Body mass index, diet, physical inactivity, and the incidence of dementia in 1 million UK women.
To help determine whether midlife obesity is a cause of dementia and whether low body mass index (BMI), low caloric intake, and physical inactivity are causes or merely consequences of the gradual onset of dementia by recording these factors early in a large 20-year prospective study and relating them to dementia detection rates separately during follow-up periods of <5, 5 to 9, 10 to 14, and 15+ years. A total of 1,136,846 UK women, mean age 56 (SD 5) years, were recruited in 1996 to 2001 and asked about height, weight, caloric intake, and inactivity. They were followed up until 2017 by electronic linkage to National Health Service records, detecting hospital admissions with mention of dementia. Cox regression yielded adjusted rate ratios (RRs) for first dementia detection during particular follow-up periods. Fifteen years after the baseline survey, only 1% were lost to follow-up, and 89% remained alive with no detected dementia, of whom 18,695 had dementia detected later, at a mean age of 77 (SD 4) years. Dementia detection during years 15+ was associated with baseline obesity (BMI 30+ vs 20-24 kg/m2: RR 1.21, 95% confidence interval 1.16-1.26, p < 0.0001) but not clearly with low BMI, low caloric intake, or inactivity at baseline. The latter 3 factors were associated with increased dementia rates during the first decade, but these associations weakened substantially over time, approaching null after 15 years. Midlife obesity may well be a cause of dementia. In contrast, behavioral changes due to preclinical disease could largely or wholly account for associations of low BMI, low caloric intake, and inactivity with dementia detection during the first decade of follow-up.


Ultrashort-TE stimulated echo acquisition mode (STEAM) improves the quantification of lipids and fatty acid chain unsaturation in the human liver at 7 T.
Ultrahigh-field, whole-body MR systems increase the signal-to-noise ratio (SNR) and improve the spectral resolution. Sequences with a short TE allow fast signal acquisition with low signal loss as a result of spin-spin relaxation. This is of particular importance in the liver for the precise quantification of the hepatocellular content of lipids (HCL). In this study, we introduce a spoiler Gradient-switching Ultrashort STimulated Echo AcqUisition (GUSTEAU) sequence, which is a modified version of a stimulated echo acquisition mode (STEAM) sequence, with a minimum TE of 6 ms. With the high spectral resolution at 7 T, the efficient elimination of water sidebands and the post-processing suppression of the water signal, we estimated the composition of fatty acids (FAs) via the detection of the olefinic lipid resonance and calculated the unsaturation index (UI) of hepatic FAs. The performance of the GUSTEAU sequence for the assessment of UI was validated against oil samples and provided excellent results in agreement with the data reported in the literature. When measuring HCL with GUSTEAU in 10 healthy volunteers, there was a high correlation between the results obtained at 7 and 3 T (R(2) = 0.961). The test-retest measurements yielded low coefficients of variation for HCL (4 ± 3%) and UI (11 ± 8%) when measured with the GUSTEAU sequence at 7 T. A negative correlation was found between UI and HCL (n = 10; p < 0.033). The ultrashort TE MRS sequence (GUSTEAU; TE = 6 ms) provided high repeatability for the assessment of HCL. The improved spectral resolution at 7 T with the elimination of water sidebands and the offline water subtraction also enabled an assessment of the unsaturation of FAs. This all highlights the potential use of this MRS acquisition scheme for studies of hepatic lipid composition in vivo.


Who is to blame for COVID-19? Examining politicized fear and health behavior through a mixed methods study in the United States.
Political ideologies drove public actions and health behaviors in the first year of the global pandemic. Different ideas about contagion, health behaviors, and the actions of governing bodies impacted the spread of the virus and health and life. Researchers used an immediate, mixed methods design to explore sociocultural responses to the virus and identified differences and similarities in anxiety, fear, blame, and perceptions of nation across political divides. Researchers conducted 60 in-depth, semi-structured interviews and administered over 1,000 questionnaires with people living in the United States. The team analyzed data through an exploratory and confirmatory sequential mixed methods design. In the first months of the pandemic interviewees cited economic inequality, untrustworthy corporations and other entities, and the federal government as threats to life and pandemic control. Participants invoked ideas about others to determine blame. Findings reveal heavy associations between lack of safety during a public health crisis and blame of "culture" and government power across the political spectrum. Data indicate anxiety across political differences related to ideas of contagion and the maleficence of a powerful elite. Findings on how people understand the nation, politics, and pandemic management contribute to understanding dimensions of health behaviors and underlying connections between anxiety and the uptake of conspiracy theories in public health. The article ends with recommendations drawn from project findings for future pandemic response.


Cell Penetration Profiling Using the Chloroalkane Penetration Assay.
Biotherapeutics are a promising class of molecules in drug discovery, but they are often limited to extracellular targets due to their poor cell penetration. High-throughput cell penetration assays are required for the optimization of biotherapeutics for enhanced cell penetration. We developed a HaloTag-based assay called the chloroalkane penetration assay (CAPA), which is quantitative, high-throughput, and compartment-specific. We demonstrate the ability of CAPA to profile extent of cytosolic penetration with respect to concentration, presence of serum, temperature, and time. We also used CAPA to investigate structure-penetration relationships for bioactive stapled peptides and peptides fused to cell-penetrating sequences. CAPA is not only limited to measuring cytosolic penetration. Using a cell line where HaloTag is localized to the nucleus, we show quantitative measurement of nuclear penetration. Going forward, CAPA will be a valuable method for measuring and optimizing the cell penetration of biotherapeutics.


Management of male osteoporosis: report of the UK Consensus Group.
Although osteoporosis is generally regarded as a disease of women, up to 30% of hip fractures and 20% of vertebral fractures occur in men. Risk factors for osteoporotic fractures in men include low body mass index, smoking, high alcohol consumption, corticosteroid therapy, physical inactivity, diseases that predispose to low bone mass, and conditions increasing the risk of falls. The key drugs and diseases that definitely produce a decrease in bone mineral density (BMD) and/or an increase in fracture rate in men are long-term corticosteroid use, hypogonadism, alcoholism and transplantation. Age-related bone loss may be a result of declining renal function, vitamin D deficiency, increased parathyroid hormone levels, low serum testosterone levels, low calcium intake and absorption. Osteoporosis can be diagnosed on the basis of radiological assessments of bone mass, or clinically when it becomes symptomatic. Various biochemical markers have been related to bone loss in healthy and osteoporotic men. Their use as diagnostic tools, however, needs further investigation. A practical approach would be to consider a bone density more than one SD below the age-matched mean value (Z < -1) as an indication for therapy. The treatment options for men with osteoporosis include agents to influence bone resorption or formation and specific therapy for any underlying pathological condition. Testosterone treatment increases BMD in hypogonadal men, and is most effective in those whose epiphyses have not closed completely. Bisphosphonates are the treatment of choice in idiopathic osteoporosis, with sodium fluoride and anabolic steroids to be used as alternatives.


Substrate modification with lysine 63-linked ubiquitin chains through the UBC13-UEV1A ubiquitin-conjugating enzyme.
Protein modification with lysine 63-linked ubiquitin chains has been implicated in the non-proteolytic regulation of signaling pathways. To understand the molecular mechanisms underlying this process, we have developed an in vitro system to examine the activity of the ubiquitin-conjugating enzyme UBC13-UEV1A with TRAF6 in which TRAF6 serves as both a ubiquitin ligase and substrate for modification. Although TRAF6 potently stimulates the activity of UBC13-UEV1A to synthesize ubiquitin chains, it is not appreciably ubiquitinated. We have determined that the presentation of Lys(63) of ubiquitin by UEV1A suppresses TRAF6 modification. Based on our observations, we propose that the modification of proteins with Lys(63)-linked ubiquitin chains occurs through a UEV1A-independent substrate modification and UEV1A-dependent Lys(63)-linked ubiquitin chain synthesis mechanism.


Identification of m6A-Associated RNA Binding Proteins Using an Integrative Computational Framework.
N6-methyladenosine (m6A) is an abundant modification on mRNA that plays an important role in regulating essential RNA activities. Several wet lab studies have identified some RNA binding proteins (RBPs) that are related to m6A's regulation. The objective of this study was to identify potential m6A-associated RBPs using an integrative computational framework. The framework was composed of an enrichment analysis and a classification model. Utilizing RBPs' binding data, we analyzed reproducible m6A regions from independent studies using this framework. The enrichment analysis identified known m6A-associated RBPs including YTH domain-containing proteins; it also identified RBM3 as a potential m6A-associated RBP for mouse. Furthermore, a significant correlation for the identified m6A-associated RBPs is observed at the protein expression level rather than the gene expression level. On the other hand, a Random Forest classification model was built for the reproducible m6A regions using RBPs' binding data. The RBP-based predictor demonstrated not only competitive performance when compared with sequence-based predictions but also reflected m6A's action of repelling against RBPs, which suggested that our framework can infer interaction between m6A and m6A-associated RBPs beyond sequence level when utilizing RBPs' binding data. In conclusion, we designed an integrative computational framework for the identification of known and potential m6A-associated RBPs. We hope the analysis will provide more insights on the studies of m6A and RNA modifications.


Unprecedented Carbon Signal Enhancement in Liquid-State NMR Spectroscopy.
We shall overcome: As a result of efforts to overcome the sensitivity challenge of liquid-state NMR spectroscopy, a thousand-fold signal enhancement was achieved by dynamic nuclear polarization (DNP) for 13 C signals at high magnetic field (3.4 T) and room temperature, thereby exceeding the predicted limitations of high-field liquid-state in situ DNP.


In vivo activity and in vitro specificity of CD4+ Th1 and Th2 cells derived from the spleens of diabetic NOD mice.
CD4+ T cell lines were generated from the spleens of diabetic NOD mice against crude membrane preparations derived from a rat insulinoma. Adoptive transfer of these lines into neonatal mice confirms that overt diabetes is induced by gamma-IFN-secreting Th1 cells, whereas transfer of IL-4-secreting Th2 cells resulted in a nondestructive peri-islet insulitis. Analysis of the antigens recognized by individual T cell clones from the Th1 line included reactivity against an insulinoma membrane fraction enriched in proteins of approximately 38 kD. Immune responses to the same antigen preparation have been associated with T cell clones derived from human insulin-dependent diabetes mellitus. The specificity of Th2 cells includes reactivity to a fraction enriched in proteins of 30 kD. The data suggest that in insulin-dependent diabetes mellitus the balance between beta cell destruction, associated with intra-islet infiltration, and nondestructive (potential protective) peri-islet insulitis may depend on both the antigens recognized, and the prevailing cytokine environment.


