


Transport of proteins into mitochondria. Posttranslational transfer of ADP/ATP carrier into mitochondria in vitro.
The mitochondrial ADP/ATP carrier is an integral transmembrane protein of the inner membrane. It is synthesized on cytoplasmic ribosomes. Kinetic data suggested that this protein is transferred into mitochondria in a posttranslational manner. The following results provide further evidence for such a mechanism and provide information on its details. 1. In homologous and heterologous translation systems th newly synthesized ADP/ATP carrier protein is present in the postribosomal supernatant. 2. Analysis by density gradient centrifugation and gel filtration shows, that the ADP/ATP carrier molecules in the postribosomal fraction are present as soluble complexes with apparent molecular weights of about 120 000 and 500 000 or larger. The carrier binds detergents such as Triton X-100 and deoxycholate forming mixed micelles with molecular weights of about 200 000-400 000. 3. Incubation of a postribosomal supernatant of a reticulocyte lysate containing newly synthesized ADP/ATP carrier with mitochondria isolated from Neurospora spheroplasts results in efficient transfer of the carrier into mitochondria. About 20-30% of the transferred carrier are resistant to proteinase in whole mitochondria. The authentic mature protein is also largley resistant to proteinase in whole mitochondria and sensitive after lysis of mitochondria with detergent. Integrity of mitochondria is a preprequisite for translocation into proteinase resistant position. 4. The transfer in vitro into a proteinase-resistant form is inhibited by the uncoupler carbonyl-cyanide m-chlorophenylhydrazone but not the proteinase-sensitive binding. These observations suggest that the posttranslational transfer of ADP/ATP carrier occurs via the cytosolic space through a soluble oligomeric precursor form. This precursor is taken up by intact mitochondria into an integral position in the membrane. These findings are considered to be of general importance for the intracellular transfer of insoluble membrane proteins. They support the view that such proteins can exist in a water-soluble form as precursors and upon integration into the membrane undergo a conformational change. Uptake into the membrane may involve the cleavage of an additional sequence in some proteins, but this appears not to be a prerequisite as demonstrated by the ADP/ATP carrier protein.


Amino acid- and glucose-induced cholestasis before and during secretin stimulation.
To identify the mechanisms of reduced bile flow after hypertonic amino acid and glucose infusion, acute experiments were performed on anesthetized pigs. When secretin was not administered, amino acids or glucose reduced bile acid-dependent bile secretion to 65 +/- 3% of control. During secretin stimulation amino acids or glucose diminished bile acid-independent bile secretion to 78 +/- 2% of control. No changes in serum bilirubin, alanine aminotransferase, and aspartate aminotransferase were observed. Amino acids and glucose attack different mechanisms responsible for bile formation, but the result is that when secretin is not administered, biliary secretion of bile acids is reduced, and, accordingly, bile acid-dependent bile flow diminished. During secretin stimulation biliary NaHCO3 secretion is depressed, accounting for a fall in bile acid-independent bile flow. Amino acids exert no effect on bile acid secretion or, as a result, on bile acid-dependent bile flow after secretin infusion.


A multi-scale health impact assessment of air pollution over the 21st century.
Ozone and PM₂.₅ are current risk factors for premature death all over the globe. In coming decades, substantial improvements in public health may be achieved by reducing air pollution. To better understand the potential of emissions policies, studies are needed that assess possible future health impacts under alternative assumptions about future emissions and climate across multiple spatial scales. We used consistent climate-air-quality-health modeling framework across three geographical scales (World, Europe and Ile-de-France) to assess future (2030-2050) health impacts of ozone and PM₂.₅ under two emissions scenarios (Current Legislation Emissions, CLE, and Maximum Feasible Reductions, MFR). Consistently across the scales, we found more reductions in deaths under MFR scenario compared to CLE. 1.5 [95% CI: 0.4, 2.4] million CV deaths could be delayed each year in 2030 compared to 2010 under MFR scenario, 84% of which would occur in Asia, especially in China. In Europe, the benefits under MFR scenario (219000 CV deaths) are noticeably larger than those under CLE (109,000 CV deaths). In Ile-de-France, under MFR more than 2830 annual CV deaths associated with PM₂.₅ changes could be delayed in 2050 compared to 2010. In Paris, ozone-related respiratory mortality should increase under both scenarios. Multi-scale HIAs can illustrate the difference in direct consequences of costly mitigation policies and provide results that may help decision-makers choose between different policy alternatives at different scales.


Multiple roles of Notch signaling in the regulation of epidermal development.
Recent studies have shown that Notch signaling plays an important role in epidermal development, but the underlying molecular mechanisms remain unclear. Here, by integrating loss- and gain-of-function studies of Notch receptors and Hes1, we describe molecular information about the role of Notch signaling in epidermal development. We show that Notch signaling determines spinous cell fate and induces terminal differentiation by a mechanism independent of Hes1, but Hes1 is required for maintenance of the immature state of spinous cells. Notch signaling induces Ascl2 expression to promote terminal differentiation, while simultaneously repressing Ascl2 through Hes1 to inhibit premature terminal differentiation. Despite the critical role of Hes1 in epidermal development, Hes1 null epidermis transplanted to adult mice showed no obvious defects, suggesting that this role of Hes1 may be restricted to developmental stages. Overall, we conclude that Notch signaling orchestrates the balance between differentiation and immature programs in suprabasal cells during epidermal development.


Aberrant activation of AMP-activated protein kinase remodels metabolic network in favor of cardiac glycogen storage.
AMP-activated protein kinase (AMPK) responds to impaired cellular energy status by stimulating substrate metabolism for ATP generation. Mutation of the gamma2 regulatory subunit of AMPK in humans renders the kinase insensitive to energy status and causes glycogen storage cardiomyopathy via unknown mechanisms. Using transgenic mice expressing one of the mutant gamma2 subunits (N488I) in the heart, we found that aberrant high activity of AMPK in the absence of energy deficit caused extensive remodeling of the substrate metabolism pathways to accommodate increases in both glucose uptake and fatty acid oxidation in the hearts of gamma2 mutant mice via distinct, yet synergistic mechanisms resulting in selective fuel storage as glycogen. Increased glucose entry in the gamma2 mutant mouse hearts was directed through the remodeled metabolic network toward glycogen synthesis and, at a substantially higher glycogen level, recycled through the glycogen pool to enter glycolysis. Thus, the metabolic consequences of chronic activation of AMPK in the absence of energy deficiency is distinct from those previously reported during stress conditions. These findings are of particular importance in considering AMPK as a target for the treatment of metabolic diseases.


