Regenerative principles enrich cardiac rehabilitation practice.
Cardiovascular morbidity imposes a high degree of disability and mortality, with limited therapeutic options available in end-stage disease. Integral to standard of care, cardiac rehabilitation aims on improving quality-of-life and prolonging survival. The recent advent of regenerative technologies paves the way for a transformative era in rehabilitation medicine whereby, beyond controlling risk factors and disease progression, the prospect of curative solutions is increasingly tangible. To date, the spectrum of clinical experience in cardiac regenerative medicine relies on stem cell-based therapies delivered to the diseased myocardium either acutely/subacutely, after a coronary event, or in the setting of chronic heart failure. Application of autologous/allogeneic stem cell platforms has established safety and feasibility, with encouraging signals of efficacy. Newer protocols aim to purify cell populations in an attempt to eliminate nonregenerative and enrich for regenerative cell types before use. Most advanced technologies have been developed to isolate resident cell populations directly from the heart or, alternatively, condition cells from noncardiac sources to attain a disease-targeted lineage-specified phenotype for optimized outcome. Because a multiplicity of cell-based technologies has undergone phase I/II evaluation, pivotal trials are currently underway in larger patient populations. Translation of regenerative principles into clinical practice will increasingly involve rehabilitation providers across the continuum of patient care. Regenerative rehabilitation is thus an emerging multidisciplinary field, full of opportunities and ready to be explored.


Very low PSA concentrations and deletions of the KLK3 gene.
Prostate-specific antigen (PSA), a widely used biomarker for prostate cancer (PCa), is encoded by a kallikrein gene (KLK3, kallikrein-related peptidase 3). Serum PSA concentrations vary in the population, with PCa patients generally showing higher PSA concentrations than control individuals, although a small proportion of individuals in the population display very low PSA concentrations. We hypothesized that very low PSA concentrations might reflect gene-inactivating mutations in KLK3 that lead to abnormally reduced gene expression. We have sequenced all KLK3 exons and the promoter and searched for gross deletions or duplications in KLK3 in the 30 individuals with the lowest observed PSA concentrations in a sample of approximately 85 000 men from the Prostate Testing for Cancer and Treatment (ProtecT) study. The ProtecT study examines a community-based population of men from across the UK with little prior PSA testing. We observed no stop codons or frameshift mutations, but we did find 30 single-base genetic variants, including 3 variants not described previously. These variants included missense variants that could be functionally inactivating and splicing variants. At this stage, however, we cannot confidently conclude whether these variants markedly lower PSA concentration or activity. More importantly, we identified 3 individuals with different large heterozygous deletions that encompass all KLK3 exons. The absence of a functional copy of KLK3 in these individuals is consistent with their reduced serum PSA concentrations. The clinical interpretation of the PSA test for individuals with KLK3 gene inactivation could lead to false-negative PSA findings used for screening, diagnosis, or monitoring of PCa.


GLUT2 (SLC2A2) is not the principal glucose transporter in human pancreatic beta cells: implications for understanding genetic association signals at this locus.
SLC2A2 encoding glucose transporter -2 (GLUT2) acts as the primary glucose transporter and sensor in rodent pancreatic islets and is widely assumed to play a similar role in humans. In healthy adults SLC2A2 variants are associated with elevated fasting plasma glucose (fpg) concentrations but physiological characterisation does not support a defect in pancreatic beta-cell function. Interspecies differences can create barriers for the follow up of disease association signals. We hypothesised that GLUT2 is not the principal glucose transporter in human beta-cells and that SLC2A2 variants exert their effect on fpg levels through defects in other tissues. SLC2A1-4 (GLUT 1-4) mRNA expression levels were determined in human and mouse islets, beta-cells, liver, muscle and adipose tissue by qRT-PCR whilst GLUT1-3 protein levels were examined by immunohistochemistry. The presence of all three glucose transporters was demonstrated in human and mouse islets and purified beta-cells. Quantitative expression profiling demonstrated that Slc2a2 is the predominant glucose transporter (expression >10 fold higher that Slc2a1) in mouse islets whilst SLC2A1 and SLC2A3 predominate in both human islets and beta-cells (expression 2.8 and 2.7 fold higher than SLC2A2 respectively). Our data therefore suggest that GLUT2 is unlikely to be the principal glucose transporter in human beta-cells and that SLC2A2 defects in other metabolic tissues drive the observed differences in glucose levels between carriers of SLC2A2 variants. Direct extrapolation from rodent to human islet glucose transporter activity is unlikely to be appropriate.


Cardiac screening of young athletes prior to participation in sports: difficulties in detecting the fatally flawed among the fabulously fit.
Deaths of young athletes from cardiac disease are uncommon but receive considerable media attention and intermittently galvanize debates about cardiac screening prior to participation in sports. Both the American Heart Association (AHA) and European Society of Cardiology (ESC) endorse preparticipation screening in athletes; however, there is disagreement about the best approach. The AHA recommends history and physical examination; this approach is pragmatic and relatively inexpensive but has poor sensitivity because most athletes are asymptomatic and physical examination identifies only a minority of those at risk of sudden cardiac death. The inclusion of the electrocardiogram in accordance with the recommendations of the ESC improves sensitivity for detection of serious cardiac disease but is associated with an unacceptably high false-positive rate, in part because of the overlap between the electrical manifestations of athletic training and the cardiomyopathies. For young athletes with normal electrocardiogram results, echocardiography contributes minimally to the diagnosis of serious cardiac diseases. Given all the complexities, cardiac screening of young athletes should be voluntary not mandatory and conducted by highly experienced physicians who fully understand the cardiovascular adaptation to intensive exercise.


Cardiac involvement in Kawasaki disease in Pakistani children.
Coronary artery involvement is the most dreaded long-term complication of Kawasaki disease. Our aim was to look at the pattern of cardiovascular involvement in Pakistani children admitted with Kawasaki disease. This study included children admitted with Kawasaki disease at the Aga Khan University Hospital Karachi over a period of 14 years from January 1997 to December 2010. Information gathered included patient demographics, clinical features, investigations, echocardiographic findings, treatment and follow-up. Those with coronary artery involvement on initial echocardiogram remained on long-term follow-up with clinical examination and echocardiogram. A total of 56 patients were admitted. (Mean age at diagnosis 33 ± 30 months, age range 2 months to 9 years). 18% of patients had incomplete features. Twenty-five percent (14/56) patients presented after 10 days of fever. Cardiac examination was normal except for tachycardia. Abnormal coronary arteries were seen in 23 patients (41%) - left main coronary artery in 23 (41%), left anterior descending and right main coronary artery in 20 (36%), circumflex branch in 17 (30%). Risk factors for cardiac involvement were male sex, fever >10 days duration at the time of initial presentation and neutrophil percentage >75% in the initial white blood cell counts. Fifty four of 56 cases received intravenous immunoglobulin (IVIG), Seventy-five percent of the patients received IVIG within 10 days of illness. Mean duration of follow-up was 2.5 years. Eight percent of the patients still continue to have abnormal coronaries. There was no mortality. A higher incidence of coronary artery involvement was found in our study. Presentation after 10 days of illness increases the risk of coronary artery involvement. High index of suspicion among the general pediatricians about the disease can possibly be helpful for early referral and treatment.


Gut microbiome response to a modern Paleolithic diet in a Western lifestyle context.
The modern Paleolithic diet (MPD), featured by the consumption of vegetables, fruit, nuts, seeds, eggs, fish and lean meat, while excluding grains, dairy products, salt and refined sugar, has gained substantial public attention in recent years because of its potential multiple health benefits. However, to date little is known about the actual impact of this dietary pattern on the gut microbiome (GM) and its implications for human health. In the current scenario where Western diets, low in fiber while rich in industrialized and processed foods, are considered one of the leading causes of maladaptive GM changes along human evolution, likely contributing to the increasing incidence of chronic non-communicable diseases, we hypothesize that the MPD could modulate the Western GM towards a more "ancestral" configuration. In an attempt to shed light on this, here we profiled the GM structure of urban Italian subjects adhering to the MPD, and compared data with other urban Italians following a Mediterranean Diet (MD), as well as worldwide traditional hunter-gatherer populations from previous publications. Notwithstanding a strong geography effect on the GM structure, our results show an unexpectedly high degree of biodiversity in MPD subjects, which well approximates that of traditional populations. The GM of MPD individuals also shows some peculiarities, including a high relative abundance of bile-tolerant and fat-loving microorganisms. The consumption of plant-based foods-albeit with the exclusion of grains and pulses-along with the minimization of the intake of processed foods, both hallmarks of the MPD, could therefore contribute to partially rewild the GM but caution should be taken in adhering to this dietary pattern in the long term.


Homophilic CD44 Interactions Mediate Tumor Cell Aggregation and Polyclonal Metastasis in Patient-Derived Breast Cancer Models.
Circulating tumor cells (CTC) seed cancer metastases; however, the underlying cellular and molecular mechanisms remain unclear. CTC clusters were less frequently detected but more metastatic than single CTCs of patients with triple-negative breast cancer and representative patient-derived xenograft models. Using intravital multiphoton microscopic imaging, we found that clustered tumor cells in migration and circulation resulted from aggregation of individual tumor cells rather than collective migration and cohesive shedding. Aggregated tumor cells exhibited enriched expression of the breast cancer stem cell marker CD44 and promoted tumorigenesis and polyclonal metastasis. Depletion of CD44 effectively prevented tumor cell aggregation and decreased PAK2 levels. The intercellular CD44-CD44 homophilic interactions directed multicellular aggregation, requiring its N-terminal domain, and initiated CD44-PAK2 interactions for further activation of FAK signaling. Our studies highlight that CD44+ CTC clusters, whose presence is correlated with a poor prognosis of patients with breast cancer, can serve as novel therapeutic targets of polyclonal metastasis. SIGNIFICANCE: CTCs not only serve as important biomarkers for liquid biopsies, but also mediate devastating metastases. CD44 homophilic interactions and subsequent CD44-PAK2 interactions mediate tumor cluster aggregation. This will lead to innovative biomarker applications to predict prognosis, facilitate development of new targeting strategies to block polyclonal metastasis, and improve clinical outcomes.See related commentary by Rodrigues and Vanharanta, p. 22.This article is highlighted in the In This Issue feature, p. 1.