Quantifying the relationship between co-expression, co-regulation and gene function.
It is thought that genes with similar patterns of mRNA expression and genes with similar functions are likely to be regulated via the same mechanisms. It has been difficult to quantitatively test these hypotheses on a large scale because there has been no general way of determining whether genes share a common regulatory mechanism. Here we use data from a recent genome wide binding analysis in combination with mRNA expression data and existing functional annotations to quantify the likelihood that genes with varying degrees of similarity in mRNA expression profile or function will be bound by a common transcription factor. Genes with strongly correlated mRNA expression profiles are more likely to have their promoter regions bound by a common transcription factor. This effect is present only at relatively high levels of expression similarity. In order for two genes to have a greater than 50% chance of sharing a common transcription factor binder, the correlation between their expression profiles (across the 611 microarrays used in our study) must be greater than 0.84. Genes with similar functional annotations are also more likely to be bound by a common transcription factor. Combining mRNA expression data with functional annotation results in a better predictive model than using either data source alone. We demonstrate how mRNA expression data and functional annotations can be used together to estimate the probability that genes share a common regulatory mechanism. Existing microarray data and known functional annotations are sufficient to identify only a relatively small percentage of co-regulated genes.


Dorsolateral prefrontal cortex involvement in memory post-retrieval monitoring revealed in both item and associative recognition tests.
Post-retrieval monitoring is a process that contributes to episodic memory retrieval by allowing people to evaluate the relevance of retrieved information in relation to the task requirements. Previous studies have suggested that post-retrieval monitoring is supported by the dorsolateral prefrontal cortex (DLPFC). In this study, we used functional magnetic resonance imaging (fMRI) to evaluate involvement of the DLPFC in post-retrieval monitoring in two different recognition tests (item recognition and associative recognition). The item recognition memory test required subjects to make old/new judgments and the associative recognition memory test required them to make intact/rearranged judgments. Because the post-retrieval monitoring demand increases during old (hits) relative to new (correct rejections) item recognition trials, and also during rearranged (correct rejections) relative to intact (hits) associative recognition trials, we evaluated the brain activation associated with the interaction of Memory test (item versus associative) by Recognition trial (hit versus correct rejection). As expected, the DLPFC was activated in this interaction as well as for both old relative to new item recognition trials and rearranged relative to intact associative recognition trials. This study provides strong evidence that DLPFC activation supports post-retrieval monitoring across different types of recognition tasks.


Comparison of some behavioral effects of d- and l-methamphetamine in adult male rats.
Both l- and d-methamphetamine (l- and d-MA) are more potent to release norpepinephrine (NE) than dopamine, and the selectivity is greater for l-MA than d-MA. Little is known of the in vivo pharmacology of l-MA. This study compared the effects of l-MA and d-MA in assays of nociception, behavioral disruption, and impulsivity. Antinociceptive effects of d- and l-MA were examined in two pain assays: the warm water tail withdrawal test for acute nociception and the von Frey test in complete Freund's adjuvant (CFA)-treated rats for chronic inflammatory pain. Food-maintained operant responding and locomotion tests were used to assess generalized behavioral disruption. The 5-choice serial reaction time test (5-CSRTT) was used to assess drug-induced effects on impulse control. A delay discounting procedure was used to determine drug-induced changes in sensitivity to reinforcer delay (impulsive choice). l-MA (3.2-10 mg/kg) produced dose-dependent antinociception in both pain assays, decreased the rate of food-maintained operant responding, and decreased locomotor activity at a higher dose (17.8 mg/kg). In contrast, d-MA (0.32-3.2 mg/kg) did not produce antinociception in either assay, produced biphasic effects on response rate, and increased locomotor activity. In the 5-CSRTT, d-MA but not l-MA produced significant increase in premature responses. In the delay discounting procedure, both drugs did not affect the delay function at doses that did not increase omissions. These data suggest that d- and l-MA have different behavioral profiles. Consideration should be given to these differences in future studies when l-MA is proposed for potential therapies.


A sticky sight: cyanoacrylate 'superglue' injuries of the eye.
A 64-year-old man presented to casualty with blurred vision and pain in his left eye, 2 h after inadvertently instilling clear nail glue into his eye instead of postoperative Timolol eye drops. The glue was removed at the slit lamp revealing a corneal abrasion, which was managed with topical antibiotics. Inadvertent ocular cyanoacrylate, or 'superglue', instillation has been reported frequently since 1982 when superglue was repackaged into ophthalmic style dropper bottles. This case report highlights the continuing problem of cyanoacrylate eye injuries and serves as a reminder to healthcare professionals to report such incidents to manufacturers and regulatory bodies, on behalf of their patients, to promote the introduction of universal safety mechanisms on all household chemical containers. Failure of glue manufacturers to introduce safety cap mechanisms has resulted in significant ocular morbidity over the last 27 years, and such incidents are expected to occur until superglue bottles are redesigned.


Arterial duct angioplasty as an adjunct to dilatation of the valve for critical pulmonary stenosis.
To assess the efficacy of arterial duct angioplasty in maintaining adequate ductal patency in neonates with critical pulmonary valve stenosis. Two neonates presenting with cyanosis due to critical pulmonary valve stenosis with severe right ventricular hypoplasia underwent percutaneous balloon dilatation of the pulmonary valve. Despite successful dilatation, both remained cyanosed while receiving prostaglandin E2 infusions. Angioplasty of the arterial duct resulted in increased arterial oxygen saturations. Adequate arterial duct patency was maintained for three months during which time right ventricular dimensions increased enough to allow sufficient pulmonary circulation without the duct. Arterial duct angioplasty is an effective additional treatment for patients with critical pulmonary valve stenosis whose right ventricle is too small to provide adequate forward flow after balloon dilatation of the valve. Arterial duct angioplasty sustains adequate patency of the duct while the right ventricle grows sufficiently to undertake the pulmonary circulation.


Always around, never the same: pathways of amyloid beta induced neurodegeneration throughout the pathogenic cascade of Alzheimer's disease.
There is an increasing amount of evidence showing the importance of intermediate aggregation species of amyloid beta (Abeta) in the pathogenic cascade of Alzheimer's disease (AD). Different Abeta assembly forms may mediate diverse toxic effects at different stages of the disease. Mouse models for AD suggest that intraneuronal accumulation of Abeta oligomers might be involved in AD pathogenesis at a very early stage of the disease. The detrimental effect of oligomeric Abeta on synaptic efficacy is suggested to be an early event in the pathogenic cascade. Also early neuronal responses as activation of the unfolded protein response are processes likely to be associated with the increased occurrence of oligomeric or low fibrillar Abeta in AD pathology. In later stages of AD pathology, the fibrillarity of Abeta increases, concomitantly with a neuroinflammatory response, followed by tau related neurofibrillary changes in end stage pathology. We will review recent findings in in vitro cell models, in vivo mouse models, and post mortem AD brain tissue in view of the effects of different Abeta peptide species on neurodegeneration during AD pathogenesis. Insight into the role of different Abeta species during AD pathogenesis is essential for the development of disease modifying drugs and therapeutical strategies.


Manipulating the mitochondria activity in human hepatic cell line Huh7 by low-power laser irradiation.
Low-power laser irradiation of red light has been recognized as a promising tool across a vast variety of biomedical applications. However, deep understanding of the molecular mechanisms behind laser-induced cellular effects remains a significant challenge. Here, we investigated mechanisms involved in the death process in human hepatic cell line Huh7 at a laser irradiation. We decoupled distinct cell death pathways targeted by laser irradiations of different powers. Our data demonstrate that high dose laser irradiation exhibited the highest levels of total reactive oxygen species production, leading to cyclophilin D-related necrosis via the mitochondrial permeability transition. On the contrary, low dose laser irradiation resulted in the nuclear accumulation of superoxide and apoptosis execution. Our findings offer a novel insight into laser-induced cellular responses, and reveal distinct cell death pathways triggered by laser irradiation. The observed link between mitochondria depolarization and triggering ROS could be a fundamental phenomenon in laser-induced cellular responses.


Back to the future: community involvement in the Healthy Start Program.
This article discusses how community involvement is incorporated into Healthy Start, a major initiative to reduce infant mortality in selected communities with disproportionately high levels of infant mortality. Based on site visits to each of the fifteen original Healthy Start project areas, we discovered that two main community involvement strategies were used: a service consortium model and a community empowerment model. In the service consortium model, the community is involved primarily through a consortium of local providers, other professionals, and some governmental representatives who help to plan services. The community empowerment model involves the community by engaging neighborhood-based groups, contracting with community-based organizations, employing community residents as lay workers in the Healthy Start program, and creating other economic development initiatives. Important lessons drawn from this study are that the purpose and commitment to community involvement is not always clear; that it is difficult to involve community residents; that efforts to involve the community are extremely labor intensive; that given monetary incentives, it is easier to involve community providers than residents; that community involvement may conflict with efficient program operations; that increased community involvement may create program goals that differ from the program's original goals; and that community involvement may slow program development.


Dopamine invigorates reward seeking by promoting cue-evoked excitation in the nucleus accumbens.
Approach to reward is a fundamental adaptive behavior, disruption of which is a core symptom of addiction and depression. Nucleus accumbens (NAc) dopamine is required for reward-predictive cues to activate vigorous reward seeking, but the underlying neural mechanism is unknown. Reward-predictive cues elicit both dopamine release in the NAc and excitations and inhibitions in NAc neurons. However, a direct link has not been established between dopamine receptor activation, NAc cue-evoked neuronal activity, and reward-seeking behavior. Here, we use a novel microelectrode array that enables simultaneous recording of neuronal firing and local dopamine receptor antagonist injection. We demonstrate that, in the NAc of rats performing a discriminative stimulus task for sucrose reward, blockade of either D1 or D2 receptors selectively attenuates excitation, but not inhibition, evoked by reward-predictive cues. Furthermore, we establish that this dopamine-dependent signal is necessary for reward-seeking behavior. These results demonstrate a neural mechanism by which NAc dopamine invigorates environmentally cued reward-seeking behavior.