Fine structure mapping and deletion analysis of the murine piebald locus.
piebald (s) is a recessive mutation that affects the development of two cell types of neural crest origin: the melanocytes, responsible for pigment synthesis in the skin, and enteric ganglia, which innervate the lower bowel. As a result, mice carrying piebald mutations exhibit white spotting in the coat and aganglionic megacolon. Previously the gene had been localized to the distal half of mouse chromosome 14. To determine its precise location relative to molecular markers, an intersubspecific backcross was generated. Two anchor loci of chromosome 14, slaty and hypogonadal, in addition to simple sequence length repeat markers, were used to localize s to a 2-cM interval defined by the markers D14Mit38 and D14Mit42. The molecular markers were also used to characterize nine induced s alleles. Three of these mutations exhibited no deletions or rearrangements of the flanking markers, whereas the other six had two or more of these markers deleted. The extent of the deletions was found to be consistent with the severity of the homozygous phenotype. The location of deletion breakpoints in the induced alleles, coupled with the recombination breakpoints in the backcross progeny, provide useful molecular landmarks to define the location of the piebald gene.


Effects of mining-derived metals on riffle-dwelling benthic fishes in Southeast Missouri, USA.
We studied the ecological effects of mining-derived metals on riffle-dwelling benthic fishes at 16 sites in the Viburnum Trend lead-zinc mining district of southeast Missouri. Fish community attributes were compared to watershed features and to physical and chemical variables including metal concentrations in sediment pore water and fish. Ozark sculpin (Cottus hypselurus), rainbow darter (Etheostoma caeruleum), Ozark madtom (Noturus albater), and banded sculpin (Cottus carolinae) were the most abundant fishes collected. Species richness and density of riffle-dwelling benthic fishes were negatively correlated with metal concentrations in pore water and in fish. Sculpin densities were also negatively correlated with metal concentrations in pore water and in fish, but positively correlated with distance from mines and upstream watershed area. These findings indicate that metals associated with active lead-zinc mining adversely affect riffle-dwelling benthic fishes downstream of mining areas in the Viburnum Trend. Sculpins may be useful as a sentinel species for assessing mining-related impacts on fish communities.


Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study.
To examine whether the association of inadequate or unclear allocation concealment and lack of blinding with biased estimates of intervention effects varies with the nature of the intervention or outcome. Combined analysis of data from three meta-epidemiological studies based on collections of meta-analyses. 146 meta-analyses including 1346 trials examining a wide range of interventions and outcomes. Ratios of odds ratios quantifying the degree of bias associated with inadequate or unclear allocation concealment, and lack of blinding, for trials with different types of intervention and outcome. A ratio of odds ratios <1 implies that inadequately concealed or non-blinded trials exaggerate intervention effect estimates. In trials with subjective outcomes effect estimates were exaggerated when there was inadequate or unclear allocation concealment (ratio of odds ratios 0.69 (95% CI 0.59 to 0.82)) or lack of blinding (0.75 (0.61 to 0.93)). In contrast, there was little evidence of bias in trials with objective outcomes: ratios of odds ratios 0.91 (0.80 to 1.03) for inadequate or unclear allocation concealment and 1.01 (0.92 to 1.10) for lack of blinding. There was little evidence for a difference between trials of drug and non-drug interventions. Except for trials with all cause mortality as the outcome, the magnitude of bias varied between meta-analyses. The average bias associated with defects in the conduct of randomised trials varies with the type of outcome. Systematic reviewers should routinely assess the risk of bias in the results of trials, and should report meta-analyses restricted to trials at low risk of bias either as the primary analysis or in conjunction with less restrictive analyses.


Analysis and annotation of DNA methylation in two nonhuman primate species using the Infinium Human Methylation 450K and EPIC BeadChips.
Aim: Nonhuman primates are essential for research on many human diseases. The Infinium Human Methylation450/EPIC BeadChips are popular tools for the study of the methylation state across the human genome at affordable cost. Methods: We performed a precise evaluation and re-annotation of the BeadChip probes for the analysis of genome-wide DNA methylation patterns in rhesus macaques and African green monkeys through in silico analyses combined with functional validation by pyrosequencing. Results: Up to 165,847 of the 450K and 261,545 probes of the EPIC BeadChip can be reliably used. The annotation files are provided in a format compatible with a variety of standard bioinformatic pipelines. Conclusion: Our study will facilitate high-throughput DNA methylation analyses in Macaca mulatta and Chlorocebus sabaeus.


A Modified mRNA Vaccine Targeting Immunodominant NS Epitopes Protects Against Dengue Virus Infection in HLA Class I Transgenic Mice.
Dengue virus (DENV) induces strong T and B cell responses upon infection. Hence, it is difficult to determine the contribution of cell-mediated immunity alone in the long lasting protection against DENV infection and disease. Numerous CD4+ and CD8+ T cell epitopes have been identified, mainly in the non-structural proteins of DENV. Taking into account the immunogenicity and peptide sequence conservation among the different DENV serotypes, a minimal DENV antigen, called DENV1-NS, has been designed. This antigen is enriched in conserved and highly antigenic epitopes located in the NS3, NS4B, and NS5 regions of DENV1. To evaluate the ability of the DENV1-NS poly-epitope to express the antigenic peptides in the context of different HLA class I molecules, we established its in vivo immunogenicity by measuring, after DNA immunization and electroporation, the activation of DENV-specific CD8 T cells in transgenic mice expressing the human HLA-A*0201, -A*2402, -B*0702, and -B*3502 class I alleles. We then engineered a lipid nanoparticle (LNP) encapsulated modified mRNA vaccine encoding DENV1-NS and tested immunogenicity and protection in these human HLA class I transgenic mice, after transient blockade of the interferon (IFN) type I receptor. Significant protection was observed, after two injections of the mRNA vaccine. Collectively, these data strongly support the development of T cell-based vaccines targeting immunodominant T cell epitopes that generate potent virus-specific T cell responses conferring immunity against DENV infection.


