Are Edentulousness, Oral Health Problems and Poor Health-Related Quality of Life Associated with Malnutrition in Community-Dwelling Elderly (Aged 75 Years and Over)? A Cross-Sectional Study.
As the population ages, the risk of becoming malnourished increases. Research has shown that poor oral health can be a risk factor for malnutrition in institutionalized elderly. However, it remains unclear whether oral health problems, edentulousness and health-related quality of life also pose a risk for malnutrition in community-dwelling older adults. In this cross-sectional observational study, 1325 community-living elderly (≥75 years) were asked to complete questionnaires regarding nutritional status, oral status (edentulous, remaining teeth, or implant-supported overdentures), oral health problems, health-related quality of life (HRQoL), frailty, activities of daily living (ADL) and complexity of care needs. Univariate and multivariate logistic regression analyses were performed with nutritional status as dependent variable. Of the respondents, 51% (n = 521) were edentulous, 38.8% (n = 397) had remaining teeth and 10.2% (n = 104) had an implant-supported overdenture. Elderly with complex care needs were malnourished most frequently, followed by frail and robust elderly (10%, 4.5% and 2.9%, respectively). Malnourished elderly reported more frequent problems with chewing and speech when compared with well-nourished elderly (univariate analysis). However, multivariate analysis did not show an association between malnutrition and oral health problems and edentulousness, although HRQoL was associated with malnutrition (odds ratio (OR) 0.972, confidence interval (CI) 0.951⁻0.955). Based on the results of this cross-sectional study, it can be concluded that poor HRQoL is significantly associated with malnutrition; however, edentulousness and oral health problems are not.


Strengthening insurance partnerships in the face of climate change - Insights from an agent-based model of flood insurance in the UK.
Multisectoral partnerships are increasingly cited as a mechanism to deliver and improve disaster risk management. Yet, partnerships are not a panacea and more research is required to understand the role that they can play in disaster risk management and particularly disaster risk reduction. This paper investigates how partnerships can incentivise flood risk reduction by focusing on the UK public-private partnership on flood insurance. Developing the right flood insurance arrangements to incentivise flood risk reduction and adaptation to climate change is a key challenge. In the face of rising flood risks due to climate change and socio-economic development insurance partnerships can no longer afford to focus only on the risk transfer function. However, while expectations of the insurance industry have traditionally been high when it comes to flood risk management, the insurance industry alone will not provide the solution to the challenge of rising risks. The case of flood insurance in the UK illustrates this: even national government and industry together cannot fully address these risks and other actors need to be involved to create strong incentives for risk reduction. Using an agent-based model focused on surface water flood risk in London we analyse how other partners could strengthen the insurance partnership by reducing flood risk and thus helping to maintain affordable insurance premiums. Our findings are relevant for wider discussions on the potential of insurance schemes to incentivise flood risk management and climate adaptation in the UK and also internationally.


Bacillus anthracis phospholipases C facilitate macrophage-associated growth and contribute to virulence in a murine model of inhalation anthrax.
Several models of anthrax pathogenesis suggest that early in the infectious process Bacillus anthracis endospores germinate and outgrow into vegetative bacilli within phagocytes before being released into the blood. Here, we define the respective contributions of three phospholipases C (PLCs) to the pathogenesis of B. anthracis. Genetic deletions of the PLCs were made in the Sterne 7702 background, resulting in the respective loss of their activities. The PLCs were redundant both in tissue culture and in murine models of anthrax. Deletion of all three PLC genes was required for attenuation of virulence in mice after intratracheal inoculation. This attenuation may be attributed to the inability of the PLC-null strain to grow in association with the macrophage. Complementation of these defects in both models of anthrax was achieved by expression of the PLC genes in trans. The functional redundancy between PLCs in the virulence of B. anthracis implies that their activities are important for anthrax pathogenesis.


Association among sickle cell trait, fitness, and cardiovascular risk factors in CARDIA.
The contribution of sickle cell trait (SCT) to racial disparities in cardiopulmonary fitness is not known, despite concerns that SCT is associated with exertion-related sudden death. We evaluated the association of SCT status with cross-sectional and longitudinal changes in fitness and risk for hypertension, diabetes, and metabolic syndrome over the course of 25 years among 1995 African Americans (56% women, 18-30 years old) in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Overall, the prevalence of SCT was 6.8% (136/1995) in CARDIA, and over the course of 25 years, 46% (738/1590), 18% (288/1631), and 40% (645/1,611) of all participants developed hypertension, diabetes, and metabolic syndrome, respectively. Compared with participants without SCT, participants with SCT had similar baseline measures of fitness in cross-section, including exercise duration (535 vs 540 seconds; P = .62), estimated metabolic equivalent of tasks (METs; 11.6 vs 11.7; P = .80), maximum heart rate (174 vs 175 beats/min; P = .41), and heart rate at 2 minutes recovery (44 vs 43 beats/min; P = .28). In our secondary analysis, there was neither an association of SCT status with longitudinal changes in fitness nor an association with development of hypertension, diabetes, or metabolic syndrome after adjustment for sex, baseline age, body mass index, fitness, and physical activity. SCT is not associated with reduced fitness in this longitudinal study of young African American adults, suggesting the increased risk for exertion-related sudden death in SCT carriers is unlikely related to fitness. SCT status also is not an independent risk factor for developing hypertension, diabetes, or metabolic syndrome.


Cultured dermal papilla cells from androgen-dependent human hair follicles (e.g. beard) contain more androgen receptors than those from non-balding areas of scalp.
Androgens stimulate hair growth in many areas, e.g. the beard; they also induce regression and balding on the scalp with increasing age in genetically disposed individuals. The cause(s) of this biological conundrum is unknown but age-related; androgen-potentiated changes also occur in the prostate. The mesenchyme-derived dermal papilla situated at the base of the hair follicle is thought to play an important role in regulating the growth and development of the follicular epithelium. Since androgens probably act on the hair follicle via the dermal papilla, cultures of dermal papilla cells from human hair follicles with differing responses to androgens in vivo have been established and their ability to bind androgens assessed. Receptor binding was assayed by saturation analysis (0.05-10 nmol/l) using the synthetic non-metabolizable androgen, [3H]mibolerone. Shionogi 115 cells were also assayed as a positive control. Specific high-affinity low-capacity androgen receptors were identified in 12 dermal papilla primary cell lines with similar characteristics to established androgen receptors. Cells from androgen-sensitive follicles (beard, scrotum and pubis) contained higher levels of androgen receptors than those derived from relatively androgen-insensitive non-balding scalp follicles whether the receptor content was calculated in relation to cell number, protein or DNA content of the cells. These results support the hypothesis that androgens act on hair follicles via the dermal papilla in vivo and demonstrate that dermal papilla cells exhibit an altered phenotype in culture which depends on the body site from which they were derived.(ABSTRACT TRUNCATED AT 250 WORDS)


Renal function of patients in long-term treatment with lithium citrate alone or in combination with neuroleptics and antidepressant drugs.
Renal function was studied in patients given lithium citrate alone or in combination with neuroleptics or tricyclic antidepressants or both. No other drugs were given. None of the groups given lithium citrate with other drugs had lithium ion clearances that differed significantly from the groups given lithium citrate alone, nor was there any difference in the clearances of sodium, potassium, or creatinine between these groups. The 24-hour urine volume of patients receiving antidepressant drugs was similar to that of the patients receiving lithium citrate monotherapy but was significantly higher in patients given neuroleptics. The increase in urine volume could not be ascribed to alterations in glomerular filtration rate or proximal tubular resorption but could be accounted for entirely by lowered resorption of water in the distal tubules. We concluded that no change of lithium citrate dose is required when patients so treated are given additional neuroleptic or tricyclic antidepressant drugs.


Acute doxorubicin cardiotoxicity is successfully treated with the phytochemical oleuropein through suppression of oxidative and nitrosative stress.
Oleuropein (oleu) is a natural phenolic antioxidant, which is present in elevated concentration in olives, olive oil and olive tree leaves. Doxorubicin (DXR) induced cardiotoxicity is mainly induced by oxidative stress but the precise mechanism remains obscure. However, there is evidence that high concentration of nitric oxide (NO) occurring as a result of iNOS induction and peroxynitrite formation may be involved in DXR cardiotoxicity. The aim of the present study was to evaluate a possible protective role of oleu in DXR induced cardiotoxicity in vivo. Fifty rats were divided into 6 groups and treated as follows: control group with a single injection of 2 ml normal saline intraperitoneally (i.p.), DXR group with a single dose of 20 mg/kg i.p, and DXR plus oleu groups with 20 mg/kg DXR i.p. and 100 or 200 mg/kg/BW of oleu i.p. for 5 or 3 consecutive days starting either 2 days before or on the day of DXR administration. Seventy-two hours after DXR treatment blood samples were collected for creatine phosphokinase (CPK), creatine phosphokinase-MB (CPK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) assessments and the rats were then sacrificed. Hearts were used for general histology, iNOS immunohistochemical and Western blot analysis, and for determination of tissue concentrations of lipid peroxidation products, protein carbonyls (PCs), and nitrotyrosine (NT). DXR treated animals demonstrated very extensive cytoplasmic vacuolisation whereas much less vacuolisation was found in oleu treated groups. They also revealed a significant elevation of cardiac enzymes release into systemic circulation (P<0.05 vs saline). Both doses of Oleu tested and both treatment protocols reduced DXR elevated serum levels of CPK, CPK-MB, LDH, AST and ALT (P<0.05). Furthermore, it reduced DXR induced lipid peroxidation, PCs content, NT concentration and iNOS induction in myocardial tissue (P<0.05). Oleu exerts a protective effect by eliminating DXR induced cardiotoxicity expressed by the alteration of intracellular and peripheral markers. Combined oleu and DXR treatment improves the therapeutic outcome by preventing undesirable toxicity.