The 2007 National Asthma Education and Prevention Program asthma guidelines: accelerating their implementation and facilitating their impact on children with asthma.
Nearly 2 decades have elapsed since the National Center for Health Statistics raised concerns regarding the trends in increasing asthma prevalence. Additional research highlighted the large racial disparities and geographic variations in asthma morbidity and mortality rates. Although there was little national consensus on the care of children with asthma at the time, there were improvements in the understanding of the mechanisms and treatment of asthma. It was in this context that the National Heart, Lung, and Blood Institute launched the National Asthma Education and Prevention Program, which convened its first panel of experts to create the national consensus clinical practice guidelines on the treatment of asthma. More than 15 years have passed since the publication of those first guidelines and, in August 2007, the National Heart, Lung, and Blood Institute released its newest updates, which are the product of the National Asthma Education and Prevention Program third expert panel. The release of the updated guidelines serves as an occasion to examine important issues regarding the dissemination and clinical implementation of National Asthma Education and Prevention Program guidelines. The goals of this report are to examine the adoption of earlier versions of the National Asthma Education and Prevention Program guidelines and to suggest opportunities for rapid adoption of the newly released guidelines.


Supramolecular amphipathicity for probing antimicrobial propensity of host defence peptides.
Host defence peptides (HDPs) are effector components of innate immunity that provide defence against pathogens. These are small-to-medium sized proteins which fold into amphipathic conformations toxic to microbial membranes. Here we explore the concept of supramolecular amphipathicity for probing antimicrobial propensity of HDPs using elementary HDP-like amphiphiles. Such amphiphiles are individually inactive, but when ordered into microscopic micellar assemblies, respond to membrane binding according to the orthogonal type of their primary structure. The study demonstrates that inducible supramolecular amphipathicity can discriminate against bacterial growth and colonisation thereby offering a physico-chemical rationale for tuneable targeting of biological membranes.


A longitudinal study of urea cycle disorders.
The Urea Cycle Disorders Consortium (UCDC) is a member of the NIH funded Rare Diseases Clinical Research Network and is performing a longitudinal study of 8 urea cycle disorders (UCDs) with initial enrollment beginning in 2006. The consortium consists of 14 sites in the U.S., Canada and Europe. This report summarizes data mining studies of 614 patients with UCDs enrolled in the UCDC's longitudinal study protocol. The most common disorder is ornithine transcarbamylase deficiency, accounting for more than half of the participants. We calculated the overall prevalence of urea cycle disorders to be 1/35,000, with 2/3rds presenting initial symptoms after the newborn period. We found the mortality rate to be 24% in neonatal onset cases and 11% in late onset cases. The most common precipitant of clinical hyperammonemic episodes in the post-neonatal period was intercurrent infections. Elevations in both blood ammonia and glutamine appeared to be biomarkers for neurocognitive outcome. In terms of chronic treatment, low protein diet appeared to result in normal weight but decreased linear growth while N-scavenger therapy with phenylbutyrate resulted in low levels of branched chain amino acids. Finally, we found an unexpectedly high risk for hepatic dysfunction in patients with ornithine transcarbamylase deficiency. This natural history study illustrates how a collaborative study of a rare genetic disorder can result in an improved understanding of morbidity and disease outcome.


Systematic review of medium-term weight loss after bariatric operations.
Although bariatric surgery is known to be effective in the short term, the durability of that effect has not been convincingly demonstrated over the medium term (> 3 years) and the long term (> 10 years). The authors studied the durability of weight loss after bariatric surgery based on a systematic review of the published literature. All reports published up to September, 2005 were included if they were full papers in refereed journals published in English, of outcomes after Roux-en-Y gastric bypass (RYGBP), and its hybrid procedures of banded bypass (Banded RYGBP) and longlimb bypass (LL-RYGBP), biliopancreatic diversion with or without duodenal switch (BPD+/-DS) or laparoscopic adjustable gastric banding (LAGB). All reports that had at least 100 patients at commencement, and provided > or = 3 years of follow-up data were included. From a total of 1,703 reports extracted, 43 reports fulfilled the entry criteria (18 RYGBP; 18 LAGB; 7 BPD). Pooled data from all the bariatric operations showed effective and durable weight loss to 10 years. Mean %EWL for standard RYGBP was higher than for LAGB at years 1 and 2 (67 vs 42; 67 vs 53) but not different at 3, 4, 5, 6 or 7 years (62 vs 55; 58 vs 55; 58 vs 55; 53 vs 50; and 55 vs 51). There was 59 %EWL for LAGB at 8 years, and 52 %EWL for RYGBP at 10 years. Both the BPD+/-DS and the Banded RYGBP appeared to show better weight loss than standard RYGBP and LAGB, but with statistically significant differences present at year 5 alone. The LL-RYGBP was not associated with improved %EWL. Important limitations include lack of data on loss to follow-up, failure to identify numbers of patients measured at each data point and lack of data beyond 10 years. All current bariatric operations lead to major weight loss in the medium term. BPD and Banded RYGBP appear to be more effective than both RYGBP and LAGB which are equal in the medium term.


Dysgraphia Phenotypes in Native Chinese Speakers With Primary Progressive Aphasia.
Most primary progressive aphasia (PPA) literature is based on English language users. Linguistic features that vary from English, such as logographic writing systems, are underinvestigated. The current study characterized the dysgraphia phenotypes of patients with PPA who write in Chinese and investigated their diagnostic utility in classifying PPA variants. This study recruited 40 participants with PPA and 20 cognitively normal participants from San Francisco, Hong Kong, and Taiwan. We measured dictation accuracy using the Chinese Language Assessment for PPA (CLAP) 60-character orthographic dictation test and examined the occurrence of various writing errors across the study groups. We also performed voxel-based morphometry analysis to identify the gray matter regions correlated with dictation accuracy and prevalence of writing errors. All PPA groups produced significantly less accurate writing responses than the control group and no significant differences in dictation accuracy were noted among the PPA variants. With a cut score of 36 out of 60 in the CLAP orthographic dictation task, the test achieved sensitivity and specificity of 90% and 95% in identifying Chinese participants with PPA vs controls. In addition to a character frequency effect, dictation accuracy was affected by homophone density and the number of strokes in semantic variant PPA and logopenic variant PPA groups. Dictation accuracy was correlated with volumetric changes over left ventral temporal cortices, regions known to be critical for orthographic long-term memory. Individuals with semantic variant PPA frequently presented with phonologically plausible errors at lexical level, patients with logopenic variant PPA showed higher preponderance towards visual and stroke errors, and patients with nonfluent/agrammatic variant PPA commonly exhibited compound word and radical errors. The prevalence of phonologically plausible, visual, and compound word errors was negatively correlated with cortical volume over the bilateral temporal regions, left temporo-occipital area, and bilateral orbitofrontal gyri, respectively. The findings demonstrate the potential role of the orthographic dictation task as a screening tool and PPA classification indicator in Chinese language users. Each PPA variant had specific Chinese dysgraphia phenotypes that vary from those previously reported in English-speaking patients with PPA, highlighting the importance of language diversity in PPA.


The decision to repair or replace a defective restoration is affected by who placed the original restoration: findings from the National Dental PBRN.
To evaluate how restoration characteristics are associated with the decision to repair or replace an existing restoration. The following hypotheses were studied: dentists who placed the original restoration are more likely to repair instead of replace restorations (H1) that are in molar teeth; (H2) that are in the upper arch; (H3) that have amalgam restorative material; (H4) if a fracture is not the primary reason for the defect; and (H5) when the restoration comprises more than one surface. This cross-sectional study used a consecutive patient/restoration recruitment design. 194 dentists members of a dental practice-based research network recorded data on restorations in permanent teeth that needed repair or replacement. For 6623 of the 8770 defective restorations in 6643 patients, the treatment was provided by the dentist who had not placed the original restoration (75%). The 2-way interaction revealed that dentists who had placed the original restoration often chose to repair when the defective restoration was in a molar, relative to premolar or anterior teeth (OR=2.2, p<.001); and chose to replace when the restoration had amalgam (OR=0.5, p<.001), and when it was a fracture compared to another reason (OR=0.8, p=001). Most dentists are not conservative when they revisit a restoration that they originally placed regardless of type of failure, number of surfaces or material used. However, dentists who had placed the original restoration were significantly more likely to repair it when the defective restoration was in a molar tooth. Most dentists who placed the original restoration were prone to replace it, however if the defective restoration was located in a molar tooth they would consider repairing it.


High Expression of P38α and Preoperative Carbohydrate Antigen 19-9 Indicate Poor Prognosis in Patients with Pancreatic Ductal Adenocarcinoma.
Background: P38α is a ubiquitous protein kinase, which plays diverse roles in cancers. Surprisingly, P38α functions vary markedly in different cancers (e.g., cancer suppressor vs cancer promoter). However, there is no report on the expression of P38α, the family's most important member, in pancreatic ductal adenocarcinoma (PDAC) and its association with clinicoathological parameters and patients' prognosis. Materials and methods: We retrospectively analyzed 152 patients who underwent surgery and were pathologically diagnosed with PDAC from September 2013 to September 2015. We used immunohistochemistry to detect P38α expression in tumor and adjacent normal tissues. The significance of the association between P38α and clinicopathological parameters was evaluated using the χ² test and t tests. The Kaplan-Meier method was used to assess the association between P38α expression and preoperative carbohydrate antigen 19-9 (CA19-9) levels and patients' overall survival. The Cox regression model was used to analyze the association between clinicopathological parameters, P38α and preoperative CA19-9 levels, and prognosis. Statistical significance was defined as P < 0.05. Results: P38α was expressed in 63.16% tumor tissues of PDAC, which was significantly higher compared with the adjacent normal tissues (26.32%, P < 0.001). High expression of P38α was associated with patients' histological grade (P = 0.013), lymphatic metastasis (P = 0.025) and TNM stage (P = 0.048). The median survival time of the P38α-high group was 9.2 months, which was shorter compared with that of the P38α-low group (17.3 months, P = 0.011). The median survival time of the CA19-9 > 43.63 group was 11.1 months shorter than that of the CA19-9 < 43.63 group (24.8 months, P < 0.001). The Cox regression model revealed that age (P = 0.003), lymphatic invasion (P = 0.015), TNM stage (P = 0.003), histological grade (P < 0.001), preoperative CA19-9 (P = 0.049), and P38α expression (P = 0.008) were statistically significant independent risk factors affecting prognosis. Specifically, overall survival was 28.4 months in the P38α-low and CA19-9 < 43.63 groups, 16.3 months in the P38α-high or CA19-9 > 43.63 groups, and 9.7 months in the P38α-high and CA19-9 > 43.63 groups (P < 0.001). Conclusions: High expression of P38α was significantly associated with histological grade, lymphatic metastasis, TNM stage and prognosis in patients with PDAC. P38α and preoperative CA19-9 levels were independent risk factors affecting the prognosis of PDAC patients. High expression of p38α and preoperative carbohydrate antigen 19-9 indicate poor prognosis in patients with PDAC.


