Alteration of in vivo cellulose ribbon assembly by carboxymethylcellulose and other cellulose derivatives.
In vivo cellulose ribbon assembly by the Gram-negative bacterium Acetobacter xylinum can be altered by incubation in carboxymethylcellulose (CMC), a negatively charged water-soluble cellulose derivative, and also by incubation in a variety of neutral, water-soluble cellulose derivatives. In the presence of all of these substituted celluloses, normal fasciation of microfibril bundles to form the typical twisting ribbon is prevented. Alteration of ribbon assembly is most extensive in the presence of CMC, which often induces synthesis of separate, intertwining bundles of microfibrils. Freeze-etch preparations of the bacterial outer membrane suggest that particles that are thought to be associated with cellulose synthesis or extrusion may be specifically organized to mediate synthesis of microfibril bundles. These data support the previous hypothesis that the cellulose ribbon of A. xylinum is formed by a hierarchical, cell-directed, self-assembly process. The relationship of these results to the regulation of cellulose microfibril size and wall extensibility in plant cell walls is discussed.


MicroRNA-320 suppresses the stem cell-like characteristics of prostate cancer cells by downregulating the Wnt/beta-catenin signaling pathway.
Prostate cancer (PCa) is a leading cause of mortality and morbidity in men worldwide, and emerging evidence suggests that the CD44(high) prostate tumor-initiating cells (TICs) are associated with its poor prognosis. Although microRNAs are frequently dysregulated in human cancers, the influence of microRNAs on PCa malignancy and whether targeting TIC-associated microRNAs inhibit PCa progression remain unclear. In this study, we found that miR-320 is significantly downregulated in PCa. Overexpression of miR-320 in PCa cells decreases PCa tumorigenesis in vitro and in vivo. Global gene expression profiling of miR-320-overexpressing PCa cells reveals that downstream target genes of Wnt/β-catenin pathway and cancer stem cell markers are significantly decreased. MicroRNA-320 inhibits β-catenin expression by targeting the 3'-untranslated region of β-catenin mRNA. The reduction of miR-320 associated with increased β-catenin was also found in CD44(high) subpopulation of prostate cancer cells and clinical PCa specimens. Interestingly, knockdown of miR-320 significantly increases the cancer stem-like properties, such as tumorsphere formation, chemoresistance and tumorigenic abilities, although enriching the population of stem-like TICs among PCa cells. Furthermore, increased miR-320 expression in prostate stem-like TICs significantly suppresses stem cell-like properties of PCa cells. These results support that miR-320 is a key negative regulator in prostate TICs, and suggest developing miR-320 as a novel therapeutic agent may offer benefits for PCa treatment.


IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism.
Germinal centers (GCs) are sites of B cell proliferation, somatic hypermutation, and selection of variants with improved affinity for antigen. Long-lived memory B cells and plasma cells are also generated in GCs, although how B cell differentiation in GCs is regulated is unclear. IL-21, secreted by T follicular helper cells, is important for adaptive immune responses, although there are conflicting reports on its target cells and mode of action in vivo. We show that the absence of IL-21 signaling profoundly affects the B cell response to protein antigen, reducing splenic and bone marrow plasma cell formation and GC persistence and function, influencing their proliferation, transition into memory B cells, and affinity maturation. Using bone marrow chimeras, we show that these activities are primarily a result of CD3-expressing cells producing IL-21 that acts directly on B cells. Molecularly, IL-21 maintains expression of Bcl-6 in GC B cells. The absence of IL-21 or IL-21 receptor does not abrogate the appearance of T cells in GCs or the appearance of CD4 T cells with a follicular helper phenotype. IL-21 thus controls fate choices of GC B cells directly.


Oxidative stress in arterial hypertension: role of NAD(P)H oxidase.
Increased vascular reactive oxygen species production, especially superoxide anion, contributes significantly in the functional and structural alterations present in hypertension. An enhanced superoxide production causes a diminished NO bioavailability by an oxidative reaction that inactivates NO. Exaggerated superoxide levels and a low NO bioavailability lead to endothelial dysfunction and hypertrophy of vascular cells. It has been shown that the enzyme NAD(P)H oxidase plays a major role as the most important source of superoxide anion in vascular cells. Several experimental observations have shown an enhanced superoxide generation as a result of the activation of vascular NAD(P)H oxidase in hypertension. Although this enzyme responds to stimuli such as vasoactive factors, growth factors, and cytokines, some recent data suggest the existence of a genetic background modulating the expression of its different components. New polymorphisms have been identified in the promoter of the p22(phox) gene, an essential subunit of NAD(P)H oxidase, influencing the activity of this enzyme. Genetic investigations of these polymorphisms will provide novel markers for determination of genetic susceptibility to oxidative stress in hypertension.


