Group differences in risk across three domains using an expanded measure of sexual orientation.
The purpose of this study was to highlight associations between sexual orientation and risk outcomes in late adolescence and early adulthood using an expanded measure of sexual orientation. Recent data indicate higher levels of risk behavior in a newly identified population, mostly heterosexuals, as compared to heterosexuals. Comparisons among groups using an expanded measure of sexual orientation such as this, however, often do not include all possible groups or may restrict comparisons between groups. Data were derived from the National Longitudinal Study of Adolescent Health (Add Health); participants identified as heterosexual, mostly heterosexual, bisexual, mostly gay, or gay. Main risk outcomes were parental mistreatment, home displacement, thoughts of suicide, depressive symptoms, frequency of drinking, and delinquency. A priori planned comparisons examined differences between: (a) heterosexual vs. mostly heterosexual, (b) gay vs. mostly gay, (c) mostly heterosexual vs. bisexual, (d) mostly gay vs. bisexual, (e) mostly heterosexual vs. mostly gay, (f) heterosexual vs. gay, (g) heterosexual vs. bisexual, and (h) gay vs. bisexual. Mostly heterosexual youth were at significantly greater risk than heterosexual youth on all outcomes but did not differ from bisexual or mostly gay youth. Heterosexuals were at lower risk as compared to mostly heterosexuals and bisexuals. This study provides further evidence of differential risk associations for sexual minorities.


Usage and impact of patient-reported outcomes in epilepsy.
The use of patient-reported outcomes (PRO) in clinical practice is gaining increasing attention. This study aimed to provide a critical assessment of the current state-of-the-art and beliefs about the use of PRO in the management of people with epilepsy across some European countries. Structured interviews were conducted with European experts to collect insights about (I) the personal experience with PRO; (II) the value and impact of PRO in the decision-making process at the national level; and (III) the interest for and use of PRO by national health authorities. Nine neurologists (Austria, Belgium, Czechia, Denmark, France, Greece, Italy, Poland, and United Kingdom), three health economists (Portugal, Romania, and Sweden), and one epidemiologist (Slovakia) participated. They all stated that PRO are collected at their own countries in the context of clinical trials and/or specific projects. During everyday clinical practice, PRO are collected routinely/almost routinely in Austria and Sweden and only at the discretion of the treating physicians in Czechia, Denmark, France, Greece, and Portugal. There was complete consensus about the favorable impact that the PRO can have in terms of clinical outcomes, healthcare resources utilization, and general patient satisfaction. Only participants from Portugal and Sweden answered that the PRO are perceived as very important by the National Health Authorities of their respective countries. Differences exist in attitudes and perspectives about PRO in epilepsy across Europe. An active plan is warranted to harmonize the measurement of PRO and ensure they can be relevant to people with epilepsy and health services.


Adherence to nutrition-based cancer prevention guidelines and breast, prostate and colorectal cancer risk in the MCC-Spain case-control study.
Prostate, breast and colorectal cancer are the most common tumours in Spain. The aim of the present study was to evaluate the association between adherence to nutrition-based guidelines for cancer prevention and prostate, breast and colorectal cancer, in the MCC-Spain case-control study. A total of 1,718 colorectal, 1,343 breast and 864 prostate cancer cases and 3,431 population-based controls recruited between 2007 and 2012, were included in the present study. The World Cancer Research Fund/American Institute for Cancer Research (WCRC/AICR) score based on six recommendations for cancer prevention (on body fatness, physical activity, foods and drinks that promote weight gain, plant foods, animal foods and alcoholic drinks; score range 0-6) was constructed. We used unconditional logistic regression analysis adjusting for potential confounders. One-point increment in the WCRF/AICR score was associated with 25% (95% CI 19-30%) lower risk of colorectal, and 15% (95% CI 7-22%) lower risk of breast cancer; no association with prostate cancer was detected, except for cases with a Gleason score ≥7 (poorly differentiated/undifferentiated tumours) (OR 0.87, 95% CI 0.76-0.99). These results add to the wealth of evidence indicating that a great proportion of common cancer cases could be avoided by adopting healthy lifestyle habits.


Current status of pyrazoloacridine as an anticancer agent.
Pyrazoloacridine (PZA) is the first of a new class of rationally synthesized acridine derivatives to undergo clinical testing as an anticancer agent. Recent studies suggest that PZA might be a dual inhibitor of DNA topoisomerase I and DNA topoisomerase II that exerts its effects by diminishing the formation of topoisomerase-DNA adducts. Consistent with this unique mechanism of action, PZA exhibits broad spectrum antitumor activity in preclinical models in vivo. In addition, this agent displays several unique properties including solid tumor selectivity, activity against hypoxic cells, and cytotoxicity in noncycling cells. PZA also retains full activity against cells that are resistant to other agents on the basis of overexpression of P-glycoprotein or the multidrug resistance-associated protein (MRP). PZA has been studied in phase I trials in adults and children, and is currently undergoing broad phase II trials in a number of tumor types. No significant anti-tumor activity has been seen in gastrointestinal malignancies and prostate cancer. Results from ongoing or recently completed trials are awaited before the utility of this agent in our current armamentarium can be defined. Because of its unique properties, combination studies with other antineoplastic agents are warranted.


Genetic and functional characterization of disease associations explains comorbidity.
Understanding relationships between diseases, such as comorbidities, has important socio-economic implications, ranging from clinical study design to health care planning. Most studies characterize disease comorbidity using shared genetic origins, ignoring pathway-based commonalities between diseases. In this study, we define the disease pathways using an interactome-based extension of known disease-genes and introduce several measures of functional overlap. The analysis reveals 206 significant links among 94 diseases, giving rise to a highly clustered disease association network. We observe that around 95% of the links in the disease network, though not identified by genetic overlap, are discovered by functional overlap. This disease network portraits rheumatoid arthritis, asthma, atherosclerosis, pulmonary diseases and Crohn's disease as hubs and thus pointing to common inflammatory processes underlying disease pathophysiology. We identify several described associations such as the inverse comorbidity relationship between Alzheimer's disease and neoplasms. Furthermore, we investigate the disruptions in protein interactions by mapping mutations onto the domains involved in the interaction, suggesting hypotheses on the causal link between diseases. Finally, we provide several proof-of-principle examples in which we model the effect of the mutation and the change of the association strength, which could explain the observed comorbidity between diseases caused by the same genetic alterations.


Regional outbreak of community-associated methicillin-resistant Staphylococcus aureus ST834 in Japanese children.
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infection has recently become a challenging problem worldwide and in Japan. We experienced 10 pediatric patients infected with CA-MRSA and hospitalized from 2011 to 2014 in a tertiary care hospital in Saitama, Japan, and assessed the characteristic of the strains using a whole genome sequencing (WGS)-based approach. CA-MRSA strains isolated from infected patients who required hospitalization for treatment were evaluated in this study. Antimicrobial susceptibility tests, molecular typing by PCR and pulse-field gel electrophoresis (PFGE) were performed to characterize MRSA strains. WGS was performed for detailed genetic analysis. A total of 582 MRSA strains (35.2%) were identified among 1625 S. aureus strains collected during the study period. Ten MRSA strains (1.7%) were defined as CA-MRSA clinically, and all were isolated from pediatric patients. All strains mainly caused purulent lymphadenitis, were susceptible to fluoroquinolone and tetracycline, exhibited sequence type (ST) 834 or its single-locus variants and contained staphylococcal cassette chromosome mec (SCCmec) type IVc. Phylogenic analysis by PFGE and WGS revealed close relatedness of all strains, with the number of single nucleotide polymorphisms ranging from 35 to 119 by WGS. Out of the ten strains, nine possessed the genomic island SaPISaitama2 containing tst, sec and sel genes. SaPISaitama2 comprises a mosaic of genomic islands SaPIm4 and SaPIm1 harbored by a hospital-associated MRSA strain Mu50. This study describes a regional outbreak of ST834-related CA-MRSA in children with a unique pathogenicity island in Japan. Pediatric patient tropism of this clone could be enhanced by susceptibility to fluoroquinolones and tetracyclines, which cannot be prescribed to children.


Bone and Cartilage Interfaces With Orthopedic Implants: A Literature Review.
The interface between a surgical implant and tissue consists of a complex and dynamic environment characterized by mechanical and biological interactions between the implant and surrounding tissue. The implantation process leads to injury which needs to heal over time and the rapidity of this process as well as the property of restored tissue impact directly the strength of the interface. Bleeding is the first and most relevant step of the healing process because blood provides growth factors and cellular material necessary for tissue repair. Integration of the implants placed in poorly vascularized tissue such as articular cartilage is, therefore, more challenging than compared with the implants placed in well-vascularized tissues such as bone. Bleeding is followed by the establishment of a provisional matrix that is gradually transformed into the native tissue. The ultimate goal of implantation is to obtain a complete integration between the implant and tissue resulting in long-term stability. The stability of the implant has been defined as primary (mechanical) and secondary (biological integration) stability. Successful integration of an implant within the tissue depends on both stabilities and is vital for short- and long-term surgical outcomes. Advances in research aim to improve implant integration resulting in enhanced implant and tissue interface. Numerous methods have been employed to improve the process of modifying both stability types. This review provides a comprehensive discussion of current knowledge regarding implant-tissue interfaces within bone and cartilage as well as novel approaches to strengthen the implant-tissue interface. Furthermore, it gives an insight into the current state-of-art biomechanical testing of the stability of the implants. Current knowledge reveals that the design of the implants closely mimicking the native structure is more likely to become well integrated. The literature provides however several other techniques such as coating with a bioactive compound that will stimulate the integration and successful outcome for the patient.


The comparison of ZFNs, TALENs, and SpCas9 by GUIDE-seq in HPV-targeted gene therapy.
Zinc-finger nucleases (ZFNs), transcription activator-like endonucleases (TALENs), and CRISPR-associated Cas9 endonucleases are three major generations of genome editing tools. However, no parallel comparison about the efficiencies and off-target activity of the three nucleases has been reported, which is critical for the final clinical decision. We for the first time developed the genome-wide unbiased identification of double-stranded breaks enabled by sequencing (GUIDE-seq) method in ZFNs and TALENs with novel bioinformatics algorithms to evaluate the off-targets. By targeting human papillomavirus 16 (HPV16), we compared the performance of ZFNs, TALENs, and SpCas9 in vivo. Our data showed that ZFNs with similar targets could generate distinct massive off-targets (287-1,856), and the specificity could be reversely correlated with the counts of middle "G" in zinc finger proteins (ZFPs). We also compared the TALENs with different N-terminal domains (wild-type [WT]/αN/βN) and G recognition modules (NN/NH) and found the design (αN or NN) to improve the efficiency of TALEN inevitably increased off-targets. Finally, our results showed that SpCas9 was more efficient and specific than ZFNs and TALENs. Specifically, SpCas9 had fewer off-target counts in URR (SpCas9, n = 0; TALEN, n = 1; ZFN, n = 287), E6 (SpCas9, n = 0; TALEN, n = 7), and E7 (SpCas9, n = 4; TALEN, n = 36). Taken together, we suggest that for HPV gene therapies, SpCas9 is a more efficient and safer genome editing tool. Our off-target data could be used to improve the design of ZFNs and TALENs, and the universal in vivo off-target detection pipeline for three generations of artificial nucleases provided useful tools for genome engineering-based gene therapy.