Informatics methods for laboratory evaluation of HPV ordering patterns with an example from a nationwide sample in the United States, 2003-2009.
Laboratory data is a rich source of information that can be used to estimate adherence to physician guidelines and motivate improvement in clinical practice. Human papillomavirus (HPV) testing is an important component of cervical cancer screening programs with established screening guidelines. The purpose of this study was to develop methods to estimate concordance with published guidelines for HPV testing in order to provide clinicians and payors specific feedback about overscreening. This retrospective analysis of laboratory test ordering patterns evaluated 454,532 HPV tests ordered from September 2003 to October 2009 from 110 facilities and performed at ARUP laboratories. We used laboratory data including patient demographics, ordering frequency, timestamps and results to examine the proportion of HPV tests ordered on women under 21 years, ordered on women between 21 and 29 years apparently before cytological examination, repeated less than 1 year after a positive HPV result in women over 30 years, and repeated less than 3 years after a negative HPV result in women over 30 years. The absolute number and proportion of HPV tests performed on women under 21 years declined from 20% in 2005 to 5% in October 2009. The proportion of HPV tests performed women between 21 and 29 years also declined during this period. Approximately one-third of HPV tests performed on women between 21 and 29 years arrived for HPV testing before cervical screening had presumably been completed. The most common follow-up intervals for HPV testing on women over 30 years were 6 months following a positive HPV result and 12 months following a negative HPV result. Only 6% of repeat HPV testing in women over 30 years followed a negative HPV result by 3 years or more. Approximately one-fourth of HPV tests ordered the year ending October 2009 were unnecessary based on the American Society for Colposcopy and Cervical Pathology guideline. We demonstrate simple methods to evaluate appropriate utilization of HPV testing using laboratory data. Our data illustrates that some aspects of HPV test ordering have become more consistent with guidelines over time. However, a large portion of HPV testing in the United States is unnecessary. This highlights opportunities for optimization of a rational cancer prevention strategy to reduce unnecessary screening, colposcopy and biopsies.


Therapeutic effect of green tea extract on oxidative stress in aorta and heart of streptozotocin diabetic rats.
Hyperglycemia induced oxidative stress has been proposed as a cause of many complications of diabetes including cardiac dysfunction. The present study depicts the therapeutic effect of green tea extract on oxidative stress in aorta as well as heart of streptozotocin diabetic rats. Six weeks after diabetes induction, green tea was administered orally for 4 weeks [300 mg (kg body weight)(-1) day (-1)]. In aorta and heart of diabetic rats there was a significant increase in the activity of superoxide dismutase, catalase and glutathione peroxidase with an increase in lipid peroxides. Diabetic rats showed a significant decrease in the levels of serum and cardiac glutathione. Green tea administration to diabetic rats reduced lipid peroxides and activity of antioxidant enzymes whereas increased glutathione content. The results demonstrate that the induction of antioxidant enzymes in diabetic rats is not efficient and sufficient to reduce the oxidative stress. But green tea by providing a competent antioxidative mechanism ameliorates the oxidative stress in the aorta and heart of diabetic rats. The study suggests that green tea may provide a useful therapeutic option in the reversal of oxidative stress induced cardiac dysfunction in diabetes mellitus.


Perinatal citalopram does not prevent the effect of prenatal stress on anxiety, depressive-like behaviour and serotonergic transmission in adult rat offspring.
It is still not clear whether the selective serotonin reuptake inhibitors frequently prescribed to depressed pregnant women improve the behavioural outcome in their children. The current study investigated whether administration of citalopram to pregnant rats could prevent anxiety and depressive-like behaviour induced by gestational stress in their offspring, and restore the expression of serotonin 1A autoreceptors in GABAergic interneurons in the medial prefrontal cortex and dorsal raphe nuclei in males, and of corticotropin-releasing factor type 2 receptors in GABAergic interneurons in the dorsal raphe nuclei in females. Activation of these receptors modulates serotonergic transmission to target areas and is reduced in a sex-dependent manner by prenatal stress. Citalopram (10 mg/kg/day), administered orally from day 7 of gestation until 21 days postpartum, prevented the increase in anxiety in stressed mothers but did not reduce anxiety and depressive-like behaviour in their offspring and even induced depressive-like behaviour in the offspring of control mothers. Citalopram failed to restore the reduction in the expression of serotonin 1A autoreceptors in the prefrontal cortex of males and in corticotropin-releasing factor type 2 receptors in the dorsal raphe nuclei of females induced by prenatal stress. Prenatal citalopram did not prevent the behavioural changes or reduction in serotonergic transmission to target areas induced by prenatal stress. It had adverse behavioural effects in the offspring of control rats, which, together with the lack of any change in prenatally-stressed rats, may be due to inhibition of the foetal serotonin transporter thereby preventing normal development of the serotonin system.


GPR41 modulates insulin secretion and gene expression in pancreatic β-cells and modifies metabolic homeostasis in fed and fasting states.
Insulin secretion by pancreatic β-cells is primarily regulated by glucose; however, hormones and additional nutrients, such as long-chain fatty acids, also play an important role in adjusting insulin output to physiologic needs. To examine the role of short-chain fatty acids (SCFAs) in β-cell function, we analyzed mouse models of gain and loss of function of GPR41 (FFAR3), a receptor for SCFAs, vs. wild-type control mice. GPR41 gain of function [GPR41-overexpressing transgenic (41 Tg) model] and GPR41 loss of function [GPR41-knockout (KO 41) model] resulted in complementary changes in glucose tolerance, without significant effects on insulin sensitivity. KO 41 mice showed fasting hypoglycemia, which was consistent with increased basal and glucose-induced insulin secretion by islets in vitro Mirroring this, 41 Tg islets showed impaired glucose responsiveness in vitro Microarray analysis of islets from 41 Tg mice indicated significant alterations in gene expression patterns; several of the altered genes were chosen for further analysis and were also observed to change upon incubation of islets and cultured β-cells with SCFAs in a GPR41-dependent manner. Taken together, our results indicate that GPR41 and its ligands, SCFAs, may play an important role in the fine-tuning of insulin secretion in fed and fasting states.-Veprik, A., Laufer, D., Weiss, S., Rubins, N., Walker, M. D. GPR41 modulates insulin secretion and gene expression in pancreatic β-cells and modifies metabolic homeostasis in fed and fasting states.


Complete Genome Sequence of Germline Chromosomally Integrated Human Herpesvirus 6A and Analyses Integration Sites Define a New Human Endogenous Virus with Potential to Reactivate as an Emerging Infection.
Human herpesvirus-6A and B (HHV-6A, HHV-6B) have recently defined endogenous genomes, resulting from integration into the germline: chromosomally-integrated "CiHHV-6A/B". These affect approximately 1.0% of human populations, giving potential for virus gene expression in every cell. We previously showed that CiHHV-6A was more divergent than CiHHV-6B by examining four genes in 44 European CiHHV-6A/B cardiac/haematology patients. There was evidence for gene expression/reactivation, implying functional non-defective genomes. To further define the relationship between HHV-6A and CiHHV-6A we used next-generation sequencing to characterize genomes from three CiHHV-6A cardiac patients. Comparisons to known exogenous HHV-6A showed CiHHV-6A genomes formed a separate clade; including all 85 non-interrupted genes and necessary cis-acting signals for reactivation as infectious virus. Greater single nucleotide polymorphism (SNP) density was defined in 16 genes and the direct repeats (DR) terminal regions. Using these SNPs, deep sequencing analyses demonstrated superinfection with exogenous HHV-6A in two of the CiHHV-6A patients with recurrent cardiac disease. Characterisation of the integration sites in twelve patients identified the human chromosome 17p subtelomere as a prevalent site, which had specific repeat structures and phylogenetically related CiHHV-6A coding sequences indicating common ancestral origins. Overall CiHHV-6A genomes were similar, but distinct from known exogenous HHV-6A virus, and have the capacity to reactivate as emerging virus infections.


Trophic magnification factors: considerations of ecology, ecosystems, and study design.
Recent reviews by researchers from academia, industry, and government have revealed that the criteria used by the Stockholm Convention on persistent organic pollutants under the United Nations Environment Programme are not always able to identify the actual bioaccumulative capacity of some substances, by use of chemical properties such as the octanol-water partitioning coefficient. Trophic magnification factors (TMFs) were suggested as a more reliable tool for bioaccumulation assessment of chemicals that have been in commerce long enough to be quantitatively measured in environmental samples. TMFs are increasingly used to quantify biomagnification and represent the average diet-to-consumer transfer of a chemical through food webs. They differ from biomagnification factors, which apply to individual species and can be highly variable between predator-prey combinations. The TMF is calculated from the slope of a regression between the chemical concentration and trophic level of organisms in the food web. The trophic level can be determined from stable N isotope ratios (δ(15) N). In this article, we give the background for the development of TMFs, identify and discuss impacts of ecosystem and ecological variables on their values, and discuss challenges and uncertainties associated with contaminant measurements and the use of δ(15) N for trophic level estimations. Recommendations are provided for experimental design, data treatment, and statistical analyses, including advice for users on reporting and interpreting TMF data. Interspecies intrinsic ecological and organismal properties such as thermoregulation, reproductive status, migration, and age, particularly among species at higher trophic levels with high contaminant concentrations, can influence the TMF (i.e., regression slope). Following recommendations herein for study design, empirical TMFs are likely to be useful for understanding the food web biomagnification potential of chemicals, where the target is to definitively identify if chemicals biomagnify (i.e., TMF > or < 1). TMFs may be less useful in species- and site-specific risk assessments, where the goal is to predict absolute contaminant concentrations in organisms in relation to threshold levels.