[Pseudomonas aeruginosa: frequency of resistance to multiple drugs and cross-resistance between antimicrobials in Recife/PE].
The frequency of multiple-antibiotic resistant bacteria has been increasing in recent years. Among the gram-negative bacteria Pseudomonas aeruginosa (P. aeruginosa) shows a great propensity for the development of multidrug resistance mechanisms. The objective of this study was to identify the profile of susceptibility to antibiotics, the frequency of multidrug resistance and the cross-resistance between drugs of P. aeruginosa strains in two tertiary hospitals in Recife, Pernambuco. The study was carried out between September 2004 and January 2006. The antimicrobial susceptibility testing was performed in 304 strains of P. aeruginosa by the disc diffusion method in accordance with National Committee for Clinical and Laboratory Standards (NCCLS) guidelines. The most frequent materials were urine (26.7%) and respiratory tract secretion (26.1%) The antibiotics tested and their respective susceptibilities were as follows: piperacillin-tazobactam (66.2%); aztreonam (59.8%); amikacin (59.4%); meropenem (58.2%); imipenem (57.7%); ciprofloxacin (49.7%); gentamicin and cefepime (48.6%); ceftazidime (30%) and cefotaxime (6.8%). A high prevalence of multi-resistance was detected. Half (49.7%) the strains showed resistance to three or more antibiotics and 28% were resistant to six antimicrobials or more. Also, cross-resistance between the beta-lactams (carbapenems and piperacilin/tazobactam) and aminoglicosides and quinolones was between 22.9% and 38.1%. These drugs are commonly combined in the treatment of severe infections caused by Pseudomonas, which reflects the difficulty in choosing the appropriate option for combination therapy. The frequency of multidrug-resistant strains of P. aeruginosa in this study was similar to other hospitals in Brazil and higher than in other countries. In order to reduce the frequency of these multiresistant clones, epidemiologic surveillance and the rational use of antibiotic protocols need to be urgently implemented.


Regional Body Fat Changes and Metabolic Complications in Children With Dunnigan Lipodystrophy-Causing LMNA Variants.
Familial partial lipodystrophy, Dunnigan variety (FPLD2) is a rare autosomal-dominant disorder due to heterozygous missense lamin A/C (LMNA) mutations. Subjects with FPLD2 gradually lose fat from the upper and lower extremities but gain fat in the face and neck around puberty. However, the precise onset of body fat changes and metabolic complications during childhood remains unknown. To compare metabolic parameters and regional body fat in children with FPLD2 with the sex- and age-matched controls from the National Health and Nutrition Examination Survey (NHANES) 2005 to 2010. We measured fasting serum triglycerides, glucose, and skinfold thicknesses in all children (aged 1 to 18 years) harboring FPLD2-causing LMNA mutations and determined regional body fat by dual-energy X-ray absorptiometry in those aged ≥8 years. Thirty-two affected females and 14 males participated. The lower limb fat in all affected females, except one, was below or equal to the first percentile and in two affected males was below the fifth percentile for NHANES. One female subject with FPLD2 followed from age 6 to 16 years revealed marked loss of extremity fat much before thelarche. Serum triglycerides were higher in females with FPLD2 aged 7 to 18 years compared with controls (median 208 vs 70 mg/dL; P < 0.0001) and showed inverse correlation with extremity skinfolds. Serum triglycerides in males with FPLD2 were not significantly different than controls. The onset of fat loss from the extremities, especially in girls with FPLD2, occurs well before the onset of puberty. High serum triglycerides are seen in young females with FPLD2 with severe loss of fat from the extremities.


Molecular characterization of the pathogen-specific, 34-kilodalton membrane immunogen of Treponema pallidum.
The 34-kilodalton (kDa) antigen of Treponema pallidum subsp. pallidum (T. pallidum) is a pathogen-specific integral membrane protein. DNA sequence analysis of the cloned gene revealed an open reading frame encoding a primary product of 204 residues with a molecular mass of 22,087 daltons. Sequences that correspond to a consensus Escherichia coli promoter and a ribosome-binding site were found upstream from the AUG start codon that begins the open reading frame, suggesting that the cloned gene can use its own regulatory sequences for expression. Examination of the deduced amino acid sequence revealed the presence of a typical procaryotic leader peptide 19 amino acids long; processing results in a mature molecule with a molecular mass of 20,123 daltons. Pulse-chase experiments with E. coli minicells confirmed that the 34-kDa antigen is synthesized as a higher-molecular-weight precursor that is processed to a mature form with the electrophoretic mobility that is characteristic for this protein. The presence in the leader peptide of the sequence Phe-Ser-Ala-Cys suggested that the 34-kDa antigen is a proteolipid. Although hydropathy analysis of the deduced amino acid sequence of the mature 34-kDa antigen predicted that the molecule was primarily hydrophilic, both the native and recombinant 34-kDa molecules displayed hydrophobic biochemical behavior by fractionating into the detergent phase after extraction of intact organisms with Triton X-114. Cell fractionation experiments with E. coli showed that the 34-kDa molecule was localized in both the inner and outer membranes of the recombinant host. The combined data demonstrate that the 34-kDa antigen is an integral membrane protein that behaves in a biochemically consistent manner in both T. pallidum and E. coli.


Urine 5MedC, a Marker of DNA Methylation, in the Progression of Chronic Kidney Disease.
Alterations in DNA methylation may be involved in disease progression in patients with chronic kidney disease (CKD). Recent studies have suggested that 5-methyl-2'-deoxycytidine (5MedC) may be a marker of hypermethylation of DNA. Currently, there is no information available regarding the urine levels of 5MedC and its association with the progression of CKD. We examined the urine levels of 5MedC in spot urine samples from 308 patients with CKD (median age: 56 years, male: 53.2%, and glomerulonephritis: 51.0%) using a competitive enzyme-linked immunosorbent assay and investigated the relationships among urine 5MedC, urine albumin, urine α1-microglobulin (α1MG), and the laboratory parameters associated with CKD. The patients were followed for three years to evaluate renal endpoints in a prospective manner. The urine 5MedC level was significantly increased in the later stages of CKD compared to the early to middle stages of CKD. In multiple logistic regression models, urine 5MedC was significantly associated with the prediction of later CKD stages. Urine 5MedC (median value, 65.9 μmol/gCr) was significantly able to predict a 30% decline in the estimated GFR or a development of end-stage renal disease when combined with macroalbuminuria or an increased level of urine α1MG (median value, 5.7 mg/gCr). The present data demonstrate that the urine 5MedC level is associated with a reduced renal function and can serve as a novel and potent biomarker for predicting the renal outcome in CKD patients. Further studies will be necessary to elucidate the role of urine DNA methylation in the progression of CKD.


Gastroesophageal reflux disease: diagnosis and management.
Gastroesophageal reflux disease (GERD) is a chronic, relapsing condition with associated morbidity and an adverse impact on quality of life. The disease is common, with an estimated lifetime prevalence of 25 to 35 percent in the U.S. population. GERD can usually be diagnosed based on the clinical presentation alone. In some patients, however, the diagnosis may require endoscopy and, rarely, ambulatory pH monitoring. Management includes lifestyle modifications and pharmacologic therapy; refractory disease requires surgery. The therapeutic goals are to control symptoms, heal esophagitis and maintain remission so that morbidity is decreased and quality of life is improved.


Lung volume reduction surgery combined with cardiac interventions.
Postoperative course and functional outcome were evaluated in patients who underwent lung volume reduction surgery (LVRS) or in combination with valve replacement (VR), percutaneous transluminal coronary angioplasty (PTCA), placement of a stent, or coronary artery bypass grafting (CABG). Patients with severe bronchial obstruction and hyperinflation due to pulmonary emphysema were evaluated for lung volume reduction surgery. Cardiac disorders were screened by history and physical examination and assessed by coronary angiography. Nine patients were accepted for LVRS in combination with an intervention for coronary artery disease (CAD). In addition, three patients with valve disease and severe emphysema were accepted for valve replacement (two aortic-, one mitral valve) only in combination with LVRS. Functional results over the first 6 months were analysed. Pulmonary function testing demonstrates a significant improvement in postoperative FEV1 in patients who underwent LVRS combined with an intervention for CAD. This was reflected in reduction of overinflation (residual volume/total lung capacity (RV/TLC)), and improvement in the 12-min walking distance and dyspnea. Median hospital stay was 15 days (10-33). One patient in the CAD group died due to pulmonary edema on day 2 postoperatively. One of the three patients who underwent valve replacement and LVRS died on day 14 postoperatively following intestinal infarction. Both survivors improved in pulmonary function, dyspnea score and exercise capacity. Complications in all 12 patients included pneumothorax (n = 2), hematothorax (n = 1) and urosepsis (n = 1). Functional improvement after LVRS in patients with CAD is equal to patients without CAD. Mortality in patients who underwent LVRS after PTCA or CABG was comparable to patients without CAD. LVRS enables valve replacement in selected patients with severe emphysema otherwise inoperable.


Microfluidic train station: highly robust and multiplexable sorting of droplets on electric rails.
Fluorescence-activated droplet sorting (FADS) has become a widely used technique for high-throughput screening applications. However, existing methods are very sensitive to fluctuating flow rates at the sorting junction, which can be caused by the pulsing effects of mechanical pumps, droplet aggregates or the accumulation of precipitates during lengthy biological screening applications. Furthermore, existing sorting devices allow only 2-way sorting. We present here a dielectrophoretic sorting system in which the droplets are sorted along multiple electrode pairs that run parallel to the channels. This enables highly reliable sorting (no errors were detected for more than 2000 sorting events) even when inverting the relative flow rates at a 2-way sorting junction from 80 : 20 to 20 : 80. Furthermore, our toolbox is scalable: we demonstrate on the example of a triple-colour sorting experiment with a total of four decoupled electrodes that multi-way sorting is feasible.


Identification and typing of herpes simplex virus by enzyme immunoassay with monoclonal antibodies.
A double-antibody enzyme immunoassay was developed for the identification and typing of herpes simplex virus (HSV) by employing a polyclonal rabbit capture antiserum together with type-common and type 2-specific monoclonal antibodies as detectors. The test successfully identified 45 type I isolates and 30 type 2 isolates as HSVs. Compared with immunofluorescent staining and restriction endonuclease analysis, enzyme immunoassay correctly typed 45 type 1 and 30 type 2 HSV isolates. Enzyme immunoassay was 100% sensitive for identification of HSV as compared with cell culture and 100% specific for typing as compared with immunofluorescence and restriction endonuclease analysis. Electron microscopy analysis suggested that approximately 10(6) virus particles were required for the identification and typing of HSV by enzyme immunoassay.