Real-Time Monitoring of Cancer Cells in Live Mouse Bone Marrow.
Disseminated tumor cells in the bone marrow environment are the main cause of systemic metastasis after curative treatment for major solid tumors. However, the detailed biological processes of tumor biology in bone marrow have not been well defined in a real-time manner, because of a lack of a proper in vivo experimental model thereof. In this study, we established intravital imaging models of the bone marrow environment to enable real-time observation of cancer cells in the bone marrow. Using these novel imaging models of intact bone marrow and transplanted bone marrow of mice, respectively, via two-photon microscopy, we could first successfully track and analyze both the distribution and the phenotype of cancer cells in bone marrow of live mouse. Therefore, these novel in vivo imaging models for the bone marrow would provide a valuable tool to identify the biologic processes of cancer cells in a real-time manner in a live animal model.


The glycosylation status of the murine hepatitis coronavirus M protein affects the interferogenic capacity of the virus in vitro and its ability to replicate in the liver but not the brain.
The coronavirus M protein, the most abundant coronaviral envelope component, is invariably glycosylated, which provides the virion with a diffuse, hydrophilic cover on its outer surface. Remarkably, while the group 1 and group 3 coronaviruses all have M proteins with N-linked sugars, the M proteins of the group 2 coronaviruses [e.g., mouse hepatitis virus (MHV)] are O-glycosylated. The conservation of the N- and O-glycosylation motifs suggests that each of these types of carbohydrate modifications is beneficial to their respective virus. Since glycosylation of the M protein is not required for virus assembly, the oligosaccharides are likely to be involved in the virus-host interaction. In order to investigate the role of the M protein glycosylation in the host, two genetically modified MHVs were generated by using targeted RNA recombination. The recombinant viruses carried M proteins that were either N-glycosylated or not glycosylated at all, and these were compared with the parental, O-glycosylated, virus. The M protein glycosylation state did not influence the tissue culture growth characteristics of the recombinant viruses. However, it affected their interferogenic capacity as measured using fixed, virus-infected cells. Viruses containing M proteins with N-linked sugars induced type I interferons to higher levels than viruses carrying M proteins with O-linked sugars. MHV with unglycosylated M proteins appeared to be a poor interferon inducer. In mice, the recombinant viruses differed in their ability to replicate in the liver, but not in the brain, whereas their in vivo interferogenic capacity did not appear to be affected by their glycosylation status. Strikingly, their abilities to replicate in the liver correlated with their in vitro interferogenic capacity. This apparent correlation might be explained by the functioning of lectins, such as the mannose receptor, which are abundantly expressed in the liver but also play a role in the induction of interferon-alpha by dendritic cells.


[Abdominopelvic recurrence of leiomyosarcoma. Echographic aspects apropos of 19 cases].
The recurrence rate after initial surgery of pelvis and abdominal leiomyosarcomas is significant. Quick but silent growth of these tumors requires a regular and frequent follow-up in order to improve the prognosis. Ultrasonography is the simplest way for such a follow-up. We present our experience about 23 operated cases of leiomyosarcomas followed by ultrason; 19 of them recurred with 1 to 6 abdominal and/or pelvic masses. The echographic patterns of recurrences are detailed.


Serum alpha-fetoprotein and its lectin reactivity in liver diseases: a review.
Increased serum concentration of alpha-fetoprotein (AFP) can be found in benign and malignant liver diseases, in yolk sac tumors, and in several nonhepatic neoplasms at advanced stage. The frequency and level of elevated serum AFP are highest in hepatocellular carcinoma (HCC) and yolk sac tumors. Most levels of serum AFP in HCC are greater than 500 ng per mL, whereas the serum AFP in most of the benign liver diseases is only moderately elevated and is transient in nature. Determination of lectin reactivity of serum AFP is helpful for the differentiation of HCC from other diseases associated with elevated serum AFP. Determination of Len culinaris agglutinin (LCA) reactivity of serum AFP is useful for the differentiation of HCC from benign liver diseases, and for early detection of hepatoma. Determination of concanavalin A (Con A) nonreactive AFP variant is useful for the differentiation of HCC from yolk sac tumors and may also allow for the differentiation of HCC from nonhepatic neoplasms. However, reaction with several lectins may be required if differentiation among various nonhepatic neoplasms is needed.


The trend of national and sub-national burden of gastrointestinal and liver diseases in Iran 1990 to 2013; study protocol.
It is expected that gastrointestinal (GI) and liver diseases inflict considerable burden on health systems in Iran; therefore, highlighting the significance of GI disorders across the other most burdensome diseases requires comprehensive assessment and regular updates of the statistics of such diseases in Iran. To assess in-depth sub-national estimates and trends for the incidence and prevalence of selected GI and liver diseases by age, gender and province over the period 1990 - 2013 in Iran. This is a national and sub-national burden of disease study on 21 GI diseases using all available data sources, including cancer registry, death registration system data, hospital data, and all available published data. Analyses will be performed separately by gender, age groups, year, and province. We will conduct 21 separated systematic reviews of the literature for 21 diseases categories through searching online international electronic databases (i.e. the Medline database of the National Library of Medicine, Web of Science, and Scopus), Iranian search engines (i.e., IranMedex, Scientific Information Database (SID), and IRANDOC), and gray literature. We will search the medical literature published between January 1985 and December 2013. We generated two models, Spatio-temporal and Multilevel Autoregressive models, to estimate mean and uncertainty interval for the parameters of interest by gender, age, year, and province. The models will be informed by data of gender, age, year, and province. Markov Chain Monte Carlo (MCMC) methods will be used to perform Bayesian inference in both modeling framework. All programs will be written in R statistical packages (version 3.0.1). We will calculate and present 1990 to 2013 trends in terms of prevalence, years of life lost due to premature mortality (YLLs), years lived with disability (YLDs), and disability-adjusted life years DALYs for the 21 selected GI diseases by gender, and province. We will also quantify the uncertainty interval for the estimates of interest. Results of the present study will have implications for policy making; as they allow for understanding geographic distributions of the selected GI diseases, and identifying health disparities across provinces.


Cushing's disease: dilemmas of diagnosis and management.
Determining the cause of Cushing's disease and correcting the abnormality presents a continuing challenge to the clinician despite remarkable advances in diagnostic and therapeutic techniques. We present seven cases to illustrate 1) the classic disorder cured by pituitary adenomectomy; 2) persistence of the disease after adenomectomy; 3) Cushing's disease manifesting in the puerperium and remitting with dopamine agonist therapy; 4) a patient whose disease relapsed at least five times during 20 years of treatment by adrenalectomy, pituitary radiation, mitotane, and pituitary adenomectomy; 5) the Nelson syndrome; 6) the ectopic adrenocorticotropic hormone (ACTH) syndrome in a patient with dexamethasone suppressible urinary cortisol who had a pituitary adenoma which stained positively for ACTH but who was not cured by total hypophysectomy; and 7) a patient whose ACTH-secreting tumor proved fatal despite repeated surgical, radiologic and pharmacologic measures.


[Decentralization of the HIV/AIDS epidemic and inter-municipal flow of hospital admissions in the Zona da Mata, Minas Gerais State, Brazil: a spatial analysis].
The aim of this article was to analyze the decentralization of the HIV/AIDS epidemic (a shift towards rural areas or away from the coast) and to investigate access to HIV/AIDS services from 1988 to 2002 in the Zona da Mata, Minas Gerais State, Brazil. An ecological study was performed using temporal and spatial approaches. A hospital admissions flow between municipalities developed, and the reference group was AIDS patients over 15 years of age admitted in 1996 and 2004, residing in municipalities in the Zona da Mata. There were 2,469 reported AIDS cases in individuals over 15 during the period. Mean incidence and mortality rates were calculated and recalculated by a local empirical Bayesian method in order to more clearly represent the municipalities with the highest concentration of cases and deaths. Decentralization of the epidemic was observed. Juiz de Fora was the municipality with the most cases and may have acted as a hub for spread of HIV in the region. Hospital care for AIDS cases in the Zona da Mata was concentrated in that municipality. There is a strong need to further investigate why referral hospitals in other municipalities in the region have not participated in providing management and care for HIV/AIDS patients.


Improvements in sleep problems among the chronic disease self-management program participants.
Sleep is increasingly important in public health because sleep problems are associated with multiple negative health and quality-of-life outcomes, especially among those with chronic conditions. While evidence-based self-management programs have been widely studied, little is known about their specific impacts on sleep. Using data from the National Study of Chronic Disease Self-Management Program (n = 1168), improvements in sleep problems were observed for all subgroups except men. More sleep problem reductions were observed among younger participants compared with their older counterparts. This study confirmed the value of self-management programs for ameliorating sleep problems across diverse participant groups.


Genomic features of an extensively drug-resistant and NDM-1-positive Klebsiella pneumoniae ST340 isolated from river water.
The environmental contamination plays a significant role in the emergence of antimicrobial resistance. In this study, we report a genomic analysis of an extensively drug-resistant and blaNDM-1-producing Klebsiella pneumoniae (EW807) strain recovered from a surface water sample. Strain EW807 belonged to sequence type (ST) 340 and serotype O4:KL15, a high-risk clone of the clonal group 258. This strain carried a broad resistome, including blaNDM-1 and blaCTX-M-15. The core genome multilocus sequence typing phylogenetic analysis revealed that the EW807 strain was most related to strains from Brazil and the USA. An IncX3 plasmid was identified harboring the blaNDM-1 gene, while an IncFIB(K) plasmid was detected carrying the blaCTX-M-15 in addition to multidrug resistance and multimetal tolerance regions. IncX3 and IncFIB(K) plasmids shared high similarity with plasmids from a human in China and a dog in Brazil, respectively. The regions harboring the blaNDM-1 and blaCTX-M-15 genes contained sequences from the Tn3 family. These findings suggest that IncX3 plasmid could play a role in the spread of NDM-1 in a post-pandemic scenario. To the best of our knowledge, this is the first report of blaNDM-1-producing K. pneumoniae ST340 O4:KL15 strain in the environment. Therefore, the presence of high-risk clones of K. pneumoniae carrying carbapenemases in the environment requires strict surveillance.