Local adaptation in migrated interior Douglas-fir seedlings is mediated by ectomycorrhizas and other soil factors.
Separating edaphic impacts on tree distributions from those of climate and geography is notoriously difficult. Aboveground and belowground factors play important roles, and determining their relative contribution to tree success will greatly assist in refining predictive models and forestry strategies in a changing climate. In a common glasshouse, seedlings of interior Douglas-fir (Pseudotsuga menziesii var. glauca) from multiple populations were grown in multiple forest soils. Fungicide was applied to half of the seedlings to separate soil fungal and nonfungal impacts on seedling performance. Soils of varying geographic and climatic distance from seed origin were compared, using a transfer function approach. Seedling height and biomass were optimized following seed transfer into drier soils, whereas survival was optimized when elevation transfer was minimised. Fungicide application reduced ectomycorrhizal root colonization by c. 50%, with treated seedlings exhibiting greater survival but reduced biomass. Local adaptation of Douglas-fir populations to soils was mediated by soil fungi to some extent in 56% of soil origin by response variable combinations. Mediation by edaphic factors in general occurred in 81% of combinations. Soil biota, hitherto unaccounted for in climate models, interacts with biogeography to influence plant ranges in a changing climate.


[Stigma, discrimination and HIV/AIDS in the Brazilian context, 1998 and 2005].
To identify discriminatory attitudes in two moments of the Brazilian HIV/AIDS epidemic, as well as the occurrence of possible changes. The Intention of Discrimination Index was obtained by scoring 1 for discriminatory situations or 0, when the opposite was the case. Intention of discrimination ranges were established by means of the clustering technique, and made compatible between the 1998 and 2005 surveys. Mean comparisons, chi-square test and ordered logit adjusted regression models were used to verify association between the index and socio-demographic variables. Between the 1998 and 2005 surveys, there was a statistically significant reduction in the proportion of people who answered "yes" to anti-HIV test's being mandatory in the following cases: admission for employment, before getting married, when joining the military service, drug users, foreigners entering the country, sex professionals, and for all the people. To have lower level of education, to be female, to live in the North/Northeast regions of Brazil, and to be aged over 45 years are factors associated with higher intention of discrimination level. The growth of intention of discrimination shows that information about ways of AIDS transmission and non-transmission still needs to be better planned and promoted, especially among populations that have lower level of education, live in the North/Northeast regions, are female and aged over 45 years.


Familial forms of disorders of sex development may be common if infertility is considered a comorbidity.
Families with 46,XY Disorders of Sex Development (DSD) have been reported, but they are considered to be exceptionally rare, with the exception of the familial forms of disorders affecting androgen synthesis or action. The families of some patients with anorchia may include individuals with 46,XY gonadal dysgenesis. We therefore analysed a large series of patients with 46,XY DSD or anorchia for the occurrence in their family of one of these phenotypes and/or ovarian insufficiency and/or infertility and/or cryptorchidism. A retrospective study chart review was performed for 114 patients with 46,XY DSD and 26 patients with 46,XY bilateral anorchia examined at a single institution over a 33 year period. Of the 140 patients, 25 probands with DSD belonged to 21 families and 7 with anorchia belonged to 7 families. Familial forms represent 22% (25/114) of the 46,XY DSD and 27% (7/26) of the anorchia cases. No case had disorders affecting androgen synthesis or action or 5 α-reductase deficiency. The presenting symptom was genital ambiguity (n = 12), hypospadias (n = 11) or discordance between 46,XY karyotyping performed in utero to exclude trisomy and female external genitalia (n = 2) or anorchia (n = 7). Other familial affected individuals presented with DSD and/or premature menopause (4 families) or male infertility (4 families) and/or cryptorchidism. In four families mutations were identified in the genes SRY, NR5A1, GATA4 and FOG2/ZFPM2. Surgery discovered dysgerminoma or gonadoblastoma in two cases with gonadal dysgenesis. This study reveals a surprisingly high frequency of familial forms of 46,XY DSD and anorchia when premature menopause or male factor infertility are included. It also demonstrates the variability of the expression of the phenotype within the families. It highlights the need to the physician to take a full family history including fertility status. This could be important to identify familial cases, understand modes of transmission of the phenotype and eventually understand the genetic factors that are involved.


Nanotopographical Modulation of Cell Function through Nuclear Deformation.
Although nanotopography has been shown to be a potent modulator of cell behavior, it is unclear how the nanotopographical cue, through focal adhesions, affects the nucleus, eventually influencing cell phenotype and function. Thus, current methods to apply nanotopography to regulate cell behavior are basically empirical. We, herein, engineered nanotopographies of various shapes (gratings and pillars) and dimensions (feature size, spacing and height), and thoroughly investigated cell spreading, focal adhesion organization and nuclear deformation of human primary fibroblasts as the model cell grown on the nanotopographies. We examined the correlation between nuclear deformation and cell functions such as cell proliferation, transfection and extracellular matrix protein type I collagen production. It was found that the nanoscale gratings and pillars could facilitate focal adhesion elongation by providing anchoring sites, and the nanogratings could orient focal adhesions and nuclei along the nanograting direction, depending on not only the feature size but also the spacing of the nanogratings. Compared with continuous nanogratings, discrete nanopillars tended to disrupt the formation and growth of focal adhesions and thus had less profound effects on nuclear deformation. Notably, nuclear volume could be effectively modulated by the height of nanotopography. Further, we demonstrated that cell proliferation, transfection, and type I collagen production were strongly associated with the nuclear volume, indicating that the nucleus serves as a critical mechanosensor for cell regulation. Our study delineated the relationships between focal adhesions, nucleus and cell function and highlighted that the nanotopography could regulate cell phenotype and function by modulating nuclear deformation. This study provides insight into the rational design of nanotopography for new biomaterials and the cell-substrate interfaces of implants and medical devices.


Synthesis and Characterization of 8-Nitroguanosine 3',5'-Cyclic Monophosphorothioate Rp-Isomer as a Potent Inhibitor of Protein Kinase G1α.
Guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinases (PKG) are kinases regulating diverse physiological functions including vascular smooth muscle relaxation, neuronal synaptic plasticity, and platelet activities. Certain PKG inhibitors, such as Rp-diastereomers of derivatives of guanosine 3',5'-cyclic monophosphorothioate (Rp-cGMPS), have been designed and used to study PKG-regulated cell signaling. 8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) is an endogenous cGMP derivative formed as a result of excess production of reactive oxygen species and nitric oxide. 8-Nitro-cGMP causes persistent activation of PKG1α through covalent attachment of cGMP moieties to cysteine residues of the enzyme (i.e., the process called protein S-guanylation). In this study, we synthesized a nitrated analogue of Rp-cGMPS, 8-nitroguanosine 3',5'-cyclic monophosphorothioate Rp-isomer (Rp-8-nitro-cGMPS), and investigated its effects on PKG1α activity. We synthesized Rp-8-nitro-cGMPS by reacting Rp-8-bromoguanosine 3',5'-cyclic monophosphorothioate (Rp-8-bromo-cGMPS) with sodium nitrite. Rp-8-Nitro-cGMPS reacted with the thiol compounds cysteine and glutathione to form Rp-8-thioalkoxy-cGMPS adducts to a similar extent as did 8-nitro-cGMP. As an important finding, a protein S-guanylation-like modification was clearly observed, by using Western blotting, in the reaction between recombinant PKG1α and Rp-8-nitro-cGMPS. Rp-8-Nitro-cGMPS inhibited PKG1α activity with an inhibitory constant of 22 µM in a competitive manner. An organ bath assay with mouse aorta demonstrated that Rp-8-nitro-cGMPS inhibited vascular relaxation induced by acetylcholine or 8-bromo-cGMP more than Rp-8-bromo-cGMPS did. These findings suggest that Rp-8-nitro-cGMPS inhibits PKG through induction of an S-guanylation-like modification by attaching the Rp-cGMPS moiety to the enzyme. Additional study is warranted to explore the potential application of Rp-8-nitro-cGMPS to biochemical and therapeutic research involving PKG1α activation.


Amyloid-beta and mitochondria in aging and Alzheimer's disease: implications for synaptic damage and cognitive decline.
This article reviews the role of amyloid-beta (Abeta) and mitochondria in synaptic damage and cognitive decline found in patients with Alzheimer's disease (AD). Recent molecular, cellular, animal model, and postmortem brain studies have revealed that Abeta and mitochondrial abnormalities are key factors that cause synaptic damage and cognitive decline in AD. Abeta is reported to accumulate in subcellular compartments and to impair the normal function of neurons in AD patients. Further, recent studies using biochemical methods and electron microscopy have revealed that the accumulation of Abeta at nerve terminals affect synaptic activities, including the release of neurotransmitters and synaptic vesicles. Recent studies of the relationship between mitochondria and Abeta in AD patients suggest that in mitochondria, structural changes caused by Abeta result in increased mitochondrial fragmentation, decreased mitochondrial fusion, mitochondrial dysfunction, and synaptic damage. This paper discusses the latest research on Abeta, mitochondria, age-dependent factors of AD in the brain, and synaptic damage in AD. This paper also briefly discusses potential mitochondrial therapeutics in the treatment of patients with AD.


Status of management effort in 153 marine protected areas across the English Channel.
A conceptual framework was developed for assessing the sub-level of protection in 185 multiple-use marine protected areas (MPAs) in the English Channel through a survey on management effort. Data were retrieved from 153 MPAs: 4.56% were assigned low management effort, 83.70% were assigned medium management effort, and 11.76% were assigned high management effort. Overall, French MPAs performed better in terms of management effort than English MPAs and lack of consistency in ratings by different management bodies in England was found. Lack of correlation between management effort and conservation status within an available subset of 13 MPAs suggests that management may not be as influential a factor for the effective conservation of MPAs, especially in marine environments under heavy human pressure such as the English Channel. It is suggested that MPAs in such areas may therefore require an upgrade of their legal level of protection to be effective.