Optimal management of skin cancer in immunosuppressed patients.
Skin cancer is the most common malignancy in humans with basal cell carcinoma representing the majority of cases in the general population. The prevalence of skin cancer is increased amongst immunosuppressed patients such as those with lymphoproliferative disorders including non-Hodgkin lymphoma and chronic lymphocytic leukemia or those with iatrogenic immunosuppression following organ transplantation. In addition, these patients experience greater morbidity and mortality associated with skin cancers. The most common skin cancer in immunosuppressed patients is squamous cell carcinoma, which often presents with more aggressive features and has a greater rate of metastasis. This article reviews the risk factors, etiology, clinical presentation, and prevalence of skin cancer amongst immunosuppressed patients, including organ transplant, lymphoproliferative disorders, autoimmune disorders, and human immunodeficiency virus. We also provide a comprehensive review of treatment guidelines for immunosuppressed patients with cutaneous malignancy. Surgical therapy is the cornerstone of treatment; however, we also discuss pharmacologic treatment options, lifestyle modifications, and revision of immunosuppressive regimens.


Quantification of ortholog losses in insects and vertebrates.
The increasing number of sequenced insect and vertebrate genomes of variable divergence enables refined comparative analyses to quantify the major modes of animal genome evolution and allows tracing of gene genealogy (orthology) and pinpointing of gene extinctions (losses), which can reveal lineage-specific traits. To consistently quantify losses of orthologous groups of genes, we compared the gene repertoires of five vertebrates and five insects, including honeybee and Tribolium beetle, that represent insect orders outside the previously sequenced Diptera. We found hundreds of lost Urbilateria genes in each of the lineages and assessed their phylogenetic origin. The rate of losses correlates well with the species' rates of molecular evolution and radiation times, without distinction between insects and vertebrates, indicating their stochastic nature. Remarkably, this extends to the universal single-copy orthologs, losses of dozens of which have been tolerated in each species. Nevertheless, the propensity for loss differs substantially among genes, where roughly 20% of the orthologs have an 8-fold higher chance of becoming extinct. Extrapolation of our data also suggests that the Urbilateria genome contained more than 7,000 genes. Our results indicate that the seemingly higher number of observed gene losses in insects can be explained by their two- to three-fold higher evolutionary rate. Despite the profound effect of many losses on cellular machinery, overall, they seem to be guided by neutral evolution.


Hepatic receptor that specifically binds oligosaccharides containing fucosyl alpha1 leads to 3 N-acetylglucosamine linkages.
Evidence is presented suggesting that hepatocytes contain a receptor that binds glycoproteins specifically through fucose in alpha1-->3 linkage to N-acetylglucosamine. Human lactoferrin, which contains this type of linkage, is rapidly cleared from the circulation of mice after intravenous injection, and greater than 90% of the injected material is found in hepatocytes. Binding of lactoferrin is mediated through its carbohydrate groups, since its clearance is prolonged after periodate oxidation or after its oligosaccharide groups are extensively degraded with glycosidases. In addition, glycopeptides from lactoferrin inhibit lactoferrin clearance. That lactoferrin clearance is mediated through binding to its fucosyl groups is suggested for several reasons. First, transferrin and asialotransferrin, whose oligosaccharide groups are essentially structurally identical to those of lactoferrin but devoid of fucose, are not cleared on intravenous injection. Second, when fucose is incorporated into asialotransferrin by alpha1-->3 N-acetylglucosamine fucosyl transferase, the resulting fucosylated derivative is cleared rapidly. Neither mannan nor derivatives of orosomucoid that are cleared by binding to receptors for galactose, N-acetylglucosamine, or mannose, inhibit clearance of lactoferrin although clearance is inhibited by fucoidin. Finally, glycoproteins containing fucose in alpha1 --> 2 linkage to galactose or alpha1 --> 6 linkage to N-acetylglucosamine do not inhibit lactoferrin clerance by the liver. Since clearance of other glycoproteins, such as human lactoperoxidase, also appears to be mediated through binding to the same hepatocyte receptor as lactoferrin, it is concluded that the fucose-specific receptor studied here may fulfill other functions than binding lactoferrin. Preliminary studies with liver homogenates and detergent extracts of liver show binding in vitro.


Smartphone Accelerometry: A Smart and Reliable Measurement of Real-Life Physical Activity in Multiple Sclerosis and Healthy Individuals.
Background: Mobility impairment is common in persons with multiple sclerosis (pwMS) and can be assessed with clinical tests and surveys that have restricted ecological validity. Commercial research-based accelerometers are considered to be more valuable as they measure real-life mobility. Smartphone accelerometry might be an easily accessible alternative. Objective: To explore smartphone accelerometry in comparison to clinical tests, surveys, and a wrist-worn ActiGraph in pwMS and controls. Methods: Sixty-seven pwMS and 70 matched controls underwent mobility tests and surveys. Real-life data were collected with a smartphone and an ActiGraph over 7 days. We explored different smartphone metrics in a technical validation course and computed afterward correlation between ActiGraph (steps per minute), smartphone accelerometry (variance of vector magnitude), clinical tests, and surveys. We also determined the ability to separate between patients and controls as well as between different disability groups. Results: Based on the technical validation, we found the variance of the vector magnitude as a reliable estimate to discriminate wear time and no wear-time of the smartphone. Due to a further association with different activity levels, it was selected for real-life analyses. In the cross-sectional study, ActiGraph correlated moderately (r = 0.43, p < 0.05) with the smartphone but less with clinical tests (rho between |0.211| and |0.337|). Smartphone data showed stronger correlations with age (rho = -0.487) and clinical tests (rho between |0.565| and |0.605|). ActiGraph only differed between pwMS and controls (p < 0.001) but not between disability groups. At the same time, the smartphone showed differences between pwMS and controls, between RRMS and PP-/SPMS, and between participants with/without ambulatory impairment (all p < 0.001). Conclusions: Smartphone accelerometry provides better estimates of mobility and disability than a wrist-worn standard accelerometer in a free-living context for both controls and pwMS. Given the fact that no additional device is needed, smartphone accelerometry might be a convenient outcome of real-life ambulation in healthy individuals and chronic diseases such as MS.


Quetiapine for schizophrenia.
Quetiapine is an atypical antipsychotic with, theoretically, a low propensity for movement disorder adverse effects. It is used for the treatment of schizophrenia and other psychoses. To determine the effects of quetiapine for schizophrenia in comparison to placebo, and other antipsychotics. Electronic searches of the Cochrane Schizophrenia Group's Register of Trials (February 2003), Biological Abstracts (1982-2000), CINAHL (1982-2000), the Cochrane Library (2000, Issue 1),EMBASE (1980-2000), MEDLINE (1966-2000), PsycLIT (1974-2000), SIGLE on CD (1980-1997), SocioFile (1974-1997) and many conference proceedings and hand searches of specific journals were undertaken. We contacted AstraZeneca Pharmaceuticals for information regarding unpublished trials. The review was updated in February 2003. All randomised controlled trials where adults with schizophrenia or similar illnesses were assigned to quetiapine, placebo or other neuroleptic drugs and where clinically relevant outcomes were reported. Citations and, where possible, abstracts were inspected independently by reviewers, papers ordered, re-inspected and quality assessed. We independently extracted data. We analysed data using fixed effects relative risk (RR) and estimated the 95% confidence interval (CI). Only homogeneous data were interpreted as favouring treatment or control. Where possible we calculated the number needed to treat (NNT) or number needed to harm statistics (NNH). We calculated relative risk (RR) for dichotomous data, and weighted mean differences (WMD) for continuous data. Despite the fact that 3443 people were randomised in 12 quetiapine studies, there are almost no data on service utilisation, economic outcomes, social functioning and quality of life. Over half of those within the quetiapine versus placebo comparison were lost to follow up (53% quetiapine vs 61% placebo, n=716, 4RCTs, RR 0.84 CI 0.7 to 0.9, NNT 11 CI 7 to 55) so it is impossible to interpret any ratings of global or mental state within this comparison with confidence. People allocated quetiapine, however, did not have more movement disorders than those given placebo (n=395, 2 RCTs, RR needing medication for EPSE 0.62 CI 0.3 to 1.2). The same applies to the comparison of >/= 250 mg/day quetiapine with < 250 mg/day quetiapine (49% dropout >/= 250 mg/day vs 58% < 250 mg/day, n=1066, 3 RCTs, RR 0.84 CI 0.8 to 0.9, NNT 11 CI 7 to 29). It should be noted that two deaths occurred in the higher dose group (n=618, 1 RCT, RR 0.1 CI 0.0 to 2.1). When quetiapine was compared with typical antipsychotics, about 36% of both groups failed to complete the short-term studies (n=1624, 6 RCTs, RR 0.87 CI 0.8 to 1.0). Average change in global state was heterogeneous and equivocal (n=762, 3 RCTs, WMD in short term 0.19 CI 0.00 to 0.38, I squared 76%). Mental state measures were also equivocal (n=1247, RR not improved 0.97 CI 0.9 to 1.1) including specific measures of negative symptoms (n=305, 1 RCT, MD change in SANS short term 0.94 CI -0.2 to 2.0). Movement disorders were less prevalent for those allocated quetiapine (n=1117, 4 RCTs, RR needing medication for extrapyramidal adverse effects 0.47 CI 0.4 to 0.6, NNT 4 CI 4 to 5, I squared 88%). Dry mouth (n=649, 2 RCTs, RR short term 2.85 CI 1.5 to 5.6, NNH 17 CI 7 to 65) and sleepiness (n=959, 3 RCTs, RR 1.51 CI 1.1 to 2.2, NNH 18 CI 8 to 181) may also be more prevalent for people given quetiapine compared with the older drugs. In the quetiapine versus risperidone comparison, over 30% of people left the study before completion (n=728, 1 RCT, RR 0.94 CI 0.7 to 1.2). Four people, all treated with quetiapine, died during the study (n=728, 1 RCT, RR 2.86 CI 0.2 to 52.8). Continuous mental state measures did not show clear differences between the two drugs (n=637, 1 RCT, MD PANSS 1.2 CI -2.0 to 4.4). However, considerably fewer people given quetiapine needed medication for extrapyramidal side effects compared with those allocated to risperidone (n=712, 1 RCT, RR 0.27 CI 0.2 to 0.5, NNT 11 CI 10 to 16). Quetiapine caused more dizziness (n=728, 1 RCT, RR 1.85 CI 1.0 to 3.3, NNH 18 CI 7 to 487), more dry mouth (n=728, 1 RCT, RR 2.11 CI 1.2 to 3.8, NNH 14 CI 6 to 82) and more sleepiness than risperidone (n=728, 1 RCT, RR 2.03 CI 1.4 to 2.9, NNH 7 CI 4 to 17). Quetiapine is effective for the treatment of schizophrenia, but it is not much different from first-generation antipsychotics and risperidone with respect to treatment withdrawal and efficacy. In comparison to first-generation antipsychotics and risperidone, quetiapine has a lower risk of movement disorders but higher risks of dizziness, dry mouth and sleepiness. More clearly reported pragmatic randomised controlled trials should be carried out to determine its position in everyday clinical practice. Studies of medium and long-term effects, including cost-effectiveness, quality of life, social functioning and service utilisation, in comparison with the effects of typical and atypical antipsychotics should be priority areas.