In-Home Mobility Frequency and Stability in Older Adults Living Alone With or Without MCI: Introduction of New Metrics.
Background: Older adults spend a considerable amount of time inside their residences; however, most research investigates out-of-home mobility and its health correlates. We measured indoor mobility using room-to-room transitions, tested their psychometric properties, and correlated indoor mobility with cognitive and functional status. Materials and Methods: Community-dwelling older adults living alone (n = 139; age = 78.1 ± 8.6 years) from the Oregon Center for Aging & Technology (ORCATECH) and Minority Aging Research Study (MARS) were included in the study. Two indoor mobility features were developed using non-parametric parameters (frequency; stability): Indoor mobility frequency (room-to-room transitions/day) was detected using passive infrared (PIR) motion sensors fixed on the walls in four geographic locations (bathroom; bedroom; kitchen; living room) and using door contact sensors attached to the egress door in the entrance. Indoor mobility stability was estimated by variances of number of room-to-room transitions over a week. Test-retest reliability (Intra-class coefficient, ICC) and the minimal clinically important difference (MCID) defined as the standard error of measurement (SEM) were generated. Generalized estimating equations models related mobility features with mild cognitive impairment (MCI) and functional status (gait speed). Results: An average of 206 days (±127) of sensor data were analyzed per individual. Indoor mobility frequency and stability showed good to excellent test-retest reliability (ICCs = 0.91[0.88-0.94]; 0.59[0.48-0.70]). The MCIDs of mobility frequency and mobility stability were 18 and 0.09, respectively. On average, a higher indoor mobility frequency was associated with faster gait speed (β = 0.53, p = 0.04), suggesting an increase of 5.3 room-to-room transitions per day was associated with an increase of 10 cm/s gait speed. A decrease in mobility stability was associated with MCI (β = -0.04, p = 0.03). Discussion: Mobility frequency and stability in the home are clinically meaningful and reliable features. Pervasive-sensing systems deployed in homes can objectively reveal cognitive and functional status in older adults who live alone.


Pain and chronic pancreatitis: a complex interplay of multiple mechanisms.
Despite multiple theories on the pathogenesis of pain in chronic pancreatitis, no uniform and consistently successful treatment strategy exists and abdominal pain still remains the dominating symptom for most patients and a major challenge for clinicians. Traditional theories focussed on a mechanical cause of pain related to anatomical changes and evidence of increased ductal and interstitial pressures. These observations form the basis for surgical and endoscopic drainage procedures, but the outcome is variable and often unsatisfactory. This underscores the fact that other factors must contribute to pathogenesis of pain, and has shifted the focus towards a more complex neurobiological understanding of pain generation. Amongst other explanations for pain, experimental and human studies have provided evidence that pain perception at the peripheral level and central pain processing of the nociceptive information is altered in patients with chronic pancreatitis, and resembles that seen in neuropathic and chronic pain disorders. However, pain due to e.g., complications to the disease and adverse effects to treatment must not be overlooked as an additional source of pain. This review outlines the current theories on pain generation in chronic pancreatitis which is crucial in order to understand the complexity and limitations of current therapeutic approaches. Furthermore, it may also serve as an inspiration for further research and development of methods that can evaluate the relative contribution and interplay of different pain mechanisms in the individual patients, before they are subjected to more or less empirical treatment.


Mineralocorticoid receptor overexpression differentially modulates specific phases of spatial and nonspatial memory.
Glucocorticoids (GCs) and stress modulate specific phases of information processing. The modulatory affects of GCs on hippocampal function are thought to be mediated by the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). The GR plays a critical role in mediating the impairing effects of GCs on hippocampal function. Conversely, activation of MR facilitates hippocampal function. The high affinity of MR for GCs suggests that the receptor protein levels play a key role in regulating the beneficial effects of MR-mediated gene transcription. Using herpes simplex vectors, we transiently increased MR levels in dentate gyrus granule cells, which in turn enhanced MR signaling. We then examined its effects on spatial and nonspatial memory consolidation and retrieval using the object placement and object recognition task. Additionally, we assessed whether an increased MR signal could block the impairing effects of high GCs on memory retrieval. Rats overexpressing MR displayed an enhancement in the consolidation of nonspatial memory relative to rats expressing green fluorescent protein and suggest the potential for gene transfer techniques for enhancing cognition during stress. Moreover, rats overexpressing MR were spared from the disruptive effects of high GCs on the retrieval of nonspatial memory. Thus, this study illustrates the critical role of MR in mediating the retrieval and consolidation of nonspatial memory.


Facilitators, barriers and expectations in the self-management of type 2 diabetes--a qualitative study from Portugal.
Patients with type 2 diabetes mellitus (DM) have a central role in managing their disease, but the effective adoption of self-management behaviours is often challenging. The main objective of this study was to assess the facilitators, barriers and expectations in the self-management of type 2 DM, as perceived by patients. Patients with type 2 DM were recruited at the Portuguese Diabetes Association outpatient clinic, using a convenient sampling technique. Qualitative data was obtained using video-recorded focus groups. Each session had a moderator and an observer, and followed a pre-tested questioning route. Two independent researchers transcribed and analysed the focus groups. Three major themes were identified: diet, physical exercise, and glycaemic control. Difficulties in changing dietary habits were grouped in four main categories: decisional, food quality, food quantity, and dietary schedule. Barriers related to physical exercise also included decisional aspects, as well as fatigue, muscle and joint pain, and other co-morbidities. Information and knowledge translation, as well as family and social ties, were commonly explored aspects across the three themes and were regarded as facilitators in some situations and as barriers in others. This study provided new insight on the barriers, facilitators and expectations in type 2 DM self-management, pointing out the importance of tailored guidance. Future research should explore interventions designed to promote and facilitate behaviour change in this population.


Identifying Genetic Biomarkers Predicting Response to Anti-Vascular Endothelial Growth Factor Injections in Diabetic Macular Edema.
Intraocular anti-vascular endothelial growth factor (VEGF) therapies are the front-line treatment for diabetic macular edema (DME); however, treatment response varies widely. This study aimed to identify genetic determinants associated with anti-VEGF treatment response in DME. We performed a genome-wide association study on 220 Australian patients with DME treated with anti-VEGF therapy, genotyped on the Illumina Global Screening Array, and imputed to the Haplotype Reference Consortium panel. The primary outcome measures were changes in central macular thickness (CMT in microns) and best-corrected visual acuity (BCVA in ETDRS letters) after 12 months. Association between single nucleotide polymorphism (SNP) genotypes and DME outcomes were evaluated by linear regression, adjusting for the first three principal components, age, baseline CMT/BCVA, duration of diabetic retinopathy, and HbA1c. Two loci reached genome-wide significance (p < 5 × 10−8) for association with increased CMT: a single SNP on chromosome 6 near CASC15 (rs78466540, p = 1.16 × 10−9) and a locus on chromosome 12 near RP11-116D17.1 (top SNP rs11614480, p = 2.69 × 10−8). Four loci were significantly associated with reduction in BCVA: two loci on chromosome 11, downstream of NTM (top SNP rs148980760, p = 5.30 × 10−9) and intronic in RP11-744N12.3 (top SNP rs57801753, p = 1.71 × 10−8); one near PGAM1P1 on chromosome 5 (rs187876551, p = 1.52 × 10−8); and one near TBC1D32 on chromosome 6 (rs118074968, p = 4.94 × 10−8). In silico investigations of each locus identified multiple expression quantitative trait loci and potentially relevant candidate genes warranting further analysis. Thus, we identified multiple genetic loci predicting treatment outcomes for anti-VEGF therapies in DME. This work may potentially lead to managing DME using personalized treatment approaches.


The effects of taxonomy, diet, and ecology on the microbiota of riverine macroinvertebrates.
Freshwater macroinvertebrates play key ecological roles in riverine food webs, such as the transfer of nutrients to consumers and decomposition of organic matter. Although local habitat quality drives macroinvertebrate diversity and abundance, little is known about their microbiota. In most animals, the microbiota provides benefits, such as increasing the rate at which nutrients are metabolized, facilitating immune system development, and defending against pathogenic attack. Our objectives were to identify the bacteria within aquatic invertebrates and determine whether their composition varied with taxonomy, habitat, diet, and time of sample collection. In 2016 and 2017, we collected 264 aquatic invertebrates from the mainstem Saint John (Wolastoq) River in New Brunswick, Canada, representing 15 orders. We then amplified the V3-V4 hypervariable region of the 16S rRNA gene within each individual, which revealed nearly 20,000 bacterial operational taxonomic units (OTUs). The microbiota across all aquatic invertebrates were dominated by Proteobacteria (69.25% of the total sequence reads), but they differed significantly in beta diversity, both among host invertebrate taxa (genus-, family-, and order-levels) and temporally. In contrast to previous work, we observed no microbiota differences among functional feeding groups or traditional feeding habits, and neither water velocity nor microhabitat type structured microbiota variability. Our findings suggest that host invertebrate taxonomy was the most important factor in modulating the composition of the microbiota, likely through a combination of vertical and horizontal bacterial transmission, and evolutionary processes. This is one of the most comprehensive studies of freshwater invertebrate microbiota to date, and it underscores the need for future studies of invertebrate microbiota evolution and linkages to environmental bacteria and physico-chemical conditions.


The Effect of Homoeologous Meiotic Pairing in Tetraploid Hordeum bulbosum L. × H. vulgare L. Hybrids on Alien Introgressions in Offspring.
The pairing behaviour of the individual chromosome arms of Hordeum vulgare (Hv) with their homoeologous arms of H. bulbosum (Hb) at metaphase I of meiosis in tetraploid Hb × Hv hybrids and the frequencies of recombined Hv chromosome arms in selfed offspring were studied on differentially visualized chromosomes after fluorescent in situ hybridisation. The frequencies of paired Hv-Hb arms in the F2 and F3 hybrids were correlated with the frequencies of recombined Hv chromosomes in progenies. Self-generation of hybrids, the number of Hv and Hb chromosomes, and the number of recombined Hv chromosomes of the hybrids strongly influenced the Hv-Hb pairing frequency in meiosis. Within the offspring of F2 and F3 hybrids both Hv plants and hybrids were detected. In contrast, all progenies of the F4 hybrid were hybrids which exhibited centromere misdivisions. The highest frequencies of homoeologous pairing in hybrids and most recombinants were obtained for the barley chromosome 1HL. Recombinants for 4HL, 5HS, 6HS, and 7HS were rarely found. Meiotic pairing and recombinants involving chromosome 1HS were never observed. The results of this study demonstrate that fertile tetraploid interspecific hybrids with a high intergenomic pairing at meiosis are valuable basic material for introgression breeding in barley.