Tumor necrosis factor induces rapid production of 1'2'diacylglycerol by a phosphatidylcholine-specific phospholipase C.
Tumor necrosis factor (TNF) is a proinflammatory polypeptide that is able to induce a great diversity of cellular responses via modulating the expression of a number of different genes. One major pathway by which TNF receptors communicate signals from the membrane to the cell nucleus involves protein kinase C (PKC). In the present study, we have addressed the molecular mechanism of TNF-induced PKC activation. To this, membrane lipids of the human histiocytic cell line U937 were labeled by incubation with various radioactive precursors, and TNF-induced changes in phospholipid, neutral lipid, and water-soluble metabolites were analyzed by thin layer chromatography. TNF treatment of U937 cells resulted in a rapid and transient increase of 1'2'diacylglycerol (DAG), a well-known activator of PKC. The increase in DAG was detectable as early as 15 s after TNF treatment and peaked at 60 s. DAG increments were most pronounced (approximately 360% of basal levels) when cells were preincubated with [14C]lysophosphatidylcholine, which was predominantly incorporated into the phosphatidylcholine (PC) pool of the plasma-membranes. Further extensive examination of changes in metabolically labeled phospholipids indicated that TNF-stimulated hydrolysis of PC is accompanied by the generation of phosphorylcholine and DAG. These results suggest the operation of a PC-specific phospholipase C. Since no changes in phosphatidic acid (PA) and choline were observed and the production of DAG by TNF could not be blocked by either propranolol or ethanol, a combined activation of phospholipase D and PA-phosphohydrolase in DAG production appears unlikely. TNF-stimulated DAG production as well as PKC activation could be blocked by the phospholipase inhibitor p-bromophenacylbromide (BPB). Since BPB did not inactivate PKC directly, these findings underscore that TNF activates PKC via formation of DAG. TNF stimulation of DAG production could be inhibited by preincubation of cells with a monoclonal anti-TNF receptor (p55-60) antibody, indicating that activation of a PC-specific phospholipase C is a TNF receptor-mediated event.


The Effect of the COVID-19 Pandemic on Glycemic Monitoring and Other Processes of Care for Type 2 Diabetes: Protocol for a Retrospective Cohort Study.
Social distancing and other nonpharmaceutical interventions to reduce the spread of COVID-19 infection in the United Kingdom have led to substantial changes in delivering ongoing care for patients with chronic conditions, including type 2 diabetes mellitus (T2DM). Clinical guidelines for the management and prevention of complications for people with T2DM delivered in primary care services advise routine annual reviews and were developed when face-to-face consultations were the norm. The shift in consultations from face-to-face to remote consultations caused a reduction in direct clinical contact and may impact the process of care for people with T2DM. The aim of this study is to explore the impact of the COVID-19 pandemic's first year on the monitoring of people with T2DM using routine annual reviews from a national primary care perspective in England. A retrospective cohort study of adults with T2DM will be performed using routinely collected primary care data from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC). We will describe the change in the rate of monitoring of hemoglobin A1c (HbA1c) between the first year of the COVID-19 pandemic (2020) and the preceding year (2019). We will also report any change in the eight checks that make up the components of these reviews. The change in HbA1c monitoring rates will be determined using a multilevel logistic regression model, adjusting for patient and practice characteristics, and similarly, the change in a composite measure of the completeness of all eight checks will be modeled using ordinal regression. The models will be adjusted for the following patient-level variables: age, gender, socioeconomic status, ethnicity, COVID-19 shielding status, duration of diabetes, and comorbidities. The model will also be adjusted for the following practice-level variables: urban versus rural, practice size, Quality and Outcomes Framework achievement, the National Health Service region, and the proportion of face-to-face consultations. Ethical approval was provided by the University of Oxford Medical Sciences Interdivisional Research Ethics Committee (September 2, 2021, reference R77306/RE001). The analysis of the data extract will include 3.96 million patients with T2DM across 700 practices, which is 6% of the available Oxford-RCGP RSC adult population. The preliminary results will be submitted to a conference under the domain of primary care. The resulting publication will be submitted to a peer-reviewed journal on diabetes and endocrinology. The COVID-19 pandemic has impacted the delivery of care, but little is known about the process of caring for people with T2DM. This study will report the impact of the COVID-19 pandemic on these processes of care. DERR1-10.2196/35971.


A comparative investigation in dogs: 2-year morphometric results of the dental implant--bone interface.
One hundred twenty titanium and ceramic root-form and titanium blade implants were placed into 30 dog mandibles. Twenty-four implants in six control dogs (in situ for 5 months) did not receive prostheses. Ninety-six implants in 24 dogs supported prostheses for 6, 12, 18, or 24 months. Computerized morphometry data presented the percent of the implant surface apposed directly by bone. A three-way factorial analysis of variance was used to assess significance. Individual implant means ranged from 0% (mobile implant) to 71% bone adaptation. From these data, two-stage titanium root-form implants were shown to be apposed by more bone than the other five systems, and overall, titanium implant systems were apposed by more bone than ceramic systems. Between 41% and 50% of the surface of integrated ceramic implants were apposed by bone, whereas between 50% and 65% of the surfaces of titanium implants were apposed by bone. Also, two-stage surgery for blade implants appears important for implant success. Furthermore, the use of Nomarski differential illumination appears to be useful for examining the quality of interfacial bone to correlate with the amount of bone quantified by morphometric protocols.


Epithelial-to-mesenchymal transition confers pericyte properties on cancer cells.
Carcinoma cells can acquire increased motility and invasiveness through epithelial-to-mesenchymal transition (EMT). However, the significance of EMT in cancer metastasis has been controversial, and the exact fates and functions of EMT cancer cells in vivo remain inadequately understood. Here, we tracked epithelial cancer cells that underwent inducible or spontaneous EMT in various tumor transplantation models. Unlike epithelial cells, the majority of EMT cancer cells were specifically located in the perivascular space and closely associated with blood vessels. EMT markedly activated multiple pericyte markers in carcinoma cells, in particular PDGFR-β and N-cadherin, which enabled EMT cells to be chemoattracted towards and physically interact with endothelium. In tumor xenografts generated from carcinoma cells that were prone to spontaneous EMT, a substantial fraction of the pericytes associated with tumor vasculature were derived from EMT cancer cells. Depletion of such EMT cells in transplanted tumors diminished pericyte coverage, impaired vascular integrity, and attenuated tumor growth. These findings suggest that EMT confers key pericyte attributes on cancer cells. The resulting EMT cells phenotypically and functionally resemble pericytes and are indispensable for vascular stabilization and sustained tumor growth. This study thus proposes a previously unrecognized role for EMT in cancer.


Cognitive function among sons of women who worked in dentistry.
Exposure to elemental mercury vapor can impair neurological function as it is neurotoxic in doses higher than usually found in dentistry. Little is known about the potential effects of fetal exposure to elemental mercury among offspring of female dental workers. We investigated cognitive function among offspring of women working in dentistry at the time of their pregnancy. We compared results for cognitive function examinations taken by the majority of young men in Sweden at the time of compulsory military enlistment (age 17-18 years). Sons of female dentists (N=365) and dental nurses (N=3181) born during the 1960-1970s were compared with sons of female physicians (N=378) and assistant nurses (N=12 667). Analysis by linear regression showed that sons of dental workers had similar or higher cognitive function test results compared to their matched cohorts. We found no evidence of poorer cognitive function among male offspring of female dentists or dental nurses.


Prospective evaluation of the pyramid plus psychosocial intervention for shy withdrawn children: an assessment of efficacy in 7- to 8-year-old school children in Northern Ireland.
Social withdrawal is known to precede and contribute to the development of internalization problems in shy children. This study examined the efficacy of a selective primary school-based psychosocial intervention for withdrawn children. The sample comprised 82 Primary 4 children aged between 7 and 8 years from 7 schools across Northern Ireland. There were 31 children in the comparison group (50.6% male) and 57 children received the intervention (41.7% male). A 2 × 2 mixed-model design was used: group (intervention group vs. comparison group) × 3 time points (pre- vs. 10 postintervention vs. 12-week follow-up) with repeated measures on the time factor. Teachers completed the SDQ at the three time points to assess participants' socio-emotional health status. Pyramid participants showed greater reductions than the comparison group on the Emotional Symptom and Peer Problem factors following the intervention and their scores did not return to baseline levels at follow-up. Pyramid attendance accounted for approximately 12% and 9% of the variance in the Emotional Symptom and Peer Problems decreases respectively. Pyramid Plus helped to alleviate internalization problems in participants and initially had a positive impact on social re-integration. The incorporation of cognitive restructuring techniques may be a necessary intervention modification to affect participants' emotion regulation strategies.


Neuropeptides and peptide hormones identified in codling moth, Cydia pomonella (Lepidoptera: Tortricidae).
The codling moth, Cydia pomonella, is a worldwide pest of pome fruits. Neuropeptides regulate most physiological functions in insects and represent new targets for the development of control agents. The only neuropeptides reported from the codling moth to date are the allatostatin A family peptides. To identify other neuropeptides and peptide hormones from codling moth, we analyzed head transcriptomes, identified 50 transcripts, and predicted 120 prepropeptides for the codling moth neuropeptides and peptide hormones. All transcripts were amplified, and these sequences were verified. One of the notable findings in this study is that diapause hormones (DHs) reported from Tortricid moths, including the codling moth, do not have the WFGPRL sequence in C-terminal ends in the pban genes. The C-terminal motif is critical to characterize insect DH peptides, and always conserved in pban/dh genes in Lepidoptera and many insect orders. Interestingly, the WFGPRL sequence was produced only from the capa gene in the codling moth. The allatostatin A-family encoding transcript predicted nine peptides, seven of which, as expected, are identical to those previously isolated from the moth. We also identified new codling moth orthologs of insect neuropeptides including CCHamides, allatostatin CC, RYamides, and natalisins. The information provided in this study will benefit future codling moth investigations using peptidoproteomics to determine peptide presence and functions.