Caco-2 cell transfection by rat intestinal alkaline phosphatase cDNA increases surfactant-like particles.
The rat enterocyte produces a particle with surfactant-like properties (including a whorled appearance, enrichment for dipalmitoyl phosphatidylcholine, and ability to lower surface tension) that also is enriched for intestinal alkaline phosphatase. Human Caco-2 cells grown on polycarbonate filters were utilized to study the secretion of these particles and exhibited whorls and strands of unilamellar membranes, particularly concentrated at the apical pole or near junctional complexes. Concentrated culture medium from these cells separated on continuous NaBr gradients revealed a fraction at density = 1.07 g/l enriched for phosphatidylcholine and intestinal alkaline phosphatase. This fraction contained membranous sheets containing alkaline phosphatase, detected by immunolocalization. Phosphatidylcholine comprised 54% of phospholipid in this fraction, compared with 20% in brush borders. When Caco-2 cells were transfected with cDNA encoding rat intestinal alkaline phosphatase, cellular phosphatase activity increased twofold, but activity in the medium increased 14-fold to > 200 (average 32)-fold. Ultrastructurally, compared with mock-transfected cells or cells transfected with human placental alkaline phosphatase, transfection with rat intestinal alkaline phosphatase cDNA led to intracellular and extracellular accumulation of surfactant-like particles. We conclude that surfactant-like particles are produced by Caco-2 cells, and their production can be enhanced by transfection with a cDNA encoding a protein known to be associated with such particles.


Heterogeneous genetic diversity pattern in Plasmodium vivax genes encoding merozoite surface proteins (MSP) -7E, -7F and -7L.
The msp-7 gene has become differentially expanded in the Plasmodium genus; Plasmodium vivax has the highest copy number of this gene, several of which encode antigenic proteins in merozoites. DNA sequences from thirty-six Colombian clinical isolates from P. vivax (pv) msp-7E, -7F and -7L genes were analysed for characterizing and studying the genetic diversity of these pvmsp-7 members which are expressed during the intra-erythrocyte stage; natural selection signals producing the variation pattern so observed were evaluated. The pvmsp-7E gene was highly polymorphic compared to pvmsp-7F and pvmsp-7L which were seen to have limited genetic diversity; pvmsp-7E polymorphism was seen to have been maintained by different types of positive selection. Even though these copies seemed to be species-specific duplications, a search in the Plasmodium cynomolgi genome (P. vivax sister taxon) showed that both species shared the whole msp-7 repertoire. This led to exploring the long-term effect of natural selection by comparing the orthologous sequences which led to finding signatures for lineage-specific positive selection. The results confirmed that the P. vivax msp-7 family has a heterogeneous genetic diversity pattern; some members are highly conserved whilst others are highly diverse. The results suggested that the 3'-end of these genes encode MSP-7 proteins' functional region whilst the central region of pvmsp-7E has evolved rapidly. The lineage-specific positive selection signals found suggested that mutations occurring in msp-7s genes during host switch may have succeeded in adapting the ancestral P. vivax parasite population to humans.


AHR2-Mediated transcriptomic responses underlying the synergistic cardiac developmental toxicity of PAHs.
Polycyclic aromatic hydrocarbons (PAHs) induce developmental defects including cardiac deformities in fish. The aryl hydrocarbon receptor (AHR) mediates the toxicity of some PAHs. Exposure to a simple PAH mixture during embryo development consisting of an AHR agonist (benzo(a)pyrene-BaP) with fluoranthene (FL), an inhibitor of cytochrome p450 1(CYP1)--a gene induced by AHR activation--results in cardiac deformities. Exposure to BaP or FL alone at similar concentrations alters heart rates, but does not induce morphological deformities. Furthermore, AHR2 knockdown prevents the toxicity of BaP + FL mixture. Here, we used a zebrafish microarray analysis to identify heart-specific transcriptomic changes during early development that might underlie cardiotoxicity of BaP + FL. We used AHR2 morphant embryos to determine the role of this receptor in mediating toxicity. Control and knockdown embryos at 36 h post-fertilization were exposed to DMSO, 100 μg/l BaP, 500 μg/l FL, or 100 μg/l BaP + 500 μg/l FL, and heart tissues for RNA were extracted at 2, 6, 12, and 18 h-post-exposure (hpe), prior to the appearance of cardiac deformities. Data show AHR2-dependent BaP + FL effects on expression of genes involved in protein biosynthesis and neuronal development in addition to signaling molecules and their associated molecular pathways. Ca(2+)-cycling and muscle contraction genes were the most significantly differentially expressed category of transcripts when comparing BaP + FL-treated AHR2 morphant and control embryos. These differences were most prominent at 2 and 6 hpe. Therefore, we postulate that BaP + FL may affect cellular Ca(2+) levels and subsequently cardiac muscle function, potentially underlying BaP + FL cardiotoxicity.


Fatty acid composition of muscle tissue measured in amphibians living in radiologically contaminated and non-contaminated environments.
Fatty acid composition was identified as a potential biological indicator of the effects of environmental exposure to radiological contaminants. This end point was measured in muscle tissues of Mink frogs ( Rana septentrionalis ) obtained from a radiologically contaminated pond and from a non-contaminated pond. It was also measured after the frogs obtained from both ponds were exposed to a 4 Gy (60)Co γ radiation dose delivered in vivo at a dose rate of approximately 8 Gy/min. Statistically significant differences for the increase of a couple of polyunsaturated omega-3 fatty acid residues and the decrease of a polyunsaturated omega-6 fatty acid residue were observed between radiologically contaminated and non-contaminated frogs, indicating a partial remodeling of muscle lipids in response to a chronic low-dose tritium exposure. The effects of an acute high-dose exposure to (60)Co γ radiation, either for the radiologically contaminated or non-contaminated frogs indicated fast post-irradiation fatty acid changes with an increase of polyunsaturated and decrease of saturated fatty acid contents. Fatty acid composition was found to be a sensitive marker that may be useful to study and monitor biota health in environments that are radiologically contaminated, as well as for understanding the differences between low chronic and high acute stress responses.


Automatic Cochlear Duct Length Estimation for Selection of Cochlear Implant Electrode Arrays.
Cochlear duct length (CDL) can be automatically measured for custom selection of cochlear implant (CI) electrode arrays. CI electrode array selection can be influenced by measuring the CDL, which is estimated based on the length of the line that connects the round window and the lateral wall of the cochlea when passing through the modiolus. CDL measurement remains time consuming and inter-observer variability has not been studied. We evaluate an automatic approach to directly measure the two-turn (2T) CDL using existing algorithms for localizing cochlear anatomy in computed tomography (CT). Pre-op CT images of 309 ears were evaluated. Two fellowship-trained neurotologists manually and independently measured CDL. Inter-observer variability between measurements across expert and automatic observers is assessed. Inter-observer differences for choice of electrode type are also investigated. Manual measurement of CDL by experts tends to underestimate cochlea size and has high inter-observer variability, with mean absolute differences between expert CDL estimations of 1.15 mm. Our results show that this can lead to a large number of cochleae for which a different electrode array type would be selected by different observers, depending on the specific threshold value of CDL used to decide between array type. Choosing the best CI electrode array is an important task for optimizing hearing outcomes. Manual cochleae length measurements are user-dependent, and errors impact upon the CI electrode array choice for certain patients. Measuring cochlea length automatically is less time consuming and generates more repeatable results. Our automatic approach could make use of CDL for patient-customized treatment more clinically adoptable.


Consensus statements that fail to recognise dissent are flawed by design: a narrative review with 10 suggested improvements.
Consensus statements have the potential to be very influential. Recently, such statements in sport and exercise medicine appear more prescriptive, strongly recommending particular approaches to research or treatment. In 2020, a statement on methods for reporting sport injury surveillance studies included an extension to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines; STROBE guidelines are now official requirements for many journals. This suggests that investigators who use methods outside of these guidelines may have difficulty publishing their results. By definition, consensus is not unanimity, and consensus recommendations are sometimes considered flawed at a later date. This is expected as a discipline benefits from new knowledge. However, the consensus methods themselves may also inadvertently suppress contrary-but valid-opinions. I point to a different model for consensus meetings and statements that embraces dissenting opinions and is more transparent than common current methods in sport and exercise medicine. The method, based on how Supreme Courts function in many countries, allows for both majority and one or more minority opinions. I illustrate how a consensus statement might be written using examples from four previous sport and exercise medicine consensus statements. By adopting the 'Supreme Court' approach, important disagreements about the strength and interpretation of evidence will be far more visible than is currently the case in most consensus meetings. The benefit of the Supreme Court model is that it will ensure that clinicians, researchers and journals are not inappropriately influenced by recommendations from consensus statements where uncertainty remains.


Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsin-dependent emphysema.
Cigarette smoke exposure is the major cause of chronic obstructive pulmonary disease (COPD). However, only a minority of smokers develop significant COPD, and patients with asthma or asthma-like airway hyperresponsiveness or eosinophilia experience accelerated loss of lung function after cigarette smoke exposure. Pulmonary inflammation is a characteristic feature of lungs from patients with COPD. Surprisingly, the mediators of this inflammation and their contributions to the pathogenesis and varied natural history of COPD are not well defined. Here we show that IL-13, a critical cytokine in asthma, causes emphysema with enhanced lung volumes and compliance, mucus metaplasia, and inflammation, when inducibly overexpressed in the adult murine lung. MMP-2, -9, -12, -13, and -14 and cathepsins B, S, L, H, and K were induced by IL-13 in this setting. In addition, treatment with MMP or cysteine proteinase antagonists significantly decreased the emphysema and inflammation, but not the mucus in these animals. These studies demonstrate that IL-13 is a potent stimulator of MMP and cathepsin-based proteolytic pathways in the lung. They also demonstrate that IL-13 causes emphysema via a MMP- and cathepsin-dependent mechanism(s) and highlight common mechanisms that may underlie COPD and asthma.