Protoporphyrin IX-β-cyclodextrin bimodal conjugate: nanosized drug transporter and potent phototoxin.
Topical or systemic administration of 5-aminolevulinic acid (ALA) and its esters results in increased production and accumulation of protoporphyrin IX (PpIX) in cancerous lesions allowing effective application of photodynamic therapy (PDT). The large concentrations of exogenous ALA practically required to bypass the negative feedback control exerted by heme on enzymatic ALA synthesis and the strong dimerization propensity of ALA are shortcomings of the otherwise attractive PpIX biosynthesis. To circumvent these limitations and possibly enhance the phototoxicity of PpIX by adjuvant chemotherapy, covalent bonding of PpIX with a drug carrier, β-cyclodextrin (βCD) was implemented. The resulting PpIX + βCD product had both carboxylic termini of PpIX connected to the CD. PpIX + βCD was water soluble, was found to preferentially localize in mitochondria rather than in lysosomes both in MCF7 and DU145 cell lines while its phototoxiciy was comparable to that of PpIX. Moreover, PpIX + βCD effectively solubilized the breast cancer drug tamoxifen metabolite N-desmethyltamoxifen (NDMTAM) in water. The PpIX + βCD/NDMTAM complex was readily internalized by both cell lines employed. Furthermore, the multimodal action of PpIX + βCD was demonstrated in MCF7 cells: while it retains the phototoxic profile of PpIX and its fluorescence for imaging purposes, PpIX + βCD can efficiently transport tamoxifen citrate intracellularly and confer cell death through a synergy of photo- and chemotoxicity.


Association study of CREB1 with Major Depressive Disorder and related phenotypes.
Cyclic AMP response element binding protein (CREB) has been implicated in behavioral models of anxiety and depression, antidepressant response in humans, and suicide. One group reported a female-specific association of the CREB1 gene in early-onset Major Depressive Disorder (MDD), while another found no evidence of association with this phenotype. In this study, we sought to examine the evidence for association of the CREB1 gene to MDD and related phenotypes. We used multivariate structural equation modeling to identify and select twin pairs that scored at the extremes of a latent genetic risk factor shared by MDD, neuroticism, and several anxiety disorders from the Virginia Twin Registry. Using one member from each of these pairs, the resulting sample of 589 cases (including 473 subjects with lifetime MDD) and 539 controls were entered into a 2-stage association study in which genetic markers were screened in stage 1, the positive results of which were tested for replication in stage 2. Eight SNP markers selected to capture the major allelic variation across the haplotype block containing CREB1 were analyzed for differences between cases and controls. Several markers showed criterion differences between cases and controls in the stage 1 sample with some evidence of sex specific effects. However, none of these markers were significant in stage 2 in either sex individually or combined. Our data suggests that common variations in the CREB1 gene do not appear to increase susceptibility for MDD or related phenotypes.


Use of multiresolution wavelet feature pyramids for automatic registration of multisensor imagery.
The problem of image registration, or the alignment of two or more images representing the same scene or object, has to be addressed in various disciplines that employ digital imaging. In the area of remote sensing, just like in medical imaging or computer vision, it is necessary to design robust, fast, and widely applicable algorithms that would allow automatic registration of images generated by various imaging platforms at the same or different times and that would provide subpixel accuracy. One of the main issues that needs to be addressed when developing a registration algorithm is what type of information should be extracted from the images being registered, to be used in the search for the geometric transformation that best aligns them. The main objective of this paper is to evaluate several wavelet pyramids that may be used both for invariant feature extraction and for representing images at multiple spatial resolutions to accelerate registration. We find that the bandpass wavelets obtained from the steerable pyramid due to Simoncelli performs best in terms of accuracy and consistency, while the low-pass wavelets obtained from the same pyramid give the best results in terms of the radius of convergence. Based on these findings, we propose a modification of a gradient-based registration algorithm that has recently been developed for medical data. We test the modified algorithm on several sets of real and synthetic satellite imagery.


Integrated Three-Electrode Dual-Mode Detection Chip for Place Cell Analysis: Dopamine Facilitates the Role of Place Cells in Encoding Spatial Locations of Novel Environments and Rewards.
The functioning of place cells requires the involvement of multiple neurotransmitters, with dopamine playing a critical role in hippocampal place cell activity. However, the exact mechanisms through which dopamine influences place cell activity remain largely unknown. Herein, we present the development of the integrated three-electrode dual-mode detection chip (ITDDC), which enables simultaneous recording of the place cell activity and dopamine concentration fluctuation. The working electrode, reference electrode, and counter electrode are all integrated within the ITDDC in electrochemical detection, enabling the real-time in situ monitoring of dopamine concentrations in animals in motion. The reference, working, and counter electrodes are surface-modified using PtNPs and polypyrrole, PtNPs and PEDOT:PSS, and PtNPs, respectively. This modification allows for the detection of dopamine concentrations as low as 20 nM. We conducted dual-mode testing on mice in a novel environment and an environment with food rewards. We found distinct dopamine concentration variations along different paths within a novel environment, implying that different dopamine levels may contribute to spatial memory. Moreover, environmental food rewards elevate dopamine significantly, followed by the intense firing of reward place cells, suggesting a crucial role of dopamine in facilitating the encoding of reward-associated locations in animals. The real-time and in situ recording capabilities of ITDDC offer new opportunities to investigate the interplay between electrophysiology and dopamine during animal exploration and reward-based memory and provide a novel glimpse into the correlation between dopamine levels and place cell activity.


Environmentally-friendly lithium recycling from a spent organic li-ion battery.
A simple and straightforward method using non-polluting solvents and a single thermal treatment step at moderate temperature was investigated as an environmentally-friendly process to recycle lithium from organic electrode materials for secondary lithium batteries. This method, highly dependent on the choice of electrolyte, gives up to 99% of sustained capacity for the recycled materials used in a second life-cycle battery when compared with the original. The best results were obtained using a dimethyl carbonate/lithium bis(trifluoromethane sulfonyl) imide electrolyte that does not decompose in presence of water. The process implies a thermal decomposition step at a moderate temperature of the extracted organic material into lithium carbonate, which is then used as a lithiation agent for the preparation of fresh electrode material without loss of lithium.


HIMF (Hypoxia-Induced Mitogenic Factor) Signaling Mediates the HMGB1 (High Mobility Group Box 1)-Dependent Endothelial and Smooth Muscle Cell Crosstalk in Pulmonary Hypertension.
HIMF (hypoxia-induced mitogenic factor; also known as FIZZ1 [found in inflammatory zone-1] or RELM [resistin-like molecule-α]) is an etiological factor of pulmonary hypertension (PH) in rodents, but its underlying mechanism is unclear. We investigated the immunomodulatory properties of HIMF signaling in PH pathogenesis. Approach and Results: Gene-modified mice that lacked HIMF (KO [knockout]) or overexpressed HIMF human homolog resistin (hResistin) were used for in vivo experiments. The pro-PH role of HIMF was verified in HIMF-KO mice exposed to chronic hypoxia or sugen/hypoxia. Mechanistically, HIMF/hResistin activation triggered the HMGB1 (high mobility group box 1) pathway and RAGE (receptor for advanced glycation end products) in pulmonary endothelial cells (ECs) of hypoxic mouse lungs in vivo and in human pulmonary microvascular ECs in vitro. Treatment with conditioned medium from hResistin-stimulated human pulmonary microvascular ECs induced an autophagic response, BMPR2 (bone morphogenetic protein receptor 2) defects, and subsequent apoptosis-resistant proliferation in human pulmonary artery (vascular) smooth muscle cells in an HMGB1-dependent manner. These effects were confirmed in ECs and smooth muscle cells isolated from pulmonary arteries of patients with idiopathic PH. HIMF/HMGB1/RAGE-mediated autophagy and BMPR2 impairment were also observed in pulmonary artery (vascular) smooth muscle cells of hypoxic mice, effects perhaps related to FoxO1 (forkhead box O1) dampening by HIMF. Experiments in EC-specific hResistin-overexpressing transgenic mice confirmed that EC-derived HMGB1 mediated the hResistin-driven pulmonary vascular remodeling and PH. In HIMF-induced PH, HMGB1-RAGE signaling is pivotal for mediating EC-smooth muscle cell crosstalk. The humanized mouse data further support clinical implications for the HIMF/HMGB1 signaling axis and indicate that hResistin and its downstream pathway may constitute targets for the development of novel anti-PH therapeutics in humans.


More vasopressin mRNA in the paraventricular hypothalamic nucleus of alcohol-preferring rats and high alcohol-drinking rats selectively bred for high alcohol preference.
Both the selectively bred alcohol-preferring (P) and high alcohol-drinking (HAD) rats exhibit alcohol preference, and develop tolerance to alcohol more quickly than their counterparts, the alcohol-nonpreferring (NP) and low alcohol-drinking (LAD) rats, respectively. It has been shown that the P rats retain developed tolerance longer than do NP rats, and alcohol drinking increases concurrently with the development of tolerance. Although alcohol preference and tolerance are fundamental elements of alcoholism, the exact mechanisms underlying these two phenotypes in P and HAD rats are not well understood. Recent studies have suggested that arginine vasopressin (AVP) may be involved in modulation of alcohol tolerance. Accordingly, this study was designed to examine whether the AVP mRNA level in the hypothalamus differs in rats that have been selectively bred for alcohol preference and nonpreference. A 35S-AVP antisense oligodeoxynucleotide probe was used for in situ hybridization to localize AVP mRNA in the paraventricular hypothalamic nucleus (PVN) and supraoptic nucleus (SON), two major sites for AVP synthesis in the hypothalamus. Quantitative autoradiography demonstrated that P rats had higher levels of AVP mRNA in the PVN than NP rats. Similarly, higher levels of AVP mRNA were also found in the PVN of HAD rats, compared with LAD rats. The AVP mRNA levels in the SON were similar in the alcohol-preferring and alcohol-nonpreferring rat lines. Basal plasma AVP levels were higher in NP rats than in P rats as determined by radioimmunoassay, whereas plasma AVP levels were not significantly different between HAD and LAD rats. The results suggest that increased AVP gene expression in the PVN may contribute to alcohol preference and the development of alcohol tolerance.


