Exercise in muscle glycogen storage diseases.
Glycogen storage diseases (GSD) are inborn errors of glycogen or glucose metabolism. In the GSDs that affect muscle, the consequence of a block in skeletal muscle glycogen breakdown or glucose use, is an impairment of muscular performance and exercise intolerance, owing to 1) an increase in glycogen storage that disrupts contractile function and/or 2) a reduced substrate turnover below the block, which inhibits skeletal muscle ATP production. Immobility is associated with metabolic alterations in muscle leading to an increased dependence on glycogen use and a reduced capacity for fatty acid oxidation. Such changes may be detrimental for persons with GSD from a metabolic perspective. However, exercise may alter skeletal muscle substrate metabolism in ways that are beneficial for patients with GSD, such as improving exercise tolerance and increasing fatty acid oxidation. In addition, a regular exercise program has the potential to improve general health and fitness and improve quality of life, if executed properly. In this review, we describe skeletal muscle substrate use during exercise in GSDs, and how blocks in metabolic pathways affect exercise tolerance in GSDs. We review the studies that have examined the effect of regular exercise training in different types of GSD. Finally, we consider how oral substrate supplementation can improve exercise tolerance and we discuss the precautions that apply to persons with GSD that engage in exercise.


Effect of probucol, an oral hypocholesterolaemic agent, on acute tobacco smoke inhalation in rats.
1. We hypothesized that probucol, an oral hypocholesterolaemic agent, can suppress the oxidant stress induced by acute tobacco smoke inhalation in rats. We determined lung tissue glutathione (reduced and oxidized), lipid peroxide, tocopherol and plasma elastase inhibitory capacity, ferroxidase activity and lipid peroxide in rats after inhalation of tobacco smoke. 2. Rats treated with the probucol diet for 3 days or 4 weeks equally showed no suppression of plasma elastase inhibitory capacity and ferroxidase activity compared with control rats after acute tobacco smoke inhalation, although both animals treated with probucol for 3 days or 4 weeks had pharmacologically effective concentrations of probucol to lower plasma cholesterol but plasma cholesterol in rats treated with probucol for 3 days was still in the normal range. 3. Probucol treatment for 4 weeks lessened tobacco smoke-induced suppression of lung tissue glutathione, attenuated tobacco smoke-induced increases in lung tissue lipid peroxide and did not alter lung tissue tocopherol compared with control (lungs). 4. These findings demonstrate that probucol, via its antioxidant ability, confers a protective effect on lung exposed to acute tobacco smoke inhalation.


Zipcode Binding Protein 1 (ZBP1; IGF2BP1): A Model for Sequence-Specific RNA Regulation.
The fate of an RNA, from its localization, translation, and ultimate decay, is dictated by interactions with RNA binding proteins (RBPs). β-actin mRNA has functioned as the classic example of RNA localization in eukaryotic cells. Studies of β-actin mRNA over the past three decades have allowed understanding of how RBPs, such as ZBP1 (IGF2BP1), can control both RNA localization and translational status. Here, we summarize studies of β-actin mRNA and focus on how ZBP1 serves as a model for understanding interactions between RNA and their binding protein(s). Central to the study of RNA and RBPs were technological developments that occurred along the way. We conclude with a future outlook highlighting new technologies that may be used to address still unanswered questions about RBP-mediated regulation of mRNA during its life cycle, within the cell.


Contrasting genomic and phenotypic outcomes of hybridization between pairs of mimetic butterfly taxa across a suture zone.
Hybrid zones, whereby divergent lineages come into contact and eventually hybridize, can provide insights on the mechanisms involved in population differentiation and reproductive isolation, and ultimately speciation. Suture zones offer the opportunity to compare these processes across multiple species. In this paper we use reduced-complexity genomic data to compare the genetic and phenotypic structure and hybridization patterns of two mimetic butterfly species, Ithomia salapia and Oleria onega (Nymphalidae: Ithomiini), each consisting of a pair of lineages differentiated for their wing colour pattern and that come into contact in the Andean foothills of Peru. Despite similarities in their life history, we highlight major differences, both at the genomic and phenotypic level, between the two species. These differences include the presence of hybrids, variations in wing phenotype, and genomic patterns of introgression and differentiation. In I. salapia, the two lineages appear to hybridize only rarely, whereas in O. onega the hybrids are not only more common, but also genetically and phenotypically more variable. We also detected loci statistically associated with wing colour pattern variation, but in both species these loci were not over-represented among the candidate barrier loci, suggesting that traits other than wing colour pattern may be important for reproductive isolation. Our results contrast with the genomic patterns observed between hybridizing lineages in the mimetic Heliconius butterflies, and call for a broader investigation into the genomics of speciation in Ithomiini - the largest radiation of mimetic butterflies.


The Social Communication Intervention Project: a randomized controlled trial of the effectiveness of speech and language therapy for school-age children who have pragmatic and social communication problems with or without autism spectrum disorder.
Children who show disproportionate difficulty with the pragmatic as compared with the structural aspects of language are described as having pragmatic language impairment (PLI) or social communication disorder (SCD). Some children who have PLI also show mild social impairments associated with high-functioning autism or autism spectrum disorder (ASD). There is little robust evidence of effectiveness of speech-language interventions which target the language, pragmatic or social communication needs of these children. To evaluate the effectiveness of an intensive manualized social communication intervention (SCIP) for children who have PLI with or without features of ASD. In a single-blind RCT design, 88 children with pragmatic and social communication needs aged 5;11-10;8, recruited from UK speech and language therapy services, were randomly assigned in a 2:1 ratio to SCIP or to treatment-as-usual. Children in the SCIP condition received up to 20 sessions of direct intervention from a specialist research speech and language therapist working with supervised assistants. All therapy content and methodology was derived from an intervention manual. A primary outcome measure of structural language and secondary outcome measures of narrative, parent-reported pragmatic functioning and social communication, blind-rated perceptions of conversational competence and teacher-reported ratings of classroom learning skills were taken pre-intervention, immediately post-intervention and at 6-month follow-up. Analysis was by intention to treat. No significant treatment effect was found for the primary outcome measure of structural language ability or for a measure of narrative ability. Significant treatment effects were found for blind-rated perceptions of conversational competence, for parent-reported measures of pragmatic functioning and social communication, and for teacher-reported ratings of classroom learning skills. There is some evidence of an intervention effect on blind and parent/teacher-reported communication outcomes, but not standardized language assessment outcomes, for 6-11-year-old children who have pragmatic and social communication needs. These findings are discussed in the context of the increasingly central role of service user outcomes in providing evidence for an intervention. The substantial overlap between the presence of PLI and ASD (75%) across the whole cohort suggests that the intervention may also be applicable to some verbally able children with ASD who have pragmatic communication needs.


Potential renovascular hypertension, space missions, and the role of magnesium.
Space flight (SF) and dust inhalation in habitats cause hypertension whereas in SF (alone) there is no consistent hypertension but reduced diurnal blood pressure (BP) variation instead. Current pharmaceutical subcutaneous delivery systems are inadequate and there is impairment in the absorption, metabolism, excretion, and deterioration of some pharmaceuticals. Data obtained from the National Aeronautics and Space Administration through the Freedom of Information Act shows that Irwin returned from his 12-day Apollo 15 mission in 1971 and was administered a bicycle stress test. With just three minutes of exercise, his BP was >275/125 mm Hg (heart rate of only 130 beats per minute). There was no acute renal insult. Irwin's apparent spontaneous remission is suggested to be related to the increase of a protective vasodilator, and his atrial natriuretic peptide (ANP) reduced with SF because of reduced plasma volume. With invariable malabsorption and loss of bone/muscle storage sites, there are significant (P < 0.0001) reductions of magnesium (Mg) required for ANP synthesis and release. Reductions of Mg and ANP can trigger pronounced angiotensin (200%), endothelin, and catecholamine elevations (clearly shown in recent years) and vicious cycles between the latter and Mg deficits. There is proteinuria, elevated creatinine, and reduced renal concentrating ability with the potential for progressive inflammatory and oxidative stress-induced renal disease and hypertension with vicious cycles. After SF, animals show myocardial endothelial injuries and increased vascular resistance of extremities in humans. Even without dust, hypertension might eventually develop from renovascular hypertension during very long missions. Without sufficient endothelial protection from pharmaceuticals, a comprehensive gene research program should begin now.


Systemic Amyloidosis in a Patient With Familial Mediterranean Fever and Hodgkin Lymphoma: A Case Report.
Systemic amyloidosis is a clinical manifestation of the accumulation of amyloid fibrils in tissues because of persistent acute phase elevation and chronic inflammation. Its most common causes are inflammatory diseases and malignancies. Here, we present a 12-year-old girl diagnosed with systemic amyloidosis and Hodgkin lymphoma (HL) who was also previously diagnosed with familial Mediterranean fever (FMF). Despite colchicine treatment for FMF, the patient had a persistent elevation of acute phase reactants and AA-type amyloid deposits were observed in a kidney biopsy. Anakinra, an interleukin-1 antagonist, was added to the treatment. Shortly after the diagnosis of amyloidosis, mediastinal lymphadenopathy was recognized, and she was also diagnosed with HL. A chemotherapy protocol of doxorubicin, bleomycin, vinblastine, and dacarbazine was initiated. After 6 cycles of the chemotherapy and 8 months of the anakinra treatment, no recurrence or residual malignancy was observed and proteinuria was decreased. To the authors' knowledge, this is the first reported case of systemic amyloidosis in the literature associated with both FMF and HL.


Epigenetic modification of nucleic acids: from basic studies to medical applications.
The epigenetic modification of nucleic acids represents one of the most significant areas of study in the field of nucleic acids because it makes gene regulation more complex and heredity more complicated, thus indicating its profound impact on aspects of heredity, growth, and diseases. The recent characterization of epigenetic modifications of DNA and RNA using chemical labelling strategies has promoted the discovery of these modifications, and the newly developed single-base or single-cell resolution mapping strategies have enabled large-scale epigenetic studies in eukaryotes. Due to these technological breakthroughs, several new epigenetic marks have been discovered that have greatly extended the scope and impact of epigenetic modifications in nucleic acids over the past few years. Because epigenetics is reversible and susceptible to environmental factors, it could potentially be a promising direction for clinical medicine research. In this review, we have comprehensively discussed how these epigenetic marks are involved in disease, including the pathogenesis, prevention, diagnosis and treatment of disease. These findings have revealed that the epigenetic modification of nucleic acids has considerable significance in various areas from methodology to clinical medicine and even in biomedical applications.


