HFE Gene Mutations and Iron Status in 100 Healthy Polish Children.
Iron participates in oxygen transport, energetic, metabolic, and immunologic processes. There are 2 main causes of iron overload: hereditary hemochromatosis which is a primary cause, is a metabolic disorder caused by mutations of genes that control iron metabolism and secondary hemochromatosis caused by multitransfusions, chronic hemolysis, and intake of iron rich food. The most common type of hereditary hemochromatosis is caused by HFE gene mutation. In this study, we analyzed iron metabolism in 100 healthy Polish children in relation to their HFE gene status. The wild-type HFE gene was predominant being observed in 60 children (60%). Twenty-five children (25%), presented with heterozygotic H63D mutation, and 15 children (15%), presented with other mutations (heterozygotic C282Y and S65C mutation, compound heterozygotes C282Y/S65C, C282Y/H63D, H63D homozygote). The mean concentration of iron, the level of ferritin, and transferrin saturation were statistically higher in the group of HFE variants compared with the wild-type group. H63D carriers presented with higher mean concentration of iron, ferritin levels, and transferrin saturation compared with the wild-type group. Male HFE carriers presented with higher iron concentration, transferrin saturation, and ferritin levels than females. This preliminary investigation demonstrates allelic impact on potential disease progression from childhood.


Regulation of interferon-gamma receptor (INF-gammaR) chains: a peculiar way to rule the life and death of human lymphocytes.
Interferon-gamma (IFN-gamma) is a lymphokine produced by activated T lymphocytes and NK cells, that plays an important role in host defense mechanisms by exerting pleiotropic activities on a wide range of cell types. Cellular responses to IFN-gamma are mediated by its heterodimeric cell surface receptor (IFN-gammaR), which activates downstream signal transduction cascades, ultimately leading to the regulation of gene expression. Several observations suggest that the signals resulting from the binding of IFN-gamma to its receptor depend on the number of surface receptors transducing the IFN-gamma signal. This review summarizes recent advances in the understanding of the fine regulation of the response of human lymphocytes to IFN-gamma through an interplay between surface expression of IFN-gammaR and a variety of environmental factors that combine to control their fate.


Assessment of autonomic function in untreated adult coeliac disease.
Some recent studies showed that alteration of upper-gut motility in coeliac disease may be related to dysfunction of autonomic nervous system. The aim of our study was to investigate whether autonomic nervous system was altered in untreated and unselected coeliac disease patients. We studied 8 untreated and consecutive coeliac disease patients (2 males and 6 females, age range 37+/-14.5 years). Histological evaluation of duodenal mucosa, anti-gliadin antibodies (AGA), antiendomysial antibodies (EMA) and anti-tTG antibodies and sorbitol H2 breath test were performed in all patients. Extrinsic autonomic neuropathy was assessed by the standardized measurement of cardiovascular reflexes (lying-to-standing, Valsalva manoeuvre, deep breathing, sustained handgrip). The results obtained were compared with a healthy, asymptomatic control group (6 males and 7 females, age range 42.3+/-13.5 years). Coeliac patients exhibited a lower increase of PAS as a response to isometric effort, a reduction of spectral power LF as a response to clinostatic position, but without statistical significance. Also they showed a lower tolerance to orthostatic position, associated with a latent disequilibrium of sympathetic-vagal balance, a relative prevalence of parasympathetic component of the autonomic function. However, these results were not statistically significant when compared with control group (P = n.s.). And they were unchanged after 6 and 12 mo of gluten-free diet. This study failed to confirm a significant correlation between autonomic dysfunction and coeliac disease, yet we could not exclude a role of autonomic dysfunction in the genesis of systemic symptoms in some coeliacs.


Monoclonal antibodies of predetermined specificity for fibrin: a rational approach to monoclonal antibody production.
Three monoclonal antibodies (MAbs) (55D10, 59D8, and 64C5) have been produced by an immunization strategy that uses a synthetic heptapeptide from the amino terminus of the beta-chain in human fibrin. These MAbs bind to human fibrin in the presence of 4 mg/ml human fibrinogen in solid-phase radioimmunoassay. Ligand specificity studies demonstrate that antifibrin immunoreactivity is completely inhibited by a series of synthetic fibrin-like beta-peptides that bear the position-2 histidyl residue. Although the presence of this residue on the epitope is necessary for its recognition by a fibrin-specific antibody, the presence of the histidyl residue alone is not sufficient for antibody recognition.


Unnecessary Cost of Post-Mohs Permanent Pathology.
By providing tumor-free margins, Mohs micrographic surgery (MMS) results in high cure rates in the treatment of nonmelanoma skin cancers (NMSCs). However, when closure of the post-MMS defect is coordinated with reconstructive surgery, redundant tissue is sometimes submitted for permanent section evaluation. The purpose of our study was to investigate the frequency and effect of this practice. Patients (12 years and older) with NMSCs cleared by MMS with coordinated closures from 2014 to 2016 were identified. Cost analysis was performed using the 2016 Current Procedural Terminology codes and averaged nation-wide Medicare reimbursement rates. During the study period, 408 cases were coordinated with reconstructive surgeons post-MMS. Of these, 125 had specimens were submitted for permanent section with none showing residual malignancy. There were no significant differences between the cases sent for permanent section and the remaining coordinated MMS cases, with respect to patient age, to basal cell and squamous cell carcinoma histology, or to defect size (p > .05). The marginal cost of sending specimens for permanent section was $121 per case. Sending post-MMS redundant tissue for permanent sections may be of limited utility and should not be performed routinely. Additional work is warranted to determine when this practice should be used in conjunction with MMS.


Assessment and treatment of patients with haemorrhoids.
This article examines the care of patients with haemorrhoids, and explores the aetiology, epidemiology and assessment of the condition. Information is provided on the different forms of treatment, and the importance of lifestyle interventions is reinforced. The post-operative nursing care of patients undergoing surgical procedures, including haemorrhoidectomy, is discussed, emphasising pain relief, hygiene and prevention of constipation.


Changes in the Management of Patients having Radical Radiotherapy for Lung Cancer during the First Wave of the COVID-19 Pandemic in the UK.
In response to the COVID-19 pandemic, guidelines on reduced fractionation for patients treated with curative-intent radiotherapy were published, aimed at reducing the number of hospital attendances and potential exposure of vulnerable patients to minimise the risk of COVID-19 infection. We describe the changes that took place in the management of patients with stage I-III lung cancer from April to October 2020. Lung Radiotherapy during the COVID-19 Pandemic (COVID-RT Lung) is a prospective multicentre UK cohort study. The inclusion criteria were: patients with stage I-III lung cancer referred for and/or treated with radical radiotherapy between 2nd April and 2nd October 2020. Patients who had had a change in their management and those who continued with standard management were included. Data on demographics, COVID-19 diagnosis, diagnostic work-up, radiotherapy and systemic treatment were collected and reported as counts and percentages. Patient characteristics associated with a change in treatment were analysed using multivariable binary logistic regression. In total, 1553 patients were included (median age 72 years, 49% female); 93 (12%) had a change to their diagnostic investigation and 528 (34%) had a change to their treatment from their centre's standard of care as a result of the COVID-19 pandemic. Age ≥70 years, male gender and stage III disease were associated with a change in treatment on multivariable analysis. Patients who had their treatment changed had a median of 15 fractions of radiotherapy compared with a median of 20 fractions in those who did not have their treatment changed. Low rates of COVID-19 infection were seen during or after radiotherapy, with only 21 patients (1.4%) developing the disease. The COVID-19 pandemic resulted in changes to patient treatment in line with national recommendations. The main change was an increase in hypofractionation. Further work is ongoing to analyse the impact of these changes on patient outcomes.


High-sensitivity protein solid-state NMR spectroscopy.
The sensitivity of solid-state nuclear magnetic resonance (SSNMR) spectroscopy for structural biology is significantly increased by 1H detection under fast magic-angle spinning (MAS) and by dynamic nuclear polarization (DNP) from electron spins to nuclear spins. The former allows studies of the structure and dynamics of small quantities of proteins under physiological conditions, while the latter permits studies of large biomolecular complexes in lipid membranes and cells, protein intermediates, and protein conformational distributions. We highlight recent applications of these two emerging SSNMR technologies and point out areas for future development.


Are Mentalizing Abilities and Insight Related to the Severity of Obsessive-Compulsive Disorder.
The aim of this study is to investigate whether insight and mentalizing abilities are related to the severity of Obsessive Compulsive Disorder (OCD) in treatment resistant OCD. We look at the association between treatment resistance, insight, and mentalizing ability. The study was conducted with 71 OCD patients; 30 of them met the criteria for treatment resistant OCD, whereas the other 41 (57.7%) were labeled as responder group. All patients were assessed with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Reading the Mind in the Eyes Test (RMET), Brown Assessment of Beliefs Scale (BABS), Mini International Neuropsychiatric Interview, Beck Depression Inventory, and Beck Anxiety Inventory. The resistant group received higher depression and anxiety mean scores and had significantly longer illness duration. The RMET score was significantly higher for responders. The Y-BOCS insight score and the BABS score were significantly higher for the resistant group. BABS scores were negatively correlated with RMET total scores. RMET scores were found to be significant predictor of insight even when other potential factors were controlled for. suggest that better mentalizing abilities may be a predictor of better treatment outcome in patients with OCD.