Radiological risk assessment: an overview of the ERICA Integrated Approach and the ERICA Tool use.
The ERICA project (Environmental Risk from Ionising Contaminants: Assessment and Management) was co-funded by the European Union as part of the 6th Framework Programme (FP EURATOM). The project was carried out between 2004 and 2007 as the collective work of 15 organisations in seven European countries. Two significant outputs of the project are the ERICA Integrated Approach and the ERICA Tool. The ERICA Integrated Approach consists of three elements: assessment, risk characterisation and management. The ERICA Tool is a practical implementation of the assessment component of the ERICA Integrated Approach and has a three-tier structure. The aim of this review paper is to give a concise overview of ERICA project outputs and their structure, updates done since their first release in 2007, as well as to provide a context for their practical application in environmental radiation protection and radiological risk assessments for various engineering scenarios.


Blood pressure and associated factors in a North African adolescent population. a national cross-sectional study in Tunisia.
In southern and eastern Mediterranean countries, changes in lifestyle and the increasing prevalence of excess weight in childhood are risk factors for high blood pressure (BP) during adolescence and adulthood. The aim of this study was to evaluate the BP status of Tunisian adolescents and to identify associated factors. A cross-sectional study in 2005, based on a national, stratified, random cluster sample of 1294 boys and 1576 girls aged 15-19 surveyed in home visits. The socio-economic and behavioral characteristics of the adolescents were recorded. Overweight/obesity were assessed by Body Mass Index (BMI) from measured height and weight (WHO, 2007), abdominal obesity by waist circumference (WC). BP was measured twice during the same visit. Elevated BP was systolic (SBP) or diastolic blood pressure (DBP) ≥ 90th of the international reference or ≥ 120/80 mm Hg for 15-17 y., and SBP/DBP ≥ 120/80 mm Hg for 18-19 y.; hypertension was SBP/DBP ≥ 95th for 15-17 y. and ≥ 140/90 mm Hg for 18-19 y. Adjusted associations were assessed by logistic regression. The prevalence of elevated BP was 35.1%[32.9-37.4]: higher among boys (46.1% vs. 33.3%; P < 0.0001); 4.7%[3.8-5.9] of adolescents had hypertension. Associations adjusted for all covariates showed independent relationships with BMI and WC: - obesity vs. no excess weight increased elevated BP (boys OR = 2.1[1.0-4.2], girls OR = 2.3[1.3-3.9]) and hypertension (boys OR = 3.5[1.4-8.9], girls OR = 5.4[2.2-13.4]), - abdominal obesity (WC) was also associated with elevated BP in both genders (for boys: 2nd vs. 1st tertile OR = 1.7[1.3-2.3], 3rd vs.1st tertile OR = 2.8[1.9-4.2]; for girls: 2nd vs. 1st tertile OR = 1.6[1.2-2.1], 3rd vs.1st tertile OR = 2.1[1.5-3.0]) but only among boys for hypertension. Associations with other covariates were weaker: for boys, hypertension increased somewhat with sedentary lifestyle, while elevated BP was slightly more prevalent among urban girls and those not attending school. Within the limits of BP measurement on one visit only, these results suggest that Tunisian adolescents of both genders are likely not spared from early elevated BP. Though further assessment is likely needed, the strong association with overweight/obesity observed suggests that interventions aimed at changing lifestyles to reduce this main risk factor may also be appropriate for the prevention of elevated BP.


A New Foundation for the Delivery and Financing of American Health Care.
For the past decade, primary care practices across America have worked to implement a practice model called the Patient-Centered Medical Home (PCMH) to revitalize practice, better support clinicians and patients, improve efficiency, and facilitate growth in primary care capacity. In spite of substantial progress, this work has not been matched by sufficient change in the payment system to allow these goals to be accomplished. Nevertheless, improving the quality and availability of primary care remains essential to achieving the goals of the Triple Aim (better health care, better population health, and containment of health care costs). For this to occur, the PCMH model of care must be further refined, and the payment system for primary care must be completely restructured. The need for these changes is urgent. In October 2014, the discipline of family medicine announced a comprehensive strategic plan called Family Medicine for America's Health (FMAHealth). FMAHealth proposes to expand the PCMH care model by fully integrating our nation's behavioral/mental health, public health, and primary care systems to create a new foundation for American health care. Accomplishing these ambitious goals will require a broad coalition of private and public interests across the health care disciplines as well as patients, communities, government, and businesses. These changes require additional infrastructure that existing financing systems do not adequately support, so comprehensive payment reform is essential for large-scale dissemination and sustainability of this model. The new payment model must reward value rather than volume of service and must provide a secure financial foundation for practices designed to care for patients and communities at affordable costs.


Stable photorefractive square-law conversion using moving grating techniques.
We demonstrate a technique by which the temporal oscillations in the response of a photorefractive square-law converter, a recently developed high-contrast spatial light modulator, may be removed. This technique uses the translation of an amplitude grating incoherently imaged upon a photorefractive crystal to obtain a moving intensity pattern within the material. We thus obtain running-wave effects similar to those seen by previous investigators writing photorefractive gratings by using the interference of two coherent frequency-shifted beams. We show both theoretically and experimentally that the criteria for removing temporal oscillations simultaneously yields a significant improvement in the diffractionefficiency of the square-law converter.


In Vivo Assessment of Bone Regeneration in Alginate/Bone ECM Hydrogels with Incorporated Skeletal Stem Cells and Single Growth Factors.
The current study has investigated the use of decellularised, demineralised bone extracellular matrix (ECM) hydrogel constructs for in vivo tissue mineralisation and bone formation. Stro-1-enriched human bone marrow stromal cells were incorporated together with select growth factors including VEGF, TGF-β3, BMP-2, PTHrP and VitD3, to augment bone formation, and mixed with alginate for structural support. Growth factors were delivered through fast (non-osteogenic factors) and slow (osteogenic factors) release PLGA microparticles. Constructs of 5 mm length were implanted in vivo for 28 days within mice. Dense tissue assessed by micro-CT correlated with histologically assessed mineralised bone formation in all constructs. Exogenous growth factor addition did not enhance bone formation further compared to alginate/bone ECM (ALG/ECM) hydrogels alone. UV irradiation reduced bone formation through degradation of intrinsic growth factors within the bone ECM component and possibly also ECM cross-linking. BMP-2 and VitD3 rescued osteogenic induction. ALG/ECM hydrogels appeared highly osteoinductive and delivery of angiogenic or chondrogenic growth factors led to altered bone formation. All constructs demonstrated extensive host tissue invasion and vascularisation aiding integration and implant longevity. The proposed hydrogel system functioned without the need for growth factor incorporation or an exogenous inducible cell source. Optimal growth factor concentrations and spatiotemporal release profiles require further assessment, as the bone ECM component may suffer batch variability between donor materials. In summary, ALG/ECM hydrogels provide a versatile biomaterial scaffold for utilisation within regenerative medicine which may be tailored, ultimately, to form the tissue of choice through incorporation of select growth factors.


Changes in tissue and cerebral oxygenation following spinal anesthesia in infants: a prospective study.
Use of spinal anesthesia (SA) in children may address concerns about potential neurocognitive effects of general anesthesia. We used near-infrared spectroscopy (NIRS) to assess the effects of SA on cerebral and tissue oxygenation in 19 patients aged 7 ± 3 months. Prior to SA placement, NIRS monitors were placed on the forehead (cerebral) and the thigh (tissue). Intraoperative cerebral and tissue saturation were 73 ± 7 and 80 ± 11%, respectively, before SA placement. NIRS measurements were monitored every minute for 30 min after SA placement and modeled using mixed-effects linear regression. Regression estimates showed that cerebral saturation remained stable from 67% [95% confidence interval (CI) 63, 71%] after SA placement to 68% (95% CI 65, 72%) at the conclusion of monitoring. After SA placement, tissue saturation was elevated compared to baseline values; but further change [from 91% (95% CI 89, 93%) to 93% (95% CI 91, 95%) at the end of monitoring] was clinically non-significant. All patients breathed spontaneously on room air without changes in oxygen saturation. Blood pressure and heart rate decreased after SA placement, but no changes in hemodynamic parameters required treatment. These data provide further evidence of the neutral effect of SA on cerebral oxygenation 30 min after block placement.


Economic burden of colorectal cancer in Iran in 2012.
Background: Colorectal cancer is one of the most common cancers in Iran. However little is known about the economic burden associated with this cancer in Iran. The aim of this study was to estimate the economic burden of colorectal cancer in Iran in the year 2012. Methods: We used the prevalence-based approach and estimated direct and indirect costs of all colorectal cancer cases in 2012. To estimate the total direct costs, we model the treatment process of colorectal cancer patients in initial and continuing phase in Iran. Then the average cost of each treatment in each phase was multiplied by the number of patients who received the treatment in the country in 2012. We used the human capital method to estimate the indirect costs. We extracted data from several sources, including national cancer registry reports, hospital records, literature review, occupational data, and interviews with experts. Results: The incidence and 5-year prevalence of colorectal cancer in Iran in 2012 were 7,163 and 22,591 individuals respectively. The economic burden of colorectal cancer in Iran was US$298,148,718 in 2012. Most of the cost (58%) was attributed to the mortality cost, and the direct medical cost accounted for 32.14 percent of the estimated total cost. The majority of the direct medical cost was associated with chemotherapy costs (50%). Conclusion: The economic burden of colorectal cancer in Iran is substantial and will increase in the future years.


FORCe: Fully Online and Automated Artifact Removal for Brain-Computer Interfacing.
A fully automated and online artifact removal method for the electroencephalogram (EEG) is developed for use in brain-computer interfacing (BCI). The method (FORCe) is based upon a novel combination of wavelet decomposition, independent component analysis, and thresholding. FORCe is able to operate on a small channel set during online EEG acquisition and does not require additional signals (e.g., electrooculogram signals). Evaluation of FORCe is performed offline on EEG recorded from 13 BCI particpants with cerebral palsy (CP) and online with three healthy participants. The method outperforms the state-of the-art automated artifact removal methods Lagged Auto-Mutual Information Clustering (LAMIC) and Fully Automated Statistical Thresholding for EEG artifact Rejection (FASTER), and is able to remove a wide range of artifact types including blink, electromyogram (EMG), and electrooculogram (EOG) artifacts.