Fasting, food and farming: Value chains and food taboos in Ethiopia.
The impact of food taboos-often because of religion-is understudied. In Ethiopia, religious fasting by Orthodox Christians is assumed to be an important impediment for the sustainable development of a competitive dairy sector and desired higher milk consumption, especially by children. However, evidence is limited. Relying on unique data, we shed light on three major issues. First, we observe that the average annual number of fasting days that Orthodox adults are effectively adhering to is 140, less than commonly cited averages. Using this as an estimate for extrapolation, fasting is estimated to reduce annual dairy consumption by approximately 12 percent nationally. Second, farms adapt to declining milk demand during fasting by increased processing of milk into storable products-fasting contributes to larger price swings for these products. We further note continued sales of milk by non-remote farmers and reduced production-by adjusting lactation times for dairy animals-for remote farmers. Third, fasting is mostly associated with increased milk consumption by the children of dairy farmers, seemingly because of excess milk availability during fasting periods. Our results suggest that fasting habits are not a major explanation for the observed poor performance of Ethiopia's dairy sector nor low milk consumption by children. To reduce the impact of fasting on the dairy sector in Ethiopia further, investment is called for in improved milk processing, storage, and infrastructure facilities.


Frontotemporal atrophy associated with paranoid delusions in women with Alzheimer's disease.
Paranoid delusions are a common and difficult-to-manage feature of Alzheimer's disease (AD). We investigated the neuroanatomical correlates of paranoid delusions in a cohort of AD patients, using magnetic resonance imaging (MRI) to measure regional volume and regional cortical thickness. 113 participants with probable AD were assessed for severity of disease, cognitive and functional impairment. Presence and type of delusions were assessed using the Neuropsychiatric Inventory (NPI). Structural MRI images were acquired on a 1.5 T scanner, and were analyzed using an automated analysis pipeline. Paranoid delusions were experienced by 23 (20.4%) of the participants. Female participants with paranoid delusions showed reduced cortical thickness in left medial orbitofrontal and left superior temporal regions, independently of cognitive decline. Male participants with delusions did not show any significant differences compared to males without delusions. An exploratory whole brain analysis of non-hypothesized regions showed reduced cortical thickness in the left insula for female participants only. Frontotemporal atrophy is associated with paranoid delusions in females with AD. Evidence of sex differences in the neuroanatomical correlates of delusions as well as differences in regional involvement in different types of delusions may be informative in guiding management and treatment of delusions in AD.


Serum follicle-stimulating hormone and risk of epithelial ovarian cancer in postmenopausal women.
The "gonadotropin hypothesis" postulates that gonadotropin overstimulation of ovarian epithelium results in its increased proliferation and subsequent malignant transformation. To address this hypothesis, we assessed the association between prediagnostic serum levels of follicle-stimulating hormone (FSH) and the risk of epithelial ovarian cancer in postmenopausal women who were part of a case-control study nested within three prospective cohorts in New York City, Umeå, Sweden, and Milan, Italy. Case subjects were 88 women with primary invasive epithelial ovarian cancer diagnosed between 3 months and 13.1 years after the blood donation. Controls were 168 women who were free of cancer and matched the case on cohort, age, and enrollment date. Serum FSH was determined using a quantitative immunoradiometric assay. FSH concentrations were similar in women who subsequently received a diagnosis of epithelial ovarian cancer (median, 44.0 mIU/ml; range, 13.8-101.2) and in controls (median, 43.4 mIU/ml; range, 13.5-109.5; P = 0.17). Compared with women in the lowest third, women in the highest third of serum FSH were not at increased risk of epithelial ovarian cancer after an adjustment for potential confounders (odds ratio, 0.85; 95% confidence interval, 0.36-1.99). These observations provide no evidence for an association between circulating FSH and risk of epithelial ovarian cancer in postmenopausal women and do not appear to support the gonadotropin hypothesis of epithelial ovarian carcinogenesis.


Contraceptive vaccines.
The control of human fertility would be revolutionised by the development of a safe, effective, long-acting contraceptive vaccine. The pursuit of this objective has involved the selection of appropriate targets within the reproductive process that are amenable to interference with antibodies. To date, three major targets have been researched. The zona pellucida (ZP) plays key roles in folliculogenesis, fertilisation and early development, and is comprised of powerful cell-specific antigens. The induction of infertility requires high ZP antibody titres that are difficult to maintain without inducing ovarian pathology characterised by a premature loss of primordial follicles. As a premature menopause would be a high price to pay for long-term contraception, this approach to a vaccine cannot progress until the cause of the ovarian pathology has been resolved. Sperm surface antigens represent another promising approach to contraceptive vaccine development. While there is some clinical data to support the likely efficacy of this strategy, none of the gamete-specific molecules characterised to date have fulfilled this promise. Anti-human chorionic gonadotropin (hCG) vaccines terminate pregnancy by preventing the maternal recognition of pregnancy. This vaccine has reached the stage of clinical trials, and preliminary indications are that the approach is safe and potentially effective. However, reliability may be an issue, given the observed inter-individual variability in antibody generation. The future of contraceptive vaccine development will clearly involve a continuation of the intense search for suitable targets and the development of improved immunisation procedures that exploit the latest innovations in vaccine technology.


Dynamics of airborne influenza A viruses indoors and dependence on humidity.
There is mounting evidence that the aerosol transmission route plays a significant role in the spread of influenza in temperate regions and that the efficiency of this route depends on humidity. Nevertheless, the precise mechanisms by which humidity might influence transmissibility via the aerosol route have not been elucidated. We hypothesize that airborne concentrations of infectious influenza A viruses (IAVs) vary with humidity through its influence on virus inactivation rate and respiratory droplet size. To gain insight into the mechanisms by which humidity might influence aerosol transmission, we modeled the size distribution and dynamics of IAVs emitted from a cough in typical residential and public settings over a relative humidity (RH) range of 10-90%. The model incorporates the size transformation of virus-containing droplets due to evaporation and then removal by gravitational settling, ventilation, and virus inactivation. The predicted concentration of infectious IAVs in air is 2.4 times higher at 10% RH than at 90% RH after 10 min in a residential setting, and this ratio grows over time. Settling is important for removal of large droplets containing large amounts of IAVs, while ventilation and inactivation are relatively more important for removal of IAVs associated with droplets <5 µm. The inactivation rate increases linearly with RH; at the highest RH, inactivation can remove up to 28% of IAVs in 10 min. Humidity is an important variable in aerosol transmission of IAVs because it both induces droplet size transformation and affects IAV inactivation rates. Our model advances a mechanistic understanding of the aerosol transmission route, and results complement recent studies on the relationship between humidity and influenza's seasonality. Maintaining a high indoor RH and ventilation rate may help reduce chances of IAV infection.


Concentrated Bone Marrow Aspirate for the Treatment of Chondral Injuries and Osteoarthritis of the Knee: A Systematic Review of Outcomes.
Bone marrow aspirate concentrate (BMAC) has emerged as a novel treatment for pathology of the knee. Despite containing a limited number of stem cells, BMAC serves as a source of growth factors that are thought to play an important role as a result of their anabolic and anti-inflammatory effects. To our knowledge, there is no systematic review regarding the outcomes of bone marrow aspirate concentrate used for the treatment of chondral defects and osteoarthritis of the knee. To perform a systematic review on the outcomes of bone marrow aspirate concentrate for the treatment of chondral defects and osteoarthritis of the knee. Systematic review; Level of evidence, 4. A systematic review of the literature was performed using the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, PubMed, and MEDLINE from 1980 to present. Inclusion criteria were as follows: use of BMAC for treatment of chondral defects and osteoarthritis of the knee, English language, and human studies. We excluded cadaveric studies, animal studies, basic science articles, editorial articles, surveys, and studies that did not include the knee. After applying inclusion and exclusion criteria, studies were evaluated for efficacy and safety of BMAC for treatment of articular cartilage knee pathologies. Eleven studies were considered. Of these, 5 were prospective studies, 1 was a retrospective study, 2 were case series, and 3 were case reports. Three comparative studies (2 with level 2 evidence, 1 with level 3 evidence) were found in our search; none of them were randomized. Three studies investigated the clinical efficacy of BMAC in the treatment of osteoarthritis, and 8 studies evaluated the efficacy of BMAC on focal cartilage injuries. All 3 studies regarding osteoarthritis and all 8 studies regarding focal chondral defects reported good to excellent overall outcomes with the use of BMAC. Although a growing interest for biological alternatives of treating knee pathology has been observed in the past few years, there still remains a paucity of high-quality studies. The studies included in this systematic review reported varying degrees of beneficial results with the use of BMAC with and without an additional procedure for the treatment of chondral defects and early stages of osteoarthritis. Most articles present the use of BMAC as a safe procedure and report good results.


Concentrations of bioaerosols, odors, and hydrogen sulfide inside and downwind from two types of swine livestock operations.
Few data on in-barn and downwind concentrations of endotoxin, bioaerosols, and odors from livestock facilities are available, and no studies have compared conventional confinement operations with the more animal-friendly hoop operations. Hoops are open to the environment and use a composted bedding system rather than housing pigs on slatted floors over pits holding manure slurry as in conventional confinements. We assessed airborne toxicants upwind, in barns, and downwind and evaluated determinants of exposure. Inhalable particulate matter, endotoxin, odor threshold, hydrogen sulfide, culturable mesophilic bacteria, culturable fungi, and total airborne microbes, along with wind speed, temperature, and humidity were measured at separate midsized livestock facilities (one hoop, one confinement) in Central Iowa on 10 occasions over 2 years. Significant differences in contaminants were observed between hoops and confinement buildings and across seasons for endotoxin, odors, airborne microorganisms, and hydrogen sulfide. For hoops and confinements, respectively, geometric mean in-barn concentrations were 3250 and 3100 EU/m(3) for endotoxin; 1400 and 1910 microg/m(3) for particulates; 19.6 and 146 ppb for hydrogen sulfide; 137 and 428 dilutions for odor threshold; and 3.0 x 10(6) and 1.5 x 10(6) organisms/m(3) for total microbes. Endotoxin, odor, and culturable microorganisms exceeded recommended exposure limits. Reduced analysis of variance models for these contaminants demonstrated differences by barn type, season, number of pigs, and, in some cases, temperature and humidity. Both types of swine operations produced high airborne concentrations of endotoxin, odor, hydrogen sulfide, bacteria, and fungi. Endotoxin and odors were found downwind at concentrations previously associated with adverse health effects.