From the Ocean to the Lab-Assessing Iron Limitation in Cyanobacteria: An Interface Paper.
Iron is an essential, yet scarce, nutrient in marine environments. Phytoplankton, and especially cyanobacteria, have developed a wide range of mechanisms to acquire iron and maintain their iron-rich photosynthetic machinery. Iron limitation studies often utilize either oceanographic methods to understand large scale processes, or laboratory-based, molecular experiments to identify underlying molecular mechanisms on a cellular level. Here, we aim to highlight the benefits of both approaches to encourage interdisciplinary understanding of the effects of iron limitation on cyanobacteria with a focus on avoiding pitfalls in the initial phases of collaboration. In particular, we discuss the use of trace metal clean methods in combination with sterile techniques, and the challenges faced when a new collaboration is set up to combine interdisciplinary techniques. Methods necessary for producing reliable data, such as High Resolution Inductively Coupled Plasma Mass Spectrometry (HR-ICP-MS), Flow Injection Analysis Chemiluminescence (FIA-CL), and 77K fluorescence emission spectroscopy are discussed and evaluated and a technical manual, including the preparation of the artificial seawater medium Aquil, cleaning procedures, and a sampling scheme for an iron limitation experiment is included. This paper provides a reference point for researchers to implement different techniques into interdisciplinary iron studies that span cyanobacteria physiology, molecular biology, and biogeochemistry.


Observation of Topologically Protected Edge States in a Photonic Two-Dimensional Quantum Walk.
Periodically driven systems have displayed a variety of fascinating phenomena without analogies in static systems, which enrich the classification of quantum phases of matter and stimulate a wide range of research interests. Here, we employ discrete-time quantum walks to investigate a nontrivial topological effect unique to a two-dimensional periodically driven system: chiral edge states can exist at the interface of Floquet insulators whose Chern numbers vanish. Thanks to a resource-saving and flexible fiber-loop architecture, we realize inhomogeneous two-dimensional quantum walks up to 25 steps, over an effective 51×51 lattice with tunable local parameters. Spin-polarized chiral edge states are observed at the boundary of two distinct quantum walk domains. Our results contribute to establishing a well-controlled platform for exploring nontrivial topological phases.


Revealing cancer subtypes with higher-order correlations applied to imaging and omics data.
Patient stratification to identify subtypes with different disease manifestations, severity, and expected survival time is a critical task in cancer diagnosis and treatment. While stratification approaches using various biomarkers (including high-throughput gene expression measurements) for patient-to-patient comparisons have been successful in elucidating previously unseen subtypes, there remains an untapped potential of incorporating various genotypic and phenotypic data to discover novel or improved groupings. Here, we present HOCUS, a unified analytical framework for patient stratification that uses a community detection technique to extract subtypes out of sparse patient measurements. HOCUS constructs a patient-to-patient network from similarities in the data and iteratively groups and reconstructs the network into higher order clusters. We investigate the merits of using higher-order correlations to cluster samples of cancer patients in terms of their associations with survival outcomes. In an initial test of the method, the approach identifies cancer subtypes in mutation data of glioblastoma, ovarian, breast, prostate, and bladder cancers. In several cases, HOCUS provides an improvement over using the molecular features directly to compare samples. Application of HOCUS to glioblastoma images reveals a size and location classification of tumors that improves over human expert-based stratification. Subtypes based on higher order features can reveal comparable or distinct groupings. The distinct solutions can provide biologically- and treatment-relevant solutions that are just as significant as solutions based on the original data.


Ebstein anomaly associated with left ventricular noncompaction: an autosomal dominant condition that can be caused by mutations in MYH7.
Left ventricular noncompaction (LVNC) is a relatively common genetic cardiomyopathy, characterized by prominent trabeculations with deep intertrabecular recesses in mainly the left ventricle. Although LVNC often occurs in an isolated entity, it may also be present in various types of congenital heart disease (CHD). The most prevalent CHD in LVNC is Ebstein anomaly, which is a rare form of CHD characterized by apical displacement and partial fusion of the septal and posterior leaflet of the tricuspid valve with the ventricular septum. Several reports of sporadic as well as familial cases of Ebstein anomaly associated with LVNC have been reported. Recent studies identified mutations in the MYH7 gene, encoding the sarcomeric β-myosin heavy chain protein, in patients harboring this specific phenotype. Here, we will review the association between Ebstein anomaly, LVNC and mutations in MYH7, which seems to represent a subtype of Ebstein anomaly with autosomal dominant inheritance and variable penetrance.


How to develop a proactive formulary system.
To develop a quality formulary system, a proactive approach is necessary. This approach incorporates a prospective product and concurrent product analyses. A prospective product analysis, in turn, involves a review of current formulary agents, those likely to enter the marketplace shortly, and the formation of an expert review panel. This panel's tasks are to examine therapeutic, economic, and humanistic aspects of therapy and to set initial parameters for appropriate and cost-effective use of accepted products. Keys to a successful formulary system are to continuously monitor drug use and compliance with criteria and to work collaboratively with all institutional professionals in the development, implementation, and monitoring of the system.


Separation Speed and Power in Isocratic Liquid Chromatography: Loss in Performance of Poppe vs Knox-Saleem Optimization.
The best separation possible at a given analysis time and maximum system pressure is achieved by simultaneously optimizing column length, eluent velocity, and particle size. However, this three-parameter optimization is rarely practicable because only a few commercially available particle sizes exist. Practical optimization for systems described by the van Deemter equation therefore proceeds by first selecting an available particle size and then optimizing eluent velocity and column length. This two parameter ("Poppe") optimization must result in poorer performance with respect to both speed and efficiency because one fewer degree of freedom is used. A deeper analysis identifies a distinct point on each pair of "Poppe" curves beyond which the more efficient (and faster) separation is maintained by changing from smaller to larger particles. Here, we present simple equations identifying these "crossover points" in terms of analysis time and plate count thereby allowing a practitioner to rapidly identify the correct particle size for use in tackling a particular separation problem. Additionally, we can now quantitatively compare two-parameter and three-parameter optimization. Surprisingly, we find that for systems well-described by the van Deemter equation there is little separating power lost (only about 11% in the worst case) as a result of the limited availability of different particle sizes in using two-parameter optimization when compared to the ideal three-parameter optimization so long as one changes particle size at the prescribed crossover points. If these crossover times are not used, a great deal of separating power will be needlessly lost.


Psychological Effects of Screen Time in Health Care Workers During the COVID-19 Pandemic.
Objective: As the coronavirus disease (COVID-19) outbreak is the first pandemic to occur in the modern smartphone era, people universally rely on their electronic devices to stay current on the rapidly evolving circumstances. The objective of this study was to examine how daily screen time levels affect the mental health of health care workers attempting to stay up to date on the ever-changing COVID-19-related information available to them. Methods: Health care workers at an academic teaching hospital were asked to participate in a 12-question online-based survey between the dates of May 30, 2020, and June 3, 2020. The questions included their sex, age range, occupation, department, daily screen time, changes in screen time in the last 4 weeks, and mental health outcomes such as sleep, mood, anxiety, and difficulty controlling worry. Results: No association was found between age, sex, occupation, and screen time. There was a statistically significant association between the type of department and daily screen time hours (P = .012). A positive trend was noted between screen time and sleep disruption (P = .09). An increase in hours in the last 4 weeks was associated with age (P = .03). A positive trend was also noted for an increase in screen hours and sleep disruption (P = .11) and anxiety (P = .10). Conclusions: A possible explanation for our finding of screen time not being associated with mental health outcomes could be that the knowledge that information was readily available through technology provided comfort to people as the pandemic evolved and brought changes to their daily lives.


Gains from cataract surgery: visual function and quality of life.
To describe the impact of cataract surgery in terms of visual function (functioning in everyday life with respect to vision dependent activities) and health related quality of life. An observational, longitudinal study of patients undergoing cataract surgery was carried out at three district general hospitals in outer London districts of North Thames Region with follow up at 4 and 12 months postoperatively for a clinical assessment and a standardised administered interview. Patients were admitted for surgery to the first eye for age-related cataract between 1 May 1993 and 31 August 1994. Visual functioning was assessed by the VF-14, health related quality of life was assessed by the sickness impact profile (SIP), and vision related quality of life was assessed by VR-SIP (a modification of the generic SIP). Significant gains in all the outcome measures were demonstrated at 4 months postoperatively. No significant change (gain or loss) was observed between 4 and 12 months after surgery to the first eye. Postoperatively, the mean visual function (VF-14) scores, and health related (SIP) and vision related (VR-SIP) quality of life scores, indicated less reported trouble with vision dependent activities and better perceived quality of life, respectively. The average gains in visual function and quality of life (health and vision related) were apparent in groups with good visual outcome and poor visual outcome. Significant additional gains were seen at 1 year in patients who had second eye surgery in the interval between the postoperative assessments. Gains in visual functioning and quality of life (health and vision related) have been demonstrated following cataract surgery. These gains were sustained at 1 year after surgery to the first eye, with additional gains being conferred if second eye surgery had been performed. Assessment of the outcomes of cataract surgery by clinical indicators alone may underestimate the overall benefits of surgery, particularly in patients with poor visual outcome.


Telomere loss in relation to age and early environment in long-lived birds.
Shortening of telomeres, specific nucleotide repeats that cap eukaryotic chromosomes, is thought to play an important role in cellular and organismal senescence. We examined telomere dynamics in two long-lived seabirds, the European shag and the wandering albatross. Telomere length in blood cells declines between the chick stage and adulthood in both species. However, among adults, telomere length is not related to age. This is consistent with reports of most telomere loss occurring early in life in other vertebrates. Thus, caution must be used in estimating annual rates of telomere loss, as these are probably not constant with age. We also measured changes within individuals in the wild, using repeat samples taken from individual shags as chicks and adults. We found high inter-individual variation in the magnitude of telomere loss, much of which was explained by circumstances during growth. Individuals laying down high tissue mass for their size showed greater telomere shortening. Independently of this, individuals born late in the season showed more telomere loss. Early conditions, possibly through their effects on oxidative stress, appear to play an important role in telomere attrition and thus potentially in the longevity of individuals.