Enhanced balance associated with coordination training with stochastic resonance stimulation in subjects with functional ankle instability: an experimental trial.
Ankle sprains are common injuries that often lead to functional ankle instability (FAI), which is a pathology defined by sensations of instability at the ankle and recurrent ankle sprain injury. Poor postural stability has been associated with FAI, and sports medicine clinicians rehabilitate balance deficits to prevent ankle sprains. Subsensory electrical noise known as stochastic resonance (SR) stimulation has been used in conjunction with coordination training to improve dynamic postural instabilities associated with FAI. However, unlike static postural deficits, dynamic impairments have not been indicative of ankle sprain injury. Therefore, the purpose of this study was to examine the effects of coordination training with or without SR stimulation on static postural stability. Improving postural instabilities associated with FAI has implications for increasing ankle joint stability and decreasing recurrent ankle sprains. This study was conducted in a research laboratory. Thirty subjects with FAI were randomly assigned to either a: 1) conventional coordination training group (CCT); 2) SR stimulation coordination training group (SCT); or 3) control group. Training groups performed coordination exercises for six weeks. The SCT group received SR stimulation during training, while the CCT group only performed coordination training. Single leg postural stability was measured after the completion of balance training. Static postural stability was quantified on a force plate using anterior/posterior (A/P) and medial/lateral (M/L) center-of-pressure velocity (COPvel), M/L COP standard deviation (COPsd), M/L COP maximum excursion (COPmax), and COP area (COParea). Treatment effects comparing posttest to pretest COP measures were highest for the SCT group. At posttest, the SCT group had reduced A/P COPvel (2.3 +/- 0.4 cm/s vs. 2.7 +/- 0.6 cm/s), M/L COPvel (2.6 +/- 0.5 cm/s vs. 2.9 +/- 0.5 cm/s), M/L COPsd (0.63 +/- 0.12 cm vs. 0.73 +/- 0.11 cm), M/L COPmax (1.76 +/- 0.25 cm vs. 1.98 +/- 0.25 cm), and COParea (0.13 +/- 0.03 cm2 vs. 0.16 +/- 0.04 cm2) than the pooled means of the CCT and control groups (P < 0.05). Reduced values in COP measures indicated postural stability improvements. Thus, six weeks of coordination training with SR stimulation enhanced postural stability. Future research should examine the use of SR stimulation for decreasing recurrent ankle sprain injury in physically active individuals with FAI.


Stress moderates the relationship between problematic Internet use by parents and problematic Internet use by adolescents.
Based on the theoretical framework of Problem Behavior and Stress Reduction theories for problematic Internet use (PIU), this study aimed to investigate the relationship between parental PIU and the PIU among adolescents taking into consideration the stress levels of young people. This was a population-based parent and adolescent dyad health survey utilizing a random sampling technique. PIU for both parents and adolescents was measured by the Internet addiction test designed by Young. The stress level of adolescents was assessed using the stress subscale of the Depression Anxiety Stress Scale (DASS). Data were analyzed using logistic regression modeling techniques with adjustment for potential confounding factors with analysis on the modification effect of stress levels on the relationship between parent and adolescent PIU. Of the total 1,098 parent and adolescent dyads with usable information, 263 adolescents (24.0%) and 62 parents (5.7%) could be classified as moderate and severe problematic users of the Internet. About 14% (n = 157) of adolescents could be classified with moderate-to-severe stress. Regression analysis results suggested a significant interaction between parental PIU and adolescents' stress levels on adolescent PIU. Stratified regression analyses by stress level resulted in a significant parent and adolescent PIU relationship in the low stress group (odds ratio, 3.18; 95% confidence interval 1.65-6.14). However, the association between parent and adolescent PIU in the high stress group became insignificant. There was a significant parent and adolescent PIU relationship; however, this relationship is differentially affected by the stress status of the adolescent. The direct implication of the results is that parental Internet use should also be assessed and included as part of the treatment regime for adolescents.


Single cardiac vagal fiber activity, acute myocardial ischemia, and risk for sudden death.
Experimental and clinical evidence indicates that high risk for sudden death is significantly correlated with post-myocardial infarction depression in two "markers" of vagal activity, heart rate variability and baroreflex sensitivity. The present experiments were designed to answer some of the questions generated by those findings. In 33 anesthetized cats, the neural activity of single cardiac vagal efferent fibers was recorded in control conditions and after injection of phenylephrine (n = 33), before and during a 1-hour coronary artery occlusion (CAO) (n = 17), and before and after removal of the left stellate ganglion (n = 16). In the first minute after CAO, vagal activity increased by 35% from 1.66 +/- 0.37 to 2.57 +/- 0.62 impulses/sec (p less than 0.01); despite a slight decline, it remained for the entire CAO above the control values, to which it returned after CAO release. Of 17 cats, ventricular fibrillation occurred in nine (susceptible) and eight survived (resistant). Resistant and susceptible cats had different reflex vagal responses to CAO. Whereas the resistant cats had a 48% (p less than 0.01) increase by the second minute of CAO, susceptible cats had no change (-18%, p = NS) in vagal activity. These differences were independent of blood pressure changes. The increase in vagal efferent activity in response to the blood pressure rise induced by phenylephrine (baroreceptive reflex) was more marked in the resistant cats compared with the susceptible cats (+246 +/- 66% versus +80 +/- 14%, p less than 0.025). Just before the injection of phenylephrine, vagal activity was not different between resistant and susceptible cats (1.58 +/- 0.35 versus 1.48 +/- 0.30 impulses/sec, p = NS). In 16 cats, left stellectomy increased cardiac vagal efferent activity by 75% (p less than 0.01), and the reflex vagal activation secondary to phenylephrine was further enhanced (from 2.2 +/- 0.4 to 4.7 +/- 0.7 impulses/sec, p less than 0.001). These data demonstrate that 1) cardiac vagal efferent activity increases in response to acute myocardial ischemia--much more so among the animals destined to survive, 2) before CAO, susceptible and resistant animals can be identified by the vagal response to blood pressure increase (assessed clinically by baroreflex sensitivity) and not by tonic vagal activity (assessed clinically by heart rate variability), and 3) the findings with left stellectomy support the hypothesis that vagal activity decreases after myocardial infarction because of an increase, secondary to abnormal stretch of the cardiac mechanoreceptors, in cardiac sympathetic afferent traffic, which exerts a tonic restraint on vagal outflow.


Caregiver burden and health in bipolar disorder: a cluster analytic approach.
To identify caregivers at risk for adverse health effects associated with caregiving, the stress, coping, health and service use of 500 primary caregivers of patients with bipolar disorder were assessed at baseline, 6, and 12 months. K-means cluster analysis and ANOVA identified and characterized groups with differing baseline stress/coping profiles. Mixed effects models examined the effects of cluster, time, and covariates on health outcomes. Three groups were identified. Burdened caregivers had higher burden and avoidance coping levels, and lower mastery and social support than effective and stigmatized caregivers; stigmatized caregivers reported the highest perceived stigma (p < 0.05). Effective and stigmatized groups had better health outcomes and less service use than the burdened group over time; stigmatized caregivers had poorer self-care than effective caregivers. Cluster analysis is a promising method for identifying subgroups of caregivers with different stress and coping profiles associated with different health-related outcomes.


Formation and Characterization of Hydrogen Boride Sheets Derived from MgB2 by Cation Exchange.
Two-dimensional (2D) materials are promising for applications in a wide range of fields because of their unique properties. Hydrogen boride sheets, a new 2D material recently predicted from theory, exhibit intriguing electronic and mechanical properties as well as hydrogen storage capacity. Here, we report the experimental realization of 2D hydrogen boride sheets with an empirical formula of H1B1, produced by exfoliation and complete ion-exchange between protons and magnesium cations in magnesium diboride (MgB2) with an average yield of 42.3% at room temperature. The sheets feature an sp2-bonded boron planar structure without any long-range order. A hexagonal boron network with bridge hydrogens is suggested as the possible local structure, where the absence of long-range order was ascribed to the presence of three different anisotropic domains originating from the 2-fold symmetry of the hydrogen positions against the 6-fold symmetry of the boron networks, based on X-ray diffraction, X-ray atomic pair distribution functions, electron diffraction, transmission electron microscopy, photo absorption, core-level binding energy data, infrared absorption, electron energy loss spectroscopy, and density functional theory calculations. The established cation-exchange method for metal diboride opens new avenues for the mass production of several types of boron-based 2D materials by countercation selection and functionalization.


Real world heart failure epidemiology and outcome: A population-based analysis of 88,195 patients.
Heart failure (HF) is frequent and its prevalence is increasing. We aimed to evaluate the epidemiologic features of HF patients, the 1-year follow-up outcomes and the independent predictors of those outcomes at a population level. Population-based longitudinal study including all prevalent HF cases in Catalonia (Spain) on December 31st, 2012. Patients were divided in 3 groups: patients without a previous HF hospitalization, patients with a remote (>1 year) HF hospitalization and patients with a recent (<1 year) HF admission. We analyzed 1year all-cause and HF hospitalizations, and all-cause mortality. Logistic regression was used to identify the independent predictors of each of those outcomes. A total of 88,195 patients were included. Mean age was 77 years, 55% were women. Comorbidities were frequent. Fourteen percent of patients had never been hospitalized, 71% had a remote HF hospitalization and 15% a recent hospitalization. At 1-year follow-up, all-cause and HF hospitalization were 53% and 8.8%, respectively. One-year all-cause mortality rate was 14%, and was higher in patients with a recent HF hospitalization (24%). The presence of diabetes mellitus, atrial fibrillation or chronic kidney disease was independently associated with all-cause and HF hospitalization and all-cause mortality. Hospital admissions and emergency department visits the previous year were also found to be independently associated with the three study outcomes. Outcomes are different depending on the HF population studied. Some comorbidity, an all-cause hospitalization or emergency department visit the previous year were associated with a worse outcome.