Disinfection efficacy of photon-induced photoacoustic streaming on root canals infected with Enterococcus faecalis: an ex vivo study.
In 2010, one of the authors proposed that lasers could be used to enhance the decontaminating action of sodium hypochlorite (NaOCl). The authors conducted a study to compare the disinfection efficacy of laser-activated irrigation (LAI) by using a photon-induced photoacoustic streaming (PIPS) tip with conventional irrigation and specifically LAI's ability to remove bacterial film formed on root canal walls. The authors shaped 26 human anterior teeth to a master apical file size of International Organization for Standardization 25/06 (size 25 tip and size .06 taper) and then sterilized the teeth, infected them with Enterococcus faecalis and incubated them for four weeks. The authors used two irrigation protocols. Group A received two cycles of 30 seconds each of 5 percent NaOCl laser activation and one cycle of 30 seconds with laser activation involving the use of 17 percent ethylenediaminetetraacetic acid (EDTA). The erbium:yttrium-aluminum-garnet (Er:YAG) laser's settings were 20 millijoules, 15 hertz, 50-microsecond pulse duration, and it had a 600-micrometer PIPS tip. Group B received two cycles of 30 seconds each of 5 percent NaOCl and 17 percent EDTA irrigation alone, delivered via a syringe with a 25-gauge needle. The authors found that group A had significantly better disinfection compared with group B (P < .05). The results of cultures obtained after 48 hours showed that disinfection was maintained better in group A compared with group B (P < .0001). Scanning electron microscopic images showed absence of bacterial biofilm remaining after LAI using PIPS. Er:YAG laser activation of 5 percent NaOCl and 17 percent EDTA was more effective than conventional irrigation for eradicating E. faecalis and preventing new bacterial growth ex vivo. Additional clinical studies are needed to clarify the effect on endodontic treatment outcomes. PIPS appears to be effective in enhancing the effect of the irrigants commonly used in endodontics.


Activation of unfolded protein response and autophagy during HCV infection modulates innate immune response.
Autophagy, a process for catabolizing cytoplasmic components, has been implicated in the modulation of interactions between RNA viruses and their host. However, the mechanism underlying the functional role of autophagy in the viral life cycle still remains unclear. Hepatitis C virus (HCV) is a single-stranded, positive-sense, membrane-enveloped RNA virus that can cause chronic liver disease. Here we report that HCV induces the unfolded protein response (UPR), which in turn activates the autophagic pathway to promote HCV RNA replication in human hepatoma cells. Further analysis revealed that the entire autophagic process through to complete autolysosome maturation was required to promote HCV RNA replication and that it did so by suppressing innate antiviral immunity. Gene silencing or activation of the UPR-autophagy pathway activated or repressed, respectively, IFN-β activation mediated by an HCV-derived pathogen-associated molecular pattern (PAMP). Similar results were achieved with a PAMP derived from Dengue virus (DEV), indicating that HCV and DEV may both exploit the UPR-autophagy pathway to escape the innate immune response. Taken together, these results not only define the physiological significance of HCV-induced autophagy, but also shed light on the knowledge of host cellular responses upon HCV infection as well as on exploration of therapeutic targets for controlling HCV infection.


Relation between in-game role and service characteristics in elite women's volleyball.
The aim of this study was to determine whether the in-game role of players (setter, outside, middle, or opposite player) in elite women's volleyball is significantly related to the characteristics of their service. The sample consisted of 1,300 service deliveries (total serves for all matches) made by players in the 8 teams participating in 2 Final 4 stages of the Indesit European Champions League. The variables recorded were in-game role of the server, service type, speed of delivery, service area, target zone, and effectiveness of delivery. Results showed a significant relation between the server's in-game role and service type (p <or= 0.01), service speed (p <or= 0.01), service area (p <or= 0.01), and effectiveness of delivery (p <or= 0.001). The most significant relation observed was with the service area, primarily because of the server having to make a quick transition to the defense zone. Setters and opposite players most commonly served from behind zone 1 (100 and 80% of serves, respectively), which they defended after serving. Similarly, middle players served most frequently from behind zone 5 (47% of serves), the zone they subsequently defended.


MicroRNA-Mediated Downregulation of the Potassium Channel Kv4.2 Contributes to Seizure Onset.
Seizures are bursts of excessive synchronized neuronal activity, suggesting that mechanisms controlling brain excitability are compromised. The voltage-gated potassium channel Kv4.2, a major mediator of hyperpolarizing A-type currents in the brain, is a crucial regulator of neuronal excitability. Kv4.2 expression levels are reduced following seizures and in epilepsy, but the underlying mechanisms remain unclear. Here, we report that Kv4.2 mRNA is recruited to the RNA-induced silencing complex shortly after status epilepticus in mice and after kainic acid treatment of hippocampal neurons, coincident with reduction of Kv4.2 protein. We show that the microRNA miR-324-5p inhibits Kv4.2 protein expression and that antagonizing miR-324-5p is neuroprotective and seizure suppressive. MiR-324-5p inhibition also blocks kainic-acid-induced reduction of Kv4.2 protein in vitro and in vivo and delays kainic-acid-induced seizure onset in wild-type but not in Kcnd2 knockout mice. These results reveal an important role for miR-324-5p-mediated silencing of Kv4.2 in seizure onset.


[Characteristics of heterosexually acquired AIDS in Japan. An inter-country comparison using AIDS Surveillance data].
To identify epidemiological characteristics of heterosexually acquired AIDS in Japan, with emphasis on potential influence on future trends. National AIDS Surveillance data in Japan were compared with those in the UK and US, where detailed information is available from well-established surveillance procedures. Data on AIDS cases diagnosed until the end of 1996, particularly those acquired heterosexually, were analyzed by year of diagnosis, gender and age group. The number of heterosexually acquired AIDS cases in Japan has continued to increase, while those in the UK and US leveled out or decreased recently. The increase during a two-year period after reaching a certain number of cases per year was found to be 2.3-fold in Japanese, 2.4-fold in UK whites and 5-fold in US whites. The male to female ratio (M/F) for heterosexually acquired AIDS was 6.3 among Japanese, while the ratio was 1.1 and 0.5 in the UK and US, respectively. The age distribution at AIDS diagnosis demonstrated a peak from 35 to 54 years of age among Japanese males, as compared to 30 to 34 among males in the UK and the US. No significant difference was apparent in the age distribution among females in the three countries. The relatively small number of AIDS cases in Japan is attributable to the late introduction of HIV and the limited chance of heterosexual transmission from homosexual/bisexual men and injecting drug users. In addition, transmission has probably most often occurred between middle-aged Japanese males and non-Japanese females. As there is a growing risk of HIV infection among Japanese females and young Japanese males, new prevention strategies targeting these groups are urgently required.


Cohort study on clustering of lifestyle risk factors and understanding its association with stress on health and wellbeing among school teachers in Malaysia (CLUSTer)--a study protocol.
The study on Clustering of Lifestyle risk factors and Understanding its association with Stress on health and wellbeing among school Teachers in Malaysia (CLUSTer) is a prospective cohort study which aims to extensively study teachers in Malaysia with respect to clustering of lifestyle risk factors and stress, and subsequently, to follow-up the population for important health outcomes. This study is being conducted in six states within Peninsular Malaysia. From each state, schools from each district are randomly selected and invited to participate in the study. Once the schools agree to participate, all teachers who fulfilled the inclusion criteria are invited to participate. Data collection includes a questionnaire survey and health assessment. Information collected in the questionnaire includes socio-demographic characteristics, participants' medical history and family history of chronic diseases, teaching characteristics and burden, questions on smoking, alcohol consumption and physical activities (IPAQ); a food frequency questionnaire, the job content questionnaire (JCQ); depression, anxiety and stress scale (DASS21); health related quality of life (SF12-V2); Voice Handicap Index 10 on voice disorder, questions on chronic pain, sleep duration and obstetric history for female participants. Following blood drawn for predefined clinical tests, additional blood and urine specimens are collected and stored for future analysis. Active follow up of exposure and health outcomes will be carried out every two years via telephone or face to face contact. Data collection started in March 2013 and as of the end of March 2014 has been completed for four states: Kuala Lumpur, Selangor, Melaka and Penang. Approximately 6580 participants have been recruited. The first round of data collection and blood sampling is expected to be completed by the end of 2014 with an expected 10,000 participants recruited. Our study will provide a good basis for exploring the clustering of lifestyle risk factors and stress and its association with major chronic medical conditions such as obesity, hypertension, impaired glucose tolerance, diabetes mellitus, coronary heart diseases, kidney failure and cancers among teachers.


The impact of educational status on the clinical features of major depressive disorder among Chinese women.
Years of education are inversely related to the prevalence of major depressive disorder (MDD), but the relationship between the clinical features of MDD and educational status is poorly understood. We investigated this in 1970 Chinese women with recurrent MDD identified in a clinical setting. Clinical and demographic features were obtained from 1970 Han Chinese women with DSM-IV major depression between 30 and 60 years of age across China. Analysis of linear, logistic and multiple logistic regression models were used to determine the association between educational level and clinical features of MDD. Subjects with more years of education are more likely to have MDD, with an odds ratio of 1.14 for those with more than ten years. Low educational status is not associated with an increase in the number of episodes, nor with increased rates of co-morbidity with anxiety disorders. Education impacts differentially on the symptoms of depression: lower educational attainment is associated with more biological symptoms and increased suicidal ideation and plans to commit suicide. Findings may not generalize to males or to other patient populations. Since the threshold for treatment seeking differs as a function of education there may an ascertainment bias in the sample. The relationship between symptoms of MDD and educational status in Chinese women is unexpectedly complex. Our findings are inconsistent with the simple hypothesis from European and US reports that low levels of educational attainment increase the risk and severity of MDD.