Dynamics of immunocyte activation during intravenous immunoglobulin treatment in Kawasaki disease.
Objectives: Kawasaki disease (KD) is a systemic vasculitis of early childhood. Intravenous immunoglobulin (IVIG) is the standard treatment for KD. However, IVIG is not effective in approximately 15% of children with KD, and the mechanisms for this are unclear. We investigated changes in monocyte and T-cell activation from pre- to post-IVIG in IVIG-effective and IVIG-resistant KD.Method: We analysed peripheral CD14+CD16+ cells and human leucocyte antigen-DR (HLA-DR) expression on CD4+ and CD8+ cells in 46 children with KD who were admitted to Yamaguchi University Hospital between January 2011 and May 2016. We compared the kinetics in the absolute numbers of CD14+CD16+ cells, CD4+HLA-DR+ cells, and CD8+HLA-DR+ cells before and after IVIG treatment between IVIG-effective and IVIG-resistant groups.Results: Among the 46 subjects, 30 had IVIG-effective KD and 16 had IVIG-resistant KD. The absolute number of CD14+CD16+ cells in the IVIG-effective group decreased significantly after IVIG, while that in the IVIG-resistant group showed no change after IVIG. The absolute number of CD4+HLA-DR+ cells increased significantly after IVIG in both groups. The absolute number of CD8+HLA-DR+ cells before IVIG was low and significantly increased after IVIG in the IVIG-resistant group, while that in the IVIG-effective group showed no change after IVIG.Conclusions: Our results suggest that insufficient control of monocyte suppression and T-cell activation, especially in terms of the CD8-related immune system, are associated with IVIG resistance. The restoration of T-cell suppression may be important for KD recovery. These findings provide insight into the mechanism of IVIG resistance.


The E7 gene of human papillomavirus type 16 is sufficient for immortalization of human epithelial cells.
The contribution of the E6 and E7 open reading frames of human papillomavirus type 6b (HPV6b) and HPV16 to immortalization of human keratinocytes was evaluated by using amphotropic recombinant retroviruses. The HPV16 E7 gene could immortalize primary human keratinocytes without the cooperation of the viral E6 gene; however, E6 was able to contribute significantly to the efficiency of the E7 immortalizing function. Infection of HFE cells with retroviruses carrying the 16E6, 6bE6, or 6bE6E7 open reading frame did not result in immortalization.


Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes.
Individuals with PTEN mutations have Cowden syndrome (CS), associated with breast, thyroid, and endometrial neoplasias. Many more patients with features of CS, not meeting diagnostic criteria (termed CS-like), are evaluated by clinicians for CS-related cancer risk. Germline mutations in succinate dehydrogenase subunits SDHB-D cause pheochromocytoma-paraganglioma syndrome. One to five percent of SDHB/SDHD mutation carriers have renal cell or papillary thyroid carcinomas, which are also CS-related features. SDHB-D may be candidate susceptibility genes for some PTEN mutation-negative individuals with CS-like cancers. To address this hypothesis, germline SDHB-D mutation analysis in 375 PTEN mutation-negative CS/CS-like individuals was performed, followed by functional analysis of identified SDH mutations/variants. Of 375 PTEN mutation-negative CS/CS-like individuals, 74 (20%) had increased manganese superoxide dismutase (MnSOD) expression, a manifestation of mitochondrial dysfunction. Among these, 10 (13.5%) had germline mutations/variants in SDHB (n = 3) or SDHD (7), not found in 700 controls (p < 0.001). Compared to PTEN mutation-positive CS/CS-like individuals, those with SDH mutations/variants were enriched for carcinomas of the female breast (6/9 SDH versus 30/107 PTEN, p < 0.001), thyroid (5/10 versus 15/106, p < 0.001), and kidney (2/10 versus 4/230, p = 0.026). In the absence of PTEN alteration, CS/CS-like-related SDH mutations/variants show increased phosphorylation of AKT and/or MAPK, downstream manifestations of PTEN dysfunction. Germline SDH mutations/variants occur in a subset of PTEN mutation-negative CS/CS-like individuals and are associated with increased frequencies of breast, thyroid, and renal cancers beyond those conferred by germline PTEN mutations. SDH testing should be considered for germline PTEN mutation-negative CS/CS-like individuals, especially in the setting of breast, thyroid, and/or renal cancers.