Open versus laparoscopic pyloromyotomy for pyloric stenosis: a prospective, randomized trial.
Pyloric stenosis, the most common surgical condition of infants, is treated by longitudinal myotomy of the pylorus. Comparative studies to date between open and laparoscopic pyloromyotomy have been retrospective and report conflicting results. To scientifically compare the 2 techniques, we conducted the first large prospective, randomized trial between the 2 approaches. After obtaining IRB approval, subjects with ultrasound-proven pyloric stenosis were randomized to either open or laparoscopic pyloromyotomy. Postoperative pain management, feeding schedule, and discharge criteria were identical for both groups. Operating time, postoperative emesis, analgesia requirements, time to full feeding, length of hospitalization after operation, and complications were compared. From April 2003 through March 2006, 200 patients were enrolled in the study. There were no significant differences in operating time, time to full feeding, or length of stay. There were significantly fewer number of emesis episodes and doses of analgesia given in the laparoscopic group. One mucosal perforation and one incisional hernia occurred in the open group. Late in the study, 1 patient in the laparoscopic group was converted to the open operation. A wound infection occurred in 4 of the open patients compared with 2 of the laparoscopic patients (P = 0.68). There is no difference in operating time or length of recovery between open and laparoscopic pyloromyotomy. However, the laparoscopic approach results in less postoperative pain and reduced postoperative emesis. In addition, there was a fewer number of complications in the laparoscopic group. Finally, patients approached laparoscopically will likely display superior cosmetic outcomes with long-term follow-up.


Frameworks for supporting patient and public involvement in research: Systematic review and co-design pilot.
Numerous frameworks for supporting, evaluating and reporting patient and public involvement in research exist. The literature is diverse and theoretically heterogeneous. To identify and synthesize published frameworks, consider whether and how these have been used, and apply design principles to improve usability. Keyword search of six databases; hand search of eight journals; ancestry and snowball search; requests to experts. Published, systematic approaches (frameworks) designed to support, evaluate or report on patient or public involvement in health-related research. Data were extracted on provenance; collaborators and sponsors; theoretical basis; lay input; intended user(s) and use(s); topics covered; examples of use; critiques; and updates. We used the Canadian Centre for Excellence on Partnerships with Patients and Public (CEPPP) evaluation tool and hermeneutic methodology to grade and synthesize the frameworks. In five co-design workshops, we tested evidence-based resources based on the review findings. Our final data set consisted of 65 frameworks, most of which scored highly on the CEPPP tool. They had different provenances, intended purposes, strengths and limitations. We grouped them into five categories: power-focused; priority-setting; study-focused; report-focused; and partnership-focused. Frameworks were used mainly by the groups who developed them. The empirical component of our study generated a structured format and evidence-based facilitator notes for a "build your own framework" co-design workshop. The plethora of frameworks combined with evidence of limited transferability suggests that a single, off-the-shelf framework may be less useful than a menu of evidence-based resources which stakeholders can use to co-design their own frameworks.


Associations between intake of folate and related micronutrients with molecularly defined colorectal cancer risks in the Iowa Women's Health Study.
Folate and related micronturients may affect colorectal cancer (CRC) risk, but the molecular mechanism(s) remain incompletely defined. We analyzed associations between dietary folate, vitamin B6, vitamin B12, and methionine with incident CRC, overall and by microsatellite instability (MSS/MSI-L or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive), BRAF mutation (negative or positive), and KRAS mutation (negative or positive) status in the prospective, population-based Iowa Women's Health Study (IWHS; 55-69 years at baseline; n = 41,836). Intake estimates were obtained from baseline, self-reported food frequency questionnaires. Molecular marker data were obtained for 514 incident CRC cases. Folate intake was inversely associated with overall CRC risk in age-adjusted Cox regression models, whereas methionine intake was inversely associated with overall CRC risk in multivariable-adjusted models [relative risk (RR) = 0.81; 95% CI = 0.69-0.95; P trend = 0.001 and RR = 0.72; 95% CI = 0.54-0.96; P trend = 0.03 for highest vs. lowest quartiles, respectively]. None of the dietary exposures were associated with MSI, CIMP, BRAF, or KRAS defined CRC subtypes. These data provide minimal support for major effects from the examined micronutrients on overall or molecularly defined CRC risks in the IWHS cohort.


Adherence index based on the AHA 2006 diet and lifestyle recommendations is associated with select cardiovascular disease risk factors in older Puerto Ricans.
In 2006, the AHA released diet and lifestyle recommendations (AHA-DLR) for cardiovascular disease (CVD) risk reduction. The effect of adherence to these recommendations on CVD risk is unknown. Our objective was to develop a unique diet and lifestyle score based on the AHA-DLR and to evaluate this score in relation to available CVD risk factors. In a cross-sectional study of Puerto Rican adults aged 45-75 y living in the greater Boston area, information was available for the following variables: diet (semiquantitative FFQ), blood pressure, waist circumference (WC), 10-y risk of coronary heart disease (CHD) (Framingham risk score), and fasting plasma lipids, serum glucose, insulin, and C-reactive protein (CRP) concentrations. We developed a diet and lifestyle score (AHA-DLS) based on the AHA-DLR. The AHA-DLS had both internal consistency and content validity. It was associated with plasma HDL cholesterol (P = 0.001), serum insulin (P = 0.0003), and CRP concentrations (P = 0.02), WC (P < 0.0001), and 10-y risk of CHD score (P = 0.01 in women). The AHA-DLS was inversely associated with serum glucose among those with a BMI < 25 (P = 0.01). Women and men in the highest quartile of the AHA-DLS had lower serum insulin (P-trend = 0.0003) and CRP concentrations (P-trend = 0.002), WC (P-trend = 0.0003), and higher HDL cholesterol (P-trend = 0.008). The AHA-DLS is a useful tool to measure adherence to the AHA-DLR and may be used to examine associations between diet and lifestyle behaviors and CVD risk.


Hormone cross-talk during seed germination.
Hormones are chemical substances that can affect many cellular and developmental processes at low concentrations. Plant hormones co-ordinate growth and development at almost all stages of the plant's life cycle by integrating endogenous signals and environmental cues. Much debate in hormone biology revolves around specificity and redundancy of hormone signalling. Genetic and molecular studies have shown that these small molecules can affect a given process through a signalling pathway that is specific for each hormone. However, classical physiological and genetic studies have also demonstrated that the same biological process can be regulated by many hormones through independent pathways (co-regulation) or shared pathways (cross-talk or cross-regulation). Interactions between hormone pathways are spatiotemporally controlled and thus can vary depending on the stage of development or the organ being considered. In this chapter we discuss interactions between abscisic acid, gibberellic acid and ethylene in the regulation of seed germination as an example of hormone cross-talk. We also consider hormone interactions in response to environmental signals, in particular light and temperature. We focus our discussion on the model plant Arabidopsis thaliana.


Land use change and El Niño-Southern Oscillation drive decadal carbon balance shifts in Southeast Asia.
An integrated understanding of the biogeochemical consequences of climate extremes and land use changes is needed to constrain land-surface feedbacks to atmospheric CO2 from associated climate change. Past assessments of the global carbon balance have shown particularly high uncertainty in Southeast Asia. Here, we use a combination of model ensembles to show that intensified land use change made Southeast Asia a strong source of CO2 from the 1980s to 1990s, whereas the region was close to carbon neutral in the 2000s due to an enhanced CO2 fertilization effect and absence of moderate-to-strong El Niño events. Our findings suggest that despite ongoing deforestation, CO2 emissions were substantially decreased during the 2000s, largely owing to milder climate that restores photosynthetic capacity and suppresses peat and deforestation fire emissions. The occurrence of strong El Niño events after 2009 suggests that the region has returned to conditions of increased vulnerability of carbon stocks.


Escherichia coli mar and acrAB mutants display no tolerance to simple alcohols.
The inducible Mar phenotype of Escherichia coli is associated with increased tolerance to multiple hydrophobic antibiotics as well as some highly hydrophobic organic solvents such as cyclohexane, mediated mainly through the AcrAB/TolC efflux system. The influence of water miscible alcohols ethanol and 1-propanol on a Mar constitutive mutant and a mar deletion mutant of E. coli K-12, as well as the corresponding strains carrying the additional acrAB deletion, was investigated. In contrast to hydrophobic solvents, all strains were killed in exponential phase by 1-propanol and ethanol at rates comparable to the parent strain. Thus, the Mar phenotype does not protect E. coli from killing by these more polar solvents. Surprisingly, AcrAB does not contribute to an increased alcohol tolerance. In addition, sodium salicylate, at concentrations known to induce the mar operon, was unable to increase 1-propanol or ethanol tolerance. Rather, the toxicity of both solvents was increased in the presence of sodium salicylate. Collectively, the results imply that the resilience of E. coli to water miscible alcohols, in contrast to more hydrophobic solvents, does not depend upon the AcrAB/TolC efflux system, and suggests a lower limit for substrate molecular size and functionality. Implications for the application of microbiological systems in environments containing high contents of water miscible organic solvents, e.g., phage display screening, are discussed.