Subwavelength-width optical tunnel junctions for ultracold atoms.
We propose a method for creating far-field optical barrier potentials for ultracold atoms with widths that are narrower than the diffraction limit and can approach tens of nanometers. The reduced widths stem from the nonlinear atomic response to control fields that create spatially varying dark resonances. The subwavelength barrier is the result of the geometric scalar potential experienced by an atom prepared in such a spatially varying dark state. The performance of this technique, as well as its applications to the study of many-body physics and to the implementation of quantum-information protocols with ultracold atoms, are discussed, with a focus on the implementation of tunnel junctions.


Synthesis of highly functionalized C60 fullerene derivatives and their applications in material and life sciences.
Highly functionalized fullerenes can be efficiently constructed by various techniques. However, the challenge is to synthesize highly symmetrical fullerenes. Recently, a number of X-ray structures have been disclosed showing the high symmetry of substituted fullerenes. By reviewing the major types of multi functionalized fullerenes through selected examples with a link to the structural assignments, the authors intend to give a concise overview to the specialist in the field and to provide the non-specialist with a tool box of possibilities.


Surface electromyography signal processing and classification techniques.
Electromyography (EMG) signals are becoming increasingly important in many applications, including clinical/biomedical, prosthesis or rehabilitation devices, human machine interactions, and more. However, noisy EMG signals are the major hurdles to be overcome in order to achieve improved performance in the above applications. Detection, processing and classification analysis in electromyography (EMG) is very desirable because it allows a more standardized and precise evaluation of the neurophysiological, rehabitational and assistive technological findings. This paper reviews two prominent areas; first: the pre-processing method for eliminating possible artifacts via appropriate preparation at the time of recording EMG signals, and second: a brief explanation of the different methods for processing and classifying EMG signals. This study then compares the numerous methods of analyzing EMG signals, in terms of their performance. The crux of this paper is to review the most recent developments and research studies related to the issues mentioned above.


Dynamic regulation of Schwann cell enhancers after peripheral nerve injury.
Myelination of the peripheral nervous system is required for axonal function and long term stability. After peripheral nerve injury, Schwann cells transition from axon myelination to a demyelinated state that supports neuronal survival and ultimately remyelination of axons. Reprogramming of gene expression patterns during development and injury responses is shaped by the actions of distal regulatory elements that integrate the actions of multiple transcription factors. We used ChIP-seq to measure changes in histone H3K27 acetylation, a mark of active enhancers, to identify enhancers in myelinating rat peripheral nerve and their dynamics after demyelinating nerve injury. Analysis of injury-induced enhancers identified enriched motifs for c-Jun, a transcription factor required for Schwann cells to support nerve regeneration. We identify a c-Jun-bound enhancer in the gene for Runx2, a transcription factor induced after nerve injury, and we show that Runx2 is required for activation of other induced genes. In contrast, enhancers that lose H3K27ac after nerve injury are enriched for binding sites of the Sox10 and early growth response 2 (Egr2/Krox20) transcription factors, which are critical determinants of Schwann cell differentiation. Egr2 expression is lost after nerve injury, and many Egr2-binding sites lose H3K27ac after nerve injury. However, the majority of Egr2-bound enhancers retain H3K27ac, indicating that other transcription factors maintain active enhancer status after nerve injury. The global epigenomic changes in H3K27ac deposition pinpoint dynamic changes in enhancers that mediate the effects of transcription factors that control Schwann cell myelination and peripheral nervous system responses to nerve injury.


Interaction of perfluorooctanoic acid with human serum albumin.
Recently, perfluorooctanoic acid (PFOA) has become a significant issue in many aspects of environmental ecology, toxicology, pathology and life sciences because it may have serious effects on the endocrine, immune and nervous systems and can lead to embryonic deformities and other diseases. Human serum albumin (HSA) is the major protein component of blood plasma and is called a multifunctional plasma carrier protein because of its ability to bind an unusually broad spectrum of ligands. The interaction of PFOA with HSA was investigated in the normal physiological condition by equilibrium dialysis, fluorospectrometry, isothermal titration calorimetry (ITC) and circular dichroism (CD). The non-covalent interaction is resulted from hydrogen bond, van der Waals force and hydrophobic stack. PFOA binding to HSA accorded with two-step binding model with the saturation binding numbers of PFOA, only 1 in the hydrophobic intracavity of HSA and 12 on the exposed outer surface. The interaction of PFOA with HSA is spontaneous and results in change of HSA conformation. The possible binding sites were speculated. The present work suggested a characterization method for the intermolecular weak interaction. It is potentially useful for elucidating the toxigenicity of perfluorochemicals when combined with biomolecular function effect, transmembrane transport, toxicological testing and the other experiments.


Tests of the mitigating effects of caring and supportive relationships in the study of abusive disciplining over two generations.
To examine evidence of the continuity in abusive discipline across two generations (G1 and G2) and the role of safe, stable, and nurturing relationships (SSNRs) as protective factors. Data are from the Lehigh Longitudinal Study, a prospective investigation of the causes and consequences child maltreatment that began in the 1970s with a sample of 457 children and their parents. Data were most recently collected in 2008-2010 from 80% of the original child sample (N = 357) when they were adults age 36 years on average. Of those assessed as adults, 268 participants (G2s) were parenting children and thus comprise the analysis sample. Analyses examined the association between harsh physical discipline practices by G1 parents and G2's reports of similarly severe discipline practices used in parenting their own children. Analyses also investigated the direct and interactive (protective) effects of SSNR variables that pertain to the care, warmth, and support children received from their mothers, fathers, and siblings over their lifetimes. A measure of an adult partner's warmth and support was also included. A case-level examination of G2 harsh discipliners was included to investigate other forms of past and more recent forms of abuse exposure. Results show a significant predictive association between physical discipline by G1 and G2 parents (β = .30; p < .05; odds ratio, 1.14; confidence interval, 1.04-1.26), after accounting for childhood socioeconomic status and gender. Whereas being harshly disciplined as a child was inversely related to reports of having had a caring relationship with one's mother (r = -.25; p < .01), only care and support from one's father predicted a lower risk of harsh physical discipline by G2s (β = -.24; p < .05; odds ratio, .74; confidence interval, .59-.92). None of the SSNR variables moderated the effect of G1 discipline on G2 discipline. A case-level examination of the abusive histories of G2 harsh discipliners found they had in some instances been exposed to physical and emotional abuse by multiple caregivers and by adult partners. There is continuity in physical disciplining over two generations. SSNRs measured in this study did not mediate or moderate the effect of G1 on G2 harsh physical discipline, although care and support from fathers was inversely related to the likelihood of G2 harsh physical discipline. This relationship is independent of abuse in childhood. Research is needed to identify factors that interrupt the intergenerational continuity of harsh physical (abusive) disciplining so that promising interventions can be developed and implemented.


Vitamin D, and Maternal and Child Health.
Vitamin D has important roles in calcium metabolism and in the prevention of rickets and osteomalacia; low levels of 25-hydroxyvitamin D are common in the general population and amongst pregnant women. Whilst there is a wealth of observational evidence linking vitamin D deficiency to a wide range of disease outcomes, there are currently few high-quality randomised controlled trials to confirm any causal associations, although many are currently in progress. Furthermore, currently, the vast majority of published guidelines recommend standard supplemental vitamin D doses for children and pregnant women, yet there is increasing recognition that individual characteristics and genetic factors may influence the response to supplementation. As such, future research needs to concentrate on documenting definite beneficial clinical outcomes of vitamin D supplementation, and establishing personalised dosing schedules and demonstrating effective approaches to optimising initiation and adherence.


A general total variation minimization theorem for compressed sensing based interior tomography.
Recently, in the compressed sensing framework we found that a two-dimensional interior region-of-interest (ROI) can be exactly reconstructed via the total variation minimization if the ROI is piecewise constant (Yu and Wang, 2009). Here we present a general theorem charactering a minimization property for a piecewise constant function defined on a domain in any dimension. Our major mathematical tool to prove this result is functional analysis without involving the Dirac delta function, which was heuristically used by Yu and Wang (2009).


A computational analysis of the relationship between neuronal and behavioral responses to visual motion.
We have documented previously a close relationship between neuronal activity in the middle temporal visual area (MT or V5) and behavioral judgments of motion (Newsome et al., 1989; Salzman et al., 1990; Britten et al., 1992; Britten et al., 1996). We have now used numerical simulations to try to understand how neural signals in area MT support psychophysical decisions. We developed a model that pools neuronal responses drawn from our physiological data set and compares average responses in different pools to produce psychophysical decisions. The structure of the model allows us to assess the relationship between "neuronal" input signals and simulated psychophysical performance using the same methods we have applied to real experimental data. We sought to reconcile three experimental observations: psychophysical performance (threshold sensitivity to motion stimuli embedded in noise), a trial-by-trial covariation between the neural response and the monkey's choices, and a modest correlation between pairs of MT neurons in their variable responses to identical visual stimuli. Our results can be most accurately simulated if psychophysical decisions are based on pools of at least 100 weakly correlated sensory neurons. The neurons composing the pools must include a broader range of sensitivities than we encountered in our MT recordings, presumably because of the inclusion of neurons whose optimal stimulus is different from the one being discriminated. Central sources of noise degrade the signal-to-noise ratio of the pooled signal, but this degradation is relatively small compared with the noise typically carried by single cortical neurons. This suggests that our monkeys base near-threshold psychophysical judgments on signals carried by populations of weakly interacting neurons; these populations include many neurons that are not tuned optimally for the particular stimuli being discriminated.


Observed interannual changes beneath Filchner-Ronne Ice Shelf linked to large-scale atmospheric circulation.
Floating ice shelves are the Achilles' heel of the Antarctic Ice Sheet. They limit Antarctica's contribution to global sea level rise, yet they can be rapidly melted from beneath by a warming ocean. At Filchner-Ronne Ice Shelf, a decline in sea ice formation may increase basal melt rates and accelerate marine ice sheet mass loss within this century. However, the understanding of this tipping-point behavior largely relies on numerical models. Our new multi-annual observations from five hot-water drilled boreholes through Filchner-Ronne Ice Shelf show that since 2015 there has been an intensification of the density-driven ice shelf cavity-wide circulation in response to reinforced wind-driven sea ice formation in the Ronne polynya. Enhanced southerly winds over Ronne Ice Shelf coincide with westward displacements of the Amundsen Sea Low position, connecting the cavity circulation with changes in large-scale atmospheric circulation patterns as a new aspect of the atmosphere-ocean-ice shelf system.