Chorioamnionitis reduces placental endocrine functions: the role of bacterial lipopolysaccharide and superoxide anion.
Chorioamnionitis has been shown to be one of the most important factors in inducing preterm delivery. The present study was undertaken to examine the effects of chorioamnionitis on placental endocrine functions. Preterm placentas with histologic chorioamnionitis produced smaller amounts of human chorionic gonadotropin (hCG) and human placental lactogen (hPL) than those without chorioamnionitis (P < 0.001). To examine the mechanism involved in the suppression of placental endocrine functions induced by chorioamnionitis, we initially confirmed the expression of lipopolysaccharide (LPS) receptor, i.e. the CD14 molecule, on trophoblasts by Northern blot analysis and immunohistochemistry. We then stimulated purified trophoblasts with LPS, which is the major agent which induces inflammatory responses in the host via the LPS receptor. The trophoblasts stimulated with LPS produced reduced amounts of hCG, hPL, and progesterone in a time- and dose-dependent fashion in spite of the induced manganese-superoxide dismutase (SOD) synthesis. Stimulation of trophoblasts with hypoxanthine and xanthine oxidase resulted in suppressed hCG production, while the simultaneous addition of SOD into the culture medium reversed the suppression of hCG production. LPS in the placenta with chorioamnionitis might directly stimulate trophoblasts through the LPS receptor (CD14), thus reducing placental endocrine functions. Superoxide anions which exogenously act on trophoblasts might be generated by simultaneous stimulation of neutrophils and monocytes at the feto-maternal interface by LPS, and additively reduce placental endocrine functions.


Airway tissue engineering: an update.
Prosthetic materials, autologous tissues, cryopreserved homografts and allogeneic tissues have thus far proven unsuccessful in providing long-term functional solutions to extensive upper airway disease and damage. Research is therefore focusing on the rapidly expanding fields of regenerative medicine and tissue engineering in order to provide stem cell-based constructs for airway reconstruction, substitution and/or regeneration. Advances in stem cell technology, biomaterials and growth factor interactions have been instrumental in guiding optimization of tissue-engineered airways, leading to several first-in-man studies investigating stem cell-based tissue-engineered tracheal transplants in patients. Here, we summarize current progress, outstanding research questions, as well as future directions within the field. The complex immune interaction between the transplant and host in vivo is only beginning to be untangled. Recent progress in our understanding of stem cell biology, decellularization techniques, biomaterials and transplantation immunobiology offers the prospect of transplanting airways without the need for lifelong immunosuppression. In addition, progress in airway revascularization, reinnervation and ever-increasingly sophisticated bioreactor design is opening up new avenues for the construction of a tissue-engineered larynx. Finally, 3D printing is a novel technique with the potential to render microscopic control over how cells are incorporated and grown onto the tissue-engineered airway.


Exacerbating Inequalities: Social Networks, Racial/Ethnic Disparities, and the COVID-19 Pandemic in the United States.
The disruption and contraction of older adults' social networks are among the less discussed consequences of the COVID-19 pandemic. Our objective was to provide an evidence-based commentary on racial/ethnic disparities in social network resources and draw attention to the ways in which disasters differentially affect social networks, with meaningful insight for the ongoing pandemic. We draw upon prior research on social networks and past natural disasters to identify major areas of network inequality. Attention is given to how pre-pandemic racial/ethnic network disparities are exacerbated during the current crisis, with implications for physical and mental health outcomes. Evidence from the literature shows a robust association between strong social networks and physical and mental health outcomes. During times of crisis, access to social networks for older adults is disrupted, particularly for marginalized groups. We document pre-pandemic disparities in social networks resources and offer insight for examining the impact of COVID-19 on disrupting social networks among older adults. Importantly, racial/ethnic disparities in social networks both prior to and as a result of the pandemic intensify existing inequalities and demonstrate the necessity of better understanding social network inequalities for marginalized older adults, particularly in the context of the COVID-19 health crisis.


[Fibromyalgia. A critical review].
Fibromyalgia is a chronic pain syndrome, more common in women. Its prevalence is estimated around 2% in the general population, and up to 20% among rheumatology outpatients. Besides musculoskeletal pain, symptoms as fatigue and sleep disturbance are considered characteristic. Research criteria have been set up, but their seemingly preciseness is unable to distinguish clearly between fibromyalgia and other functional somatic syndromes (chronic fatigue syndrome, irritable bowel syndrome) and psychiatric disorders (depression, anxiety), with which a striking comorbidity is documented. The diagnosis of fibromyalgia does not theoretically require the exclusion of muscle, joint, or metabolic diseases, but in clinical practice this problem proves to be of crucial importance. There are numbers of pathophysiological hypothesis for fibromyalgia, but none of them is fully satisfying: muscle is probably innocent; sleep disturbance, although sometimes considered a landmark of the syndrome, is unspecific; stress response studies show subtle anomaly; psychiatric disorders may represent factors of vulnerability and perpetuation rather than causes. We propose to include some of these etiological contributors in vicious circles leading to a "final common pathway" characterized by generalized hyperalgesia. Treatments of fibromyalgia, whether pharmacological (antidepressants) or psychological (cognitive-behavioral therapies) are of little efficacy, and the global prognosis of fibromyalgia is poor. However, the outcome might prove better outside the specialized clinics in which studies of chronic sufferers with severe abnormal illness behaviors are done. The social consequences of the popularization of the diagnosis of fibromyalgia should not be neglected.


Latent class models for testing monotonicity and invariant item ordering for polytomous items.
Two assumptions that are relevant to many applications using item response theory are the assumptions of monotonicity (M) and invariant item ordering (IIO). A latent class model is proposed for ordinal items with inequality constraints on the class-specific item means. This model is used as a tool for testing for violations of M and IIO. A Gibbs sampling scheme is used for estimating the model parameters. It is shown that the deviance information criterion can be used as an overall test of M and IIO, while posterior predictive checks can be used to test these assumptions at the item level. A real data application illustrates a model-fitting strategy for detecting items that violate M and IIO.


Development of genomic resources for Citrus clementina: characterization of three deep-coverage BAC libraries and analysis of 46,000 BAC end sequences.
Citrus species constitute one of the major tree fruit crops of the subtropical regions with great economic importance. However, their peculiar reproductive characteristics, low genetic diversity and the long-term nature of tree breeding mostly impair citrus variety improvement. In woody plants, genomic science holds promise of improvements and in the Citrus genera the development of genomic tools may be crucial for further crop improvements. In this work we report the characterization of three BAC libraries from Clementine (Citrus clementina), one of the most relevant citrus fresh fruit market cultivars, and the analyses of 46.000 BAC end sequences. Clementine is a diploid plant with an estimated haploid genome size of 367 Mb and 2n = 18 chromosomes, which makes feasible the use of genomics tools to boost genetic improvement. Three genomic BAC libraries of Citrus clementina were constructed through EcoRI, MboI and HindIII digestions and 56,000 clones, representing an estimated genomic coverage of 19.5 haploid genome-equivalents, were picked. BAC end sequencing (BES) of 28,000 clones produced 28.1 Mb of genomic sequence that allowed the identification of the repetitive fraction (12.5% of the genome) and estimation of gene content (31,000 genes) of this species. BES analyses identified 3,800 SSRs and 6,617 putative SNPs. Comparative genomic studies showed that citrus gene homology and microsyntheny with Populus trichocarpa was rather higher than with Arabidopsis thaliana, a species phylogenetically closer to citrus. In this work, we report the characterization of three BAC libraries from C. clementina, and a new set of genomic resources that may be useful for isolation of genes underlying economically important traits, physical mapping and eventually crop improvement in Citrus species. In addition, BAC end sequencing has provided a first insight on the basic structure and organization of the citrus genome and has yielded valuable molecular markers for genetic mapping and cloning of genes of agricultural interest. Paired end sequences also may be very helpful for whole-genome sequencing programs.


Plasmonic graded nano-disks as nano-optical conveyor belt.
We propose a plasmonic system consisting of nano-disks (NDs) with graded diameters for the realization of nano-optical conveyor belt. The system contains a couple of NDs with individual elements coded with different resonant wavelengths. By sequentially switching the wavelength and polarization of the excitation source, optically trapped target nano-particle can be transferred from one ND to another. The feasibility of such function is verified based on the three-dimensional finite-difference time-domain technique and the Maxwell stress tensor method. Our design may provide an alternative way to construct nano-optical conveyor belt with which target molecules can be delivered between trapping sites, thus enabling many on-chip optofluidic applications.


Seasonality of hepatitis: a review update.
Viral hepatitis is an infection that has been reported to be present throughout the year, but some particular months are associated with higher incidences. The primary objective was to review and report on the current knowledge and evidence that existed on seasonality of different type of acute viral hepatitis worldwide in order to develop recommendations for future research, prevention and control. A systematic literature review was performed to identify all the primary reports and studies published during 1970-2013 on acute hepatitis A, B, C and E (AHA, AHB, AHC and AHE) in human subjects by searching PubMed, reference lists of major articles and correspondence with scientific experts. For each report or study included, the following information was extracted (as applicable to study): Location (country and setting), study population (number of cases, patients), seasonal or monthly rate and study duration. There is no definite and consistent seasonal pattern has been observed on AHA; AHB; AHE and AHC, although evidence points towards spring and summer peak for hepatitis A, B, C and E. Multiple source of transmission such as; summer travel to an endemic area, swimming habits of the population in hot months, increase sexual contact, tattoo, poor hygiene and environmental sanitation and food habits (feco-oral transmission of viral hepatitis) probably exists and should be further investigated through analytical and epidemiological.