Effects of blood pressure-lowering treatment on cardiovascular outcomes and mortality: 13 - benefits and adverse events in older and younger patients with hypertension: overview, meta-analyses and meta-regression analyses of randomized trials.
There is overwhelming evidence that blood pressure (BP)-lowering treatment can reduce cardiovascular outcomes also in the elderly, but some important aspects influencing medical practice are controversial as sufficient evidence has not been provided by single randomized controlled trials (RCTs), whereas evidence may result from a systematic search and meta-analysis of all available data. The following clinically relevant issues concerning the effects of BP lowering in older and younger individuals have been investigated: differences in benefits; the oldest and the youngest age range for which evidence of BP-lowering effects is available; the SBP level at which BP-lowering treatment should be initiated; the SBP and DBP levels treatment should be aimed at; differences in treatment burdens and harms. A database we previously identified of 72 BP-lowering RCTs in 260 210 patients was searched for separately reported data on older and younger individuals [cutoffs of 65 (primary analyses), 70, 75, 80, 60 and 55 years). The data were further stratified according to the levels of baseline (untreated) BP, and of on-treatment achieved SBP or DBP. Seven fatal and nonfatal outcomes were considered for benefits. Burdens and harms were investigated as permanent treatment discontinuations for adverse events, and hypotension/syncope. Risk ratios and absolute risk changes were calculated by a random effects model. Effects at older and younger ages were compared by heterogeneity test. Thirty-two RCTs provided data on 96 549 patients older than 65 years, and 31 RCTs on 114 009 patients younger than 65 years. All cardiovascular outcomes were significantly reduced by treatment both in older and younger individuals, without significant age-dependent differences in relative risk reduction but with significantly higher absolute risk reductions in older individuals. The extreme age ranges for which evidence of significant benefits of treatment were available was greater than 80 and less than 55 years. Only one RCT provided data on benefits of BP-lowering at age greater than 65 when treatment was initiated at SBP values in the grade 1 range, but more consistent evidence was provided when age was greater than 60 years. Both in patients older and younger than 65 years, significant reductions of cardiovascular outcomes were found at on-treatment SBP less than 140 mmHg and DBP less than 80 mmHg. There was no evidence that treatment discontinuations for adverse events or hypotension/syncope were more frequent at age greater than 65. Antihypertensive treatment should be recommended to all individuals with elevated BP, independent of age. The prudent recommendation to initiate treatment at SBP values 140-159 mmHg is supported at older age defined as greater than 60 years. SBP and DBP values lower than 140 mmHg and, respectively, 80 mmHg can be aimed at with incremental benefits without disproportionate burdens until age 80 years, above which available evidence is for benefits at on-treatment SBP 140-149 mmHg.


Metabolic and functional connectivity changes in mal de debarquement syndrome.
Individuals with mal de debarquement syndrome (MdDS) experience a chronic illusion of self-motion triggered by prolonged exposure to passive motion, such as from sea or air travel. The experience is one of rocking dizziness similar to when the individual was originally on the motion trigger such as a boat or airplane. MdDS represents a prolonged version of a normal phenomenon familiar to most individuals but which persists for months or years in others. It represents a natural example of the neuroplasticity of motion adaptation. However, the localization of where that motion adaptation occurs is unknown. Our goal was to localize metabolic and functional connectivity changes associated with persistent MdDS. Twenty subjects with MdDS lasting a median duration of 17.5 months were compared to 20 normal controls with (18)F FDG PET and resting state fMRI. Resting state metabolism and functional connectivity were calculated using age, grey matter volume, and mood and anxiety scores as nuisance covariates. MdDS subjects showed increased metabolism in the left entorhinal cortex and amygdala (z>3.3). Areas of relative hypometabolism included the left superior medial gyrus, left middle frontal gyrus, right amygdala, right insula, and clusters in the left superior, middle, and inferior temporal gyri. MdDS subjects showed increased connectivity between the entorhinal cortex/amygdala cluster and posterior visual and vestibular processing areas including middle temporal gyrus, motion sensitive area MT/V5, superior parietal lobule, and primary visual cortex, while showing decreased connectivity to multiple prefrontal areas. These data show an association between resting state metabolic activity and functional connectivity between the entorhinal cortex and amygdala in a human disorder of abnormal motion perception. We propose a model for how these biological substrates can allow a limited period of motion exposure to lead to chronic perceptions of self-motion.


Typing expertise in a large student population.
Typing has become a pervasive mode of language production worldwide, with keyboards fully integrated in a large part of many daily activities. The bulk of the literature on typing expertise concerns highly trained professional touch-typists, but contemporary typing skills mostly result from unconstrained sustained practice. We measured the typing performance of a large cohort of 1301 university students through an online platform and followed a preregistered plan to analyse performance distributions, practice factors, and cognitive variables. The results suggest that the standard model with a sharp distinction between novice and expert typists may be inaccurate to account for the performance of the current generation of young typists. More generally, this study shows how the mere frequent use of a new tool can lead to the incidental development of high expertise.


Relapse-related molecular signature in lung adenocarcinomas identifies patients with dismal prognosis.
In order to aid the development of patient-tailored therapeutics, we attempted to identify a relapse-related signature that allows selection of a group of adenocarcinoma patients with a high probability of relapse. Whole-genome expression profiles were analyzed in 117 lung adenocarcinoma samples using microarrays consisting of 41,000 probes. A weighted voting classifier for identifying patients with a relapse-related signature was constructed with an approach that allowed no information leakage during each training step, using 10-fold cross-validation and 100 random partitioning procedures. We identified a relapse-related molecular signature represented by 82 probes (RRS-82) through genome-wide expression profiling analysis of a training set of 60 patients. The robustness of RRS-82 in the selection of patients with a high probability of relapse was then validated with a completely blinded test set of 27 adenocarcinoma patients, showing a clear association of high risk RRS-82 with very poor patient prognosis regardless of disease stage. The discriminatory power of RRS-82 was further validated using an additional independent cohort of 30 stage I patients who underwent surgery at a distinct period of time as well as with the Duke data set on a different platform. Furthermore, completely separate training and validation procedures using another data set recently reported by the Director's Challenge Consortium also successfully confirmed the predictive power of the genes comprising RRS-82. RRS-82 may be useful for identifying adenocarcinoma patients at very high risk for relapse, even those with cancer in the early stage.


The impact of patient self-testing of prothrombin time for managing anticoagulation: rationale and design of VA Cooperative Study #481--the Home INR Study (THINRS).
Anticoagulation (AC) with warfarin reduces the risk of thromboembolism (TE) in a variety of applications, yet despite compelling evidence of the value and importance of high quality AC, warfarin remains underused, and dosing is often suboptimal. Approaches to improve AC quality include (1) an AC service (ACS), which allows the physician to delegate day-to-day details of AC management to another provider dedicated to AC care, and (2) incorporating into the treatment plan patient self-testing (PST) under which, after completing a training program, patients perform their own blood testing (typically, using a finger-stick blood analyzer), have dosage adjustments guided by a standard protocol, and forward test results, dosing and other information to the provider. Studies have suggested that PST can improve the quality of AC and perhaps lower TE and bleed rates. The purpose of Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) #481, "The Home INR Study" (THINRS) is to compare AC management with frequent PST using a home monitoring device to high quality AC management (HQACM) implemented by an ACS with conventional monitoring of prothrombin time by international normalized ratio (INR) on major health outcomes. PST in THINRS involves use of an INR monitoring device that is FDA approved for home use. Sites are VA Medical Centers where the ACS has an active roster of more than 400 patients. THINRS includes patients with atrial fibrillation (AF) and/or mechanical heart valve (MHV) expected to be anticoagulated indefinitely. THINRS has two parts. In Part 1, candidates for PST are evaluated for 2 to 4 weeks for their ability to use home monitoring devices. In Part 2, individuals capable of performing PST are randomized to (1) HQACM with testing every 4 weeks and as indicated for out of range values, medication/clinical changes, or (2) PST with testing every week and as indicated for out of range values, medication/clinical changes. The primary outcome measure is event rates, defined as the percent of patients who have a stroke, major bleed, or die. Secondary outcomes include total time in range (TTR), other events (myocardial infarction (MI), non-stroke TE, minor bleeds), competence and compliance with PST, satisfaction with AC, AC associated quality of life (QOL), and cost-effectiveness. To assess the effect of PST frequency on TTR and other outcomes, at selected sites patients randomized to perform PST are assigned one of three test frequencies (weekly, twice weekly, or once every four weeks).


The discharge variability of neocortical neurons during high-conductance states.
In vivo recordings have shown that the discharge of cortical neurons is often highly variable and can have statistics similar to a Poisson process with a coefficient of variation around unity. To investigate the determinants of this high variability, we analyzed the spontaneous discharge of Hodgkin-Huxley type models of cortical neurons, in which in vivo-like synaptic background activity was modeled by random release events at excitatory and inhibitory synapses. By using compartmental models with active dendrites, or single compartment models with fluctuating conductances and fluctuating currents, we found that a high discharge variability was always paralleled with a high-conductance state, while some active and passive cellular properties had only a minor impact. Furthermore, a balance between excitation and inhibition was not a necessary condition for high discharge variability. We conclude that the fluctuating high-conductance state caused by the ongoing activity in the cortical network in vivo may be viewed as a natural determinant of the highly variable discharges of these neurons.


Chloracidobacterium thermophilum gen. nov., sp. nov.: an anoxygenic microaerophilic chlorophotoheterotrophic acidobacterium.
A novel anoxygenic photoheterotrophic member of the phylum Acidobacteria , Chloracidobacterium thermophilum strain B sp. nov., was isolated from a cyanobacterial enrichment culture derived from microbial mats associated with Octopus Spring, Yellowstone National Park, WY. C. thermophilum sp. nov. was a Gram-stain-negative rod (diameter, approximately 0.8-1.0 µm; variable length, approximately 2.5 µm), which formed greenish-brown liquid suspension cultures. It was a moderately thermophilic microaerophile and grew in a defined medium at 51 °C (T(opt); range 44 to 58 °C) and in the pH range 5.5 to 9.5 (pH(opt) = ~7.0). The DNA G+C content was 61.3 mol%, and phylogenetic analysis, based on the 16S rRNA sequence, showed that C. thermophilum sp. nov. belongs to subdivision 4 ( Acidobacteriaceae ) of the Acidobacteria . C. thermophilum sp. nov. was unable to synthesize branched-chain amino acids, L-lysine, and vitamin B12, which were required for growth. Although the organism lacked genes/enzymes for autotrophic carbon fixation, bicarbonate was required. Growth was stimulated by other amino acids and 2-oxoglutarate. Cells produced chlorosomes containing a diverse mixture of bacteriochlorophyll (BChl) c derivatives, and additionally, synthesized BChl a P, Chl a PD, and Zn-BChl a'P, which occurred in type-1 homodimeric reaction centres. The carotenoids included echinenone, canthaxanthin, lycopene, γ-carotene and β-carotene. C. thermophilum sp. nov. produced iso-diabolic acid as its major fatty acid and synthesized three hopanoids (diploptene, bacteriohopanetetrol and bacteriohopanetetrol cyclitol ether). Based upon its phenotypic and genotypic properties, the name Chloracidobacterium thermophilum gen. nov., sp. nov. is proposed for this isolate; the type strain is C. thermophilum strain B(T) (ATCC BAA-2647 = JCM 30199).