Exposure to Polycyclic Aromatic Hydrocarbons Leads to Non-monotonic Modulation of DNA and RNA (hydroxy)methylation in a Rat Model.
Besides genetic modifications, rapidly growing evidence has linked environmental pollutants with epigenetic variations. To date, only a few studies have been performed on DNA methylation changes of polycyclic aromatic hydrocarbons (PAH), which showed contradictory results. These discrepancies might be partially explained by differences in used agents. Generally in in vitro studies, a single compound is used, while in humans environmental studies, multi-residue exposure is investigated. The present study aimed to study epigenetic alterations induced by multi-residue exposure to PAH. Female Long Evans rats were exposed to a mixture of 16 US-EPA priority PAH, 3 times per week over a 90-day period. The livers were used to assess the (hydroxy)methylation status of genomic DNA/RNA, together with reduced and oxidized forms of glutathione. The results of this study demonstrate that a multi-residue exposure to PAH affects glutathione status, DNA (hydroxy)methylation, and RNA (hydroxy)methylation, together with DNA PAH-adducts formation. In addition, a non-monotonic response relationship was demonstrated between PAH concentration, the levels of glutathione and DNA (hydroxy)methylation levels at environmental relevant doses. This hormetic response gives a novel insight concerning the toxicity of environmental pollutants such as PAH and the biological response that may be different depending on the level of exposure.


Primary prophylaxis of variceal bleeding in children and the role of MesoRex Bypass: Summary of the Baveno VI Pediatric Satellite Symposium.
Approaches to the management of portal hypertension and variceal hemorrhage in pediatrics remain controversial, in large part because they are not well informed by rigorous clinical studies. Fundamental biological and clinical differences preclude automatic application of approaches used for adults to children. On April 11-12, 2015, experts in the field convened at the first Baveno Pediatric Satellite Meeting to discuss and explore current available evidence regarding indications for MesoRex bypass (MRB) in extrahepatic portal vein obstruction and the role of primary prophylaxis of variceal hemorrhage in children. Consensus was reached regarding MRB. The vast majority of children with extrahepatic portal vein obstruction will experience complications that can be prevented by successful MRB surgery. Therefore, children with extrahepatic portal vein obstruction should be offered MRB for primary and secondary prophylaxis of variceal bleeding and other complications, if appropriate surgical expertise is available, if preoperative and intraoperative evaluation demonstrates favorable anatomy, and if appropriate multidisciplinary care is available for postoperative evaluation and management of shunt thrombosis or stenosis. In contrast, consensus was not achieved regarding primary prophylaxis of varices. Although variceal hemorrhage is a concerning complication of portal hypertension in children, the first bleed appears to be only rarely fatal and the associated morbidity has not been well characterized. There are few pediatric data to indicate the efficacy and safety of pharmacologic or endoscopic therapies as primary prophylaxis or that prevention of a sentinel variceal bleed will ultimately improve survival; therefore, no recommendation for primary prophylaxis with endoscopic variceal ligation, sclerotherapy, or nonspecific beta-blockade in children was proposed.


Outer membrane protein B1, an iron-repressible protein conserved in the outer membrane of Moraxella (Branhamella) catarrhalis, binds human transferrin.
Moraxella (Branhamella) catarrhalis is a gram-negative human mucosal pathogen, which primarily causes otitis media in young children. However, this bacterium is also a common cause of lower respiratory tract infections in adults with underlying lung disease. Our previous data have shown that M. catarrhalis expresses iron-repressible outer membrane proteins in response to iron limitation. We have extended these observations to demonstrate that one of these proteins, termed outer membrane protein (OMP) B1, binds human transferrin. Using a newly developed monoclonal antibody to OMP B1, we determined that this protein is conserved in the iron-stressed outer membranes of all clinical isolates of M. catarrhalis tested to date. Furthermore, our data have confirmed that children infected with M. catarrhalis have immunoglobulin G antibodies to OMP B1 in their convalescent sera. These current data suggest that OMP B1 is immunogenic and expressed in vivo and may be involved in an iron uptake mechanism utilized by M. catarrhalis.


Outcome of pregnancy in women with valve prostheses.
To study the outcome of pregnancy in women with artificial heart valves treated in major European centres, and to compare the safety and efficacy of different anticoagulant regimens and of mechanical and bioprosthetic valves. Retrospective study. The information was obtained by questionnaire sent to all major cardiac centres in Europe sending one cardiologist from each centre a covering letter suggesting that the questionnaire be handed on where appropriate to the most relevant colleague. 214 pregnancies were reported in 182 women; 151 pregnancies in 133 women with mechanical valves, and 63 pregnancies in 45 women with bioprostheses. Most women were in New York Heart Association class I or II and in sinus rhythm. 150 women with mechanical valves and 11 (17%) with bioprostheses received anticoagulants during pregnancy. One patient with an aortic valve prosthesis refused to take anticoagulants. Including the spontaneous abortions reported as well as the therapeutic abortions 83% of the pregnancies in women with bioprostheses and 73% in those with mechanical valves resulted in a healthy baby, full term or premature, who did well (NS). The incidence of stillbirths (3% and 6%) and of reported spontaneous abortions are excluded (because they are unlikely to have been fully reported), the success rate was 91% for women with bioprosthetic valves and 84% for women with mechanical valves (NS). 114 (53%) of the women had taken warfarin for some part of the pregnancy (46 (40%) of these during the first trimester) but there were no embryopathies. There were 13 valve thromboses (four fatal), eight embolic events (two fatal), and seven bleeds in women with mechanical valves. Most of these complications occurred with heparin but fatal aortic valve thrombosis occurred in the one woman who refused anticoagulant treatment out of the 151 women with mechanical valves. There were no maternal deaths in the bioprosthesis group but in 17/49 (35%) of these valves functional deterioration led to urgent replacement during pregnancy (two) or soon after. The outcome of pregnancy was similar for women with mechanical valves or bioprostheses. Warfarin treatment was safe and effective and was not associated with embryopathy. Heparin treatment was associated with more thromboembolic complications and more bleeding complications. Bioprostheses deteriorate rapidly during pregnancy.


Offspring of mothers fed a high fat diet display hepatic cell cycle inhibition and associated changes in gene expression and DNA methylation.
The association between an adverse early life environment and increased susceptibility to later-life metabolic disorders such as obesity, type 2 diabetes and cardiovascular disease is described by the developmental origins of health and disease hypothesis. Employing a rat model of maternal high fat (MHF) nutrition, we recently reported that offspring born to MHF mothers are small at birth and develop a postnatal phenotype that closely resembles that of the human metabolic syndrome. Livers of offspring born to MHF mothers also display a fatty phenotype reflecting hepatic steatosis and characteristics of non-alcoholic fatty liver disease. In the present study we hypothesised that a MHF diet leads to altered regulation of liver development in offspring; a derangement that may be detectable during early postnatal life. Livers were collected at postnatal days 2 (P2) and 27 (P27) from male offspring of control and MHF mothers (n = 8 per group). Cell cycle dynamics, measured by flow cytometry, revealed significant G0/G1 arrest in the livers of P2 offspring born to MHF mothers, associated with an increased expression of the hepatic cell cycle inhibitor Cdkn1a. In P2 livers, Cdkn1a was hypomethylated at specific CpG dinucleotides and first exon in offspring of MHF mothers and was shown to correlate with a demonstrable increase in mRNA expression levels. These modifications at P2 preceded observable reductions in liver weight and liver∶brain weight ratio at P27, but there were no persistent changes in cell cycle dynamics or DNA methylation in MHF offspring at this time. Since Cdkn1a up-regulation has been associated with hepatocyte growth in pathologic states, our data may be suggestive of early hepatic dysfunction in neonates born to high fat fed mothers. It is likely that these offspring are predisposed to long-term hepatic dysfunction.