Using experimental human influenza infections to validate a viral dynamic model and the implications for prediction.
The aim of this work was to use experimental infection data of human influenza to assess a simple viral dynamics model in epithelial cells and better understand the underlying complex factors governing the infection process. The developed study model expands on previous reports of a target cell-limited model with delayed virus production. Data from 10 published experimental infection studies of human influenza was used to validate the model. Our results elucidate, mechanistically, the associations between epithelial cells, human immune responses, and viral titres and were supported by the experimental infection data. We report that the maximum total number of free virions following infection is 10(3)-fold higher than the initial introduced titre. Our results indicated that the infection rates of unprotected epithelial cells probably play an important role in affecting viral dynamics. By simulating an advanced model of viral dynamics and applying it to experimental infection data of human influenza, we obtained important estimates of the infection rate. This work provides epidemiologically meaningful results, meriting further efforts to understand the causes and consequences of influenza A infection.


Tomaculocystis corpulenta n. gen., n. sp. (Apicomplexa: Eugregarinorida) parasitizing the little yellow cockroach, Cariblatta lutea (Blattodea: Ectobiidae), in Alabama and Florida with recognition of Tomaculocystis cylindrosa n. comb. and Tomaculocystis mukundai n. comb. parasitizing ectobiid cockroaches in India.
Tomaculocystis corpulenta n. gen., n. sp. (Apicomplexa: Eugregarinorida: Septatorina: Gregarinidae) is described from populations of the little yellow cockroach, Cariblatta lutea (Blattodea: Ectobiidae), established in laboratory culture from samples collected in Alabama and Florida. Tomaculocystis n. gen. are differentiated from other members of Gregarina by a markedly elliptoid gametocyst inside a persistent, lomentiform hyaline epicyst; developmental organization and growth of the spore tubes from gametocyst surface tumidi; and dehiscence by extrusion of non-chain forming oocysts through spore tubes that barely extend beyond the epicyst wall. Gregarina cylindrosa, Gregarina discocephala, and Gregarina mukundai are recognized as members of Tomaculocystis, and G. cylindrosa is recognized as the senior synonym of G. discocephala. Thus, Tomaculocystis cylindrosa n. comb. and Tomaculocystis mukundai n. comb. are formed. Species of Tomaculocystis are distinguished based on gamont deutomerite and oocyst shape and size. The oocysts of T. corpulenta are broadly dolioform, lack 4 polar knobs, and possess distinct, unique polar plates. Oocysts of all other known species in the genus are more oblong in shape, possess 4 polar knobs, and lack the distinct polar plates observed in the oocysts of T. corpulenta. Host utilization and geographic distribution among gregarine genera parasitizing the cockroach family Ectobiidae reveal a pattern of host-parasite specificity linking gregarine genera with ectobiidid subfamilies. Overall patterns suggest a hypothesis of European endemicy for Gamocystis, but hypotheses for the origin and radiation of Tomaculocystis or species of Gregarina infecting cockroaches are confounded by the cosmopolitan spread of pest cockroach species among humans.


Camelid nanobodies with high affinity for broad bean mottle virus: a possible promising tool to immunomodulate plant resistance against viruses.
Worldwide, plant viral infections decrease seriously the crop production yield, boosting the demand to develop new strategies to control viral diseases. One of these strategies to prevent viral infections, based on the immunomodulation faces many problems related to the ectopic expression of specific antibodies in planta. Camelid nanobodies, expressed in plants, may offer a solution as they are an attractive tool to bind efficiently to viral epitopes, cryptic or not accessible to conventional antibodies. Here, we report a novel, generic approach that might lead to virus resistance based on the expression of camelid specific nanobodies against Broad bean mottle virus (BBMV). Eight nanobodies, recognizing BBMV with high specificity and affinity, were retrieved after phage display from a large 'immune' library constructed from an immunized Arabic camel. By an in vitro assay we demonstrate how three nanobodies attenuate the BBMV spreading in inoculated Vicia faba plants. Furthermore, the in planta transient expression of these three selected nanobodies confirms their virus neutralizing capacity. In conclusion, this report supports that plant resistance against viral infections can be achieved by the in vivo expression of camelid nanobodies.


Identification of peroxisomal targeting signal of pumpkin catalase and the binding analysis with PTS1 receptor.
Many peroxisomal proteins are imported into peroxisomes via recognition of the peroxisomal targeting signal (PTS1) present at the C-termini by the PTS1 receptor (Pex5p). Catalase, a peroxisomal protein, has PTS1-like motifs around or at the C-terminus. However, it remains unclear whether catalase is imported into peroxisome via the PTS1 system. In this work, we analyzed the PTS of pumpkin catalase (Cat1). A full or truncated pumpkin Cat1 cDNA fused at the 3' end of the green fluorescent protein (GFP) coding sequence was introduced and stably expressed in tobacco BY-2 (Nicotiana tabacum cv. Bright Yellow 2) cells or Arabidopsis thaliana by Agrobacterium-mediated transformation. The cellular localization of GFP was analyzed by fluorescence microscopy. The results showed that the C-terminal 10-amino acid region containing an SKL motif-like tripeptide (SHL) was not required for the import into peroxisomes. Surprisingly, the C-terminal 3-amino acid region was required for the import when the fusion proteins were transiently expressed by using particle gun bombardment, suggesting that the transient expression system is inadequate to analyze the targeting signal. We proposed that the C-terminal amino acid region from 13 to 11 (QKL), which corresponds with the PTS1 consensus sequence, may function as an internal PTS1. Analysis of the binding of Cat1 to PTS1 receptor (Pex5p) by the yeast two-hybrid system revealed that Cat1 can bind with the PTS1 receptor (Pex5p), indicating that Cat1 is imported into peroxisomes by the PTS1 system.


Cannabinoid control of neurogenic inflammation.
A significant number of cannabinoids are known to have analgesic and anti-inflammatory properties in various diseases. Due to their presynaptic/terminal location, cannabinoid receptors can inhibit synaptic transmission and have the potential to regulate neurogenic inflammation. Neurogenic inflammation occurs when a noxious signal is detected in the periphery initiating an antidromic axon reflex in the same sensory neurone leading to depolarization of the afferent terminal. Neuropeptides are subsequently released and contribute to vasodilation, plasma extravasation and modulation of immune cells. Endocannabinoids, synthetic cannabinoids and phytocannabinoids can reduce neuroinflammation by inhibiting afferent firing and inflammatory neuropeptide release. Thus, in addition to a direct effect on vascular smooth muscle and inflammatory cells, cannabinoids can reduce inflammation by silencing small diameter neurones. This review examines the neuropharmacological processes involved in regulating antidromic depolarization of afferent nerve terminals by cannabinoids and the control of neurogenic inflammation in different diseases.


Acceptability and utilisation of voluntary HIV testing and nevirapine to reduce mother-to-child transmission of HIV-1 integrated into routine clinical care.
Use of nevirapine for prevention of mother-to-child transmission (PMTCT) of HIV-1 has been routine clinical care at Coronation Women and Children's Hospital since April 2000. We assessed the effect of regular audit and targeted interventions on the utilisation of the PMTCT programme. Review of antenatal cards and hospital records of women discharged following delivery, in three time periods between October 2000 and February 2002. Following the initial audit an intervention was implemented to eliminate weaknesses in our PMTCT service. Following the second audit the hospital became a pilot site for the Gauteng PMTCT programme. In the initial audit 53.2% of women (159/299) were tested for HIV and received their results, while 56% (14/25) of identified HIV-infected women, and 16% (4/25) of their infants, received nevirapine. By the third audit 74.3% of women (266/358) received their results, and 86% (43/50) of HIV-positive women and 74% (37/50) of newborns were documented to have received nevirapine. In all three audits over 90% of women initiating antenatal care at the hospital were tested for HIV, while women who initiated care at district community clinics were less likely to receive testing. Ongoing audit has been important for targeting obstacles to detection of HIV-infected women and documented nevirapine uptake by women and infants. Rates of HIV testing and nevirapine use have increased significantly. Voluntary counselling and testing for HIV and use of nevirapine are acceptable to pregnant women in our setting. Roll-out of the pilot programme to district community clinics is essential for further improvement.


How sex hormones promote skeletal muscle regeneration.
Skeletal muscle regeneration efficiency declines with age for both men and women. This decline impacts on functional capabilities in the elderly and limits their ability to engage in regular physical activity and to maintain independence. Aging is associated with a decline in sex hormone production. Therefore, elucidating the effects of sex hormone substitution on skeletal muscle homeostasis and regeneration after injury or disuse is highly relevant for the aging population, where sarcopenia affects more than 30 % of individuals over 60 years of age. While the anabolic effects of androgens are well known, the effects of estrogens on skeletal muscle anabolism have only been uncovered in recent times. Hence, the purpose of this review is to provide a mechanistic insight into the regulation of skeletal muscle regenerative processes by both androgens and estrogens. Animal studies using estrogen receptor (ER) antagonists and receptor subtype selective agonists have revealed that estrogens act through both genomic and non-genomic pathways to reduce leukocyte invasion and increase satellite cell numbers in regenerating skeletal muscle tissue. Although animal studies have been more conclusive than human studies in establishing a role for sex hormones in the attenuation of muscle damage, data from a number of recent well controlled human studies is presented to support the notion that hormonal therapies and exercise induce added positive effects on functional measures and lean tissue mass. Based on the fact that aging human skeletal muscle retains the ability to adapt to exercise with enhanced satellite cell activation, combining sex hormone therapies with exercise may induce additive effects on satellite cell accretion. There is evidence to suggest that there is a 'window of opportunity' after the onset of a hypogonadal state such as menopause, to initiate a hormonal therapy in order to achieve maximal benefits for skeletal muscle health. Novel receptor subtype selective ligands and selective estrogen and androgen receptor modulators (SERMs, SARMs) promise to reduce health risks associated with classical hormonal therapies, whilst maintaining the positive effects on muscle repair. Dietary supplements containing compounds with structural similarity to estrogens (phytoestrogens) are increasingly used as alternatives to classical hormone-replacement therapies (HRT), but the effects on skeletal muscle are currently largely unknown. Research has started to investigate the combined effects of exercise and alternative HRTs, such as soy isoflavones, on skeletal muscle regenerative processes to provide safer and more efficient therapies to promote muscle regeneration and maintenance of muscle mass and strength in the aging population.