Design and implementation of a clinical decision support tool for primary palliative Care for Emergency Medicine (PRIM-ER).
The emergency department is a critical juncture in the trajectory of care of patients with serious, life-limiting illness. Implementation of a clinical decision support (CDS) tool automates identification of older adults who may benefit from palliative care instead of relying upon providers to identify such patients, thus improving quality of care by assisting providers with adhering to guidelines. The Primary Palliative Care for Emergency Medicine (PRIM-ER) study aims to optimize the use of the electronic health record by creating a CDS tool to identify high risk patients most likely to benefit from primary palliative care and provide point-of-care clinical recommendations. A clinical decision support tool entitled Emergency Department Supportive Care Clinical Decision Support (Support-ED) was developed as part of an institutionally-sponsored value based medicine initiative at the Ronald O. Perelman Department of Emergency Medicine at NYU Langone Health. A multidisciplinary approach was used to develop Support-ED including: a scoping review of ED palliative care screening tools; launch of a workgroup to identify patient screening criteria and appropriate referral services; initial design and usability testing via the standard System Usability Scale questionnaire, education of the ED workforce on the Support-ED background, purpose and use, and; creation of a dashboard for monitoring and feedback. The scoping review identified the Palliative Care and Rapid Emergency Screening (P-CaRES) survey as a validated instrument in which to adapt and apply for the creation of the CDS tool. The multidisciplinary workshops identified two primary objectives of the CDS: to identify patients with indicators of serious life limiting illness, and to assist with referrals to services such as palliative care or social work. Additionally, the iterative design process yielded three specific patient scenarios that trigger a clinical alert to fire, including: 1) when an advance care planning document was present, 2) when a patient had a previous disposition to hospice, and 3) when historical and/or current clinical data points identify a serious life-limiting illness without an advance care planning document present. Monitoring and feedback indicated a need for several modifications to improve CDS functionality. CDS can be an effective tool in the implementation of primary palliative care quality improvement best practices. Health systems should thoughtfully consider tailoring their CDSs in order to adapt to their unique workflows and environments. The findings of this research can assist health systems in effectively integrating a primary palliative care CDS system seamlessly into their processes of care. ClinicalTrials.gov Identifier: NCT03424109. Registered 6 February 2018, Grant Number: AT009844-01.


Stuck in the middle: a systematic review of authorship in collaborative health research in Africa, 2014-2016.
Collaborations are often a cornerstone of global health research. Power dynamics can shape if and how local researchers are included in manuscripts. This article investigates how international collaborations affect the representation of local authors, overall and in first and last author positions, in African health research. We extracted papers on 'health' in sub-Saharan Africa indexed in PubMed and published between 2014 and 2016. The author's affiliation was used to classify the individual as from the country of the paper's focus, from another African country, from Europe, from the USA/Canada or from another locale. Authors classified as from the USA/Canada were further subclassified if the author was from a top US university. In primary analyses, individuals with multiple affiliations were presumed to be from a high-income country if they contained any affiliation from a high-income country. In sensitivity analyses, these individuals were presumed to be from an African country if they contained any affiliation an African country. Differences in paper characteristics and representation of local coauthors are compared by collaborative type using χ² tests. Of the 7100 articles identified, 68.3% included collaborators from the USA, Canada, Europe and/or another African country. 54.0% of all 43 429 authors and 52.9% of 7100 first authors were from the country of the paper's focus. Representation dropped if any collaborators were from USA, Canada or Europe with the lowest representation for collaborators from top US universities-for these papers, 41.3% of all authors and 23.0% of first authors were from country of paper's focus. Local representation was highest with collaborators from another African country. 13.5% of all papers had no local coauthors. Individuals, institutions and funders from high-income countries should challenge persistent power differentials in global health research. South-South collaborations can help African researchers expand technical expertise while maintaining presence on the resulting research.


Epidemiology of hospital-treated injuries sustained by fitness participants.
The purpose of this study was to provide an epidemiological profile of injuries sustained by participants in fitness activities in Victoria, Australia, based on hospital admissions and emergency department (ED) presentations and to identify the most common types, causes, and sites of these injuries. Hospital-treated fitness activity-related injury cases were identified from International Classification of Disease activity codes (for admissions) and from text narratives of injury events (for ED presentations) from 2003 to 2010, inclusive. Cases were categorized as being associated with aerobics/group exercise (n = 252), resistance/weight training (n = 830) or "other equipment" (motorized and general gym equipment; n = 1,156). Participation information was taken from the Exercise, Recreation and Sport Survey. Overall, 2,238 cases were identified and 11.6% of all patients with ED presentations were subsequently hospitalized. Those participants with aerobics cases were generally female (76.6%) and aged 25 to 34 years old (35.3%), with injuries to the lower limbs (59.1%) and due to falls (57.9%). Resistance-training injuries increased significantly during the 8-year period (by 215.7%; 95% CI [133.5, 326.9]) and generally occurred in male participants (78.0%), in people aged 15 to 24 years old (36.4%), and with injuries to the upper limbs (45.1%) caused by being hit, struck, or crushed by weights or fellow exercisers (71.4%). The "other equipment" cases were equally distributed by gender; they occurred most commonly in people aged 15 to 24 years old (27.8%), with injuries to the lower limbs (41.5%) and due to falls (57.6%). Across all categories, dislocations, sprains, and strains were the most common injury types. Fitness activity-related injury prevention strategies should be targeted at different subgroups according to the type of fitness activity being undertaken.


Determination of antibody levels to Candida albicans in healthy and hospitalised adults using a radioimmunoassay.
A radioimmunoassay for antibody to Candida albicans is described. The test used whole, killed organisms as the antigen and radiolabelled sheep anti-human globulins to quantitate different classes of antibody to C. albicans. The assay has been compared with an Ouchterlony precipitin method and found to be simpler, more rapid, and more sensitive than the latter. Results obtained from two groups of symptomless adults indicated that the range of antibody level was wider for a hospitalised group than for a group of blood transfusion donors, particularly in respect of IgG and IgA antibody. The reason for the increase of antibody in hospital patients was not clear but may have been related to antibiotic therapy. The difficulties in interpretation of Candida serology have therefore been re-assessed in the light of more detailed knowledge of the range and type of antibody to be expected in normal individuals.


Mitochondrial genomes illuminate the evolutionary history of the Western honey bee (Apis mellifera).
Western honey bees (Apis mellifera) are one of the most important pollinators of agricultural crops and wild plants. Despite the growth in the availability of sequence data for honey bees, the phylogeny of the species remains a subject of controversy. Most notably, the geographic origin of honey bees is uncertain, as are the relationships among its constituent lineages and subspecies. We aim to infer the evolutionary and biogeographical history of the honey bee from mitochondrial genomes. Here we analyse the full mitochondrial genomes of 18 A. mellifera subspecies, belonging to all major lineages, using a range of gene sampling strategies and inference models to identify factors that may have contributed to the recovery of incongruent results in previous studies. Our analyses support a northern African or Middle Eastern origin of A. mellifera. We show that the previously suggested European and Afrotropical cradles of honey bees are the result of phylogenetic error. Monophyly of the M, C, and O lineages is strongly supported, but the A lineage appears paraphyletic. A. mellifera colonised Europe through at least two pathways, across the Strait of Gibraltar and via Asia Minor.


[Surgical treatment of hepatocellular carcinoma at Landspitali The National University Hospital of Iceland 1993 - 2012].
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. The incidence in Iceland is very low probably due to a low prevalence of cirrhosis. The only curative treatment is surgery, either transplant or resections, but only about 30% of patients are operable at the time of diagnosis. The aim of this study was to determine the number of patients who undergo liver resection due to HCC and to investigate outcomes after surgery at Landspitali University Hospital in Iceland. A retrospective study of all HCC patients, 18 years of age or older, who underwent surgical resection at Landspitali University Hospital from January 1st 1993 to December 31st 2012. Data was collected from clinical records. Descriptive statistical analysis was used. During the time period 22 patients were operated with a liver resection and of those patients 12 (55%) had a major hepatectomy. 105 individuals in total were diagnosed with HCC in the time period, six patients had transplantation which results in 28 operations (27%). The average size of the tumors was 8.5 cm (3-22). Four individuals had cirrhosis. The frequency of intra-operative complications was 23% and post-operative complications 32% (Clavien-Dindo grade III and IV). A total of three individuals needed reoperation. The 30 day mortality rate was 0%. Twelve (55%) individuals were diagnosed with recurrence during the research period and eleven died. The one year mortality rate was 23%. The proportion of operable individuals with HCC in Iceland is low, few of whom have cirrhosis or other chronic liver disease. The mortality rate is comparable to other researches but the frequency of serious complications is higher probably due to tumor size.


The role of park conditions and features on park visitation and physical activity.
Neighborhood parks play an important role in promoting physical activity. We examined the effect of activity area, condition, and presence of supporting features on number of park users and park-based physical activity levels. 37 parks and 154 activity areas within parks were assessed during summer 2008 for their features and park-based physical activity. Outcomes included any park use, number of park users, mean and total energy expenditure. Independent variables included type and condition of activity area, supporting features, size of activity area, gender, and day of week. Multilevel models controlled for clustering of observations at activity area and park levels. Type of activity area was associated with number of park users, mean and total energy expenditure, with basketball courts having the highest number of users and total energy expenditure, and playgrounds having the highest mean energy expenditure. Condition of activity areas was positively associated with number of basketball court users and inversely associated with number of green space users and total green space energy expenditure. Various supporting features were both positively and negatively associated with each outcome. This study provides evidence regarding characteristics of parks that can contribute to achieving physical activity goals within recreational spaces.