Usefulness of catheter-directed thrombolysis using alteplase in peripheral vascular occlusion.
This study evaluated the safety and efficacy of alteplase in catheter-directed treatment for peripheral arterial and venous thrombosis and considered the optimal dosing regimen. Forty-four patients (49 encounters) underwent transcatheter therapy using alteplase between January and November 1999. The most common indications for thrombolysis were peripheral arterial occlusion (PAO) and venous thrombosis (38 patients, 43 encounters). Each encounter was reviewed for indication, dosage of alteplase, duration of infusion, concomitant use of anticoagulation, degree of lysis, and complications. Patients were divided into low-dose (0.5 to 1.0 mg/hr), mid-dose (1.0 to 1.5 mg/hr), and high-dose (>1.5 mg/hr) groups. For PAO, there was no significant difference in the success rate between the 3 dose groups. A lower complication rate was achieved in the low-dose group. For venous thrombosis, there was no difference in the overall success or complication rates for each of the 3 groups. Partial lysis was achieved more readily in the mid and high-dose groups, but the risk of serious complications was greater. Overall, the complete thrombolysis rate was 71% for PAO and 55% for venous thrombosis. Major and minor complication rates were 7% and 19%, respectively. An equivalent success rate with a lower complication rate can be achieved using a low-dose constant catheter-directed infusion of alteplase for cases of PAO. Cases of venous thrombosis had a lower overall success rate compared with PAO. A mid-dose infusion of alteplase can achieve greater complete and partial thrombolysis rates without increasing the complication rate. Major and minor complication rates were similar to the rates given in the published literature.


Axial arrangement of the myosin rod in vertebrate thick filaments: immunoelectron microscopy with a monoclonal antibody to light meromyosin.
A monoclonal antibody, MF20, which has been shown previously to bind the myosin heavy chain of vertebrate striated muscle, has been proven to bind the light meromyosin (LMM) fragment by solid phase radioimmune assay with alpha-chymotryptic digests of purified myosin. Epitope mapping by electron microscopy of rotary-shadowed, myosin-antibody complexes has localized the antibody binding site to LMM at a point approximately 92 nm from the C-terminus of the myosin heavy chain. Since this epitope in native thick filaments is accessible to monoclonal antibodies, we used this antibody as a high affinity ligand to analyze the packing of LMM along the backbone of the thick filament. By immunofluorescence microscopy, MF20 was shown to bind along the entire A-band of chicken pectoralis myofibrils, although the epitope accessibility was greater near the ends than at the center of the A-bands. Thin-section, transmission electron microscopy of myofibrils decorated with MF20 revealed 50 regularly spaced, cross-striations in each half A-band, with a repeat distance of approximately 13 nm. These were numbered consecutively, 1-50, from the A-band to the last stripe, approximately 68 nm from the filament tips. These same striations could be visualized by negative staining of native thick filaments labeled with MF20. All 50 striations were of a consecutive, uninterrupted repeat which approximated the 14-15-nm axial translation of cross-bridges. Each half M-region contained five MF20 striations (approximately 13 nm apart) with a distance between stripes 1 and 1', on each half of the bare zone, of approximately 18 nm. This is compatible with a packing model with full, antiparallel overlap of the myosin rods in the bare zone region. Differences in the spacings measured with negatively stained myofilaments and thin-sectioned myofibrils have been shown to arise from specimen shrinkage in the fixed and embedded preparations. These observations provide strong support for Huxley's original proposal for myosin packing in thick filaments of vertebrate muscle (Huxley, H. E., 1963, J. Mol. Biol., 7:281-308) and, for the first time, directly demonstrate that the 14-15-nm axial translation of LMM in the thick filament backbone corresponds to the cross-bridge repeat detected with x-ray diffraction of living muscle.


A Bayesian spatio-temporal approach for real-time detection of disease outbreaks: a case study.
For researchers and public health agencies, the complexity of high-dimensional spatio-temporal data in surveillance for large reporting networks presents numerous challenges, which include low signal-to-noise ratios, spatial and temporal dependencies, and the need to characterize uncertainties. Central to the problem in the context of disease outbreaks is a decision structure that requires trading off false positives for delayed detections. In this paper we apply a previously developed Bayesian hierarchical model to a data set from the Indiana Public Health Emergency Surveillance System (PHESS) containing three years of emergency department visits for influenza-like illness and respiratory illness. Among issues requiring attention were selection of the underlying network (Too few nodes attenuate important structure, while too many nodes impose barriers to both modeling and computation.); ensuring that confidentiality protections in the data do not impede important modeling day of week effects; and evaluating the performance of the model. Our results show that the model captures salient spatio-temporal dynamics that are present in public health surveillance data sets, and that it appears to detect both "annual" and "atypical" outbreaks in a timely, accurate manner. We present maps that help make model output accessible and comprehensible to public health authorities. We use an illustrative family of decision rules to show how output from the model can be used to inform false positive-delayed detection tradeoffs. The advantages of our methodology for addressing the complicated issues of real world surveillance data applications are three-fold. We can easily incorporate additional covariate information and spatio-temporal dynamics in the data. Second, we furnish a unified framework to provide uncertainties associated with each parameter. Third, we are able to handle multiplicity issues by using a Bayesian approach. The urgent need to quickly and effectively monitor the health of the public makes our methodology a potentially plausible and useful surveillance approach for health professionals.


Mechanisms and pharmacokinetic/pharmacodynamic profiles underlying the low nephrotoxicity and ototoxicity of etimicin.
Etimicin (ETM), a fourth-generation aminoglycosides (AGs), is now widely clinically used in China due to its high efficacy and low toxicity. However, the mechanisms underlying its low nephrotoxicity and ototoxicity remain unclear. In the present study we compared the antibacterial and toxicity profiles of etimicin, gentamicin (GM, a second-generation AG), and amikacin (AMK, a third-generation AG), and investigated their pharmacokinetic properties in the toxicity target organs (kidney and inner ear) and subcellular compartments. We first demonstrated that ETM exhibited superior antibacterial activities against clinical isolates to GM and AMK, and it exerted minimal nephrotoxicity and ototoxicity in rats following multi-dose administration. Then, we conducted pharmacokinetic studies in rats, showed that the three AGs accumulated in the kidney and inner ear with ETM being distributed to a lesser degree in the two toxicity target organs as compared with GM and AMK high-dose groups. Furthermore, we conducted in vitro experiments in NRK-52E rat renal tubular epithelial cells and HEI-OC1 cochlear hair cells, and revealed that all the three AGs were distributed predominantly in the mitochondria with ETM showing minimal accumulation; they not only directly inhibited the activity of mitochondrial complexes IV and V but also inhibited mitochondrial function and its related PGC-1α-NRF1-TFAM pathway; ETM caused minimal damage to the mitochondrial complex and mitochondrial biogenesis. Our results demonstrate that the minimal otonephrotoxicity of ETM results from its lesser accumulation in mitochondria of target cells and subsequently lesser inhibition of mitochondrial function. These results provide a new strategy for discovering novel AGs with high efficacy and low toxicity.


Bioethics for clinicians: 5. Substitute decision-making.
Substitute decision-making is a means of making health care decisions on behalf of people who are incapable of making these decisions for themselves. It is based on the ethical principle of respect for autonomy. Substitute decision-making poses two main questions: Who-should make the decision for the incapable person, and, How should the decision be made? Because the applicable statutory and common law varies across Canada, clinicians should become familiar with the legal requirements of their own province or territory.


Pediatricians' perspectives on the impact of MRSA in primary care: a qualitative study.
The incidence of skin and soft-tissue infections (SSTIs) has rapidly increased among children in primary care settings since the emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). Recent treatment recommendations emphasize CA-MRSA as the primary cause, performing incision and drainage (I&D) as the primary therapy, and not prescribing antibiotics for uncomplicated cases. It is unknown how this epidemic has impacted primary care pediatricians in terms of their practice patterns and barriers they face to providing recommended therapies. 3 Focus groups among 29 primary care pediatricians in the San Francisco Bay Area were conducted. Transcripts were reviewed and coded into major themes by two investigators using modified grounded theory. Substantial changes in clinical practice have occurred since the emergence of CA-MRSA. These include increased office visits for SSTIs, patients with multiple recurrences and transmission within households. Additionally, our participants reported increased visits for mild skin problems due to media reports contributing to fears about CA-MRSA. Participants routinely prescribed antibiotics for SSTIs, however, few performed I&D. Few were aware of recent SSTI treatment recommendations. Barriers to prescribing antibiotics with CA-MRSA activity included concerns about side-effects and lack of local epidemiologic data showing that it is the primary etiology. Barriers to performing I&D included lack of training, resources and skepticism about its necessity. Important clinical challenges included increased time demands for follow-up visits and patient education along with the lack of evidence-based strategies for preventing recurrent infections and household transmission. CA-MRSA has influenced the presentation and treatment of SSTIs especially in terms of case numbers and recurrences. Barriers to providing recommended therapies can be addressed through improved dissemination of treatment guidelines and epidemiologic data. Studies are urgently needed to improve the evidence-base for treatment and prevention strategies.


Exploring the bandwidth limits of ZTE imaging: Spatial response, out-of-band signals, and noise propagation.
Zero echo time (ZTE) imaging with single-pulse excitation is a fast, robust, and silent three-dimensional (3D) method for MRI of short T2 tissues. In this technique, algebraic reconstruction serves to fill gaps in the center of k-space due to finite acquisition dead time. The purpose of this study was to investigate the effect of this operation on depiction characteristics, noise behavior, and achievable bandwidth. The spatial response function (SRF) and noise covariance resulting from ZTE reconstruction were studied using formal analysis, simulations, and phantom experiments. Three prominent limiting phenomena were identified: SRF behavior within the field of view, heightened sensitivity to out-of-band signal sources, and noise amplification. The related errors all appear as image distortions of low spatial frequency and are strongly attenuated upon the transition from one-dimensional projections to 3D image data. Relying on these observations, ZTE imaging was accomplished with a previously unreached gap size, permitting the depiction of a solid sample with T2 ≈ 25 µs at a bandwidth of 500 kHz. The tightest bandwidth limits in ZTE arise from background signal and radiofrequency (RF) switching transients. Significant advances in ZTE performance will be afforded by faster transmit-receive (T/R) switching with negligible transients and RF coils free of background signal.