Molecular p-doping in organic liquid crystalline semiconductors: influence of the charge transfer complex on the properties of mesophase and bulk charge transport.
We explore the molecular nature of doping in organic semiconductors (OSCs) by employing a liquid crystalline organic semiconductor based on phenyl naphthalene as a model. The mesophase nature of composites that include a charge transfer complex (CTC) between the OSC (8-PNP-O12) and an electron acceptor (F4TCNQ) has been investigated by means of differential scanning calorimetry, polarized optical microscopy and X-ray scattering. Optical and vibrational spectroscopies allow us to explore the characteristics and the amount of charge transfer in the CTC and expose some properties that appear only in the complexed state. We have found this system to exhibit partial charge transfer, which manifests itself in all the phase states of the host 8-PNP-O12, as well as in solution. Due to the lowering of molecular symmetry as a result of the charge transfer, one of the previously IR-only vibrational bands of the nitrile group is found to be now active in the Raman spectrum. We have also made an attempt to further investigate the influence of dopant introduction on the bulk hole mobility of 8-PNP-O12. It is found that the presence of the CTC promotes the hole transport in the Smectic B mesophase, however it seems to have a somewhat negative influence in the less ordered smectic A mesophase. This work aims to establish the link between the inevitable change of molecular geometry that occurs on charge transfer with the results obtained by spectroscopic techniques and electronic charge carrier mobility measurements.


The effects of norepinephrine transporter inactivation on locomotor activity in mice.
Acute administration of different classes of antidepressants can enhance or reduce spontaneous locomotor activity in a novel environment, but the effects of chronic antidepressant treatment on spontaneous locomotor activity in novel and familiar environments are less well characterized. Because norepinephrine is an important regulator of spontaneous locomotor activity, we speculated that norepinephrine transporter blockade contributes to the effects of some antidepressants on spontaneous locomotor activity. Antidepressant drugs (reboxetine, desipramine, imipramine, venlafaxine, bupropion) were administered acutely (intraperitoneal) or chronically (via osmotic minipump) to control and norepinephrine transporter knockout mice, and spontaneous locomotor activity in novel or familiar environments was recorded. Acute treatment with most norepinephrine transporter-blocking antidepressants decreased spontaneous locomotor activity in a novel environment, whereas chronic treatment decreased spontaneous locomotor activity in both novel and familiar environments. The exception was bupropion, a dual norepinephrine transporter/dopamine transporter blocker, which tended to increase spontaneous locomotor activity. Coadministration of reboxetine and the dopamine transporter blocker GBR 12909 also increased spontaneous locomotor activity. Norepinephrine transporter knockout mice had low basal spontaneous locomotor activity, which was increased by bupropion, whereas reboxetine had no effect in norepinephrine transporter knockout mice. Acute or chronic inactivation of the norepinephrine transporter decreases spontaneous locomotor activity in novel and familiar environments unless coupled with dopamine transporter blockade.


'Lnc'-ing Wnt in female reproductive cancers: therapeutic potential of long non-coding RNAs in Wnt signalling.
Recent discoveries in the non-coding genome have challenged the original central dogma of molecular biology, as non-coding RNAs and related processes have been found to be important in regulating gene expression. MicroRNAs and long non-coding RNAs (lncRNAs) are among those that have gained attention recently in human diseases, including cancer, with the involvement of many more non-coding RNAs (ncRNAs) waiting to be discovered. ncRNAs are a group of ribonucleic acids transcribed from regions of the human genome, which do not become translated into proteins, despite having essential roles in cellular physiology. Deregulation of ncRNA expression and function has been observed in cancer pathogenesis. Recently, the roles of a group of ncRNA known as lncRNA have gained attention in cancer, with increasing reports of their oncogenic involvement. Female reproductive cancers remain a leading cause of death in the female population, accounting for almost a third of all female cancer deaths in 2016. The Wnt signalling pathway is one of the most important oncogenic signalling pathways which is hyperactivated in cancers, including female reproductive cancers. The extension of ncRNA research into their mechanistic roles in human cancers has also led to novel reported roles of ncRNAs in the Wnt pathway and Wnt-mediated oncogenesis. This review aims to provide a critical summary of the respective roles and cellular functions of Wnt-associated lncRNAs in female reproductive cancers and explores the potential of circulating cell-free lncRNAs as diagnostic markers and lncRNAs as therapeutic targets. This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc.


Developmental programming in human umbilical cord vein endothelial cells following fetal growth restriction.
Fetal growth restriction (FGR) is associated with an increased susceptibility for various noncommunicable diseases in adulthood, including cardiovascular and renal disease. During FGR, reduced uteroplacental blood flow, oxygen and nutrient supply to the fetus are hypothesized to detrimentally influence cardiovascular and renal programming. This study examined whether developmental programming profiles, especially related to the cardiovascular and renal system, differ in human umbilical vein endothelial cells (HUVECs) collected from pregnancies complicated by placental insufficiency-induced FGR compared to normal growth pregnancies. Our approach, involving transcriptomic profiling by RNA-sequencing and gene set enrichment analysis focused on cardiovascular and renal gene sets and targeted DNA methylation assays, contributes to the identification of targets underlying long-term cardiovascular and renal diseases. Gene set enrichment analysis showed several downregulated gene sets, most of them involved in immune or inflammatory pathways or cell cycle pathways. seven of the 22 significantly upregulated gene sets related to kidney development and four gene sets involved with cardiovascular health and function were downregulated in FGR (n = 11) versus control (n = 8). Transcriptomic profiling by RNA-sequencing revealed downregulated expression of LGALS1, FPR3 and NRM and upregulation of lincRNA RP5-855F14.1 in FGR compared to controls. DNA methylation was similar for LGALS1 between study groups, but relative hypomethylation of FPR3 and hypermethylation of NRM were present in FGR, especially in male offspring. Absolute differences in methylation were, however, small. This study showed upregulation of gene sets related to renal development in HUVECs collected from pregnancies complicated by FGR compared to control donors. The differentially expressed gene sets related to cardiovascular function and health might be in line with the downregulated expression of NRM and upregulated expression of lincRNA RP5-855F14.1 in FGR samples; NRM is involved in cardiac remodeling, and lincRNAs are correlated with cardiovascular diseases. Future studies should elucidate whether the downregulated LGALS1 and FPR3 expressions in FGR are angiogenesis-modulating regulators leading to placental insufficiency-induced FGR or whether the expression of these genes can be used as a biomarker for increased cardiovascular risk. Altered DNA methylation might partly underlie FPR3 and NRM differential gene expression differences in a sex-dependent manner.


The work of the Drugs Intelligence Laboratory, Home Office Forensic Science Service.
The primary purpose of the Drugs Intelligence Laboratory is to help the police identify sources of supply and manufacture of illicit drugs. This is done by providing scientific support to the Central Drugs and Illegal Immigration Intelligence Unit, a national police unit based at New Scotland Yard, London. The Laboratory provides detailed information on United Kingdom drug seizures and data obtained from a programme of comparison and characterization of seized samples. This intelligence information is then used to supplement that obtained through normal police channels in the search for illicit drug sources, manufacturers or distributors. This paper describes the techniques used for comparing and characterizing various drug preparations and outlines the type of information that can be gained from such studies.


Rehabilitation that incorporates virtual reality is more effective than standard rehabilitation for improving walking speed, balance and mobility after stroke: a systematic review.
In people after stroke, does virtual reality based rehabilitation (VRBR) improve walking speed, balance and mobility more than the same duration of standard rehabilitation? In people after stroke, does adding extra VRBR to standard rehabilitation improve the effects on gait, balance and mobility? Systematic review with meta-analysis of randomised trials. Adults with a clinical diagnosis of stroke. Eligible trials had to include one these comparisons: VRBR replacing some or all of standard rehabilitation or VRBR used as extra rehabilitation time added to a standard rehabilitation regimen. Walking speed, balance, mobility and adverse events. In total, 15 trials involving 341 participants were included. When VRBR replaced some or all of the standard rehabilitation, there were statistically significant benefits in walking speed (MD 0.15 m/s, 95% CI 0.10 to 0.19), balance (MD 2.1 points on the Berg Balance Scale, 95% CI 1.8 to 2.5) and mobility (MD 2.3 seconds on the Timed Up and Go test, 95% CI 1.2 to 3.4). When VRBR was added to standard rehabilitation, mobility showed a significant benefit (0.7 seconds on the Timed Up and Go test, 95% CI 0.4 to 1.1), but insufficient evidence was found to comment about walking speed (one trial) and balance (high heterogeneity). Substituting some or all of a standard rehabilitation regimen with VRBR elicits greater benefits in walking speed, balance and mobility in people with stroke. Although the benefits are small, the extra cost of applying virtual reality to standard rehabilitation is also small, especially when spread over many patients in a clinic. Adding extra VRBR time to standard rehabilitation also has some benefits; further research is needed to determine if these benefits are clinically worthwhile.


Gremlin in the pathogenesis of hepatocellular carcinoma complicating chronic hepatitis C: an immunohistochemical and PCR study of human liver biopsies.
The possible role of secretory products of fibrous tissue in the development of hepatocellular carcinoma (HCC) complicating chronic hepatitis C was investigated. Our hypothesis was that gremlin, secreted by fibroblasts, inhibited bone morphogenic protein (BMP), which mediates stem cell maturation into adult functioning hepatocytes, and thus, arrest stem cell maturation and promoted their proliferation in an immature state possibly culminating into development of HCCs. Protein expression of cytokeratin 19 (CK19) and fibroblast growth factor 2 (FGF-2), and mRNA expression of gremlin and BMP-7 were studied in 35 cases of chronic hepatitis, cirrhosis and HCC complicating chronic hepatitis C. CK19 expression was higher in cases of cirrhosis (0.004), which correlated with the grade (r = 0.64, p = 0.009) and stage (r = 0.71, p = 0.001). All HCCs were negative for CK19. Stem cell niche activation (as indicated as a ductular reaction) was highest in cases of cirrhosis (p = 0.001) and correlated with CK19 expression (r = 0.42, p = 0.012), the grade(r = 0.56, p = 0.024) and stage (0.66, p = 0.006). FGF-2 expression was highest in HCCs and correlated with the grade (r = 0.6, p = 0.013), stage (0.72, p = 0.002), CK19 expression (r = 0.71, p = 002) and ductular reaction (0.68, p = 0.004) in hepatitis cases. Higher numbers of cirrhosis cases and HCCs (p = 0.009) showed gremlin expression, which correlated with the stage (r = 0.7, p = 0.002). Gremlin expression correlated with that of CK19 (r = 0.699, p = 0.003) and FGF2 (r = 0.75, p = 0.001) in hepatitis cases. Fibrosis promotes carcinogenesis by fibroblast-secreted gremlin that blocks BMP function and promotes stem cell activation and proliferation as well as possibly HCC development.