Projections in Breast and Lung Cancer Mortality among Women: A Bayesian Analysis of 52 Countries Worldwide.
Among women, lung cancer mortality rates have surpassed those for breast cancer in several countries. This reflects the breast cancer mortality declines due to access to screening and effective treatment alongside the entrance of certain countries in stages of the tobacco epidemic in which smoking becomes more prevalent in women. In this study, we project lung and breast cancer mortality until 2030 in 52 countries. Cancer mortality data were obtained from the WHO Mortality Database. Age-standardized mortality rates (ASMR), per 100,000, were calculated (direct method) for 2008 to 2014 and projected for the years 2015, 2020, 2025, and 2030 using a Bayesian log-linear Poisson model. In 52 countries studied around the world, between 2015 and 2030, the median ASMR are projected to increase for lung cancer, from 11.2 to 16.0, whereas declines are expected for breast cancer, from 16.1 to 14.7. In the same period, the ASMR will decrease in 36 countries for breast cancer and in 15 countries for lung cancer. In half of the countries analyzed, and in nearly three quarters of those classified as high-income countries, the ASMR for lung cancer has already surpassed or will surpass the breast cancer ASMR before 2030. The mortality for lung and breast cancer is higher in high-income countries than in middle-income countries; lung cancer mortality is lower in the latter because the tobacco epidemic is not yet widespread. Due to these observed characteristics of lung cancer, primary prevention should still be a key factor to decrease lung cancer mortality.Significance: The mortality for lung and breast cancer is projected to be higher in high-income countries than in middle-income countries, where lung cancer mortality is expected to surpass breast cancer mortality before 2030. Cancer Res; 78(15); 4436-42. ©2018 AACR.


Treatment of obesity and disability in schizophrenia.
Despite 50 years of pharmacological and psychosocial interventions, schizophrenia remains one of the leading causes of disability. The inability to function in everyday settings includes deficits in performance of social, occupational, and independent living activities. Schizophrenia is also a life-shortening illness, caused mainly by poor physical health and its complications. Dysfunctional lifestyles including sedentary behavior and lack of physical activity prevail, while treatment with adipogenic psychotropic medication interacts with poor performance in screening, monitoring, and intervention that result in shortening of life expectancies by 25 to 30 years. Disability interferes with self-care and medical care, further worsening physical health to produce a vicious cycle of disability. Further, the neurobiological impact of obesity on brain functioning is substantial and relevant to schizophrenia. Simultaneous treatment of cognitive deficits and related deficits in functional skills, ubiquitous determinants of everyday functioning in schizophrenia, and targeted interventions aimed at poor physical health, especially obesity and associated comorbidities, may lead to additive or even interactive gains in everyday functioning in patients with schizophrenia not previously realized with other interventions.


Tuberculosis infection and disease in people living with HIV in countries with low tuberculosis incidence.
In countries with low tuberculosis (TB) incidence, TB is concentrated in vulnerable populations, including people living with the human immunodeficiency virus (PLHIV), who have a substantially greater risk of TB than people without HIV. We searched PubMed, EMBASE and Web of Science for studies evaluating the risk factors for latent tuberculous infection (LTBI) or active TB in PLHIV in countries with TB incidence 10 per 100 000 population. Due to the number of risk factors evaluated and heterogeneity in study designs, we present summary data and a narrative synthesis. We included 45 studies: 17 reported data on the risk factors for LTBI and 32 on active TB. Black, Asian or Hispanic ethnicity, birth or long-term residence in a country with high TB incidence, and HIV acquisition via injecting drug use (IDU) or heterosexual sex were strong predictors of both LTBI and active TB. History of contact, a greater degree of immunosuppression at diagnosis or higher viral load increased the TB risk. Early HIV diagnosis to allow timely initiation of antiretroviral therapy is essential for the prevention of TB in PLHIV. Screening and treating PLHIV for LTBI to reduce the risk of progression to active TB disease should also be considered to further reduce the burden of active TB in low TB incidence settings. Research to support the expansion of TB and HIV prevention and treatment globally is essential to eliminate TB in low-incidence settings.


Increased nitric oxide in exhaled gas as an early marker of lung inflammation in a model of sepsis.
Nitric Oxide (NO) has been implicated in the pathologic vasodilation of sepsis. Because NO can be measured in the exhaled gas of animals and humans, we hypothesized that increases in exhaled NO would occur in a septic model. Using a blinded design, 10 male Sprague-Dawley rats (300 to 400 g) were anesthetized, paralyzed, tracheotomized, and randomized (5/group) to receive an intravenous injection of either lipopolysaccharide (LPS) (Salmonella typhosa, 20 mg/kg) or placebo (equal volume of saline). Thereafter, exhaled gas was collected and measurements of NO concentration were made using chemiluminescence every 20 min for 300 min during ventilation (RR 40 breaths/min, VT 3 ml; PEEP 0, FIO2 0.21). Another group of 10 animals (5 LPS; 5 control) were treated in the same fashion and then killed at 240 min and an arterial blood sample obtained for blood gas and TNF alpha determinations. Pressure volume (PV) curves were constructed and lungs removed, preserved, and submitted for histologic evaluation. LPS-treated rats had lower mean arterial pressures than the control group, p < 0.0001. No significant differences in static lung compliance and PV curves were found in the two groups. TNF alpha levels were greater in the LPS group (1.40 +/- 0.24 ng/ml) versus control group (0.09 +/- 0.04 ng/ml), p < 0.001. By contrast to the control group, exhaled NO concentration rose in all LPS-treated rats at approximately 100 min and at about 160 min reached a plateau that was 6 times greater than control levels (p < 0.0001). There was greater interstitial, airspace, and total lung injury in the LPS group (p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of increased +Gz on chest wall mechanics in humans.
We studied the effects of head-to-foot acceleration (+Gz) on chest wall mechanics in five normal subjects seated in a human centrifuge. Results were compared with those previously obtained in the same subjects in microgravity during parabolic flights. In all subjects, end-expiratory abdominal pressure (Pga) and volume (Vab) increased with Gz. On average, end-expiratory Pga increased from 7.4 +/- 1.7 cmH2O at + 1 Gz to 14.9 +/- 2.8 cmH2O at + 3 Gz and end-expiratory Vab increased by 0.32 +/- 0.06 liter between + 1 and + 3 Gz. On the other hand, the abdominal contribution to tidal volume (Vab/VT) and abdominal compliance decreased from 34.7 +/- 5.9% and 52 +/- 6 ml/cmH2O at + 1 Gz to 29.3 +/- 5.1% and 26 +/- 4 ml/cmH2O at + 3 Gz, respectively. Changes in end-expiratory Pga were linear between 0 and + 3 Gz, but changes in end-expiratory Vab, Vab/VT, and abdominal compliance were greater in microgravity than in hypergravity. In contrast to weightlessness, which did not alter minute ventilation and tidal changes in Pga and transdiaphragmatic pressure, these variables increased with increasing Gz. These results indicate that, although changes in Gz have a linear effect on abdominal transmural pressure, hypergravity and weightlessness do not have symmetrical effects on chest wall mechanics.


Repetitive transcranial magnetic stimulation dissociates working memory manipulation from retention functions in the prefrontal, but not posterior parietal, cortex.
Understanding the contributions of the prefrontal cortex (PFC) to working memory is central to understanding the neural bases of high-level cognition. One question that remains controversial is whether the same areas of the dorsolateral PFC (dlPFC) that participate in the manipulation of information in working memory also contribute to its short-term retention (STR). We evaluated this question by first identifying, with functional magnetic resonance imaging (fMRI), brain areas involved in manipulation. Next, these areas were targeted with repetitive transcranial magnetic stimulation (rTMS) while subjects performed tasks requiring only the STR or the STR plus manipulation of information in working memory. fMRI indicated that manipulation-related activity was independent of retention-related activity in both the PFC and superior parietal lobule (SPL). rTMS, however, yielded a different pattern of results. Although rTMS of the dlPFC selectively disrupted manipulation, rTMS of the SPL disrupted manipulation and STR to the same extent. rTMS of the postcentral gyrus (a control region) had no effect on performance. The implications of these results are twofold. In the PFC, they are consistent with the view that this region contributes more importantly to the control of information in working memory than to its STR. In the SPL, they illustrate the importance of supplementing the fundamentally correlational data from neuroimaging with a disruptive method, which affords stronger inference about structure-function relations.


Current trends in solid-phase microextraction (SPME) fibre coatings.
This critical review presents information on known and innovative approaches to the manufacture of fibre coatings used in solid-phase microextraction (SPME). The properties, advantages and drawbacks of the different types of commercially available SPME fibre coatings are discussed in detail, as are those of novel types of coatings and the methodologies of their preparation. The applications of fibre coatings in the solid-phase microextraction of a broad spectrum of analytes are analysed, with particular emphasis on the sampling of polar analytes from polar matrices (174 references).


Heritability of human cranial dimensions: comparing the evolvability of different cranial regions.
Quantitative craniometrical traits have been successfully incorporated into population genetic methods to provide insight into human population structure. However, little is known about the degree of genetic and non-genetic influences on the phenotypic expression of functionally based traits. Many studies have assessed the heritability of craniofacial traits, but complex patterns of correlation among traits have been disregarded. This is a pitfall as the human skull is strongly integrated. Here we reconsider the evolutionary potential of craniometric traits by assessing their heritability values as well as their patterns of genetic and phenotypic correlation using a large pedigree-structured skull series from Hallstatt (Austria). The sample includes 355 complete adult skulls that have been analysed using 3D geometric morphometric techniques. Heritability estimates for 58 cranial linear distances were computed using maximum likelihood methods. These distances were assigned to the main functional and developmental regions of the skull. Results showed that the human skull has substantial amounts of genetic variation, and a t-test showed that there are no statistically significant differences among the heritabilities of facial, neurocranial and basal dimensions. However, skull evolvability is limited by complex patterns of genetic correlation. Phenotypic and genetic patterns of correlation are consistent but do not support traditional hypotheses of integration of the human shape, showing that the classification between brachy- and dolicephalic skulls is not grounded on the genetic level. Here we support previous findings in the mouse cranium and provide empirical evidence that covariation between the maximum widths of the main developmental regions of the skull is the dominant factor of integration in the human skull.