The human Rad9/Rad1/Hus1 damage sensor clamp interacts with DNA polymerase beta and increases its DNA substrate utilisation efficiency: implications for DNA repair.
In eukaryotic cells, checkpoints are activated in response to DNA damage. This requires the action of DNA damage sensors such as the Rad family proteins. The three human proteins Rad9, Rad1 and Hus1 form a heterotrimeric complex (called the 9-1-1 complex) that is recruited onto DNA upon damage. DNA damage also triggers the recruitment of DNA repair proteins at the lesion, including specialized DNA polymerases. In this work, we showed that the 9-1-1 complex can physically interact with DNA polymerase beta in vitro. Functional analysis revealed that the 9-1-1 complex had a stimulatory effect on DNA polymerase beta activity. However, the presence of 9-1-1 complex neither affected DNA polymerase lambda, another X family DNA polymerase, nor the two replicative DNA polymerases alpha and delta. DNA polymerase beta stimulation resulted from an increase in its affinity for the primer-template and the interaction with the 9-1-1 complex stimulated deoxyribonucleotides misincorporation by DNA polymerase beta. In addition, the 9-1-1 complex enhanced DNA strand displacement synthesis by DNA polymerase beta on a 1 nt gap DNA substrate. Our data raise the possibility that the 9-1-1 complex might attract DNA polymerase beta to DNA damage sites, thus connecting directly checkpoints and DNA repair.


Systemic inflammatory response syndrome in tissue-type plasminogen activator-treated patients is associated with worse short-term functional outcome.
Systemic inflammatory response syndrome (SIRS) is a generalized inflammatory state. The primary goal of the study was to determine whether differences exist in outcomes in SIRS and non-SIRS intravenous tissue-type plasminogen activator-treated patients. Consecutive patients were retrospectively reviewed for the evidence of SIRS during their admission. SIRS was defined as the presence of ≥2 of the following: body temperature<36°C or >38°C, heart rate>90, respiratory rate>20, and white blood cells<4000/mm or >12 000 mm, or >10% bands. Patients diagnosed with infection (via positive culture) were excluded. Of the 241 patients, 44 had evidence of SIRS (18%). Adjusting for pre-tissue-type plasminogen activator National Institutes of Health Stroke Scale, age, and race, SIRS remained a predictor of poor functional outcome at discharge (odds ratio [OR], 2.58; 95% confidence interval [CI], 1.16-5.73; P=0.0197). In our sample of tissue-type plasminogen activator-treated (tPA) patients, ~1 in 5 patients developed SIRS. Furthermore, we found the presence of SIRS to be associated with poor short-term functional outcomes and prolonged length of stay.


Evolution of the tenascin family--implications for function of the C-terminal fibrinogen-like domain.
The three members of the tenascin (TN) family, TN-C, TN-R, and TN-X, are apparently conserved in all vertebrates and therefore must have functions that contribute to survival. One specific domain of tenascins, the fibrinogen-like terminal knob, can be argued to have an essential function. Its position at the C-terminus makes it most vulnerable to loss through mutation or deletion, and it should have been eliminated in evolution if there were no selective pressure to maintain it. The epidermal growth factor and fibronectin III domains probably play an important role as spacers, placing the terminal knob at the end of the tribrachion or hexabrachion arms. In addition to functioning as spacers, at least some of these domains may have additional functional interactions. The conservation of these domains in evolution is comparable to that of some growth factors, consistent with this possibility. A phylogenetic tree of all known fibrinogen-related domains, including those in tenascins, is presented.


The spread of SARS-CoV-2 in Spain: Hygiene habits, sociodemographic profile, mobility patterns and comorbidities.
COVID-19 constitutes the largest pandemic in the last 100 years. In view of the rapid spread of the virus, it is necessary to study the sociodemographic characteristics, hygiene habits, activity and mobility, and comorbidities of SARS-CoV-2 infection to be able to implement prevention strategies. For this purpose, a survey including the variables of interest was designed to try to understand the exponential spread of the virus despite the implemented severe restrictive mobility measures during the period of maximum confinement in Spain. This study conducted throughout the Spanish territory aims to clarify other routes of transmission of the COVID-19 during confinement, risk factors, and the effectiveness of the recommended hygiene measures to detect critical points of exposure to the virus and thus reduce its spread in this and possible future pandemics that could compromise public health. Our results show that living with a COVID-19 patient increased the risk of contagion by 60 times. Among all the sociodemographic variables analyzed, walking the dog have shown to have the strongest effect by increasing the risk by 78%. The most effective hygiene measure reducing the prevalence of the disease was the disinfection of products purchased from the market upon arrival home (which reduced the risk by 94%), above other hygiene measures, such as wearing masks, gloves, ethanol disinfection, bleaching and others. The mobility variable studied that showed the largest increase in the prevalence of the disease was working on site at the workplace (increased the risk by 76%). A significant higher prevalence of the disease was also detected among respondents who used the modality of acquiring basic commodities using home delivery service compared to those who chose in-store shopping.


Misfolded proteins impose a dosage-dependent fitness cost and trigger a cytosolic unfolded protein response in yeast.
Evolving lineages face a constant intracellular threat: most new coding sequence mutations destabilize the folding of the encoded protein. Misfolded proteins form insoluble aggregates and are hypothesized to be intrinsically cytotoxic. Here, we experimentally isolate a fitness cost caused by toxicity of misfolded proteins. We exclude other costs of protein misfolding, such as loss of functional protein or attenuation of growth-limiting protein synthesis resources, by comparing growth rates of budding yeast expressing folded or misfolded variants of a gratuitous protein, YFP, at equal levels. We quantify a fitness cost that increases with misfolded protein abundance, up to as much as a 3.2% growth rate reduction when misfolded YFP represents less than 0.1% of total cellular protein. Comparable experiments on variants of the yeast gene orotidine-5'-phosphate decarboxylase (URA3) produce similar results. Quantitative proteomic measurements reveal that, within the cell, misfolded YFP induces coordinated synthesis of interacting cytosolic chaperone proteins in the absence of a wider stress response, providing evidence for an evolved modular response to misfolded proteins in the cytosol. These results underscore the distinct and evolutionarily relevant molecular threat of protein misfolding, independent of protein function. Assuming that most misfolded proteins impose similar costs, yeast cells express almost all proteins at steady-state levels sufficient to expose their encoding genes to selection against misfolding, lending credibility to the recent suggestion that such selection imposes a global constraint on molecular evolution.


Carpal tunnel syndrome.
Carpal tunnel syndrome is a neuropathy caused by compression of the median nerve within the carpal tunnel. However, the severity of symptoms and signs does not often correlate well with the extent of nerve damage. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments, non-drug treatments, surgical treatments, and postoperative treatments for carpal tunnel syndrome? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 53 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, carpal tunnel release surgery (open and endoscopic), diuretics, internal neurolysis, local and systemic corticosteroids, massage therapy, nerve and tendon gliding exercises, non-steroidal anti-inflammatory drugs (NSAIDs), pyridoxine, therapeutic ultrasound, and wrist splints.


[Adhesiveness concept in cancer growth].
The present review describes a hypothesis for a critical role of cell adhesive interactions in tumorigenesis. Dysregulation of tissue cell-cell interactions initiates first of all local (in the tissue) and then general (in whole body) conditions for tumor growth. Otherwise imbalance of tissue-specific adhesion factor at the very beginning of carcinogenesis is considered to trigger a cascade of pathological reactions responsible for more severe adhesive disorders that are in turn critical for the "totalitarian" behavior of a tumor and its "colonization" of other tissues and organs. Impaired disturbance is likely to be the key mechanism of carcinogenesis since it is significantly associated with the main features of a tumor: tissue proliferation control loss, anaplasia, invasion, metastasis, and immune surveillance deficit. The hypothesis is supported by evolutionary, biological, histological, immunological, and clinical arguments whose combination does not characterize any other known mechanisms of oncogenesis. The concept of adhesiveness opens new possibilities for the diagnosis, prevention, and treatment of tumors and also improves a strategy for designing.


Ultraviolet excitation of remote phosphor with symmetrical illumination used in dual-sided liquid-crystal display.
The UV-excited flat lighting (UFL) technique differs from conventional fluorescent lamp or LED illumination. It involves using a remote phosphor film to convert the wavelength of UV light to visible light, achieving high brightness and planar and uniform illumination. In particular, UFL can accomplish compact size, low power consumption, and symmetrical dual-sided illumination. Additionally, UFL utilizes a thermal radiation mechanism to release the large amount of heat that is generated upon illumination without thermal accumulation. These characteristics of the UFL technique can motivate a wide range of lighting applications in thin-film transistor LCD backlighting or general lighting.


Toward High-Throughput Predictive Modeling of Protein Binding/Unbinding Kinetics.
One of the unaddressed challenges in drug discovery is that drug potency determined in vitro is not a reliable indicator of drug activity in vivo. Accumulated evidence suggests that in vivo activity is more strongly correlated with the binding/unbinding kinetics than the equilibrium thermodynamics of protein-ligand interactions (PLIs). However, existing experimental and computational techniques are insufficient in studying the molecular details of kinetics processes of PLIs on a large scale. Consequently, we not only have limited mechanistic understanding of the kinetic processes but also lack a practical platform for high-throughput screening and optimization of drug leads on the basis of their kinetic properties. For the first time, we address this unmet need by integrating coarse-grained normal mode analysis with multitarget machine learning (MTML). To test our method, HIV-1 protease is used as a model system. We find that computational models based on the residue normal mode directionality displacement of PLIs can not only recapitulate the results from all-atom molecular dynamics simulations but also predict protein-ligand binding/unbinding kinetics accurately. When this is combined with energetic features, the accuracy of combined kon and koff prediction reaches 74.35%. Furthermore, our integrated model provides us with new insights into the molecular determinants of the kinetics of PLIs. We propose that the coherent coupling of conformational dynamics and thermodynamic interactions between the receptor and the ligand may play a critical role in determining the kinetic rate constants of PLIs. In conclusion, we demonstrate that residue normal mode directionality displacement can serve as a kinetic fingerprint to capture long-time-scale conformational dynamics of the binding/unbinding kinetics. When this is coupled with MTML, it is possible to screen and optimize compounds on the basis of their binding/unbinding kinetics in a high-throughput fashion. The further development of such computational tools will bridge one of the critical missing links between in vitro compound screening and in vivo drug activity.