Primary diffuse large B-cell lymphoma of the mandible.
Primary intraosseous non-Hodgkin lymphoma in the mandible is uncommon, representing about 0.6% of all extranodal lymphomas. We present the case of a 51-year-old male with a 4-month complaint of mandibular swelling and paresthesia, which had been previously submitted to an unsuccessful periodontal treatment. The intra-oral evaluation showed an extensive swelling with teeth mobility in the right mandible body. The panoramic radiography and computed tomography images showed an extensive osteolytic lesion. An incisional biopsy was performed and the histopathological and immunohistochemical analysis established the diagnosis of diffuse large B-cell lymphoma. The treatment included six cycles of chemotherapy with complete remission. The patient is under the seventh month of follow-up with no evidence of relapse. Although uncommon in the oral cavity, lymphoma should be considered in the differential diagnosis.


Predicting clinically significant response to cognitive behavior therapy for chronic insomnia in general medical practice: analysis of outcome data at 12 months posttreatment.
The clinical efficacy of cognitive behavior therapy (CBT) for chronic insomnia has been established, yet clinical effectiveness is less clear. This study presents data on 109 patients from general practice during a formal evaluation of clinical effectiveness. Two thirds achieved normative values of < or =30 min for sleep latency and wakefulness during the night after CBT. Furthermore, almost half of the sample reduced sleeplessness by > or =50%. Logistic regression revealed that initial severity did not contraindicate good outcome. Rather, greater sleep disturbance was positively associated with large symptom reduction, although lower endpoint scores were less likely. Similarly, symptoms of anxiety, depression, and thinking errors positively predicted good outcome. Hypnotic using patients responded equally well to CBT, and demographic factors were of no significant predictive value. It is concluded that CBT is clinically and durably effective for persistent insomnia in routine practice.


[Combined spinal-epidural and epidural anesthesia in operations on the vessels of the lower extremities].
Eighty-eight anesthesias in patients operated on the lower limb vessels are analyzed. In group 1 (77 pts) combined spinal-epidural anesthesia (CSEA) was used, in group 2 (16 pts) epidural anesthesia (EA). Segmentary blocking was induced by 2% lidocaine and 0.5% bupivacaine. CSEA was characterized by a shorter (in comparison with EA) latent period (12.9 +/- 1.3 min vs. 24.7 +/- 3.4 min, p < 0.05), a lower dose of bupivacaine (lidocaine: 735 +/- 89 mg in CSEA and 848 +/- 92 mg in EA; bupivacaine: 28.3 +/- 7.2 mg in CSEA and 92.6 +/- 8.5 mg in EA, p < 0.01), and a higher reliability. Combined anesthesia with bupivacaine is characterized by a greater contribution of the spinal component (than with lidocaine) and thus improve the quality of anesthesia, decrease the anesthetic dose, and maintain the stability of hemodynamic parameters. Four cases with inadequate blocking were due to erroneous position of the epidural catheter. Accidental perforation of the dura mater occurred in two patients, and prolonged spinal anesthesia was carried out. No headaches ensued. Hence, CSEA should be preferred to common prolonged EA in operations on the lower limb vessels.


[A meta-analysis of probiotics for the treatment of irritable bowel syndrome].
To evaluate the efficacy of probiotics to treat irritable bowel syndrome (IBS). Publications from database including PubMed, the Cochrane Library, Embase, CNKI, CBM and WanFang Data were searched up to August 31, 2014. The randomized controlled trials (RCTs) on probiotics to treat IBS were eligible. The related articles were extracted and cross-checked independently by two reviewers. Methodological quality of trials was evaluated according to Cochrane Handbook 5.1.0 criteria. Meta-analysis was conducted using RevMan 5.2 software. A total of 17 RCTs involving 1 700 patients were included. Results of meta-analyses showed that compared with the placebo, probiotics was statistically better in improving the overall symptoms integral (SMD = -0.20, 95% CI -0.33--0.07, P = 0.002), alleviating abdominal pain/discomfort (SMD = -0.19, 95% CI -0.29--0.09, P<0.001), relieving abdominal distention (SMD = -0.16, 95% CI -0.28--0.03, P = 0.020), and defecation discomfort (SMD = -0.22, 95% CI -0.42--0.02, P = 0.030). There was no statistical significance in the overall quality of life (SMD = -0.08, 95% CI -0.07-0.23, P = 0.290) and adverse effect ratio (RR = 1.08, 95% CI 0.79-1.49, P = 0.630). Probiotics have beneficial effects on IBS, which can improve the patients' symptoms and with less adverse reaction. Due to the bias, further large-scale, multicenter and high-quality RCTs are required to unify outcome indicators, further define sensitive strain, and standardize its usage, dosage and course of treatment.


Remedies for common family ailments: 10. Nasal decongestants.
Nasal congestion and sinusitis are common effects of cold and flu viruses. One treatment for nasal congestion is oral doses of vasoconstrictors such as ephedrine which mimic the action of the sympathetic nervous system. Care should be taken before these are prescribed or recommended as these drugs are contraindicated in patients on certain drugs or with certain conditions. Vasoconstrictors can also be given as nasal drops or sprays but for a limited period to avoid rebound congestion. Aromatic volatile oils, e.g. menthol, eucalyptus, can be given as rubs or inhalants (see manufacturers' instructions for use with young children).


L-carnitine infusion does not alleviate lipid-induced insulin resistance and metabolic inflexibility.
Low carnitine status may underlie the development of insulin resistance and metabolic inflexibility. Intravenous lipid infusion elevates plasma free fatty acid (FFA) concentration and is a model for simulating insulin resistance and metabolic inflexibility in healthy, insulin sensitive volunteers. Here, we hypothesized that co-infusion of L-carnitine may alleviate lipid-induced insulin resistance and metabolic inflexibility. In a randomized crossover trial, eight young healthy volunteers underwent hyperinsulinemic-euglycemic clamps (40mU/m2/min) with simultaneous infusion of saline (CON), Intralipid (20%, 90mL/h) (LIPID), or Intralipid (20%, 90mL/h) combined with L-carnitine infusion (28mg/kg) (LIPID+CAR). Ten volunteers were randomized for the intervention arms (CON, LIPID and LIPID+CAR), but two dropped-out during the study. Therefore, eight volunteers participated in all three intervention arms and were included for analysis. L-carnitine infusion elevated plasma free carnitine availability and resulted in a more pronounced increase in plasma acetylcarnitine, short-, medium-, and long-chain acylcarnitines compared to lipid infusion, however no differences in skeletal muscle free carnitine or acetylcarnitine were found. Peripheral insulin sensitivity and metabolic flexibility were blunted upon lipid infusion compared to CON but L-carnitine infusion did not alleviate this. Acute L-carnitine infusion could not alleviated lipid-induced insulin resistance and metabolic inflexibility and did not alter skeletal muscle carnitine availability. Possibly, lipid-induced insulin resistance may also have affected carnitine uptake and may have blunted the insulin-induced carnitine storage in muscle. Future studies are needed to investigate this.


SB Driver Analysis: a Sleeping Beauty cancer driver analysis framework for identifying and prioritizing experimentally actionable oncogenes and tumor suppressors.
Cancer driver prioritization for functional analysis of potential actionable therapeutic targets is a significant challenge. Meta-analyses of mutated genes across different human cancer types for driver prioritization has reaffirmed the role of major players in cancer, including KRAS, TP53 and EGFR, but has had limited success in prioritizing genes with non-recurrent mutations in specific cancer types. Sleeping Beauty (SB) insertional mutagenesis is a powerful experimental gene discovery framework to define driver genes in mouse models of human cancers. Meta-analyses of SB datasets across multiple tumor types is a potentially informative approach to prioritize drivers, and complements efforts in human cancers. Here, we report the development of SB Driver Analysis, an in-silico method for defining cancer driver genes that positively contribute to tumor initiation and progression from population-level SB insertion data sets. We demonstrate that SB Driver Analysis computationally prioritizes drivers and defines distinct driver classes from end-stage tumors that predict their putative functions during tumorigenesis. SB Driver Analysis greatly enhances our ability to analyze, interpret and prioritize drivers from SB cancer datasets and will continue to substantially increase our understanding of the genetic basis of cancer.


Substrate binding and catalysis of ecto-ADP-ribosyltransferase 2.2 from rat.
The structures of beta-methylenethiazole-4-carboxamide adenine dinucleotide (TAD), NAD(+), and NADH as bound to ecto-ADP-ribosyltransferase 2.2 from rat and to its mutants E189I and E189A, respectively, have been established. The positions and conformations of NAD(+) and its analogues agree in general with those in other ADP-ribosyltransferases. The kinetic constants for NAD(+) hydrolysis were determined by RP-HPLC. The specific activity amounts to 26 units/mg, which is 6000-fold higher than a previously reported rate and 500-fold higher than the hydrolysis rates of other ADP-ribosyltransferases, confirming that hydrolysis is the major function of this enzyme. On the basis of structures and mutant activities, a catalytic mechanism is proposed. The known auto-ADP-ribosylation of the enzyme at the suggested position R184 is supported by one of the crystal structures where the nucleophile position is occupied by an Neta atom of this arginine which in turn is backed up by the base E159.


The Expressed Genome in Cardiovascular Diseases and Stroke: Refinement, Diagnosis, and Prediction: A Scientific Statement From the American Heart Association.
There have been major advances in our knowledge of the contribution of DNA sequence variations to cardiovascular disease and stroke. However, the inner workings of the body reflect the complex interplay of factors beyond the DNA sequence, including epigenetic modifications, RNA transcripts, proteins, and metabolites, which together can be considered the "expressed genome." The emergence of high-throughput technologies, including epigenomics, transcriptomics, proteomics, and metabolomics, is now making it possible to address the contributions of the expressed genome to cardiovascular disorders. This statement describes how the expressed genome can currently and, in the future, potentially be used to diagnose diseases and to predict who will develop diseases such as coronary artery disease, stroke, heart failure, and arrhythmias.


Clinical study to compare the effectiveness of a test whitening toothpaste with a commercial whitening toothpaste at inhibiting dental stain.
A single centre, randomised single-blind, three-way crossover study was performed, to compare the effect of an experimental test toothpaste with a commercially available whitening toothpaste and water control at inhibiting extrinsic stain promoted by repeated chlorhexidine/tea rinses. This study used 23 subjects. During the week before the study the subjects received a prophylaxis to remove all staining, plaque and calculus deposits. On the Monday of the following week subjects returned to the clinic to receive their rinses and to check their dentition was stain free. Under direct supervision at both 09:00 and 13:00 hours they rinsed with either a toothpaste slurry or water control that was repeated daily up to and including the following Thursday. Additionally from the Monday to the Thursday each subject rinsed with a 0.2% chlorhexidine mouthrinse, immediately followed by a rinse with a warm black tea solution. This cycle was repeated hourly eight times throughout the day and on the following days until the Friday. Throughout this period volunteers omitted all other forms of oral hygiene except rinsing with the chlorhexidine mouthwash. On the Friday the level of stain on the teeth and dorsum of tongue was assessed using the Lobene stain index for both stain area and intensity. At the end of each trial period each subject received a thorough prophylaxis to remove all plaque, calculus and staining before starting the second and third period of the study. As expected appreciable amounts of extrinsic stain accumulated on the teeth over each study period. The amount of stain following use of the toothpastes and water control was least with the experimental toothpaste, followed by water control and lastly the commercial whitening paste. For all sites combined there was evidence that the experimental paste was significantly superior to both the commercial paste and water control at reducing stain area (p<0.001), a product of stain area and intensity (p<0.001 and 0.05, respectively) but not stain intensity (p>0.05). In this stain-prevention model the use of an experimental paste showed a significant reduction in stain accumulation on the teeth compared with a (placebo) negative water control and a commercially available whitening paste. As such the experimental paste would be expected to be of benefit in controlling extrinsic dental staining.


HBx elevates oncoprotein AEG-1 expression to promote cell migration by downregulating miR-375 and miR-136 in malignant hepatocytes.
The hepatitis B viral X protein (HBx) has been established to implicate in the development of HBV-related hepatocellular carcinoma (HCC) via multiple pathways. The oncoprotein astrocyte elevated gene-1 (AEG-1) is overexpressed in various tumors, including HCC, and plays critical roles in promoting cell migration and invasion. However, the mechanisms for AEG-1 upregulation in tumors are largely unknown. In this study, we found that HBx could elevate AEG-1 protein level without altering its mRNA level. When blocking AEG-1 expression with siRNA in HBx-transfected cells, the HBx-induced cell migration was significantly suppressed. Further study indicated that miR-375 and miR-136 that targeted AEG-1 were downregulated with HBx expression. Overexpressing miR-375 and miR-136 could effectively attenuate HBx-mediated AEG-1 elevation and cell migration. These results demonstrated that HBx enabled to increase oncoprotein AEG-1 expression to promote cell migration via downregulating miR-375 and miR-136. Our findings provide a novel insight into AEG-1 upregulation in HCC and shed new light on HBx promoting HCC progression. Meanwhile, our results also suggest that miR-375 and miR-136 may have the miRNA-based therapeutic potential in HBV-associated HCC.


Surgical treatment for squamous cell carcinoma of the temporal bone: predictors of survival.
Evaluation of the management and survival in patients treated for temporal bone squamous cell carcinoma (TBSCC) in a tertiary referral centre. Forty-nine patients underwent primary treatment for TBSCC. Thirty-six patients underwent a lateral temporal bone resection (LTBR) or subtotal temporal bone resection (STBR). Overall survival (OS) and disease-specific survival (DSS) analysis were assessed. Five-year OS of the 49 patients was 39%. Five-year OS of the 36 patients who underwent LTBR or STBR was 46%. Tumour-free margins were achieved in all patients with T1 and T2 disease, in 59% patients with T3 tumours and 0% patients with T4 disease. Five-year DSS was 85% for all T1/T2 tumours, 53% for T3 tumours and 0% for T4 tumours. Clear resection margins was the only significant predictor of DSS in our cohort. The mainstay of treatment for TBSCC is temporal bone resection with tumour free resection margins, with or without adjuvant radiotherapy. Survival is negatively influenced by non-radical resection. T1 and T2 tumours can be managed safely with LTBR. More advanced disease requires a more extensive resection, with a higher likelihood of non-radical resections and decreased survival rates.


Adsorption of alkyl polyglucosides on the solid/water interface: equilibrium effects of alkyl chain length and head group polymerization.
The equilibrium adsorption behavior of two n-alkyl-beta-D-glucosides (octyl (C8G1) and decyl (C10G1)) and four n-alkyl-beta-D-maltosides (octyl (C8G2), decyl (C10G2), dodecyl (C12G2), and tetradecyl (C14G2)) from aqueous solution on a titania surface, as measured by ellipsometry, has been investigated. The main focus has been on the effect of changes in the alkyl chain length and headgroup polymerization, but a comparison with their adsorption on the silica/water and air/water interfaces is also presented. Some comparison with the corresponding adsorption of ethylene oxide surfactants, in particular C10E6 and C12E6, is given as well. For all alkyl polyglucosides, the maximum adsorbed amount on titania is reached slightly below the critical micelle concentration (cmc), where it levels off to a plateau and the amount adsorbed corresponds roughly to a bilayer. However, there is no evidence that this is the actual conformation of the surfactant assemblies on the surface, but the surfactants could also be arranged in a micellar network. On hydrophilic silica, the adsorbed amount is a magnitude lower than on titania, corresponding roughly to a layer of surfactants lying flat on the surface. A change in the alkyl chain length does not result in any change in the plateau molar adsorbed amount at equilibrium; however, the isotherm slope for the alkyl maltosides increases with increasing chain length. Headgroup polymerization on the other hand affects the adsorbed amount. The alkyl glucosides start adsorbing at lower bulk concentrations than the maltosides and equilibrate at higher adsorbed amounts above the cmc. When compared with the ethylene oxide (EO) surfactants, it is confirmed that the EO surfactants hardly adsorb on titania, since the measured changes in the ellipsometric angles are within the noise level. They do, however, adsorb strongly on silica.


Artichoke juice improves endothelial function in hyperlipemia.
Artichoke extracts have been shown to produce various pharmacological effects, such as the inhibition of cholesterol biosynthesis and of LDL oxidation. Endothelial dysfunction represents the first stage of atherosclerotic disease; it is usually evaluated in humans by a noninvasive ultrasound method as brachial flow-mediated vasodilation (FMV) and by the determination of several humoral markers such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin. Aim of the study was to investigate the effects of dietary supplementation with artichoke juice on brachial FMV of hyperlipemics. We studied 18 moderately hyperlipemic patients (LDL cholesterol > 130 <200 mg/dl and/or triglycerides >150 <250 mg/dl) of both genders and 10 hyperlipemic patients, matched for age, sex and lipid parameters. All subjects were under isocaloric hypolipidic diet. A basal determination of serum lipids, soluble VCAM-1, ICAM-1, E-selectin and brachial FMV was performed. Thereafter patients were given 20 ml/die of frozen artichoke juice. The same parameters were repeated after 6 weeks. After artichoke treatment there was an increase of triglycerides (156 +/- 54 vs 165 +/- 76 mg/dL, p <0.05) and a reduction of total cholesterol (261 +/- 37 vs 244 +/- 38 mg/dL, p <0.05) and LDL cholesterol (174 +/- 31 vs 160 +/- 34 mg/dL, p <0.05). Controls showed a significant decrease in total and LDL cholesterol (respectively: 267 +/- 22 vs 249 +/- 20 mg/dL and 180 +/- 24 vs 164 +/- 23 mg/dL, both p <0.001). After artichoke there was a decrease in VCAM-1(1633 +/- 1293 vs 1139 +/- 883 ng/mL, p <0.05) and ICAM-1(477 +/- 123 vs 397 +/- 102 ng/mL, p <0.05), brachial FMV increased (3.3 +/- 2.7 vs 4.5 +/- 2.4%, p <0.01), while controls did not exhibit significant changes in VCAM-1, ICAM-1, E-selectin and brachial FMV. Univariate analysis showed that, in artichoke patients, changes of VCAM-1 and ICAM-1 were significantly related to changes in brachial FMV (respectively: r=-0.66 and r=-0.62; both p <0.05). In conclusion, artichoke dietary supplementation seems to positively modulate endothelial function in hypercholesterolemia.


A homogeneous immunoassay for cyclic nucleotides based on chemiluminescence energy transfer.
A chemiluminescent derivative of cyclic AMP, aminobutylethylisoluminol succinyl cyclic AMP (ABEI-scAMP), was synthesized in order to develop a homogeneous immunoassay based on non-radiative energy transfer. ABEI-scAMP was chemiluminescent (5.1 X 10(18) luminescent counts X mol-1 at pH 13), pure (greater than 95%) stable and immunologically active. A conventional immunoassay was established using ABEI-scAMP and a solid-phase anti-(cyclic AMP) immunoglobulin G which could detect cyclic AMP at least down to 25fmol. A homogeneous immunoassay for cyclic AMP was established by measuring the shift in wavelength from 460 to 525nm which occurred when ABEI-scAMP was bound to fluorescein-labelled anti-(cyclic AMP) immunoglobulin G. The assay was at least as sensitive as the conventional radioimmunoassay using cyclic [3H]AMP and could measure cyclic AMP over the range 1-1000nM. The homogeneous chemiluminescent energy transfer assay was also able to quantify the association and dissociation of antibody-antigen complexes. Chemiluminescence energy transfer occurred between fluorescein-labelled antibodies and several other ABEI-labelled antigens (Mr values 314-150000) including progesterone, cyclic GMP, complement component C9 and immunoglobulin G. The results provide a homogeneous immunoassay capable of measuring free cyclic AMP under conditions likely to exist inside cells.


Reduced numbers of circulating group 2 innate lymphoid cells in patients with common variable immunodeficiency.
Recent studies identified an emerging role of group 2 and 3 innate lymphoid cells (ILCs) as key players in the generation of T-dependent and T-independent antibody production. In this retrospective case-control study, CD117+ ILCs (including the majority of ILC2 and ILC3) were reduced in patients with common variable immunodeficiency (CVID). The reduction in CD117+ ILCs was distinctive to CVID and could not be observed in patients with X-linked agammaglobulinemia. Patients with a more pronounced reduction in CD117+ ILC numbers showed significantly lower numbers of peripheral MZ-like B cells and an increased prevalence of chronic, non-infectious enteropathy. Subsequent phenotyping of ILC subsets in CVID revealed that the reduction in CD117+ ILC numbers is due to a reduction in ILC2 numbers. In vitro expansion of CVID ILC2 in response to IL-2, IL-7, IL-25 and IL-33 was impaired. Furthermore, upregulation of MHCII and IL-2RA in response to IL-2, IL-7, IL-25 and IL-33 was impaired in CVID ILC2. Thus, our results indicate a dysregulation of ILC subsets with a reduction in ILC2 numbers in CVID, however, further studies are needed to explore whether ILC abnormalities are a primary finding or secondary to disease complications encountered in CVID.