Upper Urinary Tract Urothelial Cancer in Croatian and Bosnian Endemic Nephropathy Regions.
Endemic nephropathy (EN) is a chronic tubulointerstitial renal disease associated with increased incidence of upper urinary tract urothelial cancer (UTUC) occurring predominantly in geographically limited areas in villages along big Danube river. Based on results obtained by the research it is confirmed that aristolochic acid is causative agent of endemic nephropathy (EN). The aim of this study was to determine characteristics of UTUC in two endemic areas and analyze trends in 5-year period. This study included all patients with UTUC with or without synchronous/metachronous urothelial cancer in urinary bladder, from Croatian and Bosnian EN and non-EN regions. We analyzed archival data bases from all patients with UTUC who were admitted and operated in Department for surgery and urology, General Hospital Josip Bencevic Slavonski Brod in the time period between 2005 and 2010. Analyzed groups of patients were divided and compared as EN group (that includes patients from Croatian and Bosnian EN region) and non-EN group (that includes patients from Croatian and Bosnian non-EN region). All surgical specimens were processed according to standardized pathological procedures. Comparing patients basic characteristics from Croatian and Bosnian EN region there was no significant difference in gender (females were more frequently affected in both EN regions, p=0.99) or age (p=0.43) of patients. We found higher blood levels of urea and creatinine in group of patients from Croatian EN region when compared with group of patients from Bosnian EN region but the difference was not statistically significant (p=0.79 and p=0.44, respectively). In patients from Croatian EN group Hemoglobin levels were significantly lower than levels from Bosnian EN region patients, p=0.0049. In group of patients from Bosnian EN region ureteral tumors were more frequently observed than in Croatian group of patients, when compared with renal pelvis tumors but the difference was not statistically significant (p=0.258). Our data showed some differences in tumor localization between to investigated, relatively nearly situated, EN regions in Croatia and Bosnia. Statistically significant difference in hemoglobin levels between Croatian and Bosnian EN regions that should be further analyzed to give some reasonable explanation.


The consequences of overdiagnosis and overtreatment of Lyme disease: an observational study.
The adverse consequences associated with overdiagnosis and overtreatment of Lyme disease, although previously recognized, have received inadequate attention. To determine the use of health services and occurrence of treatment-related illness, disability, and distress among patients in whom Lyme disease is inappropriately diagnosed or treated. Observational cohort study. University-based Lyme disease clinic. 209 patients with a presumptive diagnosis of Lyme disease previously assigned by referring physicians, the patients themselves, or both. Self-reported data, review of medical records, and standardized instruments were used to determine 1) use of health services in terms of number of outpatient visits, number of physicians seen, types of serologic tests, and days of antibiotic treatment; 2) occurrence of antibiotic-related adverse events; and 3) levels of disability, depression, and stress. Of the 209 patients, 44 (21%) met criteria for active Lyme disease, 40 (19%) had previous but not active Lyme disease, and 125 (60%) had no evidence of current or previous infection. In general, patients with active Lyme disease (who were not the focus of this study) had good outcomes. Patients with previous Lyme disease and patients with no evidence of Lyme disease used considerable health resources (median number of office visits, 11 and 7; median number of serologic tests, 4 and 4; and median days of antibiotic treatment, 75 and 42), had frequent minor adverse drug events (53% and 55%), reported significant disability (proportion of symptomatic days during which normal activities could not be performed, 16% and 18%), and had high rates of depression (38% and 42%) and stress (52% and 45%). Overdiagnosis and overtreatment of Lyme disease are associated with inappropriate use of health services, avoidable treatment-related illness, and substantial disability and distress.


A case-crossover study of work-related acute traumatic hand injuries in the People's Republic of China.
The aim of this study was to quantify potential transient risk factors for occupational acute hand injury among hospitalized workers in the People's Republic of China (PRC). Participants were recruited from 11 medical facilities in 3 cities of the PRC. A face-to-face interview was used to collect information on the occurrence of 8 potential risk factors within a 90-minute time period before an acute traumatic hand injury and during a control period within the month before the injury. The reliability of reporting transient risk factors was assessed, and a case-crossover design was used to estimate the injury incidence risk ratio (IRR) of each risk factor. In total,703 hospitalized workers completed the interview (527 male, 176 female), with a mean age of 31.8 [standard deviation (SD) 10.3] years. The median time interval between injury and interview was four days. Thirty percent of participants had a crush injury and 25.7% had an amputation. Using malfunctioning machinery/tools/material, performing a task with a different method, working overtime, and wearing gloves were found to have good reliability in test-retest examination [intra-class correlation coefficient (ICC)>0.9]. The IRR of a hand injury were markedly increased while using malfunctioning machinery/tools/material [110.4, 95% confidence interval (95% CI) 97.4-125.2], performing a task with a different method than usual (84.3, 95% CI 67.7-105.1), or being distracted (69.6, 95% CI 57.9-83.7). Gender and size of company were associated with differences in glove usage. The results suggest the importance of transient, potentially modifiable factors in the etiology of occupational acute hand injury in the PRC. Regular maintenance of machinery/tools, work practice controls, and avoiding distractions should be priorities for reducing the risk of occupational acute hand injuries.