Intravenous and oral levetiracetam in patients with a suspected primary brain tumor and symptomatic seizures undergoing neurosurgery: the HELLO trial.
Levetiracetam (LEV) is a newer anticonvulsant with a favorable safety profile. There seem to be no relevant drug interactions, and an intravenous formulation is available. Therefore, LEV might be a suitable drug for the perioperative anticonvulsive therapy of patients with suspected brain tumors undergoing neurosurgery. In this prospective study (NCT00571155) patients with suspected primary brain tumors and tumor-related seizures were perioperatively treated with oral and intravenous LEV up to 4 weeks before and until 4 weeks after a planned neurosurgical procedure. Thirty patients with brain tumor-related seizures and intended neurosurgery were included. Three patients did not undergo the scheduled surgery after enrollment, and two patients were lost to follow-up. Therefore, 25 patients were fully evaluable. After initiation of therapy with LEV, 100% of the patients were seizure-free in the pre-surgery phase (3 days up to 4 weeks before surgery), 88% in the 48 h post-surgery phase and 84% in the early follow-up phase (48 h to 4 weeks post surgery). Treatment failure even after dose escalation to 3,000 mg/day occurred in three patients. No serious adverse events related to the treatment with LEV occurred. Our data show the feasibility and safety of oral and intravenous LEV in the perioperative treatment of tumor-related seizures. Although this was a single arm study, the efficacy of LEV appears promising. Considering the side effects and interactions of other anticonvulsants, LEV seems to be a favorable option in the perioperative treatment of brain tumor-related seizures.


Influence of melatonin on chicken lymphocytes in vitro: involvement of membrane receptors.
Time-dependent melatonin effects on chicken lymphocyte proliferation in vitro and the involvement of cAMP in melatonin signal transduction were examined. Splenocytes and peripheral blood mononuclear cells (PBMC) were cultured in vitro in the presence of melatonin, phytohemagglutinin, luzindole, dibutyrylcAMP (dbcAMP), forskolin and vasoactive intestine peptide (VIP). Proliferation was measured by [(3)H]-thymidine incorporation in cultures carried out for 24, 36, 48 and 72 h. Cyclic AMP formation was assessed by radioimmunoassay in cells incubated for 30 min. or 24 h. Melatonin stimulated the spontaneous proliferation in short-term (36 and 48 h) splenocyte cultures and had no effect in 72 h cultures. It inhibited mitogen-stimulated proliferation already in 24 h cultures and this effect was observed regardless of the time of the culture. Both melatonin effects were antagonized by luzindole - membrane-bound melatonin receptor antagonist. Forskolin and dbcAMP caused a significant inhibition of proliferation of splenocytes and PBMC cultured for 24 or 72 h, respectively. Melatonin inhibited the cAMP formation (30 min. of incubation) stimulated by adenosine cyclase activators - forskolin and VIP, but added alone failed to affect the cAMP concentration. In mitogen-stimulated splenocytes cultured for 24 h Mel caused an increase in cAMP correlated with the inhibition of cell proliferation. Melatonin effects on chicken splenocytes appears time- and activation-dependent: in short-term cultures it stimulates spontaneous and inhibits mitogen-activated proliferation, probably via membrane-bound, luzindole-sensitive melatonin receptors. Incubation with melatonin for 30 min. inhibits cAMP formation, but in 24 h cultures it increases cAMP concentration leading to inhibition of proliferation.


Lesions in two Escherichia coli type 1 pilus genes alter pilus number and length without affecting receptor binding.
We describe the characterization of two genes, fimF and fimG (also called pilD), that encode two minor components of type 1 pili in Escherichia coli. Defined, in-frame deletion mutations were generated in vitro in each of these two genes. A double mutation that had deletions identical to both single lesions was also constructed. Examination of minicell transcription and translation products of parental and mutant plasmids revealed that, as predicted from the nucleotide sequence and previous reports, the fimF gene product was a protein of ca. 16 kDa and that the fimG gene product was a protein of ca. 14 kDa. Each of the constructions was introduced, via homologous recombination, into the E. coli chromosome. All three of the resulting mutants produced type 1 pili and exhibited hemagglutination of guinea pig erythrocytes. The latter property was also exhibited by partially purified pili isolated from each of the mutants. Electron microscopic examination revealed that the fimF mutant had markedly reduced numbers of pili per cell, whereas the fimG mutant had very long pili. The double mutant displayed the characteristics of both single mutants. However, pili in the double mutant were even longer than those seen in the fimG mutant, and the numbers of pili were even fewer than those displayed by the fimF mutant. All three mutants could be complemented in trans with a single-copy-number plasmid bearing the appropriate parental gene or genes to give near-normal parental piliation. On the basis of the phenotypes exhibited by the single and double mutants, we believe that the fimF gene product may aid in initiating pilus assembly and that the fimG product may act as an inhibitor of pilus polymerization. In contrast to previous studies, we found that neither gene product was required for type 1 pilus receptor binding.


Toll-like receptors and rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic inflammatory disease that ultimately leads to the progressive destruction of cartilage and bone in numerous joints. There is mounting evidence for an important function of innate immunity in the pathogenesis of RA. Activation of cells by microbial components and also by endogenous molecules via Toll-like receptor (TLR) results in the production of a variety of proinflammatory cytokines, chemokines, and destructive enzymes, some of which can characteristically be found in RA.By immunohistochemistry we found elevated TLR2, 3, and 4 expressions in the rheumatoid synovium. In the synovial lining layer and at sites of invasion into cartilage, RA synovial fibroblasts (RASF) are the major cells expressing TLR2, 3, and 4. Stimulation of cultured RASF in vitro with the TLR2 ligand bacterial lipoprotein (bLP), the TLR3 ligand poly(I-C), and the TLR4 ligand LPS was shown to upregulate IL-6 as well as matrix metalloproteinases (MMPs) 1 and 3. These results suggest an important role for TLR2, 3, and 4 in the activation of synovial fibroblasts in RA leading to chronic inflammation and joint destruction.


Familial combined hyperlipidaemia linked to the apolipoprotein AI-CII-AIV gene cluster on chromosome 11q23-q24.
Familial combined hyperlipidaemia (FCHL) is a common inherited disorder of lipid metabolism with a prevalence of 0.5-2.0% (refs 1, 2). It is estimated to cause 10% of premature coronary heart disease. The underlying metabolic and genetic defects in FCHL have not been identified, but a population study has suggested an association between FCHL and an XmnI restriction fragment length polymorphism (RFLP) within the apolipoprotein AI-CIII-AIV gene cluster. Here we confirm this association and show that it results from linkage disequilibrium between FCHL and the 6.6-kilobase (kb) allele of the XmnI RFLP. Subsequent analysis in seven FCHL families, ascertained through a proband carrying the 6.6 kb XmnI allele, demonstrated linkage to the AI-CIII-AIV cluster on 11q23-q24, zeta = 6.86 with no recombinants. This assignment will facilitate the identification of the mutation that causes hyperlipidaemia in these families.


Long-interval facilitation and inhibition are differentially affected by conditioning stimulus intensity over different time courses.
Intracortical facilitatory and inhibitory processes in the primary motor cortex (M1) play an important role in both the preparation and execution of motor tasks. Here we aimed to (1) confirm the existence of, and further characterise, intracortical facilitation at long conditioning-test stimulus intervals at subthreshold conditioning stimulus (CS) intensities and (2) identify the threshold for long-interval intracortical inhibition (LICI) at different inter-stimulus intervals (ISIs). To examine facilitation, stimulus-response curves at ISIs of 100 and 150 ms were obtained using a range of subthreshold CS intensities. LICI stimulus-response curves were also obtained using varying CS intensities at ISIs of 100 (LICI100) and 150 ms (LICI150). Facilitation of the conditioned MEP was observed at subthreshold CS intensities at an ISI of 100 ms. LICI100 was observed at a lower CS intensity than LICI150. First, we provide evidence of a long-interval facilitation and provide some evidence consistent with a cortical origin of this facilitation. Second, the lower threshold for evoking LICI100 than LICI150 suggests an intensity-duration effect whereby a more intense CS results in longer duration LICI. Investigation of the interaction between LICI and long-interval facilitation might help to elucidate the functional importance of these processes.


Isolation and attempted introduction of sugar alcohol-utilizing bacteria in the sheep rumen.
Bacteria that use sorbitol, xylitol, maltitol and dulcitol (galactitol) were isolated from the sheep rumen following enrichments in which bacteria were grown in rumen fluid medium where the sugar alcohol was the only added energy source. Only isolates obtained with sorbitol and maltitol grew sufficiently rapidly to be considered for enrichment by the sugar alcohol in vivo. Isolate SS2, a strain of Selenomonas ruminantium var. lactilytica which grew on sorbitol at 0.87 h-1, was selected for further study and a rifampicin-resistant mutant, SS2/R5, was isolated to facilitate tracking in the mixed population. Despite an initial transient increase in numbers, a significant population of S. ruminantium SS2/R5 failed to establish in sheep which were dosed twice daily with 10 g of sorbitol. Continuous infusion of sorbitol increased numbers only slightly compared with twice-daily dosing. In vitro experiments indicated that strain SS2/R5 grew less well in the presence of other rumen organisms, particularly ciliate protozoa, than in pure culture. Furthermore, the concentration of sorbitol in vivo was lower than predicted from in vitro experiments, indicating that sorbitol was absorbed rapidly from the rumen. Similar observations were made with xylitol, dulcitol and maltitol. Proposed enrichment strategies that use sugar alcohols or other materials to support the growth of introduced bacteria will thus have to take account of the combined problems of microbe-microbe interactions and the loss of the compounds by absorption from the rumen.