Biodistribution and fate of core-labeled 125I polymeric nanocarriers prepared by Flash NanoPrecipitation (FNP).
Non-invasive medical imaging techniques such as positron emission tomography (PET) imaging are powerful platforms to track the fate of radiolabeled materials for diagnostic or drug delivery applications. Polymer-based nanocarriers tagged with non-standard PET radionuclides with relatively long half-lives (e.g. 64Cu: t1/2 = 12.7 h, 76Br: t1/2 = 16.2h, 89Zr: t1/2 = 3.3 d, 124I: t1/2 = 4.2 d) may greatly expand applications of nanomedicines in molecular imaging and therapy. However, radiolabeling strategies that ensure stable in vivo association of the radiolabel with the nanocarrier remain a significant challenge. In this study, we covalently attach radioiodine to the core of pre-fabricated nanocarriers. First, we encapsulated polyvinyl phenol within a poly(ethylene glycol) coating using Flash NanoPrecipitation (FNP) to produce stable 75 nm and 120 nm nanocarriers. Following FNP, we radiolabeled the encapsulated polyvinyl phenol with 125I via electrophilic aromatic substitution in high radiochemical yields (> 90%). Biodistribution studies reveal low radioactivity in the thyroid, indicating minimal leaching of the radiolabel in vivo. Further, PEGylated [125I]PVPh nanocarriers exhibited relatively long circulation half-lives (t1/2 α = 2.9 h, t1/2 β = 34.9 h) and gradual reticuloendothelial clearance, with 31% of injected dose in blood retained at 24 h post-injection.


Burn plus lipopolysaccharide augments endoplasmic reticulum stress and NLRP3 inflammasome activation and reduces PGC-1α in liver.
Extensively burned patients often suffer from sepsis (especially caused by Pseudomonas aeruginosa), which may prolong metabolic derangement, contribute to multiple organ failure, and increase mortality. The molecular and cellular mechanisms of such infection-related metabolic derangement and organ dysfunction are unclear. We have previously shown that severely burned patients have significant and persisting hepatic endoplasmic reticulum (ER) stress. We hypothesized that ER stress and the unfolded protein response correlate with NOD-like receptor, pyrin domain containing 3 (NLRP3) inflammasome activation in burn. These may trigger profound metabolic changes in the liver, which form the pathological basis of liver damage and liver dysfunction after burn injury. A two-hit rat model was established by a 60% total body surface area scald burn and intraperitoneal injection of P. aeruginosa-derived lipopolysaccharide (LPS) 3 days after burn. One day later, animals were killed, and liver tissue samples were collected for gene expression and protein analysis of NLRP3 inflammasome activation, ER stress, and glucose and lipid metabolism. Liver damage was assessed by plasma markers (alanine aminotransferase and aspartate aminotransferase) and liver immunohistochemical analysis. Our results showed that burn injury and LPS injection induced inflammasome activation in liver and augmented hepatic ER stress and liver damage. Although there was an increased metabolic demand after burn, hepatic NLRP3 inflammasome activation corresponded to inhibition of PGC-1α (peroxisome proliferator-activated receptor γ-coactivator 1α) and its upstream regulators protein kinase A catalyst unit, AMP-activated protein kinase α, and sirtuin-1 may provide a mechanism for the enhanced metabolic derangement after major burn injury plus sepsis. In conclusion, burn + LPS augments inflammasome activation and ER stress in liver, which in turn contribute to postburn metabolic derangement.


Double-blind crossover study of fenoprofen and aspirin in osteoarthritis.
In a randomized, double-blind, six-week, crossover comparison, fenoprofen (200 mg to 600 mg every six hours) had similar efficacy to aspirin (325 mg to 975 mg every six hours) in the treatment of patients with osteoarthritis affecting the spine, hip, knee, or shoulder. Both fenoprofen and aspirin had greater efficacy than placebo. The overall incidence of side effects was similar during aspirin and fenoprofen therapy.


Prognostic Nomogram Associated with Longer Survival in Amyotrophic Lateral Sclerosis Patients.
Better understanding of survival factors in amyotrophic lateral sclerosis (ALS) could help physicians and patients schedule therapeutic interventions. We conducted a study to evaluate the predictive factors associated with longer survival and construct prognostic nomogram in ALS patients. A total of 553 ALS patients were enrolled and divided into 2 groups: a training set and a validation set. Risk factors for survival were identified using logistic regression analysis, and a nomogram created by R program was performed to predict the probability of longer survival in the training set; then receiver operating characteristic (ROC) analysis was applied to assess predictive value of the nomogram model. The median survival time was 3.2 years for all patients. Multivariate analyses revealed that age of onset, rate of disease progression, hemoglobin A1c (HbA1c) level, body mass index, creatinine, creatine kinase (CK), and non-invasive positive pressure ventilation (NIPPV) were independent predictors of longer survival. A nomogram based on the above seven predictive factors was developed to predict the possibility of longer survival. The ROC curve of the nomogram demonstrated good discrimination ability with an AUC of 0.92 (95% CI: 0.88-0.96) in the validation set. In ALS, serum CK, creatinine and HbA1c levels at baseline were independent biomarkers of longer survival. The prognostic nomogram model that integrated all significant independent factors for those who survived longer than 3 years provides an effective way to predict the probability of longer survival and can help doctors evaluate the disease progression and give personalized treatment recommendations.


Control of parasitic bronchitis and gastroenteritis in grazing cattle by strategic prophylaxis with ivermectin.
In May 1985 four groups of 10 calves, aged between four and five months, were turned out on to separate, permanent pastures of equal area which had been seeded during the previous few days with larvae of Dictyocaulus viviparus. One group acted as a control, the second was vaccinated with lungworm vaccine before turnout and treated with thiabendazole three, eight and 13 weeks after turnout, while the third and fourth groups were given ivermectin three times (three, eight and 13 weeks after turnout) and twice (three and eight weeks after turnout), respectively. A severe outbreak of parasitic bronchitis resulted in the death of three control calves within five weeks of turnout and parasitic bronchitis and gastroenteritis affected the second group of calves after approximately four months at pasture. The calves given ivermectin excreted no lungworm larvae and remained free of clinical parasitism throughout the trial.


Cloning, expression and pharmacological characterization of a human glutamate receptor: hGluR4.
A member of the ionotropic family of glutamate receptors, hGluR4, was isolated from a human cDNA library and characterized following expression in mammalian cell lines. Human GluR4 possessed a 99% amino acid and 92% nucleotide homology to that of its rat counterpart with sequence differences restricted to the carboxy and amino terminal regions of the molecule. Transfection of simian kidney cells (COS-1) with an hGluR4 expression plasmid resulted in the transient formation of a membrane protein that possessed high specific binding for [3H](RS)-alpha-amino- 3-hydroxy-5-methylisoxazole-4-propionic acid ([3H]AMPA) but not [3H]kainate. Competition studies yielded a displacement profile of AMPA = quisqualate > glutamate > domoate > kainate >> N-methyl-D-aspartate (NMDA) or dihydrokainate. Whole-cell, voltage-clamp recordings from a human embryonic kidney cell line (HEK 293) stably expressing hGluR4 confirmed the presence of constitutively active, ligand-gated ion channels activated by AMPA, glutamate and kainate but not N-methyl-D-aspartate. Kainate-evoked currents were reversibly attenuated by 6-cyano-7-nitro- quinoxaline-2,3-dione (CNQX) but not DL-2-amino-5- phosphonovalerate (DL-AP5). Agonist-evoked currents exhibited inward rectification and ion substitution experiments indicated that hGluR4 receptor-linked ion channels in their homomeric state are permeable to both CA2+ and Na+ ions. In the same cell line antibody to rat GluR4 immunoprecipitated a major protein band at approximately 108 kDa and a minor one at approximately 340 kDa. The immunoblot analysis of membranes chemically crosslinked with dithiobis(succinimidylpropionate) showed a broad band at 550-600 kDa suggesting that the GluR4 receptor forms a pentamer in situ. This is the first report of the cloning of hGluR4 receptor and its stable expression in a human cell line.


Male systemic lupus erythematosus, an overlooked diagnosis.
Lupus erythematosus is a chronic autoimmune inflammatory disease of unknown cause that involves multiple systems. Autoimmune diseases that are prevalent in men usually manifest themselves clinically before the age of 50 years old and are characterized by an acute inflammation, whereas autoimmune diseases with predominance among women appear clinically in later stages of life, when chronic diseases, fibrosis and increased number of autoantibodies are present. Lupus erythematosus is more prevalent among women during the reproductive period, but the cause of this predilection is not fully established and little is known about the disease among men. We report a case of systemic lupus erythematosus (SLE) in a male patient whose diagnosis was delayed due to the systemic manifestations and because SLE is considered an uncommon disease in men.


Corals regulate the distribution and abundance of Symbiodiniaceae and biomolecules in response to changing water depth and sea surface temperature.
The Scleractinian corals Orbicella annularis and O. faveolata have survived by acclimatizing to environmental changes in water depth and sea surface temperature (SST). However, the complex physiological mechanisms by which this is achieved remain only partially understood, limiting the accurate prediction of coral response to future climate change. This study quantitatively tracks spatial and temporal changes in Symbiodiniaceae and biomolecule (chromatophores, calmodulin, carbonic anhydrase and mucus) abundance that are essential to the processes of acclimatization and biomineralization. Decalcified tissues from intact healthy Orbicella biopsies, collected across water depths and seasonal SST changes on Curaçao, were analyzed with novel autofluorescence and immunofluorescence histology techniques that included the use of custom antibodies. O. annularis at 5 m water depth exhibited decreased Symbiodiniaceae and increased chromatophore abundances, while O. faveolata at 12 m water depth exhibited inverse relationships. Analysis of seasonal acclimatization of the O. faveolata holobiont in this study, combined with previous reports, suggests that biomolecules are differentially modulated during transition from cooler to warmer SST. Warmer SST was also accompanied by decreased mucus production and decreased Symbiodiniaceae abundance, which is compensated by increased photosynthetic activity enhanced calcification. These interacting processes have facilitated the remarkable resiliency of the corals through geological time.