Clinical Study of Extrapulmonary Head and Neck Tuberculosis: A Single-Institute 10-year Experience.
Introduction Although the incidence of tuberculosis (TB) in Japan has been decreasing yearly, Japan remains ranked as an intermediate-burden country for TB. Objective This study aims to investigate the current situation of head and neck extrapulmonary TB (EPTB) diagnosed in our department. Methods We retrospectively reviewed the clinical records of 47 patients diagnosed with EPTB in the head and neck in our department between January 2005 and December 2014. The extracted data included sex and age distribution, development site, chief complaint, presence or absence of concomitant active pulmonary TB (PTB) or history of TB, tuberculin skin test (TST) results, interferon-gamma release assay (IGRA) results, and duration from the first visit to the final diagnosis of EPTB. Results The subjects consisted of 20 men and 27 women, and age ranged from 6 to 84 years. The most common site was the cervical lymph nodes (30 patients), with the supraclavicular nodes being the most commonly affected (60%). Histopathological examination was performed on 28 patients. TST was positive in 9 out of 9 patients and the IGRA was positive in 18 out of 19 patients. We observed concomitant PTB in 15 out of the 47 patients. Mean duration from the first visit to the final diagnosis of EPTB was 56 days. Conclusion The clinical symptoms of TB, especially those in the head and neck region, are varied. Otolaryngologists should be especially aware of the extrapulmonary manifestations of TB to ensure early diagnosis and treatment from the public health viewpoint.


Determinants of Walking among Middle-Aged and Older Overweight and Obese Adults: Sociodemographic, Health, and Built Environmental Factors.
This study examined the association between selected sociodemographic, health, and built environmental factors and walking behaviors of middle-aged and older overweight/obese adults. Subjective data were obtained from surveys administered to community-dwelling overweight/obese adults aged ≥50 years residing in four Texas cities from October 2013 to June 2014, along with objective data on neighborhood walkability (Walk Score™). Multivariate logistic regression identified factors predicting the odds of walking the recommended ≥150 minutes per week for any purpose. Of 253 participants, the majority were non-Hispanic white (81.8%), married (74.5%), and male (53.4%) and reported an annual income of ≥$50,000 (65.5%). Approximately, half were employed (49.6%) or had at least a college degree (51.6%). Walking the recommended ≥150 minutes per week for any purpose (n = 57, 22.5%) was significantly associated with having at least a college degree (OR = 5.55, 95% CI = 1.79-17.25), having no difficulty walking a quarter of a mile (OR = 5.18, 95% CI = 1.30-20.83), and being unemployed (OR = 3.25, 95% CI = 1.18-8.93) as well as perceived presence of sidewalks/protected walkways (OR = 3.56, 95% CI = 1.10-11.50) and perceived absence of distracted drivers in the neighborhood (OR = 4.08, 95% CI = 1.47-11.36). Addressing neighborhood conditions related to distracted drivers and pedestrian infrastructure may promote walking among middle-aged and older overweight/obese individuals.


Molecular biology of tick acetylcholinesterases.
Ticks vector many pathogens with major health and economic impacts and have developed resistance to most acaricides used for tick control. Organophosphate (OP) acaricides target acetylcholinesterase (AChE) critical to tick central nervous system function. Mutations producing tick AChEs resistant to OPs were characterized; but tick OP-resistance is not fully elucidated, due to remarkable complexity of tick cholinergic systems. Three paralogous tick AChEs exhibiting differences in primary structure and biochemical kinetics are encoded by amplified genes with developmentally regulated expression. Gene silencing data suggest tick AChEs are functional complements in vivo, and transcriptomic and genomic data suggest existence of additional tick AChEs. Cholinergic systems are crucial in neural transmission and are also regulators of vertebrate immune function. Ticks exhibit prolonged intimate host contact, suggesting adaptive functions for tick cholinergic system complexity. AChE was recently reported in tick saliva and a role in manipulation of host immune responses was hypothesized. Physiological roles and genetic control of multiple tick AChEs requires further elucidation and may provide unique opportunities to understand and manipulate cholinergic involvement in biological systems.


Assessing mobile food vendors (a.k.a. street food vendors)--methods, challenges, and lessons learned for future food-environment research.
Mobile food vendors (also known as street food vendors) may be important sources of food, particularly in minority and low-income communities. Unfortunately, there are no good data sources on where, when, or what vendors sell. The lack of a published assessment method may contribute to the relative exclusion of mobile food vendors from existing food-environment research. A goal of this study was to develop, pilot, and refine a method to assess mobile food vendors. Cross-sectional assessment of mobile food vendors through direct observations and brief interviews. Using printed maps, investigators canvassed all streets in Bronx County, NY (excluding highways but including entrance and exit ramps) in 2010, looking for mobile food vendors. For each vendor identified, researchers recorded a unique identifier, the vendor's location, and direct observations. Investigators also recorded vendors answers to where, when, and what they sold. Of 372 identified vendors, 38% did not answer brief-interview questions (19% were 'in transit', 15% refused; others were absent from their carts/trucks/stands or with customers). About 7% of vendors who ultimately answered questions were reluctant to engage with researchers. Some vendors expressed concerns about regulatory authority; only 34% of vendors had visible permits or licenses and many vendors had improvised illegitimate-appearing set-ups. The majority of vendors (75% of those responding) felt most comfortable speaking Spanish; 5% preferred other non-English languages. Nearly a third of vendors changed selling locations (streets, neighbourhoods, boroughs) day-to-day or even within a given day. There was considerable variability in times (hours, days, months) in which vendors reported doing business; for 86% of vendors, weather was a deciding factor. Mobile food vendors have a variable and fluid presence in an urban environment. Variability in hours and locations, having most comfort with languages other than English, and reluctance to interact with individuals gathering data are principal challenges to assessment. Strategies to address assessment challenges that emerged form this project may help make mobile-vendor assessments more routine in food-environment research.


Structure and function of poly(ADP-ribose) polymerase-1: role in oxidative stress-related pathologies.
Poly(ADP-ribosyl) ation is a reversible post-translational protein modification implicated in the regulation of a number of biological functions. Whereas an 18 member superfamily of poly(ADP-ribose) polymerase (PARP) enzymes synthesize poly(ADP-ribose) (PAR), a single protein, PAR glycohydrolase (PARG) is responsible for the catabolism of the polymer. PARP-1 accounts for more than 90% of the poly(ADP-ribosyl)ating capacity of the cells. PARP-1 activated by DNA breaks cleaves NAD(+) into nicotinamide and ADP-ribose and uses the latter to synthesize long branching PAR polymers covalently attached to acceptor proteins including histones, DNA repair enzymes, transcription factors and PARP-1. Whereas activation of PARP-1 by mild genotoxic stimuli may facilitate DNA repair and cell survival, irreparable DNA damage triggers apoptotic or necrotic cell death. In apoptosis, early PARP activation may assist the apoptotic cascade [e.g. by stabilizing p53, by mediating the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus or by inhibiting early activation of DNases]. In most severe oxidative stress situations, excessive DNA damage causes over activation of PARP-1, which incapacitates the apoptotic machinery and switches the mode of cell death from apoptosis to necrosis. Besides serving as a cytotoxic mediator, PARP-1 is also involved in transcriptional regulation, most notably in the NF kappaB and AP-1 driven expression of inflammatory mediators. Pharmacological inhibition or genetic ablation of PARP-1 provided remarkable protection from tissue injury in various oxidative stress-related disease models ranging from stroke, diabetes, diabetic endothelial dysfunction, myocardial ischemia-reperfusion, shock, Parkinson's disease, arthritis, colitis to dermatitis and uveitis. These beneficial effects are attributed to inhibition of the PARP-1 mediated suicidal pathway and to reduced expression of inflammatory cytokines and other mediators (e.g. inducible nitric oxide synthase).


Starting the polypill: the use of a single age cut-off in males and females.
Objective Age screening and preventive medication for future myocardial infarction and stroke has been previously described. We aimed to ascertain whether different age cut-offs are needed for males and females. Methods We determined five parameters for each sex according to age cut-off: detection rate (sensitivity), false-positive rate, proportion of the population eligible for treatment with a polypill, proportion who benefit from taking a polypill (simvastatin 20 mg, losartan 25 mg, hydrochlorothiazide 12.5 mg, amlodipine 2.5 mg), and among these, years of life gained without a first myocardial infarction or stroke. Results Approximately one-third benefit, regardless of the age cut-off. For males and females combined, using ages 40 and 80, the detection rates are 98% and 52%, false-positive rates are 51% and 7%, population percentages eligible for treatment are 52% and 7%, and years of life gained without a first myocardial infarction or stroke are 8.4 and 3.6. Using age 50, detection rates are 93% (males) 98% (females), false-positive rates 37% (males) 40% (females), percentage of the population eligible for treatment 38% (males) 41% (females), percentage who benefit 35% (males) 33% (females), and years of life gained without an event 8.5 (males) 7.0 (females). At a given age cut-off, the sex differences are relatively small. Conclusion A single age cut-off can be used for both sexes.


Synergistic Interaction of a Gabapentin- Mangiferin Combination in Formalin-Induced Secondary Mechanical Allodynia and Hyperalgesia in Rats Is Mediated by Activation of NO-Cyclic GMP-ATP-Sensitive K+ Channel Pathway.
Preclinical Research Gabapentin is an anticonvulsant used to treat neuropathic pain. Mangiferin is an antioxidant that has antinociceptive and antiallodynic effects in inflammatory and neuropathic pain models. The purpose of this study was to determine the interaction between mangiferin and gabapentin in the development and maintenance of formalin-induced secondary allodynia and hyperalgesia in rats. Gabapentin, mangiferin, or their fixed-dose ratio combination were administrated peripherally. Isobolographic analyses was used to define the nature of the interaction of antiallodynic and/or antihyperalgesic effects of the two compounds. Theoretical ED50 values for the combination were 74.31 µg/paw and 95.20 µg/paw for pre- and post-treatment, respectively. These values were higher than the experimental ED50 values, 29.45 µg/paw and 37.73 µg/paw respectively, indicating a synergistic interaction in formalin-induced secondary allodynia and hyperalgesia. The antiallodynic and antihyperalgesic effect induced by the gabapentin/mangiferin combination was blocked by administration of L-NAME, the soluble guanylyl cyclase inhibitor, ODQ and glibenclamide. These data suggest that the gabapentin- mangiferin combination produces a synergistic interaction at the peripheral level. Moreover, the antiallodynic and hyperalgesic effect induced by the combination is mediated via the activation of an NO-cyclic GMP-ATP-sensitive K+ channel pathway. Drug Dev Res 78 : 390-402, 2017. © 2017 Wiley Periodicals, Inc.