Reconstitution and analysis of the multienzyme Escherichia coli RNA degradosome.
The Escherichia coli RNA degradosome is a multienzyme assembly that functions in transcript turnover and maturation of structured RNA precursors. We have developed a procedure to reconstitute the RNA degradosome from recombinant components using modular coexpression vectors. The reconstituted assembly can be purified on a scale that has enabled biochemical and biophysical analyses, and we compare the properties of recombinant and cell-extracted RNA degradosomes. We present evidence that auxiliary protein components can be recruited to the 'superprotomer' core of the assembly through a dynamic equilibrium involving RNA intermediaries. We discuss the implications for the regulation of RNA degradosome function in vivo.


Clinical presentation of a patient with thoracic myelopathy at a chiropractic clinic.
The purpose of this case report is to describe the clinical presentation, examination findings, and management decisions of a patient with thoracic myelopathy who presented to a chiropractic clinic. After receiving a diagnosis of a diffuse arthritic condition and kidney stones based on lumbar radiograph interpretation at a local urgent care facility, a 45-year-old woman presented to an outpatient chiropractic clinic with primary complaints of generalized low back pain, bilateral lower extremity paresthesias, and difficulty walking. An abnormal neurological examination result led to an initial working diagnosis of myelopathy of unknown cause. The patient was referred for a neurological consult. Computed tomography revealed severe multilevel degenerative spondylosis with diffuse ligamentous calcification, facet joint hypertrophy, and disk protrusion at T9-10 resulting in midthoracic cord compression. The patient underwent multilevel spinal decompressive surgery. Following surgical intervention, the patient reported symptom improvement. It is important to include a neurologic examination on all patients presenting with musculoskeletal complaints, regardless of prior medical attention. The ability to recognize myelopathy and localize the lesion to a specific spinal region by clinical examination may help prioritize diagnostic imaging decisions as well as facilitate diagnosis and treatment.


Can radiographic plain film be used to determine the depth of the tumour bed in the absence of surgical clips for breast boost planning.
A number of studies have demonstrated the importance of using surgical clips to define the tumour bed in breast boost radiotherapy. In the absence of such clips, other techniques suggested to improve boost location have included CT and ultrasound (US). Determination of the depth of the tumour bed is important in the selection of electron energy. This study was conducted to prospectively compare the depth of the lumpectomy cavity as defined by ultrasound to radiographic plain film evaluation of the anterior border of the pectoralis muscle. Forty-one breast-cancer patients treated at the Division of Therapeutic Radiology and Oncology, Department of Radiology, Faculty of Medicine, Chiang Mai University between December 2004 and December 2006 were prospectively identified as having no surgical clips within the lumpectomy cavity. All patients underwent both US evaluation of the depth of tumour bed (D1) and radiographic evaluation of the depth of the anterior border of the pectoralis muscle (D2). These depth dimensions (D1 and D2) were compared using a paired t-test. The correlation of both methods was analyzed by Pearson correlation test. Depth dimensions by US were shorter than the radiographic film method in 85% of patients. The absolute mean difference of the depth (radiographic films minus US) was 0.129 cm. A paired t-test demonstrated that the difference between these two methods to be not statistically significant (p= 0.27). The absolute difference of depth between the two methods ranged from 0 to 0.5 cm. A significant correlation was found between US and radiographic film measurements (p<0.01). Plane radiographic film evaluation of the anterior border of the pectoralis muscle can be used to define the depth of the tumour bed in patients who have no surgical clips. However, the plane radiographic film method determines only the depth, not the transverse and longitudinal dimensions of the tumour bed. Additional information from US is needed to delineate the target volume for the tumour bed boost. In the absence of surgical clips, the authors recommend integration of both methods in breast boost planning process.