Exercise capacity in young patients after total repair of Tetralogy of Fallot.
Tetralogy of Fallot is the most common form of cyanotic congenital heart disease. Measurement of physical activity is usually performed as a routine part of the patient's cardiac evaluation. The aim of this study was to examine the exercise performance of young patients operated on for tetralogy of Fallot, assessing the possible influence of known negative prognostic factors related to the surgical repair. The study group comprised 41 consecutive patients (29 male and 12 female, ages 11.2 +/- 3.9 years, range 6-16 years) operated on for tetralogy of Fallot. Patients in the study group were divided in subgroups in relation to the age of surgical intervention (before or after 2 years of life), the surgical approach (combined transatrial/transpulmonary approach or right ventriculotomy), and the presence of aortopulmonary shunts prior to performing total correction. Their data were compared with those of 33 aged-matched asymptomatic control subjects (19 male and 14 female, ages 11.9 +/- 1.3 years, range 11-16 years). Blood pressure and heart rate measured at rest were similar between control and Fallot groups. A normal increase in systolic blood pressure was observed in response to exercise intensity for all subgroups. No significant difference between control and Fallot groups was found under conditions of mild or moderate exercise or for diastolic blood pressure at rest and in response to exercise. Lower maximal heart rate and systolic blood pressure values were recorded in all patients when compared with the control subjects. Significant differences in peak workload were detected between control and Fallot groups and between the control and each subgroup; however, no difference was found between subgroups. In conclusion, despite their very satisfactory clinical status, all patients showed a reduced peak workload, irrespective of the surgical approach, age at surgery, and aortopulmonary shunts prior to performing total correction.


Artificial neural network analysis of bone quality DXA parameters response to teriparatide in fractured osteoporotic patients.
Teriparatide is a bone-forming therapy for osteoporosis that increases bone quantity and texture, with uncertain action on bone geometry. No data are available regarding its influence on bone strain. To investigate teriparatide action on parameters of bone quantity and quality and on Bone Strain Index (BSI), also derived from DXA lumbar scan, based on the mathematical model finite element method. Forty osteoporotic patients with fractures were studied before and after two years of daily subcutaneous 20 mcg of teriparatide with dual X-ray photon absorptiometry to assess bone mineral density (BMD), hip structural analysis (HSA), trabecular bone score (TBS), BSI. Spine deformity index (SDI) was calculated from spine X-ray. Shapiro-Wilks, Wilcoxon and Student's t test were used for classical statistical analysis. Auto Contractive Map was used for Artificial Neural Network Analysis (ANNs). In the entire population, the ameliorations after therapy regarded BSI (-13.9%), TBS (5.08%), BMD (8.36%). HSA parameters of femoral shaft showed a worsening. Dividing patients into responders (BMD increase >10%) and non-responders, the first presented TBS and BSI ameliorations (11.87% and -25.46%, respectively). Non-responders presented an amelioration of BSI only, but less than in the other subgroup (-6.57%). ANNs maps reflect the mentioned bone quality improvements. Teriparatide appears to ameliorate not only BMD and TBS, but also BSI, suggesting an increase of bone strength that may explain the known reduction in fracture risk, not simply justified by BMD increase. BSI appears to be a sensitive index of TPD effect. ANNs appears to be a valid tool to investigate complex clinical systems.


The effect of human serum albumin on the extended storage of human oral keratinocyte viability under mild hypothermia.
Isolated oral keratinocytes in suspension provide a number of advantages for use in maxillofacial surgery, however, the poor stability of this cell preparation at physiological temperatures is an apparent barrier preventing their use. The purpose of the present study was to evaluate whether human serum albumin (HSA) could serve as an effective constituent of a storage medium to enhance human oral keratinocyte (HOK) viability under conditions of mild hypothermia. Primary human oral keratinocytes were isolated from small pieces of the non-inflamed gingival tissues obtained during the extraction of the third molars of patients. HOK were cultured on collagen type I-coated culture dishes in keratinocyte growth medium (KGM). After the trypsinization of a culture dish (passage 2 or 3), freshly isolated HOK were stored for 24, 48, and 72 h at 4 degrees C or at room temperature in KGM, saline, Dulbecco's modified Eagle's medium (DMEM), saline supplemented with 10% HSA or DMEM supplemented with 10% (v/v) HSA under one atmosphere pressure. After storage, HOK cell survival was determined by dye exclusion using trypan blue and colony-forming assay and cell cycle change was obtained by flow cytometry. Highest cell viability was obtained in saline supplemented with 10% HSA and DMEM supplemented with 10% (v/v) HSA at 4 degrees C and at room temperature. Under these conditions no significant decline in keratinocyte viability was observed for at least 48 h. The cell cycle profiles of these cells were also maintained for at least 48 h at room temperature. These observations demonstrate that HSA might be better at preserving the viability of HOK stored under hypothermic and mild hypothermic conditions up to 48 h.


Significant association of metabolic syndrome with silent brain infarction in elderly people.
A silent brain infarction (SBI) can predict clinical overt stroke or dementia. Studies focusing on the elderly population, where SBI is most common, are sparse. We examined the associations between SBI and metabolic syndrome (MetS) in healthy elderly individuals. Neurologically healthy subjects (1,254 persons, 723 males) aged > or =65 years who underwent brain MRI were evaluated. MetS was diagnosed following the AHA/NHLBI-2005 criteria. We examined associations between full syndrome (at least three of the five conditions) as well as its components and SBI while controlling for possible confounders. One hundred and ninety-seven subjects (15.7%) were found to have one or more SBIs on MRI. Age (1-year difference) was found to be significantly related to SBI prevalence (OR 1.09; 95% CI 1.05-1.12). MetS was significantly associated with SBI (OR 1.68; 95% CI 1.15-2.44). The component model of MetS showed a strong significance between elevated blood pressure (OR 1.89; 95% CI 1.23-2.91) and SBI. Subjects exhibiting more components of MetS showed more prevalent SBI and multiple SBIs. MetS was found to be significantly associated with SBI in neurologically healthy elderly people. The positive trend between the number of MetS components and SBI could be used as a diagnostic tool to predict and prevent future stroke.


Flow capacity of the canine internal mammary artery.
The internal mammary artery has excellent long-term patency when used as a conduit for coronary artery bypass, and clinical and experimental studies have shown that blood flow through an internal mammary artery graft is satisfactory for most coronary artery branches. Multiple distal anastomoses from a single internal mammary artery, either with sequential anastomoses or with a Y-graft, might require additional blood flow through the vessel, and there has been concern that the flow capacity of the internal mammary artery is insufficient with these techniques. To better define the immediate postoperative flow capacity and pattern of the internal mammary artery, we performed experiments in seven dogs in which the left internal mammary artery was anastomosed to the circumflex coronary artery. In situ, blood flow in the internal mammary artery was 27 ml/min. Blood flow was 63 ml/min in the circumflex coronary artery and 42 ml/min in the left anterior descending coronary artery. After anastomosis of the left internal mammary artery to the circumflex coronary artery, the left main coronary artery was ligated; flow through the bypass graft increased to 92 ml/min, and systemic hemodynamics remained stable. Isoproterenol stimulation further increased flow through the left internal mammary artery graft to 160 ml/min. This study suggests that the canine internal mammary artery is capable of substantial early increase in flow and can, in fact, support the entire left coronary circulation.


Equal partners: doctors and patients explore the limits of autonomy.
In recent decades medicine--like all social institutions--has fallen from public trust. Managed care has made third-party payers a partner in the physician-patient relationship. Advocate groups, some lawyers, and bioethicists have encouraged patients to demand a greater voice in medical decisions. Physicians and patients are forced to relate to each other in a narrower range, and more of the physician's actions are being dictated and standardized. Physicians are often seen as a threat to the patient's autonomy and believed to be too paternalistic, authoritarian, and too concerned with profit to be reliable partners. A review and synthesis of the literature supports the view that patients prefer to have decisional control over outcomes but leave technical decisions on how to achieve those outcomes to physicians. Good medical care is a process of having one's autonomy respected and knowing when to relinquish it. Promoting patient autonomy as an ultimate value in medicine rather than recognizing it as one value among others (such as caring, trust, and honesty) is an error. The task of medicine is not to banish paternalism, but to preserve kindness and respect for the patient as a person.


Preventing bowel cancer: an insight for clinicians.
Worldwide, colorectal cancer causes 610,000 deaths annually with 38,000 new cases diagnosed in the UK and 16,000 deaths each year. The prognosis is directly related to the staging of the cancer at diagnosis, with an overall 5-year survival rate of approximately 50%. However, for localized disease the figure is much higher at 90%, although unfortunately many cancers present at an advanced stage. Importantly, there is the potential to reduce the incidence because most tumours arise from premalignant adenomatous polyps, which if detected and removed interrupts the adenoma-adenocarcinoma sequence. In addition, identifying colorectal cancer at an early stage can impact on the mortality rates for this neoplasm. The current screening options for bowel cancer include analysis of stool for occult blood and endoscopic assessments of the colorectum, including flexible sigmoidoscopy and full colonoscopy. The aim of this review is to present information on the natural history of colorectal cancer, the evaluation of the different screening modalities and the current faecal occult blood screening program within the UK National Health Service, and to discuss how dietary factors and aspirin may affect aetiology.


Late-onset growth restriction in Galloway-Mowat syndrome: a case report.
Galloway-Mowat syndrome (GMS) is a rare autosomal recessive disorder and is characterized by marked intrauterine growth retardation, central nervous system anomalies, and early onset nephrotic syndrome. Of the reported cases in the literature, all were diagnosed postnatally. We describe a case of GMS in which only late-onset intrauterine growth restriction was detected by prenatal ultrasound. In her fourth pregnancy, the mother had delivered a male baby with clinical features of GMS who died at seven months of age due to early onset of nephrotic syndrome. In her fifth pregnancy, serial ultrasound examinations were normal during the first and second trimester of pregnancy. Growth restriction and microcephaly were not detectable until 28 to 32 weeks' gestation. At 40 weeks' gestation, a female baby was born with dysmorphic features of GMS. Nephrotic syndrome developed after birth and renal biopsy revealed minimal change nephrotic syndrome. The prenatal course of this case suggests GMS may not be diagnosed in early pregnancy and the only abnormality detected before birth was intrauterine growth restriction.


Geographic variation in Mexican jays (Aphelocoma ultramarina): local differentiation, polyphyly or hybridization?
Studies of genetic variation within highly variable taxa can provide valuable insight into the factors influencing biological diversification. We examined six microsatellite loci, a nuclear intron and the mitochondrial control region to determine if the Mexican jay subspecies Aphelocoma ultramarina couchii and A. u. potosina have hybridized with western scrub-jays (A. californica). We suspected hybridization because these Mexican Jay populations resemble scrub-jays in several traits. We sampled six Mexican jay (N = 105) and four scrub-jay (N = 78) populations. Suspected hybrid Mexican Jay populations did not share any mitochondrial types or intron alleles with scrub-jays. All microsatellite alleles found in the suspected hybrid Mexican jay populations are also found in the control Mexican jay populations. Genetic distance-based trees from microsatellites supported reciprocal monophyly of Mexican jays and scrub-jays with bootstrap support > 80%. We randomized genotypes among populations to test scenarios consistent with hybridization. In some areas where Mexican jays and scrub-jays occur in sympatry or geographical proximity, randomization tests yield results expected under hybridization (100% support for seven of nine scenarios). However, these populations were not the primary candidates for hybridization based on phenotype. Even if low-level hybridization did occur, hybridization does not appear to be the main reason some Mexican jay populations resemble scrub-jays more than others. The scrub-jay-like traits in these populations may be due to drift, adaptation or plasticity. Alternatively, ancient hybridization, followed by selection for scrub-jay like traits in some Mexican jay populations, might have given rise to the observed variation.


Tanc1/2 TPR domain interacts with Myo18a C-terminus and undergoes liquid-liquid phase separation.
Tanc1 and its homologous proteins Tanc2 are critical synaptic scaffold proteins which regulate synaptic spine densities and excitatory synapse strength. Recent studies indicated TANC1 and TANC2 are candidate genes of several neurodevelopmental disorders (NDDs). In this study, we identified and characterized a novel interaction between Tanc1/2 and Myo18a, mediated by the Tanc1/2 TPR domains and Myo18a coiled-coil domain and C-extension (CCex). Sequence analysis and size exclusion chromatography experiments reveal that high salt disrupts the interaction between Myo18a and Tanc1/2, indicating that the interaction is primarily driven by charge-charge interactions. More importantly, we found that the Tanc1-TPR/Myo18a CCex interaction could undergo liquid-liquid phase separation (LLPS) in both cultured cells and test tubes, which provides the biochemical basis and potential molecular mechanisms for the LLPS-mediated interactions between Myo18a and Tanc1/2.


Potential involvement of tumor suppressor gene expression in the formation of estrogen-inducible pituitary tumors in rats.
While pituitary tumors can be induced in rats by the administration of estrogen, susceptibility to such tumors is highly strain dependent. In this study, 21-day-old male rats of two strains-Fischer 344 (F344) strain, which is particularly susceptible to pituitary tumors, and Sprague-Dawley (SD) strain, which is relatively resistant, were treated with diethylstilbestrol (DES) over a period of 10 days. Reverse-transcriptase polymerase chain reaction (RT-PCR) was used to analyze the expression levels of two tumor suppressor genes, p53 and rb, in the pituitaries. In SD rats, both p53 and rb mRNA appeared to increase in response to DES treatment, while in F344 rats they remained undetectable. Western blot analysis revealed that protein levels of cyclin D, which is a cell cycle regulating protein thought to be a potential oncogene, decreased in response to DES treatment in F344 rats but remained constant in SD rats. The observed differences in the expression levels of p53, rb and cyclin D suggest that they might be involved in the primary process of estrogen-induced pituitary tumor development prior to detectable tumor growth.


Modulatory effects of perforin gene dosage on pathogen-associated blood-brain barrier (BBB) disruption.
CD8 T cell-mediated blood-brain barrier (BBB) disruption is dependent on the effector molecule perforin. Human perforin has extensive single nucleotide variants (SNVs), the significance of which is not fully understood. These SNVs can result in reduced, but not ablated, perforin activity or expression. However, complete loss of perforin expression or activity results in the lethal disease familial hemophagocytic lymphohistiocytosis type 2 (FHL 2). In this study, we address the hypothesis that a single perforin allele can alter the severity of BBB disruption in vivo using a well-established model of CNS vascular permeability in C57Bl/6 mice. The results of this study provide insight into the significance of perforin SNVs in the human population. We isolated the effect a single perforin allele has on CNS vascular permeability through the use of perforin-heterozygous (perforin+/-) C57BL/6 mice in the peptide-induced fatal syndrome (PIFS) model of immune-mediated BBB disruption. Seven days following Theiler's murine encephalomyelitis virus (TMEV) CNS infection, neuroinflammation and TMEV viral control were assessed through flow cytometric analysis and quantitative real-time PCR of the viral genome, respectively. Following immune-mediated BBB disruption, gadolinium-enhanced T1-weighted MRI, with 3D volumetric analysis, and confocal microscopy were used to define CNS vascular permeability. Finally, the open field behavior test was used to assess locomotor activity of mice following immune-mediated BBB disruption. Perforin-null mice had negligible CNS vascular permeability. Perforin-WT mice have extensive CNS vascular permeability. Interestingly, perforin-heterozygous mice had an intermediate level of CNS vascular permeability as measured by both gadolinium-enhanced T1-weighted MRI and fibrinogen leakage in the brain parenchyma. Differences in BBB disruption were not a result of increased CNS immune infiltrate. Additionally, TMEV was controlled in a perforin dose-dependent manner. Furthermore, a single perforin allele is sufficient to induce locomotor deficit during immune-mediated BBB disruption. Perforin modulates BBB disruption in a dose-dependent manner. This study demonstrates a potentially advantageous role for decreased perforin expression in reducing BBB disruption. This study also provides insight into the effect SNVs in a single perforin allele could have on functional deficit in neurological disease.


Challenges and Successes in Dissemination of Evidence-Based Treatments for Posttraumatic Stress: Lessons Learned From Prolonged Exposure Therapy for PTSD.
Posttraumatic stress disorder (PTSD) poses monumental public health challenges because of its contribution to mental health, physical health, and both interpersonal and social problems. Recent military engagements in Iraq and Afghanistan and the multitude of resulting cases of PTSD have highlighted the public health significance of these conditions. There are now psychological treatments that can effectively treat most individuals with PTSD, including active duty military personnel, veterans, and civilians. We begin by reviewing the effectiveness of these treatments, with a focus on prolonged exposure (PE), a cognitive-behavioral therapy (CBT) for PTSD. Many studies conducted in independent research labs have demonstrated that PE is highly efficacious in treating PTSD across a wide range of trauma types, survivor characteristics, and cultures. Furthermore, therapists without prior CBT experience can readily learn and implement the treatment successfully. Despite the existence of highly effective treatments like PE, the majority of individuals with PTSD receive treatments of unknown efficacy. Thus, it is crucial to identify the barriers and challenges that must be addressed in order to promote the widespread dissemination of effective treatments for PTSD. In this review, we first discuss some of the major challenges, such as a professional culture that often is antagonistic to evidence-based treatments (EBTs), a lack of clinician training in EBTs, limited effectiveness of commonly used dissemination techniques, and the significant cost associated with effective dissemination models. Next, we review local, national, and international efforts to disseminate PE and similar treatments and illustrate the challenges and successes involved in promoting the adoption of EBTs in mental health systems. We then consider ways in which the barriers discussed earlier can be overcome, as well as the difficulties involved in effecting sustained organizational change in mental health systems. We also present examples of efforts to disseminate PE in developing countries and the attendant challenges when mental health systems are severely underdeveloped. Finally, we present future directions for the dissemination of EBTs for PTSD, including the use of newer technologies such as web-based therapy and telemedicine. We conclude by discussing the need for concerted action among multiple interacting systems in order to overcome existing barriers to dissemination and promote widespread access to effective treatment for PTSD. These systems include graduate training programs, government agencies, health insurers, professional organizations, healthcare delivery systems, clinical researchers, and public education systems like the media. Each of these entities can play a major role in reducing the personal suffering and public health burden associated with posttraumatic stress.


Dechlorane Plus induces oxidative stress and decreases cyclooxygenase activity in the blue mussel.
Dechlorane Plus (DP) is a chlorinated flame retardant used mainly in electrical wire and cable coating, computer connectors, and plastic roofing materials. Concentrations of DP (syn and anti isomers) are increasingly being reported in aquatic ecosystems worldwide. However, there is exceedingly little information on the exposure-related toxicity of DP in aquatic organisms, especially in bivalves. The objective of this study was to investigate the in vivo and in vitro effects of DP exposure on histopathology, lipid peroxidation (LPO) levels, cyclooxygenase (COX) activity, phagocytosis capacity and efficiency, and DNA strand breakage in the blue mussel (Mytilus edulis) following a 29days exposure (0.001, 0.01, 0.1 and 1.0μg DP/L). Blue mussels accumulated DP in muscle and digestive gland in a dose-dependent manner. LPO levels in gills were found to increase by 82% and 67% at the 0.01 and 1.0μg DP/L doses, respectively, while COX activity in gills decreased by 44% at the 1μg/L dose. No histopathological lesion was found in gonads following DP exposure. Moreover, no change in hemocyte DNA strand breakage, phagocytosis rate, and viability was observed following DP exposure. Present study showed that toxicity of DP may occur primarily via oxidative stress in the blue mussel and potentially other bivalves, and that gills represent the most responsive tissue to this exposure.