Small-diameter porous poly (epsilon-caprolactone) films enhance adhesion and growth of human cultured epidermal keratinocyte and dermal fibroblast cells.
Autologous keratinocyte grafts provide clinical benefit by rapidly covering wounded areas, but they are fragile. We therefore developed biocompatible hexagonal-packed porous films with uniform, circular pore sizes to support human keratinocytes and fibroblasts. Cells were cultured on these porous poly (epsilon-calprolactone) films with pore sizes ranging from novel ultra-small 3 microm to 20 microm. These were compared with flat (pore-less) films. Cell growth rates, adhesion, migration, and ultrastructural morphology were examined. Human keratinocytes and fibroblasts attached to all films. Furthermore, small-pore (3-5 microm) films showed the highest levels of cell adhesion and survival and prevented migration into the pores and opposing film surface. Keratinocyte migration over small-pore film surface was inhibited. Keratinocytes optimally attached to 3-microm-pore films due to a combination of greater pore numbers (porosity), a greater circumference of the pore edge per unit surface area, and greater frequency of flat surface areas for attachment, allowing better cell-substrate and cell-cell attachment and growth. The 3-microm pore size allowed cell-cell communication, together with diffusion of soluble nutrients and factors from the culture medium or wound substrate. These characteristics are considered important in developing grafts for use in the treatment of human skin wounds.


Oxygen delivery is not a limiting factor during post-exercise recovery in healthy young adults.
It is still equivocal whether oxygen uptake recovery kinetics are limited by oxygen delivery and can be improved by supplementary oxygen. The present study aimed to investigate whether measurements of muscle and pulmonary oxygen uptake kinetics can be used to assess oxygen delivery limitations in healthy subjects. Sixteen healthy young adults performed three sub-maximal exercise tests (6 min at 40% Wmax) under hypoxic (14%O2), normoxic (21%O2) and hyperoxic (35%O2) conditions on separate days in randomized order. Both Pulmonary VO2 and near infra red spectroscopy (NIRS) based Tissue Saturation Index (TSI) offset kinetics were calculated using mono-exponential curve fitting models. Time constant τ of VO2 offset kinetics under hypoxic (44.9 ± 7.3s) conditions were significantly larger than τ of the offset kinetics under normoxia (37.9 ± 8.2s, p = 0.02) and hyperoxia (37±6s, p = 0.04). TSI mean response time (MRT) of the offset kinetics under hypoxic conditions (25.5 ± 13s) was significantly slower than under normoxic (15 ± 7.7, p = 0.007) and hyperoxic (13 ± 7.3, p = 0.008) conditions. The present study shows that there was no improvement in the oxygen uptake and muscle oxygenation recovery kinetics in healthy subjects under hyperoxic conditions.Slower TSI and VO2 recovery kinetics under hypoxic conditions indicate that both NIRS and spiro-ergometry are appropriate non-invasive measurement tools to assess the physiological response of a healthy individual to hypoxic exercise.


Post-Stroke Fatigue May Be Associated with the Promoter Region of a Monoamine Oxidase A Gene Polymorphism.
Post-stroke fatigue (PSF) is a common sequela of stroke. Despite reports of serotonergic involvement in the etiology of PSF, the potential contribution of serotonergic genes in the development of PSF needs to be investigated. A total of 373 patients, who experienced ischemic stroke for PSF, were evaluated 3 months after the stroke. PSF was assessed using the Fatigue Severity Scale. The genomic DNA collected and stored in a -70°C freezer was genotyped for 6 polymorphisms in genes associated with serotonin synthesis (tryptophan hydroxylase 1 (TPH1) A218C, TPH2 rs10879355, and TPH2 rs4641528), transport (the promoter region of the serotonin transporter protein), and catabolism (the 30-bp functional variable number tandem repeat) polymorphism in the promoter region of monoamine oxidase A (MAO-A). Among the 373 patients, 164 (44%) had PSF. All patients were ethnic Koreans. Of the 6 polymorphisms examined, only one marker, that is, low-activity MAO-A was associated with PSF (p < 0.05) in female patients. Multiple logistic regression analyses showed that post-stroke depression (PSD; 95% CI 1.561-14.323, p = 0.006) and low MAO-A activity (95% CI 0.166-0.722, p = 0.005) were factors associated with PSF in female patients, whereas only PSD (95% CI 5.511-65.269, p = 0.000) was associated with PSF in male patients. Our findings suggest that PSF may be associated with a genetic polymorphism involving MAO-A, at least in female stroke patients.


Daily structured approach to awareness of fetal movements and pregnancy outcome - a prospective study.
We investigated how women, seeking care due to decreased movements, had paid attention to fetal movements and if the method of monitoring was associated with pregnancy outcome. A questionnaire was distributed to women from gestational week 28, who had sought care due to decreased fetal movements in Stockholm between January 1st and December 31st, 2014. Women were included in the study if the examination did not reveal any signs of a compromised fetus requiring immediate intervention. Birth outcome and sociodemographic data were collected from the obstetric record register. There were 29166 births in Stockholm in 2014, we have information from 2683 women who sought care for decreased fetal movements. The majority (96.6%) of the women stated that they paid attention to fetal movements. Some women observed fetal movements weekly (17.2%) and 69.5% concentrated on fetal movements daily (non-structured group). One in ten (9.9%) used counting methods daily for observing fetal movements (structured group). Women in the structured group more often had caesarean section before onset of labor (RR 1.6, 95% CI 1.2-2.2) and a lower risk of their baby being transferred to neonatal nursery (RR 0.25, 95% CI 0.03-0.94) compared to women in the non-structured group. Women, who had a daily and structured approach to awareness of fetal movements, were more likely to have a caesarean section but their babies were less likely to be transferred to a neonatal nursery as compared with women who used a non-structured method daily.


Advancing the application of systems thinking in health: why cure crowds out prevention.
This paper presents a system dynamics computer simulation model to illustrate unintended consequences of apparently rational allocations to curative and preventive services. A modeled population is subject to only two diseases. Disease A is a curable disease that can be shortened by curative care. Disease B is an instantly fatal but preventable disease. Curative care workers are financed by public spending and private fees to cure disease A. Non-personal, preventive services are delivered by public health workers supported solely by public spending to prevent disease B. Each type of worker tries to tilt the balance of government spending towards their interests. Their influence on the government is proportional to their accumulated revenue. The model demonstrates effects on lost disability-adjusted life years and costs over the course of several epidemics of each disease. Policy interventions are tested including: i) an outside donor rationally donates extra money to each type of disease precisely in proportion to the size of epidemics of each disease; ii) lobbying is eliminated; iii) fees for personal health services are eliminated; iv) the government continually rebalances the funding for prevention by ring-fencing it to protect it from lobbying.The model exhibits a "spend more get less" equilibrium in which higher revenue by the curative sector is used to influence government allocations away from prevention towards cure. Spending more on curing disease A leads paradoxically to a higher overall disease burden of unprevented cases of disease B. This paradoxical behavior of the model can be stopped by eliminating lobbying, eliminating fees for curative services, and ring-fencing public health funding. We have created an artificial system as a laboratory to gain insights about the trade-offs between curative and preventive health allocations, and the effect of indicative policy interventions. The underlying dynamics of this artificial system resemble features of modern health systems where a self-perpetuating industry has grown up around disease-specific curative programs like HIV/AIDS or malaria. The model shows how the growth of curative care services can crowd both fiscal and policy space for the practice of population level prevention work, requiring dramatic interventions to overcome these trends.


NTP Toxicology and Carcinogenesis Studies of Chlorodibromomethane (CAS No. 124-48-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
Toxicology and carcinogenesis studies of chlorodibromomethane (greater than 98% pure), a trihalomethane formed after chlorination of water supplies, were conducted by administering this test chemical in corn oil gavage five times per week for 104 weeks to groups of 50 male and 50 female F344/N rats at 0,40, or 80 mg/kg per day and to groups of 50 male and 50 female B6C3F1 mice for 105 weeks at doses of 0, 50, or 100 mg/kg per day. Survival of dosed male and female rats and female mice was comparable to that of the corresponding vehicle control groups. An overdose of chemical was given to low dose male and female mice at week 58; this overdose killed 35 male mice, whereas the female mice were apparently not affected. Because this mortality significantly reduced the number of survivors, the low dose male mouse group was considered to be inadequate for analysis of neoplasms. High dose male mice had lower survival than the vehicle controls (44/50 vs 29/50; P<0.001). At week 82, nine high dose male mice had died; the cause remains unknown. High dose male rats and dosed male and female mice had lower body weights compared with those of the vehicle controls. Compound-related nonneoplastic lesions were found in the liver and kidney in male and female rats and in male mice in the 13-week studies at the highest dose (250 mg/kg). In the 2-year studies, compound-related toxicity was seen primarily in the livers of male and female rats (fatty metamorphosis and ground-glass cytoplasmic changes) and in the male mice (hepatocytomegaly, necrosis, fatty metamorphosis) and female mice (calcification and fatty metamorphosis). Toxicity was also seen in the kidneys (nephrosis) of male mice and female rats. Administration of chlorodibromomethane significantly increased the incidence of hepatocellular adenomas (vehicle control, 2/50; low dose, 4/49; high dose, 11/50) and the combined incidences of hepatocellular adenomas or carcinomas (6/50; 10/49; 19/50) in high dose female mice. The incidence of hepatocellular carcinomas (vehicle control, 10/50; high dose, 19/50) was significantly increased in high dose male mice, although the combined incidence of hepatocellular adenomas or carcinomas (vehicle control, 23/50; high dose, 27/50) was marginally significant by the life table test but not by the incidental tumor test. Negative trends in several common rodent tumors were found in dosed animals in the 2-year studies. These neoplasms included fibroadenomas of the mammary gland in female rats, endometrial stromal polyps of the uterus in female rats, and malignant lymphomas in male mice. Chlorodibromomethane was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of Aroclor-induced male Sprague-Dawley rat or male Syrian hamster liver S9. An audit of the experimental data was conducted for the 2-year toxicology and carcinogenesis studies of chlorodibromomethane. No data discrepancies were found that influenced the final interpretations. Under the conditions of these gavage studies, there was no evidence of carcinogenicity in male or female F344/N rats receiving chlorodibromomethane at doses of 40 or 80 mg/kg five times per week for 104 weeks. Fatty metamorphosis and ground-glass cytoplasmic changes of the liver in male and female F344/N rats were related to administration of chlorodibromomethane. There was equivocal evidence of carcinogenicity for male B6C3F1 mice; chlorodibromomethane caused an increased incidence of hepatocellular carcinomas, whereas the combined incidence of hepatocellular adenomas or carcinomas was only marginally increased. Some evidence of carcinogenicity was observed for female B6C3F1 mice, since chlorodibromomethane caused an increased incidence of hepatocellular adenomas and an increased combined incidence of hepatocellular adenomas or carcinomas. Synonym: Dibromochloromethane


Differential expression of mouse Disabled 2 gene in retinoic acid-treated F9 embryonal carcinoma cells and early mouse embryos.
Using a differential display PCR, we identified a differentially expressed cDNA fragment which was detectable in retinoic acid (RA) treated F9 embryonal carcinoma (EC) cells but not in untreated F9 cells. A homology search of the Gene Bank indicated that the cDNA fragment is part of the mouse homolog of the Drosophila Disabled (mDab2) gene. Aggregate cultures of F9 EC cells grown in the presence of the RA differentiated into nonmalignant cells resembling the visceral endoderm of the mouse embryo. Upon induction of endodermal differentiation with 10(-7) M RA, the gene expression of mDab2 was increased gradually during the first 96 h. Neither undifferentiated F9 cells, nor the undifferentiated aggregate cells without RA expressed mDab2. Whole-mount in situ hybridization and quantitative RT-PCR also showed that the temporal expression pattern of the mDab2 gene coincides with the initiation pattern of RA synthesis that occurs during mouse embryogenesis. Also, two alternative splicing messages of mDab2 were detected in a tissue specific manner. All the data indicate that mDab2 may play an important role in RA-induced signal transduction during mouse development.