Comparative genomics of metabolic capacities of regulons controlled by cis-regulatory RNA motifs in bacteria.
In silico comparative genomics approaches have been efficiently used for functional prediction and reconstruction of metabolic and regulatory networks. Riboswitches are metabolite-sensing structures often found in bacterial mRNA leaders controlling gene expression on transcriptional or translational levels.An increasing number of riboswitches and other cis-regulatory RNAs have been recently classified into numerous RNA families in the Rfam database. High conservation of these RNA motifs provides a unique advantage for their genomic identification and comparative analysis. A comparative genomics approach implemented in the RegPredict tool was used for reconstruction and functional annotation of regulons controlled by RNAs from 43 Rfam families in diverse taxonomic groups of Bacteria. The inferred regulons include ~5200 cis-regulatory RNAs and more than 12000 target genes in 255 microbial genomes. All predicted RNA-regulated genes were classified into specific and overall functional categories. Analysis of taxonomic distribution of these categories allowed us to establish major functional preferences for each analyzed cis-regulatory RNA motif family. Overall, most RNA motif regulons showed predictable functional content in accordance with their experimentally established effector ligands. Our results suggest that some RNA motifs (including thiamin pyrophosphate and cobalamin riboswitches that control the cofactor metabolism) are widespread and likely originated from the last common ancestor of all bacteria. However, many more analyzed RNA motifs are restricted to a narrow taxonomic group of bacteria and likely represent more recent evolutionary innovations. The reconstructed regulatory networks for major known RNA motifs substantially expand the existing knowledge of transcriptional regulation in bacteria. The inferred regulons can be used for genetic experiments, functional annotations of genes, metabolic reconstruction and evolutionary analysis. The obtained genome-wide collection of reference RNA motif regulons is available in the RegPrecise database (http://regprecise.lbl.gov/).


Antibiotic treatment based on seminal cultures from asymptomatic male partners in in-vitro fertilization is unnecessary and may be detrimental.
We questioned the policy of routine microbiological culture of semen prior to in-vitro fertilization (IVF) with a view to prescribing antibiotics to reduce the risk of introducing seminal infection into the embryo culture system. An initial retrospective study examined serum microbiology reports of 449 couples undergoing IVF or gamete intra-Fallopian transfer (GIFT). In semen samples taking >/=1 days to reach the microbiology laboratory compared with same-day delivery there was increased frequency of significant culture of enterococci (27 versus 15%, P < 0.01). In samples taking >/=2 days there was increased frequency of significant culture of Gram-negative bacilli (31 versus 12%, P < 0.01) and of overall culture of other potentially pathogenic organisms (26 versus 14%, P < 0.01). We questioned diagnostic accuracy and relevance. Therefore, in a prospective study, semen and high vaginal swabs obtained on the day of oocyte collection were cultured from 100 couples having IVF or GIFT, of whom 52 male partners had been treated with antibiotics following positive pre-IVF semen culture. The presence of bacteria in semen samples used only for IVF (n = 90) did not reduce fertilization rates nor lead to infection of the embryo culture system. However, there was an increased incidence of significant culture of vaginal Gram-negative bacilli in patients with treated partners compared with untreated partners [15/52 (29%) versus 5/48 (10%), P < 0.05]. Thus antibiotic therapy in the male partner may increase the likelihood of inoculation of antibiotic-resistant pathogenic bacteria from the vagina into the embryo culture system during vaginal oocyte collection. In asymptomatic patients, microbiological screening of semen samples prior to IVF treatment and subsequent treatment with antibiotic therapy in those with positive cultures appears to be unnecessary and may be detrimental to IVF outcome.


iPad Use in Stroke Neuro-Rehabilitation.
Neuro-rehabilitation services are essential in reducing post-stroke impairments, enhancing independence, and improving recovery in hospital and post-discharge. However these services are therapist-dependent and resource intensive. Patients' disengagement and boredom in stroke units are common which adversely affect functional and psychological outcomes. Novel techniques such as use of iPads™ are increasingly researched to overcome such challenges. The aim of this review is to determine the feasibility, effectiveness, acceptability, and barriers to the use of iPads™ in stroke neuro-rehabilitation. Four databases and manual literature search were used to identify published studies using the terms "iPad", "Stroke", and "neuro-rehabilitation". Studies were included in accordance with the review selection criteria. A total of 16 articles were included in the review. The majority of the studies focused on iPads use in speech and language therapy. Although of small scale, the studies highlighted that iPads are feasible, have the potential to improve rehabilitation outcomes, and can improve patient's social isolation. Patients' stroke severity and financial limitations are some of the barriers highlighted in this review. This review presents preliminary data supportive for the use of iPad technology in stroke neuro-rehabilitation. However, further research is needed to determine impact on rehabilitation goals acquisition, clinical efficacy, and cost-efficiency.


Peer-assisted learning in simulation-based medical education: a mixed-methods exploratory study.
Peer-assisted learning (PAL) is well described in medical education but there has been little research on its application in simulation-based education (SBE). This exploratory study aimed to determine the perceptions of senior medical students at two universities to teaching and learning in SBE using PAL (PAL-SBE). Ninety-seven medical students at two universities working in small groups with facilitator oversight wrote, ran and debriefed a simulation scenario for their peers.This was a mixed-methods study. Participants completed a written free-text and Likert survey instrument, and participated in a facilitated focus group immediately after the scenario. Thematic analysis was performed on the free-text and focus group transcripts. Student-led scenarios ran without major technical issues. Instructor presence was required throughout scenario delivery and debrief, making the exercise resource intensive. Participant responses were more positive regarding learning as peer teachers in simulation than they were regarding participation as a peer learner. Five themes were identified: learning in the simulated environment; teaching in the simulated environment; teaching peers and taking on an educator role; learning from peers; and time and effort expended. Perceived benefits included learning in depth through scenario writing, improved knowledge retention, understanding the patient's perspective and learning to give feedback through debriefing. PAL in SBE is feasible and was perceived positively by students. Perceived benefits appear to be greater for the peer teachers than for peer learners.


Manuka Honey: A Potent Cariostatic Agent- An in vitro Study.
The aim of the study was to test the antibacterial activity of manuka honey and compare its efficacy with another commercially available honey (Dabur honey) on the cariogenic bacteria on Streptococcus mutans and Lactobacillus. An in vitro study was carried out on 40 agar specimens; the samples were divided into two groups of 20 samples consisting of S. mutans and Lactobacil-lus respectively. The 20 samples in each group were further subdivided into four groups of five each, which were tested with 25% manuka honey, 100% manuka honey, 25% Dabur honey, and 100% Dabur honey for both Lactobacillus and S. mutans groups. The antibacterial activity was tested using the agar well diffusion method against S. mutans and Lacto-bacillus. Antibacterial activity was assessed by measuring the diameter of inhibition of zones surrounding the wells. The results obtained were statistically analyzed (one-way analysis of variance test, p-value). The results showed that 25% of manuka honey has statistically significant (p ≤ 0.001) antibacterial effect than 25% of Dabur honey on both Streptococcus and Lactobacillus species, and manuka honey with 100% concentration showed a statistically significant (p ≤ 0.001) antibacterial effect than 100% Dabur honey on the same species of bacteria. 100% of both the honeys showed statistically significant (p ≤ 0.001) antibacterial effect than 25% concentrations of the same on S. mutans and Lactobacillus. Manuka honey had more antibacterial activity than Dabur honey on S. mutans and Lactobacillus bacteria in the in vitro study. This effect was dependent on the concentration of honey used.How to cite this article: Beena JP, Sahoo P, Konde S, Raj SN, Kumar NC, Agarwal M. Manuka Honey: A Potent Cariostatic Agent-An in vitro Study. Int J Clin Pediatr Dent 2018;11(2):105-109.


Energy harvesting from the beating heart by a mass imbalance oscillation generator.
Energy-harvesting devices attract wide interest as power supplies of today's medical implants. Their long lifetime will spare patients from repeated surgical interventions. They also offer the opportunity to further miniaturize existing implants such as pacemakers, defibrillators or recorders of bio signals. A mass imbalance oscillation generator, which consists of a clockwork from a commercially available automatic wrist watch, was used as energy harvesting device to convert the kinetic energy from the cardiac wall motion to electrical energy. An MRI-based motion analysis of the left ventricle revealed basal regions to be energetically most favorable for the rotating unbalance of our harvester. A mathematical model was developed as a tool for optimizing the device's configuration. The model was validated by an in vitro experiment where an arm robot accelerated the harvesting device by reproducing the cardiac motion. Furthermore, in an in vivo experiment, the device was affixed onto a sheep heart for 1 h. The generated power in both experiments-in vitro (30 μW) and in vivo (16.7 μW)-is sufficient to power modern pacemakers.


Enzymatic Synthesis of Vancomycin-Modified DNA.
Many potent antibiotics fail to treat bacterial infections due to emergence of drug-resistant strains. This surge of antimicrobial resistance (AMR) calls in for the development of alternative strategies and methods for the development of drugs with restored bactericidal activities. In this context, we surmised that identifying aptamers using nucleotides connected to antibiotics will lead to chemically modified aptameric species capable of restoring the original binding activity of the drugs and hence produce active antibiotic species that could be used to combat AMR. Here, we report the synthesis of a modified nucleoside triphosphate equipped with a vancomycin moiety on the nucleobase. We demonstrate that this nucleotide analogue is suitable for polymerase-mediated synthesis of modified DNA and, importantly, highlight its compatibility with the SELEX methodology. These results pave the way for bacterial-SELEX for the identification of vancomycin-modified aptamers.


Differential effects of saturated and unsaturated fatty acids on autophagy in pancreatic β-cells.
Long-chain saturated fatty acids are lipotoxic to pancreatic β-cells, whereas most unsaturates are better tolerated and some may even be cytoprotective. Fatty acids alter autophagy in β-cells and there is increasing evidence that such alterations can impact directly on the regulation of viability. Accordingly, we have compared the effects of palmitate (C16:0) and palmitoleate (C16:1) on autophagy in cultured β-cells and human islets. Treatment of BRIN-BD11 β-cells with palmitate led to enhanced autophagic activity, as judged by cleavage of microtubule-associated protein 1 light chain 3-I (LC3-I) and this correlated with a marked loss of cell viability in the cells. In addition, transfection of these cells with an mCherry-YFP-LC3 reporter construct revealed the accumulation of autophagosomes in palmitate-treated cells, indicating an impairment of autophagosome-lysosome fusion. This was also seen upon addition of the vacuolar ATPase inhibitor, bafilomycin A1. Exposure of BRIN-BD11 cells to palmitoleate (C16:1) did not lead directly to changes in autophagic activity or flux, but it antagonised the actions of palmitate. In parallel, palmitoleate also improved the viability of palmitate-treated BRIN-BD11 cells. Equivalent responses were observed in INS-1E cells and in isolated human islets. Taken together, these data suggest that palmitate may cause an impairment of autophagosome-lysosome fusion. These effects were not reproduced by palmitoleate which, instead, antagonised the responses mediated by palmitate suggesting that attenuation of β-cell stress may contribute to the improvement in cell viability caused by the mono-unsaturated fatty acid.