Mitral valvular interstitial cell responses to substrate stiffness depend on age and anatomic region.
The material properties of heart valves depend on the subject's age, the state of the disease and the complex valvular microarchitecture. Furthermore, valvular interstitial cells (VICs) are mechanosensitive, and their synthesis of extracellular matrix not only determines the valve's material properties but also provides an adhesive substrate for VICs. However, the interrelationship between substrate stiffness and VIC phenotype and synthetic properties is poorly understood. Given that the local mechanical environment (substrate stiffness) surrounding VICs differs among different age groups and different anatomic regions of the valve, it was hypothesized that there may be an age- and valve-region-specific response of VICs to substrate stiffness. Therefore, 6-week-, 6-month- and 6-year-old porcine VICs from the center of the mitral valve anterior leaflet (MVAC) and posterior leaflet (PML) were seeded onto poly(ethylene) glycol hydrogels of different stiffnesses and stained for markers of VIC activation (smooth muscle alpha-actin (SMaA)) and collagen synthesis (heat shock protein-47 (HSP47), prolyl 4-hydroxylase (P4H)). Six-week-old MVAC demonstrated decreased SMaA, P4H and HSP47 on stiffer gels, while 6-week-old PML only demonstrated decreased HSP47. Six-month-old MVAC demonstrated no difference between substrates, while 6-month-old PML demonstrated decreased SMaA, P4H and HSP47. Six-year-old MVAC demonstrated decreased P4H and HSP47, while 6-year-old PML demonstrated decreased P4H and increased HSP47. In conclusion, the age-specific and valve-region-specific responses of VICs to substrate stiffness link VIC phenotype to the leaflet regional matrix in which the VICs reside. These data provide further rationale for investigating the role of substrate stiffness in VIC remodeling within diseased and tissue engineered valves.


Influenza vaccine preference and uptake among older people in nine countries.
This paper is a report of a study delineating factors that influence older people's preferences and uptake of the influenza vaccine in nine countries. Vaccination uptake for the aging population in many countries still remains below the World Health Organization recommended rate. Older people who perceive higher susceptibility to and severity of influenza, and more benefits from vaccination and action cues prompting vaccination, tend to accept the vaccine, but those with more perceived barriers to vaccination are less likely to accept it. A total of 208 older people from China, Indonesia, Turkey, Korea, Greece, Canada, the United Kingdom, Brazil and Nigeria were recruited to 14 vaccinated and 12 unvaccinated focus groups. They shared their experiences of influenza, and influenza vaccination, and promotion of influenza vaccination in focus groups. The data were collected in 2007. We identified five themes and generated a hypothetical framework for in-depth understanding of vaccination behaviour among older people. Participants' vaccine preferences were determined by their behavioural beliefs in vaccination, which were based on their probability calculation of susceptibility to and severity of influenza and vaccine effectiveness, and their utility calculation of vaccine, healthcare and social costs. Action cues prompting vaccination and vaccine access further affected the vaccine uptake of participants with vaccine preferences. Vaccination coverage was likely to be higher in the countries where normative beliefs in favour of vaccination had formed. The hypothetical framework can be used to guide healthcare providers in developing strategies to foster normative beliefs of older people in vaccination, provide effective action cues and promote vaccine access.


Overall hemodynamic pattern in coarctation of the abdominal aorta in conscious rats.
This study was designed to examine the total body hemodynamics of abdominal aortic coarctation hypertension. The study quantitates both regional and organ blood flow and resistance in conscious rats both above and below an experimentally produced coarctation. The experimental group consisted of 10 male Sprague-Dawley rats with a mean pressure gradient of 68 mm Hg across the coarctation. This experimental group was compared with a group of eight control rats with no pressure gradient. Flow measurements were made with radioactively labeled microspheres 4 weeks after aortic constriction. This aortic coarctation produced an increase in cardiac index (22%) and total peripheral resistance (19%). Blood flow through tissues proximal to the coarctation was not different from control; vascular resistance was increased (31%). Flow through the tissues distal to the coarctation was increased (16%); vascular resistance was decreased (-22%). The upper carcass, diaphragm, and brain were the tissues most representative of flow above the coarctation, and the lower carcass and large intestine were the tissues most representative of flow below the coarctation. Coarctation of the aorta produced cardiac hypertrophy and increased microsphere shunting to the lungs.


Structure and dynamics of a bisurea-based supramolecular polymer in n-dodecane.
The structure and dynamics of a supramolecular polymer formed by a bisurea-type compound, 2,4-bis(2-ethylhexylureido)toluene (EHUT), in an apolar solvent, n-dodecane (C12), were examined in detail. The EHUT/C12 organo-gel system forms long, dynamic chain-like supramolecular polymers, which lead to an entangled network showing remarkable viscoelastic behavior with two major relaxation modes. A slow relaxation mode with an approximately constant relaxation time, tauS, was observed in a flow region and the other, fast, relaxation mode with a time tauF1 (<tauS) was observed in a high-frequency range. Because no dielectric relaxation behavior was observed over a frequency region including the mechanical tauS and tauF1 relaxation modes, the formed supramolecular polymer does not possess any total dipole moment due to antiparallel intermolecular hydrogen bonding of the two ureido groups of each EHUT unit. A structural model for the supramolecular polymer formed in EHUT/C12 is proposed based on force-field simulations. This proposed model is consistent with all the experimental data concerning this system: flow birefringence measurements, dielectric spectroscopy, SANS, and FTIR.