Graphene on {116} faceted monocrystalline anatase nanosheet array for ultraviolet detection.
A structure composed of a nanosheet array may trap photons, which could be used to enhance the optical response via resonances; this may be highly useful in ultraviolet (UV) detection, photocatalysis, solar cells, etc. Moreover, anatase nanosheets exposed with the active {001}, {111}, and {116} facets are promising in applications such as Li-ion battery, photocatalysis, and electrochemistry. Therefore, in this study, the {116} faceted single-crystalline anatase nanosheet array with the sheet spacing in the range of several hundred nanometers was directly grown on the transparent conductive substrates. A photo-detector was fabricated by transferring a graphene electrode to the top of the anatase nanosheet array. The resultant device is inactive to visible-light irradiation and instantly responds to the UV light, which is due to the unique UV absorption property of the anatase nanosheet array and the advantage of the Schottky junction between the interfaces of graphene and anatase. The energy barrier between the two materials is 0.122 eV. We have provided a thorough research on graphene/monocrystal anatase-NSs.


Understanding Youth Perceptions of Neighborhood Disorder: The Role of Conduct Problems.
While research addresses neighborhood disorder as leading to conduct problems, the role of individual-level differences in shaping adolescent perceptions of neighborhood has been overlooked. Data on youth, over-selected for childhood conduct problems (N = 744, 58% childhood conduct problems, 47% girls), were used to examine the link between conduct problems (time 1: Mean age = 12.23) and perceived neighborhood disorder (time 3: M = 14.30). The mediating role of delinquent friends, peer victimization, depressive symptoms, and observer-rated neighborhood disorder (time 2: M = 13.23) were also tested. Conduct problems were associated with higher levels of perceived neighborhood disorder, via delinquent peers and peer victimization. These findings offer new insight into the consequences of perceived neighborhood disorder for health and wellbeing.


Clinical Course in Chronic Subdural Hematoma Patients Aged 18-49 Compared to Patients 50 Years and Above: A Multicenter Study and Meta-Analysis.
Objective: Chronic Subdural Hematoma (cSDH) is primarily a disease of elderly, and is rare in patients <50 years, and this may in part be related to the increased brain atrophy from 50 years of age. This fact may also influence clinical presentation and outcome. The aim of this study was to study the clinical course with emphasis on clinical presentation of cSDH patients in the young (<50 years). Methods: A retrospective review of a population-based cohort of 1,252 patients operated for cSDH from three Scandinavian neurosurgical centers was conducted. The primary end-point was difference in clinical presentation between the patients <50 y/o and the remaining patients (≥50 y/o group). The secondary end-points were differences in perioperative morbidity, recurrence and mortality between the two groups. In addition, a meta-analysis was performed comparing clinical patterns of cSDH in the two age groups. Results: Fifty-two patients (4.2%) were younger than 50 years. Younger patients were more likely to present with headache (86.5% vs. 37.9%, p < 0.001) and vomiting (25% vs. 5.2%, p < 0.001) than the patients ≥50 y/o, while the ≥50 y/o group more often presented with limb weakness (17.3% vs. 44.8%, p < 0.001), speech impairment (5.8% vs. 26.2%, p = 0.001) and gait disturbance or falls (23.1% vs. 50.7%, p < 0.001). There was no difference between the two groups in recurrence, overall complication rate and mortality within 90 days. Our meta-analysis confirmed that younger patients are more likely to present with headache (p = 0.015) while the hemispheric symptoms are more likely in patients ≥50 y/o (p < 0.001). Conclusion: Younger patients with cSDH present more often with signs of increased intracranial pressure, while those ≥50 y/o more often present with hemispheric symptoms. No difference exists between the two groups in terms of recurrence, morbidity, and short-term mortality. Knowledge of variations in clinical presentation is important for correct and timely diagnosis in younger cSDH patients.


Coping with problematic drug use in the family: An evaluation of the Stepping Stones program.
Problematic substance use by an individual is often highly destructive to their family, creating emotional turmoil and destroying healthy family functioning. The aim of this study was to evaluate the impact of participation in the Stepping Stones family support program on the coping capacity of family members affected by another's substance use. A pre and post study of the Stepping Stones intervention for families was conducted, involving 108 participants recruited from March 2013 to March 2014. Significant improvement in coping across all domains was observed post course and at follow up on both outcome measures (Coping Questionnaire and the Family Drug Support Questionnaire). Improvements for participants were either increased or sustained at 3 months follow up. Participants recorded high satisfaction ratings. The findings from this study demonstrate that participation in the Stepping Stones program assists family members to cope better with problematic substance use of a family member, as indicated by reductions in negative coping strategies, such as over-engagement, making excuses for the drug user or hopelessly tolerating the problem, and improvements in positive coping strategies such as self-care and engagement with their own activities and interests. [Gethin A, Trimingham T, Chang T, Farrell M, Ross J. Coping with problematic drug use in the family: An evaluation of the Stepping Stones program. Drug Alcohol Rev 2016;35:470-476].


Low-power bacteriorhodopsin-silicon n-channel metal-oxide field-effect transistor photoreceiver.
A bacteriorhodopsin (bR)-silicon n-channel metal-oxide field-effect transistor (NMOSFET) monolithically integrated photoreceiver is demonstrated. The bR film is selectively formed on an external gate electrode of the transistor by electrophoretic deposition. A modified biasing circuit is incorporated, which helps to match the resistance of the bR film to the input impedance of the NMOSFET and to shift the operating point of the transistor to coincide with the maximum gain. The photoreceiver exhibits a responsivity of 4.7 mA/W.


Neuropathology of depression in Alzheimer's disease: current knowledge and the potential for new treatments.
Depression is among the most common behavioral and psychological symptoms of dementia, and leads to more rapid decline and higher mortality. Treatment for depression in dementia has centered on conventional antidepressant drug treatment based around the monoamine hypothesis of depression. However, recent major studies have suggested that conventional antidepressant treatments that aim to correct underlying deficits in monoamine neurotransmitters are not effective for depression in dementia. Postmortem studies have also suggested that depression in dementia does not arise from serotonergic or noradrenergic abnormalities, or indeed from the degenerative pathology associated with Alzheimer's disease. In contrast, considerable recent evidence has suggested that alterations in glutamatergic transmission may contribute to the pathophysiology of depression. This supports the view that treatment-resistant depressed patients, such as many dementia patients, may benefit from agents affecting glutamate transmission. This review will thus draw together the wealth of pathological data examining the basis of depression in Alzheimer's disease and relate this to current thinking on treatment, with the aim of generating discussion on potential novel therapeutic strategies.


Subcellular localization of human voltage-dependent anion channel isoforms.
The voltage-dependent anion channel of the outer mitochondrial membrane, VDAC (also known as mitochondrial porin), is a small abundant protein which forms a voltage-gated pore when incorporated into planar lipid bilayers. This protein forms the primary pathway for movement of major metabolites through the outer membrane. Recently, it has been demonstrated that two human VDAC genes, HVDAC1 and HVDAC2, produce three proteins that differ most significantly at their amino termini. These results suggest that the distinct amino termini lead to the targeting of individual VDAC isoforms to different cellular compartments. Consistent with this hypothesis, recent reports suggest that HIV-DAC1 is found in the plasma membrane of mammalian cells. To define the subcellular location of HVDAC isoforms, HVDAC genes were modified so that the encoded proteins contain COOH-terminal epitopes recognized by either of two monoclonal antibodies. Introduction of these epitope tags had no effect on the function of modified VDAC proteins. Epitope-tagged proteins were then individually expressed in COS7 cells or rat astrocytes and the intracellular location of each isoform subsequently identified by subcellular fractionation, light level immunofluorescence, and immunoelectron microscopy. Our results demonstrate that each HVDAC protein is exclusively located in fractions or subcellular regions containing mitochondrial marker proteins. In addition, immunofluorescence and immunoelectron microscopy show that an individual mitochondrion can contain both HVDAC1 and HVDAC2. Our results call into question previous reports demonstrating VDAC molecules in the plasma membrane and suggest that functional differences between individual VDAC isoforms may result in distinct regulatory processes within a single mitochondrion.