SULT2B1b inhibits reverse cholesterol transport and promotes cholesterol accumulation and inflammation in lymphocytes from AMI patients with low LDL-C levels.
The current main treatment for coronary artery disease (CAD) is to reduce low-density lipoprotein cholesterol (LDL-C) by statins, which could decrease the incidence of major adverse cardiovascular events (MACEs) by 30%. However, many residual risks still remain. To clarify the mechanism involved, we studied patients with acute myocardial infarction (AMI) with low LDL-C levels. Lymphocytes were isolated, and it was found that despite no difference in plasma LDL-C level, the lymphocyte cholesterol content was higher in AMI patient than those in non-CAD patients; thus, the decrease in intracellular cholesterol content was inconsistent with that in the plasma. Additionally, [3H]-cholesterol efflux rates were lower and mRNA levels of the inflammatory factors tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) higher in AMI lymphocytes. It was found that sulphotransferase 2B1b (SULT2B1b) expression was higher in AMI lymphocytes. Further research using Jurkat T lymphocytes confirmed that SULT2B1b knockdown increased cholesterol efflux capacity and decreased mRNA levels of TNF-α and IFN-γ by increasing liver X receptor (LXR)-β levels. Furthermore, the degree of CpG island methylation in the SULT2B1b promoter was reduced in cells from AMI patients. In conclusion, SULT2B1b up-regulation due to hypomethylation of its promoter promotes cholesterol accumulation and inflammation by inhibiting LXR-β in lymphocytes of AMI patients with low LDL-C levels. Therefore, reducing intracellular cholesterol is also important as plasma cholesterol levels. Therapeutic approaches to decrease SULT2B1b expression might be potentially beneficial for CAD prevention by decreasing intracellular cholesterol.


Identification, distribution and physiological activity of three novel neuropeptides of Lymnaea: EFLRlamide and pQFYRlamide encoded by the FMRFamide gene, and a related peptide.
We are interested in analysing the detailed modulation of defined neuronal systems by multiple neuropeptides encoded in the FMRFamide locus of the snail Lymnaea. Cloning of the FMRFamide gene has predicted the existence of two novel peptides previously unknown from biochemical analysis, the pentapeptides EFLRlamide and QFYRlamide. These peptides may form part of a new family of peptides sharing the sequence motif -FXRlamide. In this paper we adopt a novel approach to first identify and characterize -FXRlamide-like peptides in extracts from the central nervous system of Lymnaea. By a combination of high-performance liquid chromatography (HPLC) and continuous-flow fast atom bombardment mass spectrometry, we identify three novel peptides: EFLRlamide, pQFYRlamide and pQFLRlamide. The first two are those predicted in exon II of the FMRFamide locus whereas the last is, interestingly, a product which cannot be derived from post-translational modification of the predicted peptides but must be encoded by as yet unidentified nucleotide sequences. A specific antibody raised to EFLRlamide, and immunoreactive to all three peptides, revealed EFLRlamide-like expression throughout the central nervous system in the same cells where exon II is transcribed and the peptide SEEPLY (a post-translational product of exon II) was localized. Additional cells, however, were also identified. Immunoreactivity was mapped in a number of identified neurons in the central nervous system, including two heart cardioexcitatory motoneurons, the Ehe cells (E heart excitors of the visceral ganglion) and penial motoneurons in the right cerebral ganglion. The peripheral tissues (heart and penial complex) that these respective classes of neurons innervate also exhibited EFLRlamide immunoreactivity. The central and peripheral localization of EFLRlamide-like immunoreactivity suggested that EFLRlamide/pQFYRlamide may have an important physiological role in both these peripheral systems as well as in the central nervous system. This was confirmed by physiological experiments that showed that EFLRlamide and pQFYRlamide inhibited many central neurons and in particular the Bgp neurons in the right parietal ganglion. EFLRlamide had complex biphasic effects on the frequency of heart-beat: an initial inhibitory response was followed by a long-lasting increase in the rate of beating. Taken together with earlier work, this study now completes the analysis and localization of the full set of post-translational products of the FMRFamide precursor in Lymnaea and supplies further evidence towards the characterization of the physiological systems which such peptides may modulate in concert.


Hemoglobins S and C interfere with actin remodeling in Plasmodium falciparum-infected erythrocytes.
The hemoglobins S and C protect carriers from severe Plasmodium falciparum malaria. Here, we found that these hemoglobinopathies affected the trafficking system that directs parasite-encoded proteins to the surface of infected erythrocytes. Cryoelectron tomography revealed that the parasite generated a host-derived actin cytoskeleton within the cytoplasm of wild-type red blood cells that connected the Maurer's clefts with the host cell membrane and to which transport vesicles were attached. The actin cytoskeleton and the Maurer's clefts were aberrant in erythrocytes containing hemoglobin S or C. Hemoglobin oxidation products, enriched in hemoglobin S and C erythrocytes, inhibited actin polymerization in vitro and may account for the protective role in malaria.


Intergenerational continuity in maltreatment.
Identification of the causes of child maltreatment perpetration is prerequisite for developing efficacious prevention initiatives to reduce its occurrence. Earlier maltreatment victimization is often suggested as an important cause of subsequent maltreatment perpetration. This study investigates a) whether maltreatment victimization causes subsequent perpetration and b) whether the timing of maltreatment victimization--childhood versus adolescence--alters this relationship. We use data from the Rochester Youth Development Study, a longitudinal study begun in Rochester, New York in 1988, based on a stratified random sample of 1000 seventh and eighth graders. At the most recent followup, 80 % were reinterviewed. Child Protective Services data were collected on substantiated incidents of maltreatment victimization from birth to age 17 and on maltreatment perpetration through average age 33, n = 816. Using propensity score models to control selection effects, we find that a history of maltreatment victimization significantly increases the odds of becoming a perpetrator of maltreatment. Although childhood-limited maltreatment does not significantly increase the odds of maltreatment perpetration, maltreatment that occurs in adolescence or that begins in childhood and persists into adolescence does. Adolescent maltreatment was found to be more serious in terms of type, chronicity, and severity than childhood-limited maltreatment, offering a possible explanation for this finding. Therefore, maltreatment victimization, especially during adolescence, is a likely cause of subsequent perpetration. Clinical services to interrupt the cycle of maltreatment are needed to protect subsequent generations from experiencing maltreatment and from experiencing the health-risking behaviors that often flow from maltreatment.


Calcium restriction prolongs metaphase in dividing Tradescantia stamen hair cells.
Agents that lower extracellular calcium concentration (EGTA) or modulate calcium transport (lanthanum or D600) have been applied to dividing stamen hair cells of Tradescantia and analyzed for their ability to change the following: (a) the time required to progress from nuclear envelope breakdown to the onset of anaphase (metaphase transit time), (b) the time required to progress from anaphase to the initiation of the cell plate, and (c) the rate of chromosome motion in anaphase. Control cells complete metaphase in 32 min, initiate a cell plate in 19 min, and display a chromosome motion rate of 1.45 micron/min. If cells are treated with a calcium-EGTA buffer (pCa 8) for 4 h, the metaphase transit time is increased to 53 min without any change in the time of cell plate formation or the rate of chromosome motion. Lanthanum and D600, under conditions in which their access to the plasmalemma has been facilitated by pretreating the cells with cutinase, also markedly extend metaphase and in several instances permanently arrest cells. Lanthanum, however, produce little or no change in cell plate initiation or the rate of chromosome motion. Microscopic observations of the mitotic apparatus in calcium-stressed cells reveal normal chromatin condensation and metaphase progression. Chromosomes partly untwine but remain attached at their kinetochores. It is suggested that a flux of calcium, derived from the extracellular compartment, may cause the final splitting of sister chromosomes and trigger the onset of anaphase. However, once anaphase has begun, chromosome motion and cell plate initiation proceed normally even under conditions of extracellular calcium restriction.


Reverse traffic: intersecting inequalities in human egg donation.
The paper examines a case of cross-border reproductive care that happens in reverse by looking at Israeli--Romanian transnational ova traffic. The state of Israel claims to have the most IVF clinics per capita in the world, some of the highest success rates in the use of assisted reproductive technology, very liberal regulation of these technologies and the most heavily subsidized IVF in the world. This support and the government's demographic policies are designed to encourage the growth of the Jewish population in its demographic race against Palestinians. Yet transnational egg donation is very costly and reimbursement to patients a slow and involved process. Hence, while transnational ova donation is increasing in Israel, only a few can afford to participate in this border crossing. Further, new laws are meant to forbid cross-religious donation in Israel, hardening the borders of the Jewish State. Romanian ova donors are part of the global majority, exploited by markets' incursions into new niches in bodies. The history of Romanian oppression of women's reproduction makes today's women willing to undergo invasive treatment for very little compensation, even when there is the possibility of injury. This paper documents reverse traffic reproduction, which maintains, rather than addresses, inequalities.


Patterns of violence in Karachi, Pakistan.
Government reports on violence in developing countries are almost universally based upon police data, which are typically incomplete and unreliable. Violence in Karachi was evaluated using ambulance service, not police, records. Karachi, Pakistan. The study was based on a case series of persons suffering from intentional injuries and transported by Edhi, the largest emergency service in Karachi, between October 1993 and January 1996. Main outcome variables were injury and death rates. Edhi Ambulance Service transported 4,091 intentionally injured persons during the 29 month period from October 1993 to January 1996. Ninety five per cent (n=3,864) were males; 74% (n=2,823) were 20 to 40 years of age, and 2,400 (58%) died before reaching the hospital. Firearms were the most common mode of injury (n=3,396, 83%). Forty six per cent (n= 1,828) of violent injuries occurred in four neighborhoods of Karachi--22% in Korangi (n= 884) and 8% each in Orangi (n=337), Malir Colony (n=307), and Nazimabad (n=300). On the 32 days when a political strike was called, more people were injured (mean = 10.4 v 5.0 persons, p=0.01) and killed (mean 6.6 v 3.9 persons, p<0.01) compared with days without a political strike. Violence is a major public health problem in Karachi, affecting predominantly wage earners. At least some of the violence is rooted within the political system. Detailed study of the causes of violence that explains the role that political and ethnic tensions play, may suggest strategies to lessen the toll of violence.