Off-target effects of epidermal growth factor receptor antagonists mediate retinal ganglion cell disinhibited axon growth.
Inhibition of central nervous system axon growth is reportedly mediated in part by calcium-dependent phosphorylation of axonal epidermal growth factor receptor, with local administration of the epidermal growth factor receptor kinase inhibitors AG1478 and PD168393 to an optic nerve lesion site promoting adult retinal ganglion cell axon regeneration. Here, we show that epidermal growth factor receptor was neither constitutively expressed, nor activated in optic nerve axons in our non-regenerating and regenerating optic nerve injury models, a finding that is inconsistent with phosphorylated epidermal growth factor receptor-dependent intra-axonal signalling of central nervous system myelin-related axon growth inhibitory ligands. However, epidermal growth factor receptor was localized and activated within most glia in the retina and optic nerve post-injury, and thus an indirect glial-dependent mechanism for stimulated retinal ganglion cell axon growth by epidermal growth factor receptor inhibitors seemed plausible. Using primary retinal cultures with added central nervous system myelin extracts, we confirmed previous reports that AG1478/PD168393 blocks epidermal growth factor receptor activation and promotes disinhibited neurite outgrowth. Paradoxically, neurites did not grow in central nervous system myelin extract-containing cultures after short interfering ribonucleic acid-mediated knockdown of epidermal growth factor receptor. However, addition of AG1478 restored neurite outgrowth to short interfering ribonucleic acid-treated cultures, implying that epidermal growth factor receptor does not mediate AG1478-dependent effects. TrkA-/B-/C-Fc fusion proteins and the kinase blocker K252a abrogated the neuritogenic activity in these cultures, correlating with the presence of the neurotrophins brain derived neurotrophic factor, nerve growth factor and neurotrophin-3 in the supernatant and increased intracellular cyclic adenosine monophosphate activity. Neurotrophins released by AG1478 stimulated disinhibited retinal ganglion cell axon growth in central nervous system myelin-treated cultures by the induction of regulated intramembraneous proteolysis of p75(NTR) and Rho inactivation. Retinal astrocytes/Müller cells and retinal ganglion cells were the source of neurotrophins, with neurite outgrowth halved in the presence of glial inhibitors. We attribute AG1478-stimulated neuritogenesis to the induced release of neurotrophins together with raised cyclic adenosine monophosphate levels in treated cultures, leading to axon growth and disinhibition by neurotrophin-induced regulated intramembraneous proteolysis of p75(NTR). These off-target effects of epidermal growth factor receptor kinase inhibition suggest a novel therapeutic approach for designing treatments to promote central nervous system axon regeneration.


LIMPIC: a computational method for the separation of protein MALDI-TOF-MS signals from noise.
Mass spectrometry protein profiling is a promising tool for biomarker discovery in clinical proteomics. However, the development of a reliable approach for the separation of protein signals from noise is required. In this paper, LIMPIC, a computational method for the detection of protein peaks from linear-mode MALDI-TOF data is proposed. LIMPIC is based on novel techniques for background noise reduction and baseline removal. Peak detection is performed considering the presence of a non-homogeneous noise level in the mass spectrum. A comparison of the peaks collected from multiple spectra is used to classify them on the basis of a detection rate parameter, and hence to separate the protein signals from other disturbances. LIMPIC preprocessing proves to be superior than other classical preprocessing techniques, allowing for a reliable decomposition of the background noise and the baseline drift from the MALDI-TOF mass spectra. It provides lower coefficient of variation associated with the peak intensity, improving the reliability of the information that can be extracted from single spectra. Our results show that LIMPIC peak-picking is effective even in low protein concentration regimes. The analytical comparison with commercial and freeware peak-picking algorithms demonstrates its superior performances in terms of sensitivity and specificity, both on in-vitro purified protein samples and human plasma samples. The quantitative information on the peak intensity extracted with LIMPIC could be used for the recognition of significant protein profiles by means of advanced statistic tools: LIMPIC might be valuable in the perspective of biomarker discovery.


A panel of kallikrein markers can predict outcome of prostate biopsy following clinical work-up: an independent validation study from the European Randomized Study of Prostate Cancer screening, France.
We have previously shown that a panel of kallikrein markers--total prostate-specific antigen (PSA), free PSA, intact PSA and human kallikrein-related peptidase 2 (hK2)--can predict the outcome of prostate biopsy in men with elevated PSA. Here we investigate the properties of our panel in men subject to clinical work-up before biopsy. We applied a previously published predictive model based on the kallikrein panel to 262 men undergoing prostate biopsy following an elevated PSA (≥ 3 ng/ml) and further clinical work-up during the European Randomized Study of Prostate Cancer screening, France. The predictive accuracy of the model was compared to a "base" model of PSA, age and digital rectal exam (DRE). 83 (32%) men had prostate cancer on biopsy of whom 45 (54%) had high grade disease (Gleason score 7 or higher). Our model had significantly higher accuracy than the base model in predicting cancer (area-under-the-curve [AUC] improved from 0.63 to 0.78) or high-grade cancer (AUC increased from 0.77 to 0.87). Using a decision rule to biopsy those with a 20% or higher risk of cancer from the model would reduce the number of biopsies by nearly half. For every 1000 men with elevated PSA and clinical indication for biopsy, the model would recommend against biopsy in 61 men with cancer, the majority (≈80%) of whom would have low stage and low grade disease at diagnosis. In this independent validation study, the model was highly predictive of prostate cancer in men for whom the decision to biopsy is based on both elevated PSA and clinical work-up. Use of this model would reduce a large number of biopsies while missing few cancers.


Recent Developments of Novel Pharmacologic Therapeutics for Prevention of Chemotherapy-Induced Peripheral Neuropathy.
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting toxicity, negatively affecting both quality of life and disease outcomes. To date, there is no proven preventative strategy for CIPN. Although multiple randomized trials have evaluated a variety of pharmacologic interventions for the treatment of CIPN, only duloxetine has shown clear efficacy in a phase III study. The National Cancer Institute's Symptom Management and Health-Related Quality of Life Steering Committee has identified CIPN as a priority for translational research in cancer care. Promising advances in preclinical research have identified several novel preventative and therapeutic targets, which have the potential to transform the care of patients with this debilitating neurotoxicity. Here, we provide an overarching view of emerging strategies and therapeutic targets that are currently being evaluated in CIPN.


Spatiotemporally graded NMDA spike/plateau potentials in basal dendrites of neocortical pyramidal neurons.
Glutamatergic inputs clustered over approximately 20-40 microm can elicit local N-methyl-D-aspartate (NMDA) spike/plateau potentials in terminal dendrites of cortical pyramidal neurons, inspiring the notion that a single terminal dendrite can function as a decision-making computational subunit. A typical terminal basal dendrite is approximately 100-200 microm long: could it function as multiple decision-making subunits? We test this by sequential focal stimulation of multiple sites along terminal basal dendrites of layer 5 pyramidal neurons in rat somatosensory cortical brain slices, using iontophoresis or uncaging of brief glutamate pulses. There was an approximately sevenfold spatial gradient in average spike/plateau amplitude measured at the soma, from approximately 3 mV for distal inputs to approximately 23 mV for proximal inputs. Spike/plateaus were NMDA receptor (NMDAR) conductance-dominated at all locations. Large Ca(2+) transients accompanied spike/plateaus over a approximately 10- to 40-microm zone around the input site; smaller Ca(2+) transients extended approximately uniformly to the dendritic tip. Spike/plateau duration grew with increasing glutamate and depolarization; high Ca(2+) zone size grew with spike/plateau duration. The minimum high Ca(2+) zone half-width (just above NMDA spike threshold) increased from distal (approximately 10 microm) to proximal locations (approximately 25 microm), as did the NMDA spike glutamate threshold. Depolarization reduced glutamate thresholds. Simulations exploring multi-site interactions based on this demonstrate that if appropriately timed and localized inputs occur in vivo, a single basal dendrite could correspond to a cascade of multiple co-operating dynamic decision-making subunits able to retain information for hundreds of milliseconds, with increasing influence on neural output from distal to proximal. Dendritic NMDA spike/plateaus are thus well-suited to support graded persistent firing.


Genomic, tissue expression, and protein characterization of pCLCA1, a putative modulator of cystic fibrosis in the pig.
Recent studies have identified members of the CLCA (chloride channels, calcium-activated) gene family as potential modulators of the cystic fibrosis (CF) phenotype, but differences between the human and murine CLCA genes and proteins may limit the use of murine CF models. Recently established pig models of CF are expected to mimic the human disease more closely than the available mouse models do. Here, we characterized the porcine CLCA gene locus, analyzed the expression pattern and protein processing of pCLCA1, and compared it to its human ortholog, hCLCA1. The porcine CLCA gene family is located on chromosome 4q25, with a broad synteny with the human and murine clca gene loci, except for a pig-specific gene duplication of pCLCA4. Using pCLCA1-specific antibodies, the protein was immunohistochemically localized in mucin-producing cells, including goblet cells and mucinous glands in the respiratory and alimentary tracts. Similar to hCLCA1, biochemical characterization of pCLCA1 identified a secreted soluble protein that could serve as an extracellular signaling molecule or functional constituent of the protective mucous layers. The results suggest that pCLCA1 shares essential characteristics of hCLCA1, supporting the pig model as a promising tool for studying the modulating role of pCLCA1 in the complex pathology of CF.


TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis.
Spondyloarthritis (SpA) represents a family of inflammatory diseases of the spine and peripheral joints. Ankylosing spondylitis (AS) is the prototypic form of SpA in which progressive disease can lead to fusion of the spine. Therapeutically, knowledge of type 3 immunity has translated into the development of IL-23- and IL-17A-blocking antibodies for the treatment of SpA. Despite being able to provide symptomatic control, the current biologics do not prevent the fusion of joints in AS patients. Thus, there is an unmet need for disease-modifying drugs. Genetic studies have linked the Janus kinase TYK2 to AS. TYK2 is a mediator of type 3 immunity through intracellular signaling of IL-23. Here, we describe and characterize a potentially novel small-molecule inhibitor of TYK2 that blocked IL-23 signaling in vitro and inhibited disease progression in animal models of SpA. The effect of the inhibitor appears to be TYK2 specific, using TYK2-inactive mice, which further revealed a duality in the induction of IL-17A and IL-22 by IL-23. Specifically, IL-22 production was TYK2/JAK2/STAT3 dependent, while IL-17A was mostly JAK2 dependent. Finally, we examined the effects of AS-associated TYK2 SNPs on TYK2 expression and function and correlated them with AS disease progression. This work provides evidence that TYK2 inhibitors have great potential as an orally delivered therapeutic for SpA.


Treatment with drugs to lower blood pressure and blood cholesterol based on an individual's absolute cardiovascular risk.
In this review, we outline the rationale for targeting blood pressure and blood cholesterol lowering drug treatments to patients at high absolute cardiovascular risk, irrespective of their blood pressure or blood cholesterol levels. Because the specific levels of blood pressure and cholesterol are of little clinical relevance when considered in isolation from other risk factors, terms such as hypertension or hypercholesterolaemia have limited value. Separate management guidelines for raised blood pressure and blood cholesterol need to be replaced by integrated cardiovascular risk management guidelines, and absolute cardiovascular risk prediction scores should be used routinely. Since cardiovascular risk factors interact with each other, moderate reductions in several risk factors can be more effective than major reductions in one. An affordable daily pill combining low doses of various drugs could be useful for the many individuals with slightly abnormal cardiovascular risk factors.


The sensing characteristics of plasmonic waveguide with a ring resonator.
A surface plasmon polaritons (SPPs) refractive index sensor which consists of two metal-insulator-metal (MIM) waveguides coupled to each other by a ring resonator is proposed. The transmission properties are numerically simulated by finite element method. The sensing characteristics of such structure are systematically analyzed by investigating the transmission spectrum. The results indicate that there exist three resonance peaks in the transmission spectrum, and all of which have a linear relationship with the refractive index of the material under sensing. Through the optimization of structural parameters, we achieve a theoretical value of the refractive index sensitivity as high as 3460nmRIU(-1). Furthermore, this structure can also be used as a temperature sensor with temperature sensitivity of 1.36nm/°C. This work paves the way toward sensitive nanometer scale refractive index sensor and temperature sensor for design and application.


Environmental drivers of carbon and nitrogen isotopic signatures in peatland vascular plants along an altitude gradient.
Peatlands are important sinks of atmospheric carbon (C) that, in response to climate warming, are undergoing dynamic vegetation succession. Here we examined the hypothesis that the uptake of nutrients by different plant growth forms (PGFs) is one key mechanism driving changes in species abundance in peatlands. Along an altitude gradient representing a natural climate experiment, we compared the variability of the stable C isotope composition (δ(13)C) and stable nitrogen (N) isotope composition (δ(15)N) in current-year leaves of two major PGFs, i.e. ericoids and graminoids. The climate gradient was associated with a gradient of vascular plant cover, which was parallelled by different concentrations of organic and inorganic N as well as the fungal/bacterial ratio in peat. In both PGFs the (13)C natural abundance showed a marginal spatial decrease with altitude and a temporal decrease with progression of the growing season. Our data highlight a primary physical control of foliar δ(13)C signature, which is independent from the PGFs. Natural abundance of foliar (15)N did not show any seasonal pattern and only in the ericoids showed depletion at lower elevation. This decreasing δ(15)N pattern was primarily controlled by the higher relative availability of organic versus inorganic N and, only for the ericoids, by an increased proportion of fungi to bacteria in soil. Our space-for-time approach demonstrates that a change in abundance of PGFs is associated with a different strategy of nutrient acquisition (i.e. transfer via mycorrhizal symbiosis versus direct fine-root uptake), which could likely promote observed and predicted dwarf shrub expansion under climate change.


Enteropathogen detection in children with diarrhoea, or vomiting, or both, comparing rectal flocked swabs with stool specimens: an outpatient cohort study.
Enteropathogen detection traditionally relies on diarrhoeal stool samples, but these are inconvenient to collect if they are not immediately available, leading to suboptimum return rates of samples and delayed or missed diagnostic opportunities. We sought to compare the enteropathogen yields of rectal swabs and stool specimens in children with diarrhoea or vomiting, or both. The Alberta Provincial Pediatric EnTeric Infection TEam (APPETITE) did a study in three outpatient cohorts in Calgary and Edmonton (AB, Canada)-children enrolled in the Pediatric Emergency Research Canada emergency departments, children receiving routine vaccinations at a Calgary health clinic, and symptomatic children who met criteria for treatment at home. Eligible participants were children younger than 18 years, with at least three episodes of vomiting or diarrhoea in the preceding 24 h and fewer than 7 days of symptoms. After excluding those enrolled within the previous fortnight, unable to follow-up, or having psychiatric illness, neutropenia, or requiring emergent care, we attempted to collect rectal swabs and stool from all participants. Specimens were tested with the multianalyte assay Luminex xTAG Gastrointestinal Pathogen Panel, an in-house five-virus panel and bacterial culture. Primary outcomes were comparative yield (calculated as the proportion of submitted paired specimens only in which at least one pathogen was identified) and overall yield (which calculated the proportion of study participants in whom at least one pathogen was identified in all specimens, where unsubmitted specimens were analysed as negative). We used McNemar's test to do pathogen-specific analyses, and generalised estimating equations (GEE) for the global (ie, any) pathogen analyses, with adjustments made for the presence of diarrhoea, location, and their interactions with specimen type. Between Dec 12, 2014, and Aug 31, 2016, we studied 1519 eligible participants, 1147 (76%) of whom provided stool specimens and 1514 (>99%) provided swab specimens. 871 (76%) of 1147 stool specimens and 1024 (68%) of 1514 swabs were positive for any pathogen (p<0·0001). Comparative yield adjusted odds ratios (ORs) for stool specimens relative to swabs were 1·24 (95% CI 1·11-1·38) in children with diarrhoea at presentation and 1·76 (1·47-2·11) in children without diarrhoea. GEE analysis identified an interaction between the presence of diarrhoea and specimen type (p=0·0011) and collection location (p=0·0078). In an overall yield analysis, pathogen yield was 57% (871 of 1519 children) for stool specimens and 67% (1024 of 1519 children) for rectal swabs, with an unadjusted OR of 0·65 (95% CI 0·59-0·72) for stool relative to swab. Rectal swabs should be done when enteropathogen identification and rapid detection are needed, appropriate molecular diagnostic technology is available, and a stool specimen is not immediately available. In view of their high yield, we urge that the recommendation against the use of rectal swabs as diagnostic specimens be reconsidered. Alberta Innovates-Health Solutions Team Collaborative Research Innovation Opportunity.


Quality and safety in the literature: October 2022.
Healthcare quality and safety span multiple topics across the spectrum of academic and clinical disciplines. Keeping abreast of the rapidly growing body of work can be challenging. In this series, we provide succinct summaries of selected relevant studies published in the last several months. Some articles will focus on a particular theme, whereas others will highlight unique publications from high-impact medical journals.


Comparison of rates and risk factors for development of anaemia and erythropoiesis-stimulating agent utilization after radical or partial nephrectomy.
To examine the incidence of and risk factors for the development of anaemia and erythropoiesis-stimulation agent (ESA) treatment in patients undergoing radical nephrectomy (RN) and partial nephrectomy (PN) because anaemia is a significant cause of morbidity in chronic kidney disease. The study comprised a retrospective review of 905 patients (610 RN/295 PN; mean age, 57.5 years; mean follow-up, 6.4 years) who underwent surgery for renal tumours at two institutions from July 1987 to June 2007. Demographics, disease characteristics and pre- and postoperative (i.e. renal function, metabolic parameters, anaemia and ESA treatment) were recorded. Data were analyzed within subgroups based on treatment (RN vs PN). Multivariate analysis was conducted to determine the risk factors for developing anaemia after surgery. Tumour size (cm) was significantly larger for RN (RN 7.0 vs PN 3.7; P < 0.001). No significant differences were noted with respect to demographics and preoperative anaemia (RN 16.4% vs PN 18.6%; P = 0.454) and ESA-treatment (RN 0.7% vs PN 1.4%; P = 0.499). After surgery, significantly less de novo anaemia (PN 4.1% vs RN 17.5%; P < 0.001) and ESA utilization (PN 2.7% vs RN 13.4%; P < 0.001) occurred in the PN cohort. Multivariate analysis showed that age ≥60 years (odds ratio, OR, 1.62; P = 0.008), African American ethnicity (OR, 2.30; P < 0.001), smoking (OR, 1.60; P = 0.013), glomerular filtration rate (GFR) <60 mL/min/1.73 m(2) (OR, 4.09; P < 0.001), ≥1+ proteinuria (OR, 2.19; P < 0.03), metabolic acidosis (OR, 4.08; P = 0.007) and RN (OR, 2.58; P < 0.001) were significantly associated with de novo anaemia. Patients who underwent RN had a significantly higher prevalence of anaemia and ESA-treatment compared to a well-matched cohort that underwent PN. In addition to RN, age ≥60 years, African American ethnicity, history of smoking, GFR < 60 mL/min/1.73 m(2), proteinuria and metabolic acidosis were associated with developing anaemia.


Long-Term Clinical Outcomes of Endoscopic Submucosal Dissection in Patients with Early Gastric Cancer: A Prospective Multicenter Cohort Study.
Endoscopic submucosal dissection (ESD) has been regarded as a curative treatment for early gastric cancer (EGC) in indicated cases. The aim of this study was to evaluate the nationwide long-term clinical outcomes of ESD for EGC in Korea. A prospective multicenter cohort study was performed to evaluate the long-term efficacy of ESD for EGC within pre-defined indications at 12 institutes in Korea. The cases that met the expanded criteria upon pathological review after ESD were followed for 5 years. The primary outcome was 5-year disease specific free survival. Six hundred ninety-seven patients with 722 EGCs treated with ESD were prospectively enrolled and followed for 5 years. Complete resection was achieved in 81.3% of the cases, and curative resection was achieved in 86.1%. During the 5-year follow-up, the overall survival rate was 96.6%, and the disease specific free survival rate was 90.6%. Local recurrence developed in 0.9%, and metachronous tumor development occurred in 7.8%; both conditions were treated by endoscopic or surgical treatment. Distant metastasis developed in 0.5% during follow-up. ESD showed excellent long-term clinical outcomes and can be accepted as a curative treatment for patients with EGC who meet the expanded criteria in final pathology studies.


Postzygotic mutation and germline mosaicism in the otopalatodigital syndrome spectrum disorders.
The otopalatodigital syndrome (OPD) spectrum disorders are a heterogeneous group of skeletal dysplasias caused by mutations in the X-linked gene, FLNA. All OPD spectrum disorders (otopalatodigital syndromes types 1 and 2, frontometaphyseal dysplasia and Melnick-Needles syndrome) exhibit significant interfamilial variability in their expressivity, especially in female subjects. Factors contributing to this may include allelic heterogeneity, variation in the degree of skewing of X inactivation or, conceivably, mosaicism for the underlying causative mutation. We report here monozygotic twin sisters who are discordant for the severe phenotype, Melnick-Needles syndrome, associated with the heterozygous mutation, 3596C>T. We also describe two brothers with otopalatodigital syndrome type 1 due to the FLNA mutation 620G>A. The mutation is not detectable in the blood leucocytes of their clinically unaffected mother, indicating that she is a germline mosaic for the condition. The description of somatic mutations and germline mosaicism in FLNA has implications for clinical and molecular diagnosis, phenotypic expression and genetic counseling of families with these disorders.


Prevalence of malaria parasitemia amongst asymptomatic pregnant women attending a Nigerian teaching hospital.
Malaria parasitemia among pregnant women is associated with complications to mother and the unborn fetus. There is paucity of data on asymptomatic malaria parasitemia, particularly in the northwest region of Nigeria. The objectives of this study were to determine the prevalence of malaria parasitemia in asymptomatic pregnant women and to estimate the packed cell volume (PCV) of this group of pregnant women. This was a cross-sectional, descriptive study of only well pregnant women recruited consecutively at the time of booking for antenatal care. Thick film microscopy and qualitative immunoassay test for malaria parasite (MP) were performed for all the women. PCV estimation was also done using the micro-centrifuge method and comparison was made for women with parasitemia with those without MP. Some socio-demographic variables were also analyzed. Chi-square test was used to test for significance and a P-value less than 0.05 was considered statistically significant. Two hundred and twenty-five healthy pregnant women were studied. Seven women (3.1%) had MP by direct microscopy while 11 (4.8%) were MP positive with the qualitative immunoassay test. One hundred and eighty-five (82%) of the women were literate while 128 (57%) used insecticide treated mosquito nets in their homes. The mean PCV of the women with positive MP was 30.57 ± 2.26 as against 32.89 ± 2.45 for those without parasitemia (P < 0.05). The prevalence of asymptomatic malaria parasitemia in the study group was low but there was associated anemia in those with parasitemia. The use of intermittent preventive treatment is recommended for all pregnant women including those who are asymptomatic to forestall complications like maternal anemia.


Evolution and genetic population structure of prickly lettuce (Lactuca serriola) and its RGC2 resistance gene cluster.
Genetic structure and diversity of natural populations of prickly lettuce (Lactuca serriola) were studied using AFLP markers and then compared with the diversity of the RGC2 disease resistance gene cluster. Screening of 696 accessions from 41 populations using 319 AFLP markers showed that eastern Turkish and Armenian populations were the most diverse populations and might be located in the origin and center of diversity of L. serriola. Screening 709 accessions using the microsatellite MSATE6 that is located in the coding region of most RGC2 homologs detected 366 different haplotypes. Again, the eastern Turkish and Armenian populations had the highest diversities at the RGC2 cluster. The diversities at the RGC2 cluster in different populations were significantly correlated with their genomewide diversities. There was significant variation of copy number of RGC2 homologs in different populations, ranging from 12 to 22 copies per genome. The nucleotide diversities of two conserved lineages (type II) of RGC2 genes (K and L) were not correlated with diversities calculated using the MSATE6 or AFLP data. We hypothesize that the high genomewide diversity and diversity of the RGC2 cluster in eastern Turkish and Armenian populations resulted from high abiotic and biotic stresses in the regions of origin of L. serriola.


Non-viral nanovectors for gene delivery: factors that govern successful therapeutics.
Gene therapy is regarded as one of the most promising therapeutic approaches, as it has the potential to treat disorders by correcting malformations at the nucleic acids. Some of the most recent developments in the process of plasmid DNA vector design and formulation are reviewed with a special focus on: different formulations of nanovectors and a summary of successful cases reported; requirements for systemic administration; and functionalization of the nanocarriers by use of targeting entities. An understanding of the different physiological barriers and a comprehensive review of the recent strategies used to overcome these obstacles. Particular attention is given to formulations for intravenous administration, colloidal stability properties and different targeting entities used. Overall, vector formulation must take into account the administration route and inherent physiological barriers. Critical parameters for the success of pDNA nanovectors are: particles size, colloidal stability of the formulation and interaction between the carrier and plasmid DNA. Highly relevant is the fact that this interaction should be balanced to offer protection to degradation as well as allow dissociation of the therapeutic nucleic acid for obtaining maximal activity.


Robotic leg control with EMG decoding in an amputee with nerve transfers.
The clinical application of robotic technology to powered prosthetic knees and ankles is limited by the lack of a robust control strategy. We found that the use of electromyographic (EMG) signals from natively innervated and surgically reinnervated residual thigh muscles in a patient who had undergone knee amputation improved control of a robotic leg prosthesis. EMG signals were decoded with a pattern-recognition algorithm and combined with data from sensors on the prosthesis to interpret the patient's intended movements. This provided robust and intuitive control of ambulation--with seamless transitions between walking on level ground, stairs, and ramps--and of the ability to reposition the leg while the patient was seated.