Genetic population structure of cacao plantings within a young production area in Nicaragua.
Significant cocoa production in the municipality of Waslala, Nicaragua, began in 1961. Since the 1980s, its economic importance to rural smallholders increased, and the region now contributes more than 50% of national cocoa bean production. This research aimed to assist local farmers to develop production of high-value cocoa based on optimal use of cacao biodiversity. Using microsatellite markers, the allelic composition and genetic structure of cacao was assessed from 44 representative plantings and two unmanaged trees. The population at Waslala consists of only three putative founder genotype spectra (lineages). Two (B and R) were introduced during the past 50 years and occur in >95% of all trees sampled, indicating high rates of outcrossing. Based on intermediate allelic diversity, there was large farm-to-farm multilocus genotypic variation. GIS analysis revealed unequal distribution of the genotype spectra, with R being frequent within a 2 km corridor along roads, and B at more remote sites with lower precipitation. The third lineage, Y, was detected in the two forest trees. For explaining the spatial stratification of the genotype spectra, both human intervention and a combination of management and selection driven by environmental conditions, appear responsible. Genotypes of individual trees were highly diverse across plantings, thus enabling selection for farm-specific qualities. On-farm populations can currently be most clearly recognized by the degree of the contribution of the three genotype spectra. Of two possible strategies for future development of cacao in Waslala, i.e. introducing more unrelated germplasm, or working with existing on-site diversity, the latter seems most appropriate. Superior genotypes could be selected by their specific composite genotype spectra as soon as associations with desired quality traits are established, and clonally multiplied. The two Y trees from the forest share a single multilocus genotype, possibly representing the Mayan, 'ancient Criollo' cacao.


Permissive effects of oxygen on cyclic AMP and interleukin-1 stimulation of surfactant protein A gene expression are mediated by epigenetic mechanisms.
Surfactant protein A (SP-A) is important for immune defense within the alveolus. Cyclic AMP (cAMP) stimulation of SP-A expression in lung type II cells is O(2) dependent and mediated by increased phosphorylation and binding of thyroid transcription factor 1 (TTF-1) to an upstream response element (TTF-1-binding element [TBE]). Interleukin-1 (IL-1) stimulation of SP-A expression is mediated by NF-kappaB (p65/p50) activation and increased binding to the TBE. In this study, we found that O(2) also was permissive for IL-1 induction of SP-A expression and for cAMP and IL-1 stimulation of type II cell nuclear protein binding to the TBE. Using chromatin immunoprecipitation, we observed that when type II cells were cultured in 20% O(2), cAMP and IL-1 stimulated the recruitment of TTF-1, p65, CBP, and steroid receptor coactivator 1 to the TBE region of the SP-A promoter and increased local acetylation of histone H3; these effects were prevented by hypoxia. Hypoxia markedly reduced global levels of CBP and acetylated histone H3 and increased the expression of histone deacetylases. Furthermore, hypoxia caused a global increase in histone H3 dimethylated on Lys9 and increased the association of dimethyl histone H3 with the SP-A promoter. These results, together with findings that the histone deacetylase inhibitor trichostatin A and the methyltransferase inhibitor 5'-deoxy(5'-methylthio)adenosine markedly enhanced SP-A expression in lung type II cells, suggest that increased O(2) availability to type II cells late in gestation causes epigenetic changes that permit access of TTF-1 and NF-kappaB to the SP-A promoter. The binding of these transcription factors facilitates the recruitment of coactivators, resulting in the further opening of the chromatin structure and activation of SP-A transcription.


Hemoglobin inhibits albumin uptake by proximal tubule cells: implications for sickle cell disease.
Proximal tubule (PT) dysfunction, including tubular proteinuria, is a significant complication in young sickle cell disease (SCD) that can eventually lead to chronic kidney disease. Hemoglobin (Hb) dimers released from red blood cells upon hemolysis are filtered into the kidney and internalized by megalin/cubilin receptors into PT cells. The PT is especially sensitive to heme toxicity, and tubular dysfunction in SCD is thought to result from prolonged exposure to filtered Hb. Here we show that concentrations of Hb predicted to enter the tubule lumen during hemolytic crisis competitively inhibit the uptake of another megalin/cubilin ligand (albumin) by PT cells. These effects were independent of heme reduction state. The Glu7Val mutant of Hb that causes SCD was equally effective at inhibiting albumin uptake compared with wild-type Hb. Addition of the Hb scavenger haptoglobin (Hpt) restored albumin uptake in the presence of Hb, suggesting that Hpt binding to the Hb αβ dimer-dimer interface interferes with Hb binding to megalin/cubilin. BLAST searches and structural modeling analyses revealed regions of similarity between Hb and albumin that map to this region and may represent sites of Hb interaction with megalin/cubilin. Our studies suggest that impaired endocytosis of megalin/cubilin ligands, rather than heme toxicity, may be the cause of tubular proteinuria in SCD patients. Additionally, loss of these filtered proteins into the urine may contribute to the extra-renal pathogenesis of SCD.


Reduced serum selenium concentration in miscarriage incidence of Indonesian subjects.
Selenium is an essential nutrient for human health, and maternal selenium concentration has been reported to be associated with pregnancy outcome. To further investigate the possible role of selenium (Se) in miscarriage, we conducted a case-control study to evaluate the correlations among selenium status, glutathione peroxidase activity, and spontaneous abortion. A total of 46 subjects with normal pregnancies and 25 subjects with spontaneous abortion were recruited, and their serum selenium concentrations and serum glutathione peroxidase activities were analyzed. The total serum selenium concentrations in subjects with normal pregnancies were significantly higher than those of subjects with spontaneous abortion; however, the glutathione peroxidase activities were similar in both groups. We further separated the subjects into smoking and nonsmoking groups, and the logistic regression analysis suggested that total serum selenium concentration, but not serum glutathione peroxidase activity or smoking, was significantly correlated with the incidence of miscarriage. The present study thus reaffirms that low serum selenium levels are associated with miscarriage and that selenium plays an important role in pregnancy maintenance.


Analysis of Musculoskeletal Injuries Sustained in Falls From the United States-Mexico Border Fence.
Injuries sustained by unauthorized individuals who jump or fall from the United States-Mexico border fence are frequently treated by trauma centers in border states. The authors investigated patterns of musculoskeletal injury occurring in these individuals to improve emergency department assessment and to identify strategies to prevent future injuries. A retrospective chart review was performed for patients presenting to an urban, level I trauma center with musculoskeletal injuries sustained in a jump or fall from the United States-Mexico border fence between February 2004 and February 2010. Frequency of fracture by site, frequency of open fracture, and associated patterns of injury were recorded. The population was stratified by age and sex to identify disparity in injury pattern. Average length of stay and number of surgical interventions were also recorded. During the study period, 174 individuals who had jumped or fallen from the United States-Mexico border fence were identified. The population contained 93 (53%) women and 81 (47%) men with an average age of 31.5 years (range, 11-56 years). On average (±standard error), men sustained slightly more fractures than women (1.77±0.12 vs 1.43±0.07; P=.015). There were no significant differences in the number of fractures sustained between age groups. Average length of stay for patients admitted to the hospital was 3.5 days. Patients underwent an average of 0.75 surgical interventions during admission. Falls from the United States-Mexico border fence are a significant cause of morbidity among unauthorized immigrants. [Orthopedics. 2017; 40(3):e432-e435.].


Biometric genetic analysis of blood pressure in the spontaneously hypertensive rat.
The spontaneously hypertensive rat is the most widely studied animal model of essential hypertension, yet the genetics of transmission of high blood pressure in this strain have not been clearly defined. It has been proposed that in the spontaneously hypertensive rat, blood pressure follows a simple additive mode of inheritance and that the hypertension is primarily determined by a single major locus. To investigate the genetics of transmission of increased blood pressure in the spontaneously hypertensive rat, we performed a biometric genetic analysis of multiple, direct measurements of arterial pressure in unanesthetized, unrestrained rats derived by crossing spontaneously hypertensive rats with two different inbred normotensive strains, the Charles River Wistar-Kyoto rat and the Lewis rat. In both crosses, approximately 60% of the variation in blood pressure could be assigned to genotypic variation. The data fit an additive-dominance model of inheritance in which alleles decreasing blood pressure were partially dominant. Thus, in offspring derived from crosses between spontaneously hypertensive rats and Wistar-Kyoto rats or spontaneously hypertensive rats and Lewis rats that are raised under ordinary laboratory conditions, increased blood pressure is not determined by simple additive effects of alleles at a single major locus. The current findings are consistent with the possibility that in the spontaneously hypertensive rat, hypertension may arise from mutations in alleles that ordinarily act in a dominant fashion to suppress blood pressure.


A role for receptor kinases in the regulation of class II G protein-coupled receptors. Phosphorylation and desensitization of the secretin receptor.
The secretin receptor is a member of a structurally distinct class of G protein-coupled receptors designated as Class II. The molecular mechanisms of secretin receptor signal termination are unknown. Using transiently transfected HEK 293 cells expressing the secretin receptor, we investigated its mechanisms of desensitization. Binding of [125I]-secretin to plasma membranes of receptor-expressing cells was specific, with a Kd of 2 nM. Secretin evoked an increase in cellular cAMP with an EC50 of 0.4 nM. The response was maximal by 20 min and desensitized rapidly and completely. Immunoprecipitation of a functional, N-terminal epitope-tagged secretin receptor was used to demonstrate agonist-dependent receptor phosphorylation, with an EC50 of 14 nM. Pretreatment with protein kinase A or C inhibitors failed to alter secretin-stimulated cAMP accumulation. G protein-coupled receptor kinases (GRKs) are known to be involved in the desensitization of Class I G protein-coupled receptors; therefore, the effect of cotransfection of GRKs on secretin-stimulated cAMP signaling and phosphorylation was evaluated. GRKs 2 and 5 were the most potent at augmenting desensitization, causing a 40% reduction in the maximal cAMP response to secretin. GRK 5 also caused a shift in the EC50 to the right (p < 0.05). GRK 4 and GRK 6 did not alter dose-dependent signaling, and GRK 3 was intermediate in effect. Receptor phosphorylation correlated with desensitization for each GRK studied, whereas second messenger-dependent kinase phosphorylation appeared to be less important in secretin receptor signal termination. We demonstrate agonist-dependent secretin receptor phosphorylation coincident with profound receptor desensitization of the signaling function in HEK 293 cells, suggesting a role for receptor phosphorylation in this paradigm. Although GRK activity appears important in secretin receptor desensitization in HEK 293 cells, protein kinases A and C appear to play only a minor role. These results demonstrate that the GRK-arrestin system regulates Class II G protein-coupled receptors.