Mixture effects of endocrine disrupting compounds in vitro.
Four different equi-molar mixtures were investigated for additive endocrine disrupting effects in vitro using the concentration addition model. It was found that additive effects on the same molecular target (the androgen receptor; AR) can be predicted for both mixtures of compounds with effect on the AR (flutamide, procymidone and vinclozolin) and of compounds with and without effects on the AR [finasteride, mono-(2-ethylhexyl) phthalate, prochloraz and vinclozolin]. For a paraben mixture (methyl paraben, ethyl paraben, propyl paraben, butyl paraben and iso-butyl paraben) antagonistic effect on AR could not be predicted under assumption of additivity in our model system. For a mixture containing three azole fungicides (epoxiconazole, propiconazole and tebuconazole), the observed AR antagonistic effects were close to the predicted effect assuming additivity. Azole fungicides are known inhibitors of androgen biosynthesis and in the steroid synthesis assay using H295R cells, the inhibition of testosterone production was close to additive, whereas the inhibition of oestradiol production was over-estimated for the mixture of azole fungicides, when compared with the effect predicted when assuming additivity. Overall these and other studies show that weak endocrine disrupting compounds, like parabens and azole fungicides, give rise to combination effects when they occur in mixtures. These combination effects should be taken into account in regulatory risk assessment not to under-estimate the risks for adverse effects associated with exposure to disrupting chemicals.


Predictors of atopic dermatitis phenotypes and severity: roles of serum immunoglobulins and filaggrin gene mutation R501X.
Atopic dermatitis (AD), the most common chronic relapsing skin condition of infancy and childhood, is a complex multifactorial disease, which arises from the interaction between strong genetic and environmental factors. To investigate the roles of several factors on the severity of AD including FLG R501X gene mutation, serum immunoglobulin (Ig) levels, atopy and accompanying allergic disorders. Children were genotyped for the mutation in FLG R501X gene. Serum levels of major Ig isotypes, atopy and accompanying allergic disorders were assessed. Study group consisted of 49 patients (M: 26, F: 23) with a mean age of 4.9±3.6 years and control group consisted of 50 children (M: 30, F: 20) with a mean age of 3.8±2.8 years. Genotyping of R501X mutation revealed risk alleles in none of the children in study group or control group. IgG z-scores were significantly higher in patients with AD compared to controls (-0.97±1.13 vs 1.48±1.02, p=0.026). There was a positive trend in IgG z-scores and a negative trend in IgA z-scores across the severity of AD. History of recurrent infections was significantly associated with asthma and/or AR (47.8% in patients with asthma/AR vs 3.8% in those without). Children with low IgG or IgA levels presented at an earlier age with lower rates of atopy and mild type AD. In a sample of Turkish children, FLG R501X genotyping revealed no risk alleles in variable severities of AD or healthy controls. Our data suggest that IgG and IgA levels might have a role in phenotypic features of AD in terms of severity and atopic sensitisation.


Where Does the Density Localize? Convergent Behavior for Global Hybrids, Range Separation, and DFT+U.
Approximate density functional theory (DFT) suffers from many-electron self-interaction error, otherwise known as delocalization error, that may be diagnosed and then corrected through elimination of the deviation from exact piecewise linear behavior between integer electron numbers. Although paths to correction of energetic delocalization error are well-established, the impact of these corrections on the electron density is less well-studied. Here, we compare the effect on density delocalization of DFT+U (i.e., semilocal DFT augmented with a Hubbard U correction), global hybrid tuning, and range-separated hybrid tuning on a diverse test set of 32 transition metal complexes and observe the three methods to have qualitatively equivalent effects on the ground state density. Regardless of valence orbital diffuseness (i.e., from 2p to 5p), ligand electronegativity (i.e., from Al to O), basis set (i.e., plane wave versus localized basis set), metal (i.e., Ti, Fe, Ni), and spin state, or tuning method, we consistently observe substantial charge loss at the metal and gain at ligand atoms (∼0.3-0.5 e or more). This charge loss at the metal is preferentially from the minority spin, leading to increasing magnetic moment as well. Using accurate wave function theory references, we observe that a minimum error in partial charges and magnetic moments occurs at higher tuning parameters than typically employed to eliminate energetic delocalization error. These observations motivate the need to develop multifaceted approximate-DFT error correction approaches that separately treat density delocalization and energetic errors to recover both correct density and orbital energy-derived properties.


Phylogenic Determinants of Cardiovascular Frailty, Focus on Hemodