Foot deformities, function in the lower extremities, and plantar pressure in patients with diabetes at high risk to develop foot ulcers.
Foot deformities, neuropathy, and dysfunction in the lower extremities are known risk factors that increase plantar peak pressure (PP) and, as a result, the risk of developing foot ulcers in patients with diabetes. However, knowledge about the prevalence of these factors is still limited. The aim of the present study was to describe the prevalence of risk factors observed in patients with diabetes without foot ulcers and to explore possible connections between the risk factors and high plantar pressure. Patients diagnosed with type 1 (n=27) or type 2 (n=47) diabetes (mean age 60.0±15.0 years) were included in this cross-sectional study. Assessments included the registration of foot deformities; test of gross function at the hip, knee, and ankle joints; a stratification of the risk of developing foot ulcers according to the Swedish National Diabetes Register; a walking test; and self-reported questionnaires including the SF-36 health survey. In-shoe PP was measured in seven regions of interests on the sole of the foot using F-Scan(®). An exploratory analysis of the association of risk factors with PP was performed. Neuropathy was present in 28 (38%), and 39 (53%) had callosities in the heel region. Low forefoot arch was present in 57 (77%). Gait-related parameters, such as the ability to walk on the forefoot or heel, were normal in all patients. Eighty percent had normal function at the hip and ankle joints. Gait velocity was 1.2±0.2 m/s. All patients were stratified to risk group 3. Hallux valgus and hallux rigidus were associated with an increase in the PP in the medial forefoot. A higher body mass index (BMI) was found to increase the PP at metatarsal heads 4 and 5. Pes planus was associated with a decrease in PP at metatarsal head 1. Neuropathy did not have a high association with PP. This study identified several potential risk factors for the onset of diabetic foot ulcers (DFU). Hallux valgus and hallux rigidus appeared to increase the PP under the medial forefoot and a high BMI appeared to increase the PP under the lateral forefoot. There is a need to construct a simple, valid, and reliable assessment routine to detect potential risk factors for the onset of DFU.


Hiatal hernia repair with gore bio-a tissue reinforcement: our experience.
Type I hiatal hernia is associated with gastroesophageal reflux disease (GERD) in 50-90% of cases. Several trials strongly support surgery as an effective alternative to medical therapy. Today, laparoscopic fundoplication is considered as the procedure of choice. However, primary laparoscopic hiatal hernia repair is associated with upto 42% recurrence rate. Mesh reinforcement of the crural closure decreases the recurrence but can lead to complications, above all nonabsorbable ones. We experiment a new totally absorbable mesh by Gore. Case. We present a case of a 65-year-old female patient with a 6-year classic history of GERD. Endoscopy revealed a large hiatal hernia and esophagitis. pH study was positive for acid reflux; esophageal manometry revealed LES intrathoracic dislocation. With laparoscopic approach, the hiatal hernia defect was identified and primarily repaired, by crural closure. Gore Bio-A Tissue Reinforcement was trimmed to fit the defect accommodating the esophagus. Nissen fundoplication was performed. Result. Bio-A mesh was easily placed laparoscopically. It has good handling and could be cut and tailored intraoperatively for optimal adaptation. There were no short-term complications. Conclusion. Crural closure reinforcement can be done readily with this new totally absorbable mesh replaced by soft tissue over six months. However, further data and studies are needed to evaluate long-term outcomes.


Kinetics and thermodynamics of ouabain binding by intact turkey erythrocytes: effects of external sodium ion, potassium ion, and temperature.
The kinetics of association and dissociation for the ouabain-Na+,K+-dependent ATPase complex have been studied in intact turkey erythrocytes as a function of external Na+ concentration, K+ concentration, and temperature. At free ligand concentrations substantially exceeding the concentration of available binding sites, the association reaction exhibits pseudo-first-order kinetics with an association rate constant (k1) that is conveniently determined over a wide range of temperatures (5-37 degrees C). The dissociation reaction exhibits strict first-order kinetics with a dissociation rate constant (k-1) that has the unusual property, in the turkey cell, of being sufficiently great to permit its direct determination even at temperatures as low as 5 degrees C. Values for the equilibrium binding constant for the ouabain-ATPase complex (KA) predicted from the ratio of the association and dissociation rate constants agree closely with independently measured values of KA determined directly under conditions of equilibrium binding. KA is a sensitive function of the composition of the external ionic environment, rising with increasing Na+ concentration and falling with increasing K+ concentration. These changes in KA are shown to be quantitatively attributable to changes in the rate constant k1, k-1 in contrast being unaffected at any given temperature by even very large changes in Na+ or K+ concentration. Arrhenius plots of k1 and k-1 both yield straight lines over the entire temperature range corresponding to activation energies for association and dissociation of 29.5 and 24.2 kcal/mol, respectively. These observations have made it possible to calculate the following standard values for the ouabain binding reaction in the presence of 150 mM Na+: delta G degree = -9.8 kcal/mol; delta H degree = +5.3 kcal/mol; delta S degree = +48.7 cal/degree/mol. The large positive value of delta S degree presumably reflects a highly ordered configuration of the ouabain-free ATPase molecule that is lost upon ouabain binding and that "drives" the reaction despite the positive value of delta H degree.


Rapid nongenomic effects of glucocorticoids on allergic asthma reaction in the guinea pig.
Glucocorticoids (GCs) are routinely believed to work solely through genomic mechanisms. Recent evidence indicates that GCs can act at the membrane to exert rapid nongenomic effects on various tissues and cells. To ascertain whether nongenomic effects of GCs exist on the allergic asthma reaction, Hartley guinea pigs were sensitized with ovalbumin and challenged with the same antigen given by aerosol. Some animals received inhaled budesonide (3 mg/ml suspended in Hydroxypropyl methylcellulose vehicle) for 5 minutes before ovalbumin challenge; Other animals received saline or blank vehicle as control. We measured the changes of lung resistance and dynamic lung compliance, the pulmonary function used to evaluate allergic asthma severity. Inhaled budesonide inhibited allergic reaction within 10 minutes, which would preclude genomic-mediated responses that normally takes several hours to occur. This study infers for the first time that rapid nongenomic effect of GCs exists on allergic asthma reaction, and provides a new way to investigate nongenomic mechanism of GCs. Further study would raise the possibility of new therapeutic strategies for allergic disease including asthma.


Relaxin 2/RXFP1 Signaling Induces Cell Invasion via the β-Catenin Pathway in Endometrial Cancer.
Relaxin is known to play an important role in animal pregnancies, including those of humans. It is suggested that relaxin induces aggressive cell growth and invasiveness in several types of cancer, including endometrial cancer. However, the mechanisms of relaxin remain largely unclear. In this study, we examined the effects of relaxin 2 (RLN2), the major circulating relaxin in humans, on human endometrial carcinoma cell lines. RLN2 treatment induced invasion in HEC-1B and Ishikawa cells. RLN2-induced cell invasion was significantly decreased by transfection of relaxin receptor 1 (RXFP1) siRNAs. The β-catenin inhibitor, XAV939, also significantly inhibited the RLN2-induced cell invasions. Both a decrease of cadherin expression and an increase of β-catenin phosphorylation were observed in response to the RLN2 treatment in HEC-1B and Ishikawa cells. We then examined RLN2 and RXFP1 expression in 80 human endometrioid endometrial carcinoma tissues. RLN2 immunoreactivity was detected in the human endometrial carcinoma cells and had a correlative tendency with histological grade and RXFP1. These results suggest that adherens junctions in cancer cells are weakened by the breakdown of the cadherin/catenin complex, which is induced by β-catenin phosphorylation via RLN2/RXFP1 signaling.


Persistence of traumatic memories in World War II prisoners of war.
To assess the long-term effects of the prisoner of war (POW) experience on U.S. World War II (WWII) veterans. Exploratory study. Participants were recruited through the Hines Veterans Affairs Hospital; a POW reunion in Orlando, Florida; and the WWII veterans periodical, "The QUAN." One hundred fifty-seven American military veterans who were former WWII POWs. Participants completed a mailed survey describing their POW experiences, POW effects on subsequent psychological and physical well-being, and ways in which these experiences shaped major decisions in their lives. Participants from the European and Pacific theaters reported that their captivity during WWII affected their long-term emotional well-being. Both groups reported high rates of reflection, dreaming, and flashbacks pertaining to their POW experiences, but Pacific theater POWs did so at higher rates in the present than in the past. Large portions of both groups reported greater rumination on POW experiences after retirement. Finally, 16.6% of participants met the requirements of a current, clinical diagnosis of posttraumatic stress disorder (PTSD) based on the Mississippi PTSD scale, with PTSD rates in Pacific theater POWs (34%) three times those of European theater POWs (12%). Traumatic memories and clinical levels of PTSD persist for WWII POWs as long as 65 years after their captivity. Additionally, rumination about these experiences, including flashbacks and persistent nightmares, may increase after retirement, particularly for those held in the Pacific theater. These findings inform the current therapeutic needs of this elderly population and future generations of POWs from other military conflicts.


Ovarian tumours in Papua New Guinea: relative frequency and histological features.
An analysis has been made of 447 ovarian tumours submitted for histological examination to the Department of Pathology, Port Moresby General Hospital, for the period 1978-1982. Ovarian tumours constituted 8% of all tumours submitted during this period. Of the ovarian tumours submitted 75% were benign. The ovarian tumours presented a wide range of histological features, which were analysed according to the accepted international classification.


Symmetry Breaking Charge Transfer in DNA-Templated Perylene Dimer Aggregates.
Molecular aggregates are of interest to a broad range of fields including light harvesting, organic optoelectronics, and nanoscale computing. In molecular aggregates, nonradiative decay pathways may emerge that were not present in the constituent molecules. Such nonradiative decay pathways may include singlet fission, excimer relaxation, and symmetry-breaking charge transfer. Singlet fission, sometimes referred to as excitation multiplication, is of great interest to the fields of energy conversion and quantum information. For example, endothermic singlet fission, which avoids energy loss, has been observed in covalently bound, linear perylene trimers and tetramers. In this work, the electronic structure and excited-state dynamics of dimers of a perylene derivative templated using DNA were investigated. Specifically, DNA Holliday junctions were used to template the aggregation of two perylene molecules covalently linked to a modified uracil nucleobase through an ethynyl group. The perylenes were templated in the form of monomer, transverse dimer, and adjacent dimer configurations. The electronic structure of the perylene monomers and dimers were characterized via steady-state absorption and fluorescence spectroscopy. Initial insights into their excited-state dynamics were gleaned from relative fluorescence intensity measurements, which indicated that a new nonradiative decay pathway emerges in the dimers. Femtosecond visible transient absorption spectroscopy was subsequently used to elucidate the excited-state dynamics. A new excited-state absorption feature grows in on the tens of picosecond timescale in the dimers, which is attributed to the formation of perylene anions and cations resulting from symmetry-breaking charge transfer. Given the close proximity required for symmetry-breaking charge transfer, the results shed promising light on the prospect of singlet fission in DNA-templated molecular aggregates.


Comparative study of clozapine versus risperidone in treatment-naive, first-episode schizophrenia: A pilot study.
Clozapine may be more useful in treatment-naive patients with first-episode schizophrenia for better symptoms control and improving quality of life. The current study was carried out to compare the efficacy and tolerability of clozapine versus risperidone in treatment-naive, first-episode patients of schizophrenia. This was a comparative, open-label, six months prospective study of treatment-naive, first-episode patients with schizophrenia between the age group of 18 and 40 yr diagnosed as per the International Classification of Diseases-10 (ICD-10) criteria. A total of 63 patients were recruited and randomly assigned to clozapine group or risperidone group using computer-generated random number tables. Eight patients were lost to follow up. The dosages of the respective drugs were kept in therapeutic range of 200-600 mg/day and 4-8 mg/day orally for clozapine and risperidone, respectively. On general psychopathology score, after six months of intervention, clozapine led to 60.32 per cent mean reduction in Positive and Negative Syndrome Scale (PANSS) for Schizophrenia total score while risperidone led to 56.35 per cent mean reduction in PANSS total score, which meant more improvement with clozapine. Clozapine group was found to have significant improvement in quality of life (P = 0.04339). On Glasgow Antipsychotic Side-effect Scale, clozapine was superior to risperidone. The most common side effects observed in clozapine group were oversedation (78.96%) and dizziness (55.23%), and in risperidone group, common side effects were rigidity (62.36%), sedation (38.69%), tremors (65.69%) and menstrual irregularities in 80.25 per cent of female patients. The findings of this preliminary study showed clozapine as a better choice than risperidone in terms of efficacy, tolerability and better quality of life in treatment-naive, first-episode schizophrenia. However, further studies need to be done on a larger group of patients to confirm the findings.


In vivo genotoxicity assessment of titanium, zirconium and aluminium nanoparticles, and their microparticulated forms, in Drosophila.
As in vivo system, we propose Drosophila melanogaster as a useful model for study the genotoxic risks associated with nanoparticle exposure. In this study we have carried out a genotoxic evaluation of titanium dioxide (TiO2), zirconium oxide (ZrO2) and aluminium oxide (Al2O3) nanoparticles and their microparticulated forms in D. melanogaster by using the wing somatic mutation and recombination assay. This assay is based on the principle that loss of heterozygosis and the corresponding expression of the suitable recessive markers, multiple wing hairs and flare-3, can lead to the formation of mutant clones in treated larvae, which are expressed as mutant spots on the wings of adult flies. Third instar larvae were feed with TiO2, ZrO2 and Al2O3 nanoparticles, and their microparticulated forms, at concentrations ranging from 0.1 to 10mM. Although a certain level of aggregation/agglomeration was observed in solution, it must be noted than the constant digging activity of larvae ensures that treated medium pass constantly through the digestive tract ensuring exposure. The results showed that no significant increases in the frequency of all spots (e.g. small single, large single, twin, total mwh and total spots) were observed, indicating that these nanoparticles were not able to induce genotoxic activity in the wing spot assay of D. melanogaster. Negative data were also obtained with the microparticulated forms. This indicates that the nanoparticulated form of the selected nanomaterials does not modify the potential genotoxicity of their microparticulated versions. These in vivo results contribute to increase the genotoxicity database on the TiO2, ZrO2 and Al2O3 nanoparticles.


Estimates of measles case fatality ratios: a comprehensive review of community-based studies.
Global deaths from measles have decreased notably in past decades, due to both increases in immunization rates and decreases in measles case fatality ratios (CFRs). While some aspects of the reduction in measles mortality can be monitored through increases in immunization coverage, estimating the level of measles deaths (in absolute terms) is problematic, particularly since incidence-based methods of estimation rely on accurate measures of measles CFRs. These ratios vary widely by geographic and epidemiologic context and even within the same community from year-to-year. To understand better the variations in CFRs, we reviewed community-based studies published between 1980 and 2008 reporting age-specific measles CFRs. The results of the search consistently document that measles CFRs are highest in unvaccinated children under age 5 years; in outbreaks; the lowest CFRs occur in vaccinated children regardless of setting. The broad range of case and death definitions, study populations and geography highlight the complexities in extrapolating results for global public health planning. Values for measles CFRs remain imprecise, resulting in continued uncertainty about the actual toll measles exacts.


Spaced clofazimine therapy of lepromatous leprosy.
Patients with previously untreated borderline-lepromatous or fully lepromatous leprosy were treated with one of five clofazimine (B663) regimens: 1) 200 mg daily 6 days per week; 2) 100 mg three times weekly; 3) 300 mg weekly; 4) 600 mg every other week; and 5) 600 mg on 2 consecutive days every 4 weeks. After 24 weeks of treatment, the patients were randomly allocated to treatment either with 200 mg B663 daily 6 days per week (regimen 6) or with dapsone, beginning with a small dosage and increasing over a period of 8 weeks to 100 mg daily 6 days per week (regimen 7). Death of Mycobacterium leprae was monitored by mouse inoculation with organisms recovered from skin biopsy specimens obtained at intervals during the first 24 weeks. Killing of M. leprae proceeded most rapidly in regimen 1 and 2 patients, least rapidly in the patients of regimens 4 and 5, and at an intermediate rate in regimen 3 patients. Erythema nodosum leprosum (ENL) was no more frequent nor more severe during treatment with any one of the first-24-weeks regimen. ENL was more frequent in regimen 7 than in regimen 6 patients. Pigmentation of the skin, assessed only during the first 24 weeks, occurred in patients of all regimens, but was most marked in regimen 1 patients. No evidence of B663 toxicity was noted. Although of all of the first 24-weeks regimens were effective in terms of the rate of killing of M. lepare, greater effectiveness was associated with more frequent administration of the drug. The B663 that accumulated in the tissues did not appear to be available to exert an antimicrobial effect.


Randomized trial of a shared decision-making intervention consisting of trade-offs and individualized treatment information for BRCA1/2 mutation carriers.
To evaluate a shared decision-making intervention (SDMI) for BRCA1/2 mutation carriers who have to make a choice between screening and prophylactic surgery for breasts and/or ovaries. The SDMI consisted of two value assessment sessions, using the time trade-off method, followed by individualized treatment information based on (quality-adjusted) life expectancy. After the baseline assessment (2 weeks after a positive DNA test result), women were randomly assigned to the SDMI group (n = 44), receiving the SDMI 2 months after the test result, or to the control group (n = 44). The short- and long-term effects, 3 and 9 months after the test result, were assessed using questionnaires. Data were collected on well-being, treatment choice, and decision-related outcomes. In the short term, the SDMI had no effect. In the long term, with respect to well-being, patients in the SDMI group had less intrusive thoughts (P =.05) and better general health (P =.01) and tended to be less depressed (P =.07). With respect to decision-related outcomes for the breasts, the SDMI group held stronger preferences (P =.02) and agreed more strongly to having weighed the pros and cons (P =.01). No effect was found on treatment choice. In the long term, interaction effects between the SDMI and cancer history were found. The SDMI showed an overall beneficial effect for unaffected women, whereas affected women tended to experience detrimental effects. We conclude that the SDMI improved decision making in unaffected BRCA1/2 mutation carriers. Supporting decision making in a systematic way using trade-offs is beneficial for these women.


Physiological changes induced by the quaternary ammonium compound benzyldimethyldodecylammonium chloride on Pseudomonas fluorescens.
Antimicrobial resistance is a major public health concern, particularly in hospitals and other healthcare settings. For the rational design of disinfection strategies, it is of utmost importance to understand the mechanisms of action of antimicrobials. In this study, the mechanism of action of benzyldimethyldodecylammonium chloride (BDMDAC) was assessed against Pseudomonas fluorescens. The targets of antimicrobial action were studied using different bacterial physiological indices. The MIC, MBC, membrane permeabilization, intracellular potassium release, physico-chemical surface properties, surface charge, outer membrane protein (OMP) expression and morphological changes were assessed after BDMDAC exposure. The MIC was found to be 20 mg/L and the MBC was 10 mg/L. BDMDAC led to a significant change in cell surface hydrophobicity and induced propidium iodide uptake. Such results suggest cytoplasmic membrane damage, corroborated by the release of intracellular potassium. The results obtained from the zeta potential measurement demonstrate a -31.2 mV value for untreated cells and -21.0 mV for cells at the MIC. Scanning electron microscopy revealed that cells treated with 20 mg/L were less bulky, and their membrane seemed to be rougher, wrinkled and deformed when compared with untreated cells. The overall bactericidal events occurred without detectable changes in OMP expression. BDMDAC is an effective biocide against P. fluorescens. It binds by ionic and hydrophobic interactions to the cell membrane, causing changes in membrane properties and function, as manifested by phenomena such as cellular disruption and loss of membrane integrity with consequent leakage of essential intracellular constituents.


Attention demand and postural control in children with hearing deficit.
To elucidate the mechanisms responsible for deteriorated postural control in children with hearing deficit (CwHD), we measured center-of-pressure (COP) variability, mean velocity and entropy in bipedal quiet stance (feet together) with or without the concurrent cognitive task (reaction to visual stimulus) on hard or foam surface in 29 CwHD and a control group of 29 typically developing children (CON). The CwHD displayed an overall decreased postural performance as compared to the CON in the medial-lateral plane (p<0.05). Standing on foam pad revealed slower simple reaction time in the CwHD (p<0.05) while the results on hard surface were not different. The CwHD decreased (p<0.05) the amount of attention invested in posture during dual task which accounted for the need of more cognitive resources to handle two tasks simultaneously than controls. It was unmistakable that the intergroup differences emerged when the tasks performed were relatively novel and untrained: feet together, foam pad, and reaction time. All these tasks, while being very easy for the CON, made the CwHD deteriorate postural or cognitive performance. These results unravel the difficulty in reaching the consecutive developmental stages in the CwHD and call for specific therapeutic modalities that might facilitate this development.


Simplified paraboloid phase model-based phase tracker for demodulation of a single complex fringe.
A regularized phase tracker (RPT) is an effective method for demodulation of single closed-fringe patterns. However, lengthy calculation time, specially designed scanning strategy, and sign-ambiguity problems caused by noise and saddle points reduce its effectiveness, especially for demodulating large and complex fringe patterns. In this paper, a simplified paraboloid phase model-based regularized phase tracker (SPRPT) is proposed. In SPRPT, first and second phase derivatives are pre-determined by the density-direction-combined method and discrete higher-order demodulation algorithm, respectively. Hence, cost function is effectively simplified to reduce the computation time significantly. Moreover, pre-determined phase derivatives improve the robustness of the demodulation of closed, complex fringe patterns. Thus, no specifically designed scanning strategy is needed; nevertheless, it is robust against the sign-ambiguity problem. The paraboloid phase model also assures better accuracy and robustness against noise. Both the simulated and experimental fringe patterns (obtained using electronic speckle pattern interferometry) are used to validate the proposed method, and a comparison of the proposed method with existing RPT methods is carried out. The simulation results show that the proposed method has achieved the highest accuracy with less computational time. The experimental result proves the robustness and the accuracy of the proposed method for demodulation of noisy fringe patterns and its feasibility for static and dynamic applications.


Development of a plant viral-vector-based gene expression assay for the screening of yeast cytochrome p450 monooxygenases.
Development of a gene discovery tool for heterologously expressed cytochrome P450 monooxygenases has been inherently difficult. The activity assays are labor-intensive and not amenable to parallel screening. Additionally, biochemical confirmation requires coexpression of a homologous P450 reductase or complementary heterologous activity. Plant virus gene expression systems have been utilized for a diverse group of organisms. In this study we describe a method using an RNA vector expression system to phenotypically screen for cytochrome P450-dependent fatty acid omega-hydroxylase activity. Yarrowia lipolytica CYP52 gene family members involved in n-alkane assimilation were amplified from genomic DNA, cloned into a plant virus gene expression vector, and used as a model system for determining heterologous expression. Plants infected with virus vectors expressing the yeast CYP52 genes (YlALK1-YlALK7) showed a distinct necrotic lesion phenotype on inoculated plant leaves. No phenotype was detected on negative control constructs. YlALK3-, YlALK5-, and YlALK7-inoculated plants all catalyzed the terminal hydroxylation of lauric acid as confirmed using thin-layer and gas chromatography/mass spectrometry methods. The plant-based cytochrome P450 phenotypic screen was tested on an n-alkane-induced Yarrowia lipolytica plant virus expression library. A subset of 1,025 random library clones, including YlALK1-YlALK7 constructs, were tested on plants. All YlALK gene constructs scored positive in the randomized screen. Following nucleotide sequencing of the clones that scored positive using a phenotypic screen, approximately 5% were deemed appropriate for further biochemical analysis. This report illustrates the utility of a plant-based system for expression of heterologous cytochrome P450 monooxygenases and for the assignment of gene function.


[Study of the HL-A system in Basedow's disease (author's transl)].
HL-A typing has been carried out in 100 caucasians with Graves' disease and compared with 270 healthy controls. 25 HL-A antigens were characterized using a lymphocytotoxicity microtechnique. Analysis of the results reveals an increased incidence of HL-A8 antigen (35% in patients as compared to 16,3% in controls), with a high degree of statistical significance: p=0.0002 and corrected p X 25) = 0.005. We did not observe a clearcut correlation between the presence of HL-A8 and different characteristics of the disease: sex, age of onset, familial history, exophtalmia, goiter, severity. The knowledge of the relationships between the HL-A8 gene and several auto-immune diseases is a strong argument in favor of the auto-immune nature of Graves' disease. The association between HL-A8 and Graves' disease could be explained by a close linkage between the second HL-A locus and one or several Ir-IgG loci occupied in predisposed individuals by predisposing alleles. In these subjects, an antigenic contact with an exogenous etiological agent would induce a pathological immune response, with production of thyroid stimulating IgG.


Chemokine receptors on infiltrating leucocytes in inflammatory pathologies of the central nervous system (CNS).
Haematogenous leucocytes enter the central nervous system (CNS) during diverse disorders of varied aetiologies. Understanding the trafficking cues that mediate CNS leucocyte infiltration might promote the development of flexible and selective means to modulate inflammation to achieve clinical benefit. The trafficking machinery of leucocytes has been elucidated during the past decade and consists of cell-surface adhesion molecules, chemoattractant cytokines (chemokines) and their receptors. Recent work in our laboratory characterized chemokine receptors found on T lymphocytes and monocytes in brain sections from subjects with one pathological subtype of multiple sclerosis (MS), an immune-mediated inflammatory demyelinating disease. In these tissues, the types 1 and 5 CC chemokine receptors (CCR1 and CCR5) were detected on perivascular monocytic cells whereas only CCR5 was present on parenchymal macrophages. The type 3 CXC chemokine receptor (CXCR3) was present on virtually all CD3-positive T cells. In the current study, we evaluated the expression of these receptors on the infiltrating cells present in cases of other inflammatory CNS disorders including those of dysimmune, infectious, neoplastic, and vascular aetiology. Perivascular and parenchymal monocytic cells expressed CCR1 in all cases and CXCR3 was consistently present on a substantial proportion of CD3+ T cells. The occurrence of CCR5 on parenchymal macrophages was much less uniform across the varied disorders. These data implicate CCR1 in monocyte infiltration of the CNS and are consistent with reports of studies in CCR1-deficient mice. CXCR3 is also likely to play a role in accumulation of T cells in the inflamed CNS. By contrast, our findings suggest that regulation of CCR5 on phagocytic macrophages may be contingent on the lesion environment.


Protective measures undertaken during chest tube thoracostomy in COVID-19 outbreak.
Coronavirus disease 2019 (COVID-19) is a newly emerging infectious disease that was first reported in China and has become a worldwide pandemic. Many surgical procedures are continuing to be performed during this state of pandemic as is thoracic surgery. We present six cases of tube thoracostomy in COVID-19 patients and the modifications to the routine surgical technique. We serially attached two closed underwater drainage systems (CUDS) together and added a high-efficiency particulate air (HEPA) filter to the port of the second CUDS, because the intrapleural air, which passes through the CUDS into the air in intensive care unit (ICU), may contain high concentrations of 2019 novel coronavirus (2019-nCoV). Second, we attached the chest drain to the first CUDS in order to prevent the spread of virus during the placement of drain into the pleural cavity. Third, just before opening the parietal pleura, ventilation was put on standby mode and the endotracheal tube was clamped to prevent viral dissemination to the environment. Fourth, we covered the incision with a gauze sponge soaked with sterile saline solution during pleural entry, to prevent viral dissemination into the environment. There were a total of six patients enrolled in our study. All these patients were diagnosed with COVID-19. The surgical indication for the chest tube thoracostomy was tension pneumothorax in all six patents. All patients had lung expansion defects and subcutaneous emphysema after intervention. Unfortunately, all of them succumbed to COVID-19, despite best available treatment. There was no COVID-19 infection reported in the healthcare professionals during this study. Thoracic surgical procedures may cause dissemination of high amounts of 2019-nCoV in the environment and thus are perhaps the most dangerous surgeries to perform. Variations in the thoracic surgical techniques are necessary in order to protect the healthcare providers from COVID-19.


Targeting ErbB3: the New RTK(id) on the Prostate Cancer Block.
Most prostate cancers (PCa) are critically reliant on functional androgen receptor (AR) signaling. At its onset, PCa is androgen-dependent and although temporarily halted by surgically or pharmacologically blocking the AR (androgen ablation), the disease ultimately recurs as an aggressive, fatal castration resistant prostate cancer (CRPC). FDA-approved treatments like docetaxel, a chemotherapeutic agent, and Provenge, a cancer vaccine, extend survival by a scant 3 and 4 months, respectively. It is clear that more effective drugs targeting CRPC are urgently needed. The ErbB family (EGFR/ErbB1, ErbB2/HER2/neu, ErbB3/HER3 and ErbB4/HER4) of receptor tyrosine kinases (RTKs) have long been implicated in PCa initiation and progression, but inhibitors of ErbB1 and ErbB2 (prototypic family members) fared poorly in PCa clinical trials. Recent research suggests that another family member ErbB3 abets emergence of the castration-resistant phenotype. Considerable efforts are being directed towards understanding ErbB3-mediated molecular mechanisms of castration resistance and searching for novel ways of inhibiting ErbB3 activity via rational drug design. Antibody-based therapy that prevents ligand binding to ErbB3 appears promising and fully-humanized antibodies that inhibit ligand-induced phosphorylation of ErbB3 are currently in early development. Small molecule tyrosine kinase inhibitors are also being vigorously pursued, as are siRNA-based approaches and combination treatment strategies- the simultaneous suppression of ErbB3 and its signaling partners or downstream effectors - with the primary purpose of undermining the resiliency of ErbB3-mediated signal transduction. This review summarizes the existing literature and reinforces the importance of ErbB3 as a therapeutic target in the clinical management of prostate cancer.


Mapping the serological prevalence rate of West Nile fever in equids, Tunisia.
West Nile fever (WNF) is a viral disease of wild birds transmitted by mosquitoes. Humans and equids can also be affected and suffer from meningoencephalitis. In Tunisia, two outbreaks of WNF occurred in humans in 1997 and 2003; sporadic cases were reported on several other years. Small-scale serological surveys revealed the presence of antibodies against WN virus (WNV) in equid sera. However, clinical cases were never reported in equids, although their population is abundant in Tunisia. This study was achieved to characterize the nationwide serological status of WNV in Tunisian equids. In total, 1189 sera were collected in 2009 during a cross-sectional survey. Sera were tested for IgG antibodies, using ELISA and microneutralization tests. The estimated overall seroprevalence rate was 28%, 95% confidence interval [22; 34]. The highest rates were observed (i) in the north-eastern governorates (Jendouba, 74%), (ii) on the eastern coast (Monastir, 64%) and (iii) in the lowlands of Chott El Jerid and Chott el Gharsa (Kebili, 58%; Tozeur, 52%). Environmental risk factors were assessed, including various indicators of wetlands, wild avifauna, night temperature and chlorophyllous activity (normalized difference vegetation index: NDVI). Multimodel inference showed that lower distance to ornithological sites and wetlands, lower night-time temperature, and higher NDVI in late spring and late fall were associated with higher serological prevalence rate. The model-predicted nationwide map of WNF seroprevalence rate in Tunisian equids highlighted different areas with high seroprevalence probability. These findings are discussed in the perspective of implementing a better WNF surveillance system in Tunisia. This system might rely on (i) a longitudinal survey of sentinel birds in high-risk areas and time periods for WNV transmission, (ii) investigations of bird die-offs and (iii) syndromic surveillance of equine meningoencephalitis.


Self-Healing, Highly Sensitive Electronic Sensors Enabled by Metal-Ligand Coordination and Hierarchical Structure Design.
Electronic sensors capable of capturing mechanical deformation are highly desirable for the next generation of artificial intelligence products. However, it remains a challenge to prepare self-healing, highly sensitive, and cost-efficient sensors for both tiny and large human motion monitoring. Here, a new kind of self-healing, sensitive, and versatile strain sensors has been developed by combining metal-ligand chemistry with hierarchical structure design. Specifically, a self-healing and nanostructured conductive layer is deposited onto a self-healing elastomer substrate cross-linked by metal-ligand coordinate bonds, forming a hierarchically structured sensor. The resultant sensors exhibit high sensitivity, low detection limit (0.05% strain), remarkable self-healing capability, as well as excellent reproducibility. Notably, the self-healed sensors are still capable to precisely capture not only tiny physiological activities (such as speech, swallowing, and coughing) but also large human motions (finger and neck bending, touching). Moreover, harsh treatments, including bending over 50000 times and mechanical washing, could not influence the sensitivity and stability of the self-healed sensors in human motion monitoring. This proposed strategy via alliance of metal-ligand chemistry and hierarchical structure design represents a general approach to manufacturing self-healing, robust sensors, and other electronic devices.


Phage specificity and lipopolysaccarides of stem- and root-nodulating bacteria (Azorhizobium caulinodans, Sinorhizobium spp., and Rhizobium spp.) of Sesbania spp.
Phage susceptibility pattern and its correlation with lipopolysaccharide (LPS) and plasmid profiles may help in understanding the phenotypic and genotypic diversity among highly promiscuous group of rhizobia nodulating Sesbania spp.; 43 phages were from two stem-nodulating bacteria of S. rostrata and 16 phages were from root-nodulating bacteria of S. sesban, S. aegyptica and S. rostrata. Phage susceptibility pattern of 38 Sesbania nodulating bacteria was correlated with their LPS rather than plasmid profiles. Different species of bacteria (A. caulinodans- ORS571, SRS1-3 and Sinorhizobium saheli- SRR907, SRR912) showing distinct LPS subtypes were susceptible to different group of phages. Phages could also discriminate the strains of Si. saheli (SSR312, SAR610) possessing distinct LPS subtypes. Phages of Si. meliloti (SSR302) were strain-specific. All the strains of R. huautlense having incomplete LPS (insignificant O-chain) were phage-resistant. In in vitro assay, 100% of the phages were adsorbed to LPS of indicator bacterium or its closely related strain(s) only. These observations suggest the significance of LPS in phage specificity of Sesbania nodulating rhizobia. Highly specific phages may serve as biological marker for monitoring the susceptible bacterial strains in culture collections and environment.


[The causes of hydration changes during DNA protonation].
Changes of DNA hydration provoked by protonation in the way of Na+- and H+-ions exchange, and in the way of HCl addition to Na+-DNA, were analysed by IR-spectroscopy. Water is shown not to contribute essentially to the formation and stabilization of conformations arising when DNA is protonated. The differences between hydratation of DNA protonated by different ways are in the main accounted for by alteration of the quantities of Na+ and Cl- ions forming the aqueous-salt envelope of polynucleotide.


Attempts to strengthen and simplify the tumor vascular normalization strategy using tumor vessel normalization promoting nanomedicines.
Tumor vascular normalization theory opened the door for the rational use of antiangiogenic agents and chemotherapeutics. However, efforts to seize the normalization window have constrained the development of vascular normalization therapy in clinical applications owing to the lack of circulating biomarkers and the tedious dosage regimes. Applying "Occam's Razor" to therapeutic design inspired us to construct an effective and simple tumor vascular normalization prompting strategy. Herein, we developed tumor vessel normalization prompting nanomedicine lipid derivative conjugates (LGCs) made of anti-angiogenic agents with low molecular weight heparin (LMWH) and gemcitabine (Gem). This treatment exploits the complementary action of anti-vascular endothelial growth factor (VEGF) therapy and metronomic chemotherapy (MET) to strengthen the tumor vascular normalization effect. Furthermore, by loading cytotoxic drugs, such as paclitaxel (PTX), into the LGCs we constructed a "nano-community" to simultaneously restore the tumor vasculature and deliver the loaded drugs. Accordingly, improved drug delivery and therapeutic outcomes were achieved with no need to identify the precise time of the normalization window. Overall, our studies suggest that tumor vessel normalization therapy and nanomedicine design could be combined in one entity, using two waves of normalization strategies to achieve optimal chemo drug delivery into solid tumors.


Antimicrobial resistance in the Bacteroides fragilis group in faecal samples from patients receiving broad-spectrum antibiotics.
Members of the Bacteroides fragilis group are opportunistic pathogens and cause severe infections including bacteraemia. As increased levels of antimicrobial resistance in B. fragilis group bacteria can be detected years after administration of specific antibiotics, monitoring antimicrobial susceptibility in the gut microbiota could be important. The objectives of this study were to 1) investigate the distribution of species and the occurrence of reduced antimicrobial susceptibility in the B. fragilis group from patients treated at departments with a high level of antibiotic use, 2) to determine the prevalence of the carbapenem resistance gene cfiA in B. fragilis in this patient group, and 3) to determine the association between previous antibiotic treatment and reduced susceptibility to clindamycin, meropenem, metronidazole, and piperacillin-tazobactam. Consecutive faecal samples (n = 197) were collected from patients at the departments of haematology, oncology, and infectious diseases at Odense University Hospital, Denmark. Three colonies from each sample were identified by Matrix Assisted Lazer Desorption Ionization Time of Flight Mass Spectrometry and isolates were screened for resistance to clindamycin, meropenem, metronidazole, and piperacillin-tazobactam. B. fragilis isolates were tested for the cfiA metallo-beta-lactamase gene. Fisher's Exact test was used to test for correlation between antimicrobial exposure and reduced susceptibility. A total of 359 isolates were tested for reduced susceptibility. Of these 28%, 5%, <1%, and 11% were intermediate susceptible or resistant to clindamycin, meropenem, metronidazole, and piperacillin-tazobactam respectively. Three metronidazole resistant Bacteroides spp. were isolated. The proportion of B. fragilis belonging to division II (cfiA+) was 5.3%. Previous exposure to meropenem was associated with reduced susceptibility to meropenem (p= 0.001). In conclusion, antimicrobial resistance is prevalent and the distribution of species appears to be affected in the B. fragilis group from patients receiving broad-spectrum antibiotics, with meropenem exposure being associated with meropenem resistance.


Atrial fibrillation diagnosed after stroke and dementia risk: cohort study of first-ever ischaemic stroke patients aged 65 or older.
Atrial fibrillation (AF) is a risk factor for dementia among ischaemic stroke patients in whom the AF was known before the stroke (KAF). Atrial fibrillation detected after stroke (AFDAS) has a different profile compared to KAF, including less frequent cardiovascular comorbidities and lower CHA2-DS2-VASC scores. Currently, it is unknown if AFDAS is also associated with increased dementia risk. We assessed the association between AFDAS and the incident risk of dementia. We also evaluated whether the use of oral anticoagulants (OAC) was associated with lower dementia risk among AFDAS patients. In this cohort study, we classified 9791 first-ever ischaemic stroke patients from the Ontario Stroke Registry into four groups: (i) No AF, (ii) KAF, (iii) Inpatient AFDAS (diagnosed during admission), and (iv) Outpatient AFDAS (diagnosed after discharge). We used multivariable Cox proportional models to estimate hazard ratios (HR) for the association between AFDAS and incident dementia risk. Dementia was determined through administrative datasets based on previously validated algorithms. In adjusted analyses, the dementia risk was higher for inpatient AFDAS [HR 1.78, 95% confidence interval (CI) 1.51-2.10] and outpatient AFDAS (HR 1.74, 95% CI 1.47-2.05) relative to no AF. Oral anticoagulants use was associated with lower dementia risk among patients with inpatient AFDAS (HR 0.58, 95% CI 0.43-0.79) and outpatient AFDAS (HR 0.60, 95% CI 0.43-0.83). Atrial fibrillation detected after stroke was independently associated with higher risk of dementia relative to no AF. Among patients with AFDAS, the use of OACs was associated with lower dementia risk.


The Relationship between Sleep Quality and Brain Amyloid Burden.
To evaluate the association between self-reported sleep quality and levels of brain β-amyloid (Aβ) burden, and to determine the effect of the apolipoprotein E (APOE) ε4 allele on any associations found. This study is a cross-sectional analysis of 184 cognitively healthy men and women aged over 60 y. We measured sleep quality factors: specifically, sleep duration, latency (time taken to fall asleep), disturbances, efficiency, daytime dysfunction, and overall sleep quality, using the Pittsburgh Sleep Quality Index. All participants underwent Aβ positron emission tomography imaging for the quantification of brain Aβ burden and were APOE genotyped. Linear regression analyses were used to evaluate the relationship between sleep quality factors and brain Aβ burden, adjusting for age, body mass index, cardiovascular disease, and symptoms of depression, with APOE ε4 carriage entered as a moderator. Of the sleep factors, longer sleep latency was associated with higher levels of brain Aβ (B = 0.003 [standard error = 0.001], P = 0.02). APOE ε4 allele (carrier/noncarrier) did not moderate the relationship between sleep latency and brain Aβ burden. Our findings suggest a relationship between brain Aβ burden and sleep latency, independent of APOE ε4 genotype.


Apurinic endonucleases from Saccharomyces cerevisiae also recognize urea residues in oxidized DNA.
Saccharomyces cerevisiae apurinic endonucleases E cochromatographed with activity against a DNA substrate containing urea residues. The urea-recognizing activity of endonuclease E was competitively inhibited by apurinic DNA, and the heat labilities of both activities were the same. The apparent VmaxS of endonuclease E for both substrates were about the same, while the apparent Km for urea-containing DNA was about threefold greater than that for apurinic DNA. These results were similar to those obtained previously with Escherichia coli exonuclease III (Y. Kow and S. Wallace, Proc. Natl. Acad. Sci. USA 82:8354-8358, 1985) and suggest that the ability to recognize urea residues may be a general property of apurinic endonucleases.


Venous Sinus Stenting for Low Pressure Gradient Stenoses in Idiopathic Intracranial Hypertension.
Medically refractory idiopathic intracranial hypertension (IIH) is frequently treated with venous sinus stenosis stenting with high success rates. Patient selection has been driven almost exclusively by identification of supraphysiological venous pressure gradients across stenotic regions based on theoretical assessment of likelihood of response. To explore the possibility of benefit in low venous pressure gradient patients. Using a single-center, prospectively maintained registry of patients with IIH undergoing venous stenting, we defined treatment groups by gradient pressures of ≤4, 5 to 8, and >8 mmHg based on the most frequently previously published thresholds for stenting. Baseline demographics, clinical, and neuro-ophthalmological outcomes (including optical coherence tomography and Humphrey visual fields) were compared. Among 53 patients, the mean age was 32 years and 70% female with a mean body mass index was 36 kg/m 2 . Baseline characteristics were similar between groups. The mean change in lumbar puncture opening pressure at 6 months poststenting was similar between the 3 groups (≤4, 5-8, and >8 mmHg; 13.4, 12.9, and 12.4 cmH 2 O, P = .47). Papilledema improvement was observed across groups at 6 months (100, 93, and 86, P = .7) as were all clinical symptoms. The mean changes in optical coherence tomography retinal nerve fiber layer (-30, -54, and -104, P = .5) and mean deviation in Humphrey visual fields (60, 64, and 67, P = .5) at 6 weeks were not significantly different. Patients with IH with low venous pressure gradient venous sinus stenosis seem to benefit equally from venous stenting compared with their higher gradient counterparts. Re-evaluation of our restrictive criteria for this potentially vision sparing intervention is warranted. Future prospective confirmatory studies are needed.


Genetic Association of Solute Carrier Transporter Gene Variants with Metformin Response.
Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by elevated blood glucose levels and is influenced by both genetic and environmental factors. It is treated with various classes of oral antidiabetic drugs, however, response to treatment is highly variable with patients failing to achieve adequate glycemic control. Treatment response variability has been associated with single nucleotide polymorphisms (SNPs) which influence the pharma-cokinetics and pharmacodynamics of drug(s). The aim of this study was to evaluate the genetic association of 17 SNPs and the response to metformin therapy in patients diagnosed with diabetes from the indigenous Nguni population of South Africa. One hundred and forty indigenous African patients diagnosed with T2DM were recruited and genotyped using the MassARRAY® system. Therapeutic response of patients was ascertained by a change in Hb A1c. Two SNPs (rs1801282 and rs6265) were monomorphic. All other variants were within the Hardy-Weinberg equilibrium (HWE). The T allele of the SLC variant rs316009 [odds ratio (OR) = 0.25, 95% confidence interval (95% CI) = 0.01-0.09, p value = 0.044] and the CT genotype of the PCK1 variant rs4810083 (OR = 2.80, 95% CI = 1.01-7.79, p value = 0.049) were associated with an improved response to treatment after adjustment. No association was observed with post Bonferroni correction. Moreover, this study provides important additional data regarding possible associations between genetic variants and metformin therapy outcomes. In addition, this is one of the first studies providing genetic data from the understudied indigenous sub-Saharan African populations.


Risk factors for childhood obesity in elementary school-age Taiwanese children.
A cross-sectional study design was used to examine factors that contribute to high relative weight in children in Taiwan. A total sample of 331 Chinese children (ages 7 and 8) and their parents participated in the study. Parents completed questionnaires regarding demographic information, family functioning, parenting styles, physical activity, and dietary intake. Children completed physical fitness tests and questionnaires regarding physical activity, dietary intake, coping strategies, and self-esteem. The weight-for-length index was used to measure children's relative weight. The findings revealed that four variables contributed to higher weight-for-length index in boys compared with girls and explained 37.7% of the variance: high maternal body mass index, poor aerobic capacity, healthy family role functioning, and poor family affective responsiveness. Two variables were found to contribute to higher weight-for-length index in girls and explained 12.8% of the variance: high household income and high maternal body mass index. Taken together, the results indicate the importance of assessment of children's weight status, maternal weight status, and family functioning as part of routine child health care and the need for developmentally appropriate and gender-specific approaches to prevent childhood obesity.


Mitochondrial function in neuronal cells depends on p97/VCP/Cdc48-mediated quality control.
Maintaining mitochondrial function is essential for neuronal survival and offers protection against neurodegeneration. Ubiquitin-mediated, proteasome-dependent protein degradation in the form of outer mitochondrial membrane associated degradation (OMMAD) was shown to play roles in maintenance of mitochondria on the level of proteostasis, but also mitophagy and cell death. Recently, the AAA-ATPase p97/VCP/Cdc48 was recognized as part of OMMAD acting as retrotranslocase of ubiquitinated mitochondrial proteins for proteasomal degradation. Thus, p97 likely plays a major role in mitochondrial maintenance. Support for this notion comes from mitochondrial dysfunction associated with amyotrophic lateral sclerosis and hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) caused by p97 mutation. Using SH-SY5Y cells stably expressing p97 or dominant-negative p97(QQ) treated with mitochondrial toxins rotenone, 6-OHDA, or Aβ-peptide as model for neuronal cells suffering from mitochondrial dysfunction, we found mitochondrial fragmentation under normal and stress conditions was significantly increased upon inactivation of p97. Furthermore, inactivation of p97 resulted in loss of mitochondrial membrane potential and increased production of reactive oxygen species (ROS). Under additional stress conditions, loss of mitochondrial membrane potential and increased ROS production was even more pronounced. Loss of mitochondrial fidelity upon inactivation of p97 was likely due to disturbed maintenance of mitochondrial proteostasis as the employed treatments neither induced mitophagy nor cell death. This was supported by the accumulation of oxidatively-damaged proteins on mitochondria in response to p97 inactivation. Dysfunction of p97 under normal and stress conditions in neuron-like cells severely impacts mitochondrial function, thus supporting for the first time a role for p97 as a major component of mitochondrial proteostasis.


Praziquantel for control of Hymenolepis nana in mice.
Praziquantel was blended into ground mouse feed at 35, 70, and 140 ppm in one replicate and at 140, 210, and 280 ppm in a second replicate. Mice naturally infected with Hymenolepis nana were provided this diet for 7 consecutive days. Reduction of Hymenolepis nana in mice receiving medicated feed when compared to mice receiving nonmedicated feed was 48.9, 73.2, and 87.1%, respectively in replicate 1, and 100% in all three groups in replicate 2. These data suggest that praziquantel blended into the feed at 140 ppm for 7 consecutive days will provide efficacious (87.1-100%) control of Hymenolepis nana in mice. Higher dosages may be necessary for complete elimination of this parasite.


Neuropsychiatric features of acute disseminated encephalomyelitis: a review.
Acute disseminated encephalomyelitis is a disorder associated with significant morbidity and mortality. A description and literature review are presented to focus attention on the myriad neuropsychiatric manifestations of this disease. Common psychiatric symptoms include lethargy, irritability, and confusion. Ataxia, seizures, and other signs representing involvement of various areas of the brain and spinal cord are common neurologic presentations. The cerebrospinal fluid shows only nonspecific abnormalities, whereas magnetic resonance imaging may show various lesions in the white matter representing demyelination. The treatment of choice is steroids, but there can be significant residual sequelae of the disease, including intellectual and behavioral abnormalities.


[The role of family relationships in the initiation of street drug abuse by institutionalized youths].
The objective of this study was to analyze the role of family relationships in the initiation of streetdrug abuse by youths, meeting social-educational measures, considering the severity of the problems that drug abuse brought to the youths and their families. This descriptive, cross-sectional study used a case series design and was developed in the cities of Rolândia and Cambé (Brazil), at the Vida Nova Halfway House, with institutionalized youths and their parents or responsible adults in March 2007. Data was collected from institutional records and the instruments used were two interview forms. Data comparison was performed for analysis, according to the content analysis technique. Eleven families were studied. Signs of negligence and abandonment, physical abuse, lack of family dialogue, and especially a culture of drug use in the family environment determined the initiation of street-drug abuse.


The validity of person tradeoff measurements: randomized trial of computer elicitation versus face-to-face interview.
Can person tradeoff (PTO) value judgments be elicited by a computer, or is a face-to-face interview needed? The authors randomly assigned 95 subjects to interview or computer methods for the PTO, a valuation measure that is often difficult for subjects. They measured relative values of foot numbness, leg paralysis, and quadriplegia (all 3 pairs) at 2 reference group sizes (10 or 100). Relative values did not differ between computer and interview. Overall, 21% of responses were equality responses, 13% were high extreme values, and 5% violated ordinal criteria. The groups did not differ in these measures. The authors also assessed consistency across reference group size (10 v. 100). Although relative values were significantly lower for 100 than for 10, mode did not influence the size of this effect. Subjects made, on average, equally consistent judgments for the 3 comparisons. A computerized PTO elicitation protocol produced results of similar quality to that of a face-to-face interview.


Treatment of allergic asthma: modulation of Th2 cells and their responses.
Atopic asthma is a chronic inflammatory pulmonary disease characterised by recurrent episodes of wheezy, laboured breathing with an underlying Th2 cell-mediated inflammatory response in the airways. It is currently treated and, more or less, controlled depending on severity, with bronchodilators e.g. long-acting beta agonists and long-acting muscarinic antagonists or anti-inflammatory drugs such as corticosteroids (inhaled or oral), leukotriene modifiers, theophyline and anti-IgE therapy. Unfortunately, none of these treatments are curative and some asthmatic patients do not respond to intense anti-inflammatory therapies. Additionally, the use of long-term oral steroids has many undesired side effects. For this reason, novel and more effective drugs are needed. In this review, we focus on the CD4+ Th2 cells and their products as targets for the development of new drugs to add to the current armamentarium as adjuncts or as potential stand-alone treatments for allergic asthma. We argue that in early disease, the reduction or elimination of allergen-specific Th2 cells will reduce the consequences of repeated allergic inflammatory responses such as lung remodelling without causing generalised immunosuppression.


[Correlation between membrane and soluble forms of intestinal enzymes in rat ontogenesis].
With ageing the membrane/soluble form ratio of membrane-boundenzymes increases especially in the ileum and that of peptidases changes rather insignificantly in both portions of the rat small intestine. The soluble forms are supposed to take part in assimilation of food substrates penetrating enterocytes in an unsplit form due to an enhanced permeability of the membranes, particularly those of the ileum.


[Research progress on the promotion of peri-implant soft tissue integration of dental titanium implant based on immune microenvironment regulation].
A good integration of dental implants and the surrounding soft tissue is essential to ensure the long-term effect of implant. In this review, we summarized the research progress of peri-implant soft tissue integration of dental titanium implants, with emphasis on the modification of the gingival interface of implants based on immune microenvironment regulation. This method influences the immune response around the implant by promoting the surface properties of implants, so as to enhance the peri-implant soft tissue integration. The purpose of this review is to provide reference for the related research and clinical application in the field of dental implantation.


Plasma bile salt levels in patients presenting with generalised pruritus: an improved indicator of occult liver disease.
Fasting plasma bile salt concentrations were measured in 26 patients presenting to a Skin Department who had generalised pruritus without primary skin disease, as part of a screening investigation for systemic causes of pruritus. The results were compared with conventional tests of hepatic function. Plasma-conjugated cholate measurements identified all patients with hepatobiliary disease. Conventional liver function tests were abnormal in these patients but also in five patients with no other evidence of hepatic dysfunction. Fasting conjugated-cholate measurements offer a useful screening test for identifying hepatobiliary disease in patients presenting with generalised pruritus.


Effect of an Ala81His mutation on the Met80 loop dynamics of iso-1-cytochrome c.
An A81H variant of yeast iso-1-cytochrome c is prepared to test the hypothesis that the steric size of the amino acid at sequence position 81 of cytochrome c, which has evolved from Ala in yeast to Ile in mammals, slows the dynamics of the opening of the heme crevice. The A81H mutation is used both to increase steric size and to provide a probe of the dynamics of the heme crevice through measurement of the thermodynamics and kinetics of the His81-mediated alkaline conformational transition of A81H iso-1-cytochrome c. Thermodynamic measurements show that the native conformer is more stable than the His81-heme alkaline conformer for A81H iso-1-cytochrome c. ΔGu°(H2O) is approximately 1.9 kcal/mol for formation of the His81-heme alkaline conformer. By contrast, for K79H iso-1-cytochrome c, the native conformer is less stable than the His79-heme alkaline conformer. ΔGu°(H2O) is approximately -0.34 kcal/mol for formation of the His79-heme alkaline conformer. pH jump and gated electron transfer kinetics demonstrate that this stabilization of the native conformer in A81H iso-1-cytochrome c arises primarily from a decrease in the rate constant for formation of the His81-heme alkaline conformer, kf,His81, relative to kf,His79 for formation of the His79-heme alkaline conformer, which forms by a mechanism similar to that observed for the His81-heme alkaline conformer. The result is discussed in terms of the effect of global protein stability on protein dynamics and in terms of optimization of the sequence of cytochrome c for its role as a peroxidase in the early stages of apoptosis in higher eukaryotes.


[Plastic surgery in day hospital conditions: comparison between two hospital models].
Personal experience of plastic surgery carried out in Day Hospital conditions is reported. The experience took place within the hospital structure through two different organisational models called here transversal and divisional organisation models: characteristic of the former is that it uses a dedicated interdivisional structure within the hospital involving the centralization of all day-surgery activities, whereas the latter organizes Day Surgery activities within the operating unit whose structures it shares. On the basis of a comparison between the two models we were able to note advantages and disadvantages. We can review our experience in brief by stating that our own preference went to the transversal model which presents the indubitable advantage of being a logistic structure which is hinged on daytime activity and is ready therefore to satisfy on the one hand the needs of this type of patient and, on the other, the needs of the structure itself in efficiency terms. We propose to correct the disadvantages of the transversal model which can be outlined in its lack of homogeneity in the pathology treated and in the subtraction of the criterion of clinical priority in waiting lists through the attainment of a critical dimensional threshold such as to permit programmable sessions with patients with homogeneous pathology (i.e. belonging to the same hospital unit) and through the maintenance of a certain number of Day Hospital beds (around 25%) reserved for new emergency clinical cases.


Label-free characterization of biomembranes: from structure to dynamics.
We review recent progress in the study of the structure and dynamics of phospholipid membranes and associated proteins, using novel label-free analytical tools. We describe these techniques and illustrate them with examples highlighting current capabilities and limitations. Recent advances in applying such techniques to biological and model membranes for biophysical studies and biosensing applications are presented, and future prospects are discussed.


An extended DNA-free intranuclear compartment organizes centrosome microtubules in malaria parasites.
Proliferation of Plasmodium falciparum in red blood cells is the cause of malaria and is underpinned by an unconventional cell division mode, called schizogony. Contrary to model organisms, P. falciparum replicates by multiple rounds of nuclear divisions that are not interrupted by cytokinesis. Organization and dynamics of critical nuclear division factors remain poorly understood. Centriolar plaques, the centrosomes of P. falciparum, serve as microtubule organizing centers and have an acentriolar, amorphous structure. The small size of parasite nuclei has precluded detailed analysis of intranuclear microtubule organization by classical fluorescence microscopy. We apply recently developed super-resolution and time-lapse imaging protocols to describe microtubule reconfiguration during schizogony. Analysis of centrin, nuclear pore, and microtubule positioning reveals two distinct compartments of the centriolar plaque. Whereas centrin is extranuclear, we confirm by correlative light and electron tomography that microtubules are nucleated in a previously unknown and extended intranuclear compartment, which is devoid of chromatin but protein-dense. This study generates a working model for an unconventional centrosome and enables a better understanding about the diversity of eukaryotic cell division.


Ceftazidime/avibactam versus standard-of-care agents against carbapenem-resistant Enterobacteriaceae harbouring blaKPC in a one-compartment pharmacokinetic/pharmacodynamic model.
'Last-line' antimicrobial usage has promoted the emergence of MDR bacteria. Production of Klebsiella pneumoniae carbapenemases (KPCs) is increasingly common and leads to resistance to most antimicrobials. However, ceftazidime/avibactam demonstrates activity against KPC-producing strains. Ceftazidime/avibactam in the empirical setting remains unknown. Strains underwent genetic analysis evaluating blaKPC presence/production and MICs were determined. Four strains were assessed in an in vitro, one-compartment pharmacokinetic (PK)/pharmacodynamic (PD) model for 96 h. The following bolus dosing exposures were tested: 2.5 g of ceftazidime/avibactam every 8 h, 2 g of meropenem every 8 h, 1.25 mg/kg polymyxin B every 12 h, amikacin 'once-daily dosing' (peak of 70-80 mg/L), tigecycline at 200 mg ×1 dose followed by 100 mg every 12 h, and a drug-free growth control. Thirty blaKPC-producing strains were evaluated; 97% of strains were ceftazidime/avibactam susceptible with MIC50/MIC90 values of 0.38/1.5 mg/L (range 0.032-16 mg/L). Two K. pneumoniae strains, one Klebsiella oxytoca strain and one Citrobacter freundii strain underwent further analysis in PK/PD models. Ceftazidime/avibactam displayed potent activity with a reduction of 4.23 ± 0.42 cfu/mL from the initial inoculum at 96 h. Against susceptible isolates, amikacin displayed similar activity compared with ceftazidime/avibactam at 96 h, although this was not demonstrated against all strains. Polymyxin B produced comparable activity to ceftazidime/avibactam against two strains. Neither meropenem nor tigecycline produced effective killing and were comparable to the drug-free growth control at 96 h. blaKPC-producing organisms demonstrated susceptibility to ceftazidime/avibactam and bactericidal activity was observed in the PK/PD model. Based on these data, ceftazidime/avibactam is a valuable agent for treating KPC-producing organisms and should be considered for treatment of infections caused by these pathogens.


Cervical Spine Decompression and Fusion Outcomes in Trauma Patients Actively Receiving Anticoagulation Treatment for Cerebrovascular Injury: A Retrospective Comparative Study.
Cervical spine blunt trauma patients with the presence of a cerebrovascular injury may be given initiation of heparin anticoagulation treatment prior to necessary surgical stabilization. Literature regarding the safety and efficacy of these procedures while a patient is on active anticoagulation is limited, requiring further investigation. The primary research question for this study is: Can cervical spine decompression and fusion in the context of a blunt cerebrovascular injury and anticoagulation therapy be completed safely? To accomplish this a comparison of outcomes and perioperative complications was made to a control group. A total of 63 trauma patients requiring cervical spine decompression and fusion from 2013 to 2015 were identified at our North American level 1 trauma center. Evaluation of patient injury data, bleeding events, postoperative infections, and neurologic outcomes was collected from chart review. The American Spinal Injury Association (ASIA) grading system was used to measure change in postoperative neurologic outcomes. Of 63 patients, 14 had a concomitant cerebrovascular injury that required perioperative anticoagulation treatment. In the 14 patients receiving anticoagulation, 11 had anterior and 3 had posterior stabilization. A total of 2 patients experienced a complication (pneumonia and hardware failure), but neither was related to anticoagulation. An elevated prothrombin time value was noted postoperatively in 1 patient, but with no adverse outcome. No bleeding or thrombotic events, surgical site infection, or neurologic deterioration occurred. The difference in postoperative ASIA grades between groups was not significantly different (P = .57). The operative cohort receiving anticoagulation therapy did not demonstrate an increase affinity for perioperative complications or a decline in ASIA scores postoperatively when compared to a control cohort. Patients with a cerebrovascular injury receiving anticoagulation treatment can undergo safe and successful cervical spine stabilization procedures. Therapeutic level III.


[Circadian rhythmicity of the enzyme activity of different portions of the small intestine].
The circadian rhythms of maltase, alkaline phosphatase and dipeptide hydrolase were assessed in duodenum, proximal, medial and distal parts of the rat small intestine. Functional activities were assessed every 4 hrs for 24 hrs. Patterns of all enzymatic activities were different in different parts. The mucosal protein content in each segment of intestine was constant throughout the 24-hour period.


Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout.
Gout affects approximately 1-2% of the American population. Current options for treating hyperuricemia in chronic gout are limited. The purpose of this study was to assess the safety and efficacy of febuxostat, a nonpurine selective inhibitor of xanthine oxidase, in establishing normal serum urate (sUA) concentrations in gout patients with hyperuricemia (>or=8.0 mg/dl). We conducted a phase II, randomized, double-blind, placebo-controlled trial in 153 patients (ages 23-80 years). Subjects received febuxostat (40 mg, 80 mg, 120 mg) or placebo once daily for 28 days and colchicine prophylaxis for 14 days prior to and 14 days after randomization. The primary end point was the proportion of subjects with sUA levels <6.0 mg/dl on day 28. Greater proportions of febuxostat-treated patients than placebo-treated patients achieved an sUA level <6.0 mg/dl at each visit (P < 0.001 for each comparison). The targeted sUA level was attained on day 28 in 0% of those taking placebo and in 56% of those taking 40 mg, 76% taking 80 mg, and 94% taking 120 mg of febuxostat. The mean sUA reduction from baseline to day 28 was 2% in the placebo group and 37% in the 40-mg, 44% in the 80-mg, and 59% in the 120-mg febuxostat groups. Gout flares occurred with similar frequency in the placebo (37%) and 40-mg febuxostat (35%) groups and with increased frequency in the higher dosage febuxostat groups (43% taking 80 mg; 55% taking 120 mg). During colchicine prophylaxis, gout flares occurred less frequently (8-13%). Incidences of treatment-related adverse events were similar in the febuxostat and placebo groups. Treatment with febuxostat resulted in a significant reduction of sUA levels at all dosages. Febuxostat therapy was safe and well tolerated.


[Proton therapy in clinical neurosurgery].
The use of proton beam irradiation in neurosurgical clinical practice helps to find a solution to the problem of the treatment of inoperable malformations employing this method in some cases as an alternative to surgical intervention. Hypophyseal tumors, tumors of the cavernous sinus, arteriosinusal anastomoses in the cavernous sinus area, and arteriovenous malformations are irradiated at the N. N. Burdenko Institute of Neurosurgery, USSR, AMS using the medical proton beam of the Institute of Theoretical and Experimental Physics. Methods of "piercing" irradiation and methods with the use of Bragg's peak are being developed. At present over 200 patients with hormonally active hypophyseal tumors, 30 patients with tumors of the cavernous sinus, 23 patients with deep seated arteriovenous malformations, and 10 patients with spontaneous arteriosinusal anastomoses in the cavernous sinus area have been irradiated. This method seems to hold promise in neurosurgical practice. Extension of the range of clinical applications of proton beam therapy in neurosurgery requires the development of various techniques of irradiation, all possible approaches to various targets on the basis of contemporary methods of computerized diagnosis, topometry and irradiation design.


The impact of task load on the integration of explicit contextual priors and visual information during anticipation.
There is limited knowledge about the impact of task load on experts' integration of contextual priors and visual information during dynamic and rapidly evolving anticipation tasks. We examined how experts integrate contextual priors--specifically, prior information regarding an opponent's action tendencies--with visual information such as movement kinematics, during a soccer-specific anticipation task. Furthermore, we combined psychophysiological measures and retrospective self-reports to gain insight into the cognitive load associated with this integration. Players were required to predict the action of an oncoming opponent, with and without the explicit provision of contextual priors, under two different task loads. In addition to anticipation performance, we compared continuous electroencephalography (EEG) and self-reports of cognitive load across conditions. Our data provide tentative evidence that increased task load may impair performance by disrupting the integration of contextual priors and visual information. EEG data suggest that cognitive load may increase when contextual priors are explicitly provided, whereas self-report data suggested a decrease in cognitive load. The findings provide insight into the processing demands associated with integration of contextual priors and visual information during dynamic anticipation tasks, and have implications for the utility of priors under cognitively demanding conditions. Furthermore, our findings add to the existing literature, suggesting that continuous EEG may be a more valid measure than retrospective self-reports for in-task assessment of cognitive load.


Octopamine- and cyclic AMP-stimulated phosphorylation of a protein in Limulus ventral and lateral eyes.
The biogenic amine octopamine (OCT) fulfills most of the criteria as a neurotransmitter of efferent fibers that project to lateral and ventral eyes of the horseshoe crab, Limulus polyphemus. OCT is synthesized by and released from the efferent fibers, and OCT mimics many of the effects of endogenous efferent activity. OCT stimulates an increase in intracellular adenosine 3',5'-monophosphate (cAMP) in both ventral and lateral eyes, and many of the physiological effects of OCT in these eyes appear to be mediated via cAMP-dependent mechanisms. Here we show that OCT, acting apparently through an OCT-specific receptor, stimulates the increased phosphorylation of a protein with an apparent molecular weight of 122 kDa in both ventral and lateral eyes. This protein is also phosphorylated in response to 8-bromo cAMP and forskolin, suggesting that its phosphorylation involves activation of a cAMP-dependent protein kinase. We present evidence that the 122 kDa protein may be widely distributed in the Limulus visual system but that its phosphorylation in intact tissue in response to OCT, or agents acting through cAMP, may be restricted to portions containing photoreceptor cell bodies. The 122 kDa protein is quantitatively a major cellular protein in the photoreceptor cell body enriched portions of the ventral eye, its isoelectric point is between pH 6.2 and 6.4, and it is associated with both cell membranes and the cytoplasm. The function of this protein is not yet known. It may be important in mediating one or more of the effects of octopamine on Limulus vision.


Protocol: evaluation of an optimised couples-focused intervention to increase testing for HIV in rural KwaZulu-Natal, South Africa, the Igugu Lethu ('Our treasure') cohort study.
Between 2012 and 2015, the Uthando Lwethu (UL) study demonstrated that a theory-based behavioural couples-focused intervention significantly increased participation in couples HIV testing and counselling (CHTC) among South African couples who had never previously tested for HIV together or mutually disclosed their HIV status, 42% compared to 12% of the control group at 9 months follow-up. Although effective, we were nonetheless concerned that in this high prevalence setting the majority (58%) of intervention couples chose not to test together. In response we optimised the UL intervention and in a new study, 'Igugu Lethu', we are evaluating the success of the optimised intervention in promoting CHTC. One hundred eighty heterosexual couples, who have been in a relationship together for at least 6 months, are being recruited and offered the optimised couples-focused intervention. In the Igugu Lethu study, we have expanded the health screening visit offered to couples to include other health conditions in addition to CHTC. Enrolled couples who choose to schedule CHTC will also have the opportunity to undertake a random blood glucose test, blood pressure and BMI measurements, and self-sample for STI testing as part of their health screening. Individual surveys are administered at baseline, 4 weeks and 4 months follow-up. The proportion of couples who decide to test together for HIV will be compared to the results of the intervention arm in the UL study (historical controls). To facilitate this comparison, we will use the same recruitment and follow-up strategies in the same community as the previous UL study. By strengthening communication and functioning within the relationship, the Igugu Lethu study, like the previous UL study, aims to transform the motivation of individual partners from a focus on their own health to shared health as a couple. The Igugu Lethu study findings will answer whether the optimised couples-focused behavioural intervention and offering CHTC as part of a broader health screening for couples can increase uptake of CHTC by 40%, an outcome that would be highly desirable in populations with high HIV prevalence. Retrospectively registered. ISRCTN Registry ISRCTN 46162564 Registered on 26th May 2022.


An empirical Bayes approach for multiple tissue eQTL analysis.
Expression quantitative trait locus (eQTL) analyses identify genetic markers associated with the expression of a gene. Most up-to-date eQTL studies consider the connection between genetic variation and expression in a single tissue. Multi-tissue analyses have the potential to improve findings in a single tissue, and elucidate the genotypic basis of differences between tissues. In this article, we develop a hierarchical Bayesian model (MT-eQTL) for multi-tissue eQTL analysis. MT-eQTL explicitly captures patterns of variation in the presence or absence of eQTL, as well as the heterogeneity of effect sizes across tissues. We devise an efficient Expectation-Maximization (EM) algorithm for model fitting. Inferences concerning eQTL detection and the configuration of eQTL across tissues are derived from the adaptive thresholding of local false discovery rates, and maximum a posteriori estimation, respectively. We also provide theoretical justification of the adaptive procedure. We investigate the MT-eQTL model through an extensive analysis of a 9-tissue data set from the GTEx initiative.


Imaging techniques for the vulnerable coronary plaque.
The goal of this article is to illustrate the main invasive and noninvasive diagnostic modalities to image the vulnerable coronary plaque, which is responsible for acute coronary syndrome. The main epidemiologic and histological issues are briefly discussed in order to provide an adequate background. Comprehensive coronary atherosclerosis imaging should involve visualization of the entire coronary artery tree and plaque characterization, including three-dimensional morphology, relationship with the lumen, composition, vascular remodelling and presence of inflammation. No single technique provides such a comprehensive description, and no available modality extensively identifies the vulnerable plaque. In particular, we describe multislice computed tomography, which at present seems to be the most promising noninvasive tool for an exhaustive image-based quantification of coronary atherosclerosis.


Assessment and treatment of co-occurring eating disorders in privately funded addiction treatment programs.
Privately funded addiction treatment programs were surveyed to increase understanding of assessment and current treatment options for patients with co-occurring substance use and eating disorders. Data were collected from face-to-face interviews with program administrators of a nationally representative sample of 345 private addiction treatment programs. Although the majority of programs reported screening for eating disorders, programs varied in screening instruments used. Sixty-seven percent reported admitting cases of low severity. Twenty-one percent of programs attempt to treat eating disorders. These results highlight the need for education of addiction treatment professionals in assessment, referral, and treatment of eating disorders.


Water for maize for pigs for pork: An analysis of inter-provincial trade in China.
Trade in commodities implies trade in virtual water (VW), which refers to the water that was used to produce the traded goods. Various studies have quantified international or inter-provincial virtual water (VW) flows related to the trade in crops and animal products. Until date, however, no effort has been undertaken to understand how the water embodied in traded feed crops (trade stage TS1) will be transferred further because of trade in animal products (trade stage TS2). This is the first study showing this mechanism, in a case study in China for maize (the major pig feed) and pork (the dominant meat), considering the period 2000-2013. We estimate the annual green and blue water footprints in maize production and then quantify the inter-provincial VW flows related to trade in maize (TS1) and trade in maize embodied in pork (TS2). Results show that in TS1, maize-related VW flowed from the water-scarce North to the water-rich South, with an increase of 40% over the study period (from 43 to 61 billion m3 y-1). In TS2, about 10% of the water embodied in maize exports from North to South China returns in the form of pork, with an increase in the absolute amount of 25% (from 4.8 to 6.1 billion m3 y-1). Considering blue VW flows specifically, we find that North-to-South blue VW flows decreased by 5% in TS1, while South-to-North blue VW flows increased by 23% in TS2.


Enzymatic regulation of glucose disposal in human skeletal muscle after a high-fat, low-carbohydrate diet.
Whole body glucose disposal and skeletal muscle hexokinase, glycogen synthase (GS), pyruvate dehydrogenase (PDH), and PDH kinase (PDK) activities were measured in aerobically trained men after a standardized control diet (Con; 51% carbohydrate, 29% fat, and 20% protein of total energy intake) and a 56-h eucaloric, high-fat, low-carbohydrate diet (HF/LC; 5% carbohydrate, 73% fat, and 22% protein). An oral glucose tolerance test (OGTT; 1 g/kg) was administered after the Con and HF/LC diets with vastus lateralis muscle biopsies sampled pre-OGTT and 75 min after ingestion of the oral glucose load. The 90-min area under the blood glucose and plasma insulin concentration vs. time curves increased by 2-fold and 1.25-fold, respectively, after the HF/LC diet. The pre-OGTT fraction of GS in its active form and the maximal activity of hexokinase were not affected by the HF/LC diet. However, the HF/LC diet increased PDK activity (0.19 +/- 0.05 vs. 0.08 +/- 0.02 min(-1)) and decreased PDH activation (0.38 +/- 0.08 vs. 0.79 +/- 0.10 mmol acetyl-CoA.kg wet muscle(-1).min(-1)) before the OGTT vs. Con. During the OGTT, GS and PDH activation increased by the same magnitude in both diets, such that PDH activation remained lower during the HF/LC OGTT (0.60 +/- 0.11 vs. 1.04 +/- 0.09 mmol acetyl-CoA.kg(-1).min(-1)). These data demonstrate that the decreased glucose disposal during the OGTT after the 56-h HF/LC diet was in part related to decreased oxidative carbohydrate disposal in skeletal muscle and not to decreased glycogen storage. The rapid increase in PDK activity during the HF/LC diet appeared to account for the reduced potential for oxidative carbohydrate disposal.


Cost-effectiveness of fracture prevention treatments in the elderly.
The cost-effectiveness of fracture prevention treatments (vitamin D and calcium and hip protectors) in male and female populations older than seventy years of age in the United-Kingdom was investigated. A Markov model was developed to follow up, over lifetime, a hypothetical cohort of males and females at high-risk and general risk of fracture. Patients could sustain hip, wrist, vertebral, and/or other fractures. Fracture rates were obtained from population surveys in the United Kingdom. Effectiveness and quality of life data were identified from the clinical literature. Costs were those incurred by the UK National Health Service, and were obtained from several published sources. Uncertainty was explored through probabilistic sensitivity analysis. In the general-risk female (male) population, the incremental cost per Quality Adjusted Life Year (QALY) was dollar 11,722 (dollar 47,426) for hip protectors. In the male high-risk population, the incremental cost per QALY was dollar 17,017 for hip protectors. In the female high-risk population, hip protectors were cost-saving. Vitamin D and calcium alone was dominated by hip protectors in all four subgroups. Current information available on interventions to prevent fractures in the elderly in the United Kingdom, suggests that, at the decision-maker's ceiling ratio of dollar 20,000 per QALY, hip protectors are cost-effective in the general female population and high-risk male population, and cost-saving in the high-risk female population, despite the low compliance rate with the treatment.


Complex overlapping concepts: An effective auditing methodology for families of similarly structured BioPortal ontologies.
In previous research, we have demonstrated for a number of ontologies that structurally complex concepts (for different definitions of "complex") in an ontology are more likely to exhibit errors than other concepts. Thus, such complex concepts often become fertile ground for quality assurance (QA) in ontologies. They should be audited first. One example of complex concepts is given by "overlapping concepts" (to be defined below.) Historically, a different auditing methodology had to be developed for every single ontology. For better scalability and efficiency, it is desirable to identify family-wide QA methodologies. Each such methodology would be applicable to a whole family of similar ontologies. In past research, we had divided the 685 ontologies of BioPortal into families of structurally similar ontologies. We showed for four ontologies of the same large family in BioPortal that "overlapping concepts" are indeed statistically significantly more likely to exhibit errors. In order to make an authoritative statement concerning the success of "overlapping concepts" as a methodology for a whole family of similar ontologies (or of large subhierarchies of ontologies), it is necessary to show that "overlapping concepts" have a higher likelihood of errors for six out of six ontologies of the family. In this paper, we are demonstrating for two more ontologies that "overlapping concepts" can successfully predict groups of concepts with a higher error rate than concepts from a control group. The fifth ontology is the Neoplasm subhierarchy of the National Cancer Institute thesaurus (NCIt). The sixth ontology is the Infectious Disease subhierarchy of SNOMED CT. We demonstrate quality assurance results for both of them. Furthermore, in this paper we observe two novel, important, and useful phenomena during quality assurance of "overlapping concepts." First, an erroneous "overlapping concept" can help with discovering other erroneous "non-overlapping concepts" in its vicinity. Secondly, correcting erroneous "overlapping concepts" may turn them into "non-overlapping concepts." We demonstrate that this may reduce the complexity of parts of the ontology, which in turn makes the ontology more comprehensible, simplifying maintenance and use of the ontology.


Neuronal remodeling in retinal circuit assembly, disassembly, and reassembly.
Developing neuronal circuits often undergo a period of refinement to eliminate aberrant synaptic connections. Inappropriate connections can also form among surviving neurons during neuronal degeneration. The laminar organization of the vertebrate retina enables synaptic reorganization to be readily identified. Synaptic rearrangements are shown to help sculpt developing retinal circuits, although the mechanisms involved remain debated. Structural changes in retinal diseases can also lead to functional rewiring. This poses a major challenge to retinal repair because it may be necessary to untangle the miswired connections before reconnecting with proper synaptic partners. Here, we review our current understanding of the mechanisms that underlie circuit remodeling during retinal development, and discuss how alterations in connectivity during damage could impede circuit repair.


To the fringe and back: Violent extremism and the psychology of deviance.
We outline a general psychological theory of extremism and apply it to the special case of violent extremism (VE). Extremism is defined as motivated deviance from general behavioral norms and is assumed to stem from a shift from a balanced satisfaction of basic human needs afforded by moderation to a motivational imbalance wherein a given need dominates the others. Because motivational imbalance is difficult to sustain, only few individuals do, rendering extreme behavior relatively rare, hence deviant. Thus, individual dynamics translate into social patterns wherein majorities of individuals practice moderation, whereas extremism is the province of the few. Both extremism and moderation require the ability to successfully carry out the activities that these demand. Ability is partially determined by the activities' difficulty, controllable in part by external agents who promote or oppose extremism. Application of this general framework to VE identifies the specific need that animates it and offers broad guidelines for addressing this pernicious phenomenon. (PsycINFO Database Record


PEER systematic review of randomized controlled trials: Management of chronic low back pain in primary care.
To determine the proportion of chronic low back pain patients who achieve a clinically meaningful response from different pharmacologic and nonpharmacologic treatments. MEDLINE, EMBASE, Cochrane Library, and gray literature search. Published randomized controlled trials (RCTs) that reported a responder analysis of adults with chronic low back pain treated with any of the following 15 interventions: oral or topical nonsteroidal anti-inflammatory drugs (NSAIDs), exercise, acupuncture, spinal manipulation therapy, corticosteroid injections, acetaminophen, oral opioids, anticonvulsants, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors, cannabinoids, oral muscle relaxants, or topical rubefacients. A total of 63 RCTs were included. There was moderate certainty that exercise (risk ratio [RR] of 1.71; 95% CI 1.37 to 2.15; number needed to treat [NNT] of 7), oral NSAIDs (RR = 1.44; 95% CI 1.17 to 1.78; NNT = 6), and SNRIs (duloxetine; RR = 1.25; 95% CI 1.13 to 1.38; NNT = 10) provide clinically meaningful benefits to patients with chronic low back pain. Exercise was the only intervention with sustained benefit (up to 48 weeks). There was low certainty that spinal manipulation therapy and topical rubefacients benefit patients. The benefit of acupuncture disappeared in higher-quality, longer (> 4 weeks) trials. Very low-quality evidence demonstrated that corticosteroid injections are ineffective. Patients treated with opioids had a greater likelihood of discontinuing treatment owing to an adverse event (number needed to harm of 5) than continuing treatment to derive any clinically meaningful benefit (NNT = 16), while those treated with SNRIs (duloxetine) had a similar likelihood of continuing treatment to attain benefit (NNT = 10) as those discontinuing the medication owing to an adverse event (number need to harm of 11). One trial each of anticonvulsants and topical NSAIDs found similar benefit to that of placebo. No RCTs of acetaminophen, cannabinoids, muscle relaxants, selective serotonin reuptake inhibitors, or tricyclic antidepressants met the inclusion criteria. Exercise, oral NSAIDs, and SNRIs (duloxetine) provide a clinically meaningful reduction in pain, with exercise being the only intervention that demonstrated sustained benefit after the intervention ended. Future high-quality trials that report responder analyses are required to provide a better understanding of the benefits and harms of interventions for patients with chronic low back pain.