The development of regionalized lipid diffusibility in the germ cell plasma membrane during spermatogenesis in the mouse.
The lipids and proteins of sperm cells are highly regionalized in their lateral distribution. Fluorescence recovery after photobleaching studies of sperm membrane component lateral diffusibility have shown that the sperm plasma membrane is also highly regionalized in the extents and rates of diffusion of its surface components. These studies have also shown that regionalized changes in lateral diffusibility occur during the differentiative processes of epididymal maturation and capacitation. Unlike mammalian somatic cells, sperm cells exhibit large nondiffusing lipid fractions. In this paper, we will show that both regionalized lipid diffusibility and nondiffusing lipid fractions develop with the morphogenesis of cell shape during spermatogenesis in the mouse. Pachytene spermatocytes and round spermatids show diffusion rates and the nearly complete recoveries (80-90%) typical of mammalian somatic cells. In contrast, stage 10-11 condensing spermatids, testicular spermatozoa, cauda epididymal spermatozoa, as well as the anucleate structures associated with these later stages of spermatogenesis (residual bodies and the cytoplasmic droplets of condensing spermatids and testicular spermatozoa), exhibit large nondiffusing fractions. Both the diffusion rates and diffusing fractions observed on the anterior and posterior regions of the head of stage 10-11 condensing spermatids are the same as the values obtained for these regions on testicular spermatozoa. Possible mechanisms of lipid immobilization and possible physiological implications of this nondiffusing lipid are discussed.


Propofol infusion associated metabolic acidosis in patients undergoing neurosurgical anesthesia: a retrospective study.
Propofol and volatile anesthesia have been associated with metabolic acidosis induced by increased lactate. This study was designed to evaluate changes in pH, base excess (BE), and lactate in response to different anesthetic agents and to characterize propofol infusion-associated lactic acidosis. The medical records of patients undergoing neurosurgical anesthesia between January 2005 and September 2012 were examined. Patients were divided into 2 groups : those who received propofol (total intravenous anesthesia, TIVA) and those who received sevoflurane (balanced inhalation anesthesia, BIA) anesthesia. Propensity analysis was performed (1 : 1 match, n=47), and the characteristics of the patients who developed severe acidosis were recorded. In the matched TIVA and BIA groups, the incidence of metabolic acidosis (11% vs. 13%, p=1) and base excess (p>0.05) were similar. All patients in the TIVA group who developed severe acidosis did so within 4 hours of the initiation of propofol infusion, and these patients improved when propofol was discontinued. The incidence of metabolic acidosis was similar during neurosurgical anesthesia with propofol or sevoflurane. In addition, severe acidosis associated with propofol infusion appears to be reversible when propofol is discontinued.


A computationally efficient formal optimization of regional myocardial contractility in a sheep with left ventricular aneurysm.
A non-invasive method for estimating regional myocardial contractility in vivo would be of great value in the design and evaluation of new surgical and medical strategies to treat and/or prevent infarction-induced heart failure. As a first step towards developing such a method, an explicit finite element (FE) model-based formal optimization of regional myocardial contractility in a sheep with left ventricular (LV) aneurysm was performed using tagged magnetic resonance (MR) images and cardiac catheterization pressures. From the tagged MR images, 3-dimensional (3D) myocardial strains, LV volumes and geometry for the animal-specific 3D FE model of the LV were calculated, while the LV pressures provided physiological loading conditions. Active material parameters (T(max_B) and T(max_R)) in the non-infarcted myocardium adjacent to the aneurysm (borderzone) and in myocardium remote from the aneurysm were estimated by minimizing the errors between FE model-predicted and measured systolic strains and LV volumes using the successive response surface method for optimization. The significant depression in optimized T(max_B) relative to T(max_R) was confirmed by direct ex vivo force measurements from skinned fiber preparations. The optimized values of T(max_B) and T(max_R) were not overly sensitive to the passive material parameters specified. The computation time of less than 5 hours associated with our proposed method for estimating regional myocardial contractility in vivo makes it a potentially very useful clinical tool.


Comparison of shoe-length fit between people with and without diabetic peripheral neuropathy: a case-control study.
Amongst the many identified mechanisms leading to diabetic foot ulceration, ill-fitting footwear is one. There is anecdotal evidence that people with diabetic peripheral neuropathy wear shoes that are too small in order to increase the sensation of fit. The aim of this study was to determine whether people with diabetic sensory neuropathy wear appropriate length footwear. A case-control design was used to compare internal shoe length and foot length differences between a group of people with diabetes and peripheral sensory neuropathy and a group of people without diabetes and no peripheral sensory neuropathy. Shoe and foot length measurements were taken using a calibrated Internal Shoe Size Gauge® and a Brannock Device®, respectively. Data was collected from 85 participants with diabetes and 118 participants without diabetes. The mean difference between shoe and foot length was not significantly different between the two groups. However, a significant number of participants within both groups had a shoe to foot length difference that lay outside a previously suggested 10 to 15 mm range. From the diabetic and non-diabetic groups 82% (70/85) and 66% (78/118), respectively had a foot to shoe length difference outside this same range. This study shows that although there is no significant difference in shoe-length fit between participants with and without neuropathy, a significant proportion of these populations wear shoes that are either too long or too short for their foot length according to the 10 to 15 mm value used for comparison. The study has highlighted the need for standardised approaches when considering the allowance required between foot and internal shoe length and for the measurement and comparison of foot and shoe dimensions.


Protective effects of lycopene on hippocampal neurotoxicity and memory impairment induced by bisphenol A in rats.
Bisphenol A (BPA) is used to produce polycarbonate plastic and epoxy resins which are used in many consumer products. Most people encounter BPA in their daily routines. However, it has been heavily reported that BPA has a neurotoxic effect. The present study aimed to investigate the effect of lycopene on cognitive deficits induced by a high dose of BPA focusing on mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, oxidative stress, apoptosis, and memory retrieval in adult male rats. Therefore, 72 rats were divided into four groups: control group, BPA group (50 mg/kg body weight (bw)) 3 days a week for 42 days, lycopene group (10 mg/kg bw) daily for 42 days, and lycopene + BPA group. Concurrent treatment of lycopene with BPA improved the learning and cognition memory in Morris water maze and novel object recognition tests along with an increase in acetylcholine esterase activity as well as inhibition of oxidative stress by restoring reduced glutathione and suppressing malondialdehyde hippocampal level to their normal levels. Mechanistically, lycopene upregulated the protein expression of tyrosine receptor kinase B, which resulted in an upsurge in its downstream cascades MAPK/ERK1/2/cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling pathway in the hippocampus of BPA-intoxicated rats. Furthermore, concurrent treatment of lycopene with BPA prevented apoptosis by marked decrease in Bcl-2 associated X protein (Bax) gene expression and caspase 3 activity while restoring B-cell leukemia/lymphoma-2 (Bcl-2) gene expression. In conclusion, the present study provided evidence that lycopene exerted a neuroprotective effect against BPA intoxication in hippocampi of rats via its antioxidant properties, activation of MAPK/ERK pathway, and inhibiting a neuronal apoptosis which reflected on improving the learning and cognition memory.


Plasma lecithin: cholesterol acyltransferase activity is elevated in metabolic syndrome and is an independent marker of increased carotid artery intima media thickness.
Lecithin:cholesterol acyltransferase (LCAT), which esterifies free cholesterol to cholesteryl esters, is required for normal plasma lipoprotein structure and is instrumental in high density lipoprotein (HDL) remodeling, but the relationship of variation in plasma LCAT activity with subclinical atherosclerosis is unclear. The aim of the study was to determine the effect of the metabolic syndrome (MetS) on plasma LCAT activity and its relationship with carotid artery intima media thickness (IMT). The study was conducted at the vascular laboratory of a university medical center. In 74 subjects with MetS and 90 subjects without MetS (National Cholesterol Education Program Adult Treatment Panel III criteria), mean carotid artery IMT, plasma lipids, LCAT activity (exogenous substrate method), high-sensitive C-reactive protein, and homeostasis model assessment insulin resistance (HOMA(ir)) were documented. IMT was greater (P = 0.01) and plasma LCAT activity was higher (P < 0.001) in subjects with MetS compared to subjects without MetS. Similar increases in IMT and LCAT were found in MetS subjects without type 2 diabetes mellitus. Multiple linear regression analysis demonstrated that plasma LCAT activity was independently and positively related to HOMA(ir), plasma triglycerides, non-HDL cholesterol, and HDL cholesterol (all P < 0.001). After adjustment for age and sex, IMT was positively associated with LCAT activity (P < 0.01), independently of the presence of MetS (or alternatively of plasma lipids), HOMA(ir), and high-sensitive C-reactive protein. Plasma LCAT activity is elevated in MetS and may be a marker of subclinical atherosclerosis. Our findings do not support the contention that strategies to elevate LCAT are necessarily beneficial for cardioprotection.


Absence of pyruvate decarboxylase activity in man: a cause of congenital lactic acidosis.
A complete deficiency in the pyruvate dehydrogenase system activity contributed to the death of a 6-month-old infant with congenital lactic acidosis. The enzymatic block could be isolated to the first component, pyruvate decarboxylase (E1) of the pyruvate dehydrogenase complex. This enzymatic deficiency allowed a demonstration of an "intercomplex" exchange of the components of the mammalian pyruvate dehydrogenase system and indicated that the first component is normally present in an apparent excess.


Safety assessment of propylene glycol, tripropylene glycol, and PPGs as used in cosmetics.
Propylene glycol is an aliphatic alcohol that functions as a skin conditioning agent, viscosity decreasing agent, solvent, and fragrance ingredient in cosmetics. Tripropylene glycol functions as a humectant, antioxidant, and emulsion stabilizer. Polypropylene glycols (PPGs), including PPG-3, PPG-7, PPG-9, PPG-12, PPG-13, PPG-15, PPG-16, PPG-17, PPG-20, PPG-26, PPG-30, PPG-33, PPG-34, PPG-51, PPG-52, and PPG-69, function primarily as skin conditioning agents, with some solvent use. The majority of the safety and toxicity information presented is for propylene glycol (PG). Propylene glycol is generally nontoxic and is noncarcinogenic. Clinical studies demonstrated an absence of dermal sensitization at use concentrations, although concerns about irritation remained. The CIR Expert Panel determined that the available information support the safety of tripropylene glycol as well as all the PPGs. The Expert Panel concluded that PG, tripropylene glycol, and PPGs ≥3 are safe as used in cosmetic formulations when formulated to be nonirritating.