Biomechanics of cell adhesion: how force regulates the lifetime of adhesive bonds at the single molecule level.
Cell adhesion proteins play critical roles in positioning cells during development, segregating cells into distinct tissue compartments and in maintaining tissue integrity. The principle function of these proteins is to bind cells together and resist mechanical force. Adhesive proteins also enable migrating cells to adhere and roll on surfaces even in the presence of shear forces exerted by fluid flow. Recently, several experimental and theoretical studies have provided quantitative insights into the physical mechanisms by which adhesion proteins modulate their unbinding kinetics in response to tensile force. This perspective reviews these biophysical investigations. We focus on single molecule studies of cadherins, selectins, integrins, the von Willebrand factor and FimH adhesion proteins; the effect of mechanical force on the lifetime of these interactions has been extensively characterized. We review both theoretical models and experimental investigations and discuss future directions in this exciting area of research.


The Sorghum Gene for Leaf Color Changes upon Wounding (P) Encodes a Flavanone 4-Reductase in the 3-Deoxyanthocyanidin Biosynthesis Pathway.
Upon wounding or pathogen invasion, leaves of sorghum [Sorghum bicolor (L.) Moench] plants with the P gene turn purple, whereas leaves with the recessive allele turn brown or tan. This purple phenotype is determined by the production of two 3-deoxyanthocyanidins, apigeninidin and luteolinidin, which are not produced by the tan-phenotype plants. Using map-based cloning in progeny from a cross between purple Nakei-MS3B (PP) and tan Greenleaf (pp) cultivars, we isolated this gene, which was located in a 27-kb genomic region around the 58.1 Mb position on chromosome 6. Four candidate genes identified in this region were similar to the maize leucoanthocyanidin reductase gene. None of them was expressed before wounding, and only the Sb06g029550 gene was induced in both cultivars after wounding. The Sb06g029550 protein was detected in Nakei-MS3B, but only slightly in Greenleaf, in which it may be unstable because of a Cys252Tyr substitution. A recombinant Sb06g029550 protein had a specific flavanone 4-reductase activity, and converted flavanones (naringenin or eriodictyol) to flavan-4-ols (apiforol or luteoforol) in vitro Our data indicate that the Sb06g029550 gene is involved in the 3-deoxyanthocyanidin synthesis pathway.


DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures.
The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances. We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10-10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations. Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.


Rapid Detection of Mycoplasma-Infected Cells by an ssDNA Aptamer Probe.
Mycoplasmas are unique cell wall-free bacteria. Because they lack a cell wall and have resistance to β-lactam antibiotics, mycoplasma is the major pathogen that infects cultured cells in research laboratories. For rapid detection of mycoplasma-infected cells, we developed an ssDNA aptamer sequence composed of 40 nucleotides. Flow cytometry analysis showed that the synthetic aptamer probe selectively targeted mycoplasma-infected culture cells with high specificity identical to commercially available PCR-based assays. Additionally, fluorescent microscopy studies revealed that the aptamer probe rapidly stained mycoplasma-infected cells with higher sensitivity compared to Hoechst dye-mediated cellular DNA content stains. Moreover, confocal microscopy studies of trypsin-treated cells validated that the aptamer probes selectively targeted mycoplasma components on the surface of infected cells. Finally, preclinical studies of peripheral blood cells demonstrated that the aptamer probe was able to detect in vitro mycoplasma infection of primary lymphocytes. Taken together, these findings indicate that the aptamer probe will not only allow rapid detection of mycoplasma-infected culture cells for research purposes but also provide a simple method to monitor mycoplasma infection in primary cell products for clinical use.


Structure and Analysis of R1 and R2 Pyocin Receptor-Binding Fibers.
The R-type pyocins are high-molecular weight bacteriocins produced by some strains of Pseudomonas aeruginosa to specifically kill other strains of the same species. Structurally, the R-type pyocins are similar to "simple" contractile tails, such as those of phage P2 and Mu. The pyocin recognizes and binds to its target with the help of fibers that emanate from the baseplate structure at one end of the particle. Subsequently, the pyocin contracts its sheath and drives the rigid tube through the host cell envelope. This causes depolarization of the cytoplasmic membrane and cell death. The host cell surface-binding fiber is ~340 Å-long and is attached to the baseplate with its N-terminal domain. Here, we report the crystal structures of C-terminal fragments of the R1 and R2 pyocin fibers that comprise the distal, receptor-binding part of the protein. Both proteins are ~240 Å-long homotrimers in which slender rod-like domains are interspersed with more globular domains-two tandem knob domains in the N-terminal part of the fragment and a lectin-like domain at its C-terminus. The putative substrate binding sites are separated by about 100 Å, suggesting that binding of the fiber to the cell surface causes the fiber to adopt a certain orientation relative to the baseplate and this then triggers sheath contraction.


Processing environmental stimuli in paranoid schizophrenia: recognizing facial emotions and performing executive functions.
To study the contribution of executive function to abnormal recognition of facial expressions of emotion in schizophrenia patients. Abnormal recognition of facial expressions of emotion was assayed according to Japanese and Caucasian facial expressions of emotion (JACFEE), Wisconsin card sorting test (WCST), positive and negative symptom scale, and Hamilton anxiety and depression scale, respectively, in 88 paranoid schizophrenia patients and 75 healthy volunteers. Patients scored higher on the Positive and Negative Symptom Scale and the Hamilton Anxiety and Depression Scales, displayed lower JACFEE recognition accuracies and poorer WCST performances. The JACFEE recognition accuracy of contempt and disgust was negatively correlated with the negative symptom scale score while the recognition accuracy of fear was positively with the positive symptom scale score and the recognition accuracy of surprise was negatively with the general psychopathology score in patients. Moreover, the WCST could predict the JACFEE recognition accuracy of contempt, disgust, and sadness in patients, and the perseverative errors negatively predicted the recognition accuracy of sadness in healthy volunteers. The JACFEE recognition accuracy of sadness could predict the WCST categories in paranoid schizophrenia patients. Recognition accuracy of social-/moral emotions, such as contempt, disgust and sadness is related to the executive function in paranoid schizophrenia patients, especially when regarding sadness.


Perspectives of DCDR-GERS in the analysis of amino acids.
Graphene-enhanced Raman scattering (GERS) has attracted increasing attention from many scientists in recent years as a novel and potentially strong analytical technique since its discovery in 2010. GERS combines the ultra-high sensitivity and spectral analysis of the structural properties of many molecules found in surface-enhanced Raman scattering (SERS) and graphene simple sample processing and excellent uniformity. This facilitates a fast and very sensitive analysis of a wide range of analytes. Here, we present a new method for amino acid analysis based on the combination of drop coating deposition Raman (DCDR) and GERS. The potential of the method was evaluated in the analyses of Trp, Leu, Phe, and DOPA. Achievable limits of detection for all the studied amino acids are in tens of ng mL-1.


[Spectral characteristics of the bioelectrical activity of the cerebral cortex upon electric stimulation of subcortical structures].
A spectral-correlation analysis of electrical activity of the rabbit cerebral cortex was made with the use of Dnieper computer, after electrical stimulation (100-250 c/s) of the midbrain reticular formation, the thalamic nonspecific formations (midline nuclei) and different nuclei of the posterior part of the hypothalamic area (ventromedial and posterior hypothalamic nuclei and the lateral field). The background spectrograms were characterized by a high variability; their frequencies ranged from 0,5 to 12 c/s. Under the influence of the electrical stimulation of the indicated formations, a well-pronounced, dominating peak appeared in the spectrograms of the cortical EEG, in the band from 4 to 7 c/s, and the similarity of biopotentials in this rhythm increased. The experimental data show that enhancement of spatial synchronization of the cortical biopotentials under conditions of electrical stimulation of the indicated subcortical formations is based on increased rhythmic oscillations within the theta-band and on a greater coherence in this range.


Structural insights in the permeation mechanism of an activated GIRK2 channel.
G protein-gated inwardly rectifying potassium (GIRK) channels play a significant role in physiopathology by the regulation of cell excitability. This regulation depends on the K+ ion conduction induced by structural constrictions: the selectivity filters (SFs), helix bundle crossings (HBCs), and G-loop gates. To explore why no permeation occurred when the constrictions were kept in the open state, a 4-K+-related occupancy mechanism was proposed. Unfortunately, this hypothesis was neither assessed, nor was the energetic characteristics presented. To identify the permeation mechanism on an atomic level, all-atom molecular dynamic (MD) simulations and a coupled quantum mechanics and molecular mechanics (QM/MM) method were used for the GIRK2 mutant R201A. It was found that the R201A had a moderate conductive capability in the presence of PIP2. Furthermore, the 4-K+ group of ions was found to dominate the conduction through the activated HBC gate. This shielding-like mechanism was assessed by the potential energy barrier along the conduction pathway. Mutation studies did further support the assumption that E152 was responsible for the mechanism. Moreover, E152 was most probably facilitating the inflow of ions from the SF to the cavity. On the contrary, N184 had no remarkable effect on this mechanism, except for the conduction efficiency. These findings highlighted the necessity of a multi-ion distribution for the conduction to take place, and indicated that the K+ migration was not only determined by the channel conductive state in the GIRK channel. The here presented multi-ion permeation mechanism may help to provide an effective way to regulate the channelopathies.


Improving Moderator Responsiveness in Online Peer Support Through Automated Triage.
Online peer support forums require oversight to ensure they remain safe and therapeutic. As online communities grow, they place a greater burden on their human moderators, which increases the likelihood that people at risk may be overlooked. This study evaluated the potential for machine learning to assist online peer support by directing moderators' attention where it is most needed. This study aimed to evaluate the accuracy of an automated triage system and the extent to which it influences moderator behavior. A machine learning classifier was trained to prioritize forum messages as green, amber, red, or crisis depending on how urgently they require attention from a moderator. This was then launched as a set of widgets injected into a popular online peer support forum hosted by ReachOut.com, an Australian Web-based youth mental health service that aims to intervene early in the onset of mental health problems in young people. The accuracy of the system was evaluated using a holdout test set of manually prioritized messages. The impact on moderator behavior was measured as response ratio and response latency, that is, the proportion of messages that receive at least one reply from a moderator and how long it took for these replies to be made. These measures were compared across 3 periods: before launch, after an informal launch, and after a formal launch accompanied by training. The algorithm achieved 84% f-measure in identifying content that required a moderator response. Between prelaunch and post-training periods, response ratios increased by 0.9, 4.4, and 10.5 percentage points for messages labelled as crisis, red, and green, respectively, but decreased by 5.0 percentage points for amber messages. Logistic regression indicated that the triage system was a significant contributor to response ratios for green, amber, and red messages, but not for crisis messages. Response latency was significantly reduced (P<.001), between the same periods, by factors of 80%, 80%, 77%, and 12% for crisis, red, amber, and green messages, respectively. Regression analysis indicated that the triage system made a significant and unique contribution to reducing the time taken to respond to green, amber, and red messages, but not to crisis messages, after accounting for moderator and community activity. The triage system was generally accurate, and moderators were largely in agreement with how messages were prioritized. It had a modest effect on response ratios, primarily because moderators were already more likely to respond to high priority content before the introduction of triage. However, it significantly and substantially reduced the time taken for moderators to respond to prioritized content. Further evaluations are needed to assess the impact of mistakes made by the triage algorithm and how changes to moderator responsiveness impact the well-being of forum members.


Feasibility and safety of pure single-incision laparoscopic total and proximal gastrectomy for early gastric cancer: propensity score-matched comparison to multiport totally laparoscopic approach.
There have been few studies regarding the feasibility and safety of pure single-incision laparoscopic total gastrectomy (SITG) or proximal gastrectomy (SIPG) for early gastric cancer (EGC). The purpose of this study was to analyze the surgical outcome of all consecutive SITG or SIPG cases compared with multiport laparoscopic total gastrectomy (MLTG) or proximal gastrectomy (MLPG) for EGC. We analyzed all consecutive SITG or SIPG cases with double-tract reconstruction for ECG, including the initial case, between March 2013 and December 2021. SITG/SIPG was performed on patients without significant systemic comorbidities through a 3-4 cm vertical transumbilical incision. SITG/SIPG was matched to multiport laparoscopic total or proximal gastrectomy (MLTG/MLPG) cases performed in the same period using a 1:3 propensity score matching, including sex, body mass index (BMI), age and type of resection, year of operation, and institution as covariates. We compared perioperative clinicopathological characteristics and early postoperative morbidity within 1 month after surgery between the SITG/SIPG and MLTG/MLPG groups. In total, 21 patients with SITG and 15 patients with SIPG were compared with those with MLTG (n = 264) and MLPG (n = 220). No conversion to an open or multiport approach occurred in the SITG/SIPG group. After matching, operation time was similar between SITG/SIPG and MLTG/MLPG (223.9 ± 63.5 min vs 234.8 ± 68.7 min, P = 0.402). Length of stay was not significantly different between SITG/SIPG and MLTG/MLPG (11.9 ± 15.4 days vs 8.4 ± 5.0 days, P = 0.210). The average number of retrieved lymph nodes was not significantly different between SITG and MLTG (53.1 ± 16.3 vs 63.2 ± 27.5, P = 0.115), but it was significantly higher in SIPG than MLPG (59.6 ± 27.2 vs 46.0 ± 19.7, P = 0.040). The overall complication rate (30.6% vs 25.9%, P = 0.666) and Clavien-Dindo grade III or higher complication rates (13.9% vs 6.5%, P = 0.175) were not significantly different between the SITG/SIPG and MLTG/MLPG groups. Cautious adoption of SITG/SIPG procedures for EGC is feasible and safe.


Consanguinity and hereditary hearing loss in Qatar.
Qatar is a sovereign state located on the Eastern coast of the Arabian Peninsula in the Persian Gulf. Its native population consists of 3 major subgroups: people of Arabian origin or Bedouins, those from an Eastern or Persian ancestry and individuals with African admixture. Historically, all types of consanguineous marriages have been and still are common in the Qatari population, particularly among first and double-first cousins. Thus, there is a higher risk for most inherited diseases including hereditary hearing loss (HHL). In particular, a hearing loss prevalence of 5.2% has been reported in Qatar, with parental consanguinity being more common among affected individuals as compared with unaffected ones. Our recent molecular results confirm a high homogeneity and level of inbreeding in Qatari HHL patients. Among all HHL genes, GJB2, the major player worldwide, accounts for a minor proportion of cases and at least 3 additional genes have been found to be mutated in Qatari patients. Interestingly, one gene, BDP1, has been described to cause HHL only in this country. These results point towards an unexpected level of genetic heterogeneity despite the high level of inbreeding. This review provides an up-to-date picture of HHL in Qatar and of the impact of consanguinity on this disease.


The Davida Teller Award Lecture, 2016: Visual Brain Development: A review of "Dorsal Stream Vulnerability"-motion, mathematics, amblyopia, actions, and attention.
Research in the Visual Development Unit on "dorsal stream vulnerability' (DSV) arose from research in two somewhat different areas. In the first, using cortical milestones for local and global processing from our neurobiological model, we identified cerebral visual impairment in infants in the first year of life. In the second, using photo/videorefraction in population refractive screening programs, we showed that infant spectacle wear could reduce the incidence of strabismus and amblyopia, but many preschool children, who had been significantly hyperopic earlier, showed visuo-motor and attentional deficits. This led us to compare developing dorsal and ventral streams, using sensitivity to global motion and form as signatures, finding deficits in motion sensitivity relative to form in children with Williams syndrome, or perinatal brain injury in hemiplegia or preterm birth. Later research showed that this "DSV" was common across many disorders, both genetic and acquired, from autism to amblyopia. Here, we extend DSV to be a cluster of problems, common to many disorders, including poor motion sensitivity, visuo-motor spatial integration for planning actions, attention, and number skills. In current research, we find that individual differences in motion coherence sensitivity in typically developing children are correlated with MRI measures of area variations in parietal lobe, fractional anisotropy (from TBSS) of the superior longitudinal fasciculus, and performance on tasks of mathematics and visuo-motor integration. These findings suggest that individual differences in motion sensitivity reflect decision making and attentional control rather than integration in MT/V5 or V3A. Its neural underpinnings may be related to Duncan's "multiple-demand" (MD) system.


Distinct kinetic and mechanical properties govern ALCAM-mediated interactions as shown by single-molecule force spectroscopy.
The activated leukocyte cell adhesion molecule (ALCAM) mediates dynamic homotypic and heterotypic cellular interactions. Whereas homotypic ALCAM-ALCAM interactions have been implicated in the development and maintenance of tissue architecture and tumor progression, heterotypic ALCAM-CD6 interactions act to initiate and stabilize T-cell-dendritic-cell interactions affecting T-cell activation. The ability to resist the forces acting on the individual bonds during these highly dynamic cellular contacts is thought to be crucial for the (patho)physiology of ALCAM-mediated cell adhesion. Here, we used atomic force microscopy to characterize the relationship between affinity, avidity and the stability of ALCAM-mediated interactions under external loading, at the single-molecule level. Disruption of the actin cytoskeleton resulted in enhanced ALCAM binding avidity, without affecting the tensile strength of the individual bonds. Force spectroscopy revealed that the ALCAM-CD6 bond displayed a significantly higher tensile strength, a smaller reactive compliance and an up to 100-fold lower dissociation rate in the physiological force window in comparison to the homotypic interaction. These results indicate that homotypic and heterotypic ALCAM-mediated adhesion are governed by significantly distinct kinetic and mechanical properties, providing novel insight into the role of ALCAM during highly dynamic cellular interactions.


[Treatment of patients with postgastrectomy syndromes].
An experience with treatment of 545 patients with organic, functional and combined postgastroresectional syndromes (PGRS) is analyzed. The patients are divided into groups depending on the character of the syndromes and their combinations. The most frequent causes of the development of PGRS are formulated. Special methods of preoperative examination and preparing are described which allow individual approach to choice of the method of reconstructive-restorative operations. Some technical details of the reconstructive interventions are described. In 95% of the patients operated upon long-term results of treatment were good and satisfactory.


A socio-cultural instrumental approach to emotion regulation: Culture and the regulation of positive emotions.
We propose a sociocultural instrumental approach to emotion regulation. According to this approach, cultural differences in the tendency to savor rather than dampen positive emotions should be more pronounced when people are actively pursuing goals (i.e., contexts requiring higher cognitive effort) than when they are not (i.e., contexts requiring lower cognitive efforts), because cultural beliefs about the utility of positive emotions should become most relevant when people are engaging in active goal pursuit. Four studies provided support for our theory. First, European Americans perceived more utility and less harm of positive emotions than Japanese did (Study 1). Second, European Americans reported a stronger relative preference for positive emotions than Asians, but this cultural difference was larger in high cognitive effort contexts than in moderate or low cognitive effort contexts (Study 2). Third, European Americans reported trying to savor rather than dampen positive emotions more than Asians did when preparing to take an exam, a typical high cognitive effort context (Studies 3-4), but these cultural differences were attenuated when an exam was not expected (Study 3) and disappeared when participants expected to interact with a stranger (Study 4). These findings suggest that cultural backgrounds and situational demands interact to shape how people regulate positive emotions. (PsycINFO Database Record