Ultraviolet reflection irradiances and exposures in the constructed environment for horizontal, vertical and inclined surfaces.
Ultraviolet (UV) reflection in the urban constructed environment is not well understood for topical issues such as measuring and modeling the received UV exposure due to that UV reflection for outdoor workers. Both predominantly specular and diffuse reflecting surface types have been identified and investigated for the erythemal UV reflection ratio variation due to solar zenith angle and orientation. This paper presents relationships between erythemal UV reflection ratios measured for non-horizontal and horizontal surfaces, with predominantly specular surface types indicating stronger relationships with solar zenith angles than diffuse reflecting surfaces types. Erythemal UV exposures caused by the same reflecting surface types at three inclinations are also investigated. Non-horizontal surfaces can increase erythemal UV exposures compared to erythemal UV exposures received from the same horizontal surface by factors of 1.07-1.46 for specific body sites and by 1.01-1.70 for averages of group body sites for zinc aluminium coated steel sheeting.


Health, Lifestyle, and Psycho-Social Determinants of Poor Sleep Quality During the Early Phase of the COVID-19 Pandemic: A Focus on UK Older Adults Deemed Clinically Extremely Vulnerable.
Background: Several studies have assessed the impact of COVID-19-related lockdowns on sleep quality across global populations. However, no study to date has specifically assessed at-risk populations, particularly those at highest risk of complications from coronavirus infection deemed "clinically-extremely-vulnerable-(COVID-19CEV)" (as defined by Public Health England). Methods: In this cross-sectional study, we surveyed 5,558 adults aged ≥50 years (of whom 523 met criteria for COVID-19CEV) during the first pandemic wave that resulted in a nationwide-lockdown (April-June 2020) with assessments of sleep quality (an adapted sleep scale that captured multiple sleep indices before and during the lockdown), health/medical, lifestyle, psychosocial and socio-demographic factors. We examined associations between these variables and sleep quality; and explored interactions of COVID-19CEV status with significant predictors of poor sleep, to identify potential moderating factors. Results: Thirty-seven percent of participants reported poor sleep quality which was associated with younger age, female sex and multimorbidity. Significant associations with poor sleep included health/medical factors: COVID-19CEV status, higher BMI, arthritis, pulmonary disease, and mental health disorders; and the following lifestyle and psychosocial factors: living alone, higher alcohol consumption, an unhealthy diet and higher depressive and anxiety symptoms. Moderators of the negative relationship between COVID-19CEV status and good sleep quality were marital status, loneliness, anxiety and diet. Within this subgroup, less anxious and less lonely males, as well as females with healthier diets, reported better sleep. Conclusions: Sleep quality in older adults was compromised during the sudden unprecedented nation-wide lockdown due to distinct modifiable factors. An important contribution of our study is the assessment of a "clinically-extremely-vulnerable" population and the sex differences identified within this group. Male and female older adults deemed COVID-19CEV may benefit from targeted mental health and dietary interventions, respectively. This work extends the available evidence on the notable impact of lack of social interactions during the COVID-19 pandemic on sleep, and provides recommendations toward areas for future work, including research into vulnerability factors impacting sleep disruption and COVID-19-related complications. Study results may inform tailored interventions targeted at modifiable risk factors to promote optimal sleep; additionally, providing empirical data to support health policy development in this area.


Early intervention for low birth weight, preterm infants: the role of negative emotionality in the specification of effects.
This study examined the relation of negative emotionality in infancy to child social and cognitive developmental outcomes among low birth weight (LBW) preterm infants participating in the Infant Health and Development Program (IHDP), a comprehensive compensatory education intervention beginning in infancy and lasting through age 3 years. In this analysis, intervention effects at age 36 months on maternal report of child behavior as assessed by the Child Behavior Checklist externalizing and internalizing scales and on intelligence as measured by the Stanford-Binet scale were largest among children characterized by higher levels of negative emotionality in infancy. Findings indicate that for LBW preterm infants characterized by negative emotionality at age 12 months the intervention was associated with a twofold decrease in the occurrence of clinically meaningful levels of behavior problems at age 3 years and a fourfold decrease in the occurrence of a high-risk profile in which both internalizing and externalizing scores are in the clinically meaningful range. The intervention was also associated with a fivefold decrease in the occurrence of IQ < or = 75 at age 3 years among children with higher levels of negative emotionality and heavier LBW (2001-2500 g). However, specific aspects of temperamental difficulty such as fearfulness and anger were related to internalizing and externalizing, respectively, in both the intervention and control groups. Findings are consistent with research linking negative emotionality in infancy with social and cognitive developmental outcomes in early childhood among normal birth weight infants. Results suggest the need for further attention to child temperament in early intervention research.


Synthesis of a stabilized version of the imidazolone DNA lesion.
Imidazolone (dIz) is an abundant, highly mutagenic, and rather unstable DNA lesion that can cause dG-->dC transversion mutations. dIz is generated in DNA by a variety of oxidative processes such as type I photooxidation. Herein we report the synthesis of a carbocyclic nucleoside analogue of dIz and of DNA containing this stabilized lesion analogue. The carbocyclic modification protects this lesion analogue from anomerization. As the repair of the lesion analogue by DNA glycosylases is not possible, this analogue should allow cocrystallization studies together with wild-type repair enzymes. Characterization of the lesion analogue was performed by using spectroscopic methods and enzymatic digestion experiments of the oligonucleotides.


[Opioids for Cancer Pain and its Use under Particular Conditions: A Narrative Review].
All health professionals should be aware of the importance of evaluating pain - fifth vital sign- in cancer patients. Peripheral and central acting analgesics are widely used to treat moderate to severe pain, particularly cancer pain. Many guidelines have addressed this issue. However, real life patients' have other problems and comorbidities that may raise doubts when prescribing. Authors made a literature search, trying to clarify same specific situations: loss of oral route, renal impairment (hemodialysis), hepatic impairment, frequent opiod interactions and the availability of short-acting formulations. The following medicines were included in this analysis: the natural opiates (morphine and codeine), their synthetic and semisynthetic derivatives (hydromorphone, oxycodone, and fentanyl), the partial agonist buprenorphine and finally tramadol and tapentadol. Transdermal systems are only available for buprenorphine and fentanyl. In hepatic impairment, fentanyl is safe, but with the exception of codeine and tramadol; other opioids should be used with caution. In renal failure: fentanyl, hydromorphone, and tapentadol are safe. Morphine should be avoided; other opioids should be used with caution. In hemodialysis, buprenorphine, fentanyl, hydromorphone and tramadol (at doses up to 200 mg/day) may be used. Failure to recognize the impact of various situations described throughout this work, including the bioavailability due to loss of oral route, due to pharmacokinetics and pharmacodynamics of the various drugs, either in the context of the impaired metabolism or excretion, or in due to pharmacological interactions, conditions a serious risk of subtreatment of pain and consequent impact in terms of quality of life. Opioid prescription is safe and effective, even in moderate to severe comorbidities such as renal and hepatic impairment and in patients with no oral route available. In this case, as when considering pharmacological interactions, an individualized therapeutic plan is the best solution and the patient should be assessed regularly. Unadjusted doses may relate to bad pain control and a higher prevalence of adverse events.


Gelatin-based haemostyptic Spongostan as a possible three-dimensional scaffold for a chondrocyte matrix?: an experimental study with bovine chondrocytes.
The gelatin-based haemostyptic compound Spongostan was tested as a three-dimensional (3D) chondrocyte matrix in an in vitro model for autologous chondrocyte transplantation using cells harvested from bovine knees. In a control experiment of monolayer cultures, the proliferation or de-differentiation of bovine chondrocytes was either not or only marginally influenced by the presence of Spongostan (0.3 mg/ml). In monolayers and 3-D Minusheet culture chambers, the cartilage-specific differentiation markers aggrecan and type-II collagen were ubiquitously present in a cell-associated fashion and in the pericellular matrix. The Minusheet cultures usually showed a markedly higher mRNA expression than monolayer cultures irrespective of whether Spongostan had been present or not during culture. Although the de-differentiation marker type-I collagen was also present, the ratio of type-I to type-II collagen or aggrecan to type-I collagen remained higher in Minusheet 3-D cultures than in monolayer cultures irrespective of whether Spongostan had been included in or excluded from the monolayer cultures. The concentration of GAG in Minusheet cultures reached its maximum after 14 days with a mean of 0.83 +/- 0.8 microg/10(6) cells; mean +/-, SEM, but remained considerably lower than in monolayer cultures with/without Spongostan. Our results suggest that Spongostan is in principle suitable as a 3-D chondrocyte matrix, as demonstrated in Minusheet chambers, in particular for a culture period of 14 days. Clinically, differentiating effects on chondrocytes, simple handling and optimal formability may render Spongostan an attractive 3-D scaffold for autologous chondrocyte transplantation.


Prevention of age-related changes in hippocampal levels of 5-methylcytidine by caloric restriction.
Aberrant DNA methylation patterns have been linked to molecular and cellular alterations in the aging brain. Caloric restriction (CR) and upregulation of antioxidants have been proposed as interventions to prevent or delay age-related brain pathology. Previously, we have shown in large cohorts of aging mice, that age-related increases in DNA methyltransferase 3a (Dnmt3a) immunoreactivity in the mouse hippocampus were attenuated by CR, but not by overexpression of superoxide dismutase 1 (SOD1). Here, we investigated age-related alterations of 5-methylcytidine (5-mC), a marker of DNA methylation levels, in a hippocampal subregion-specific manner. Examination of 5-mC immunoreactivity in 12- and 24-month-old wild type (WT) mice on control diet, mice overexpressing SOD1 on control diet, wild type mice on CR, and SOD1 mice on CR, indicated an age-related increase in 5-mC immunoreactivity in the hippocampal dentate gyrus, CA3, and CA1-2 regions, which was prevented by CR but not by SOD1 overexpression. Moreover, positive correlations between 5-mC and Dnmt3a immunoreactivity were observed in the CA3 and CA1-2. These findings suggest a crucial role for DNA methylation in hippocampal aging and in the mediation of the beneficial effects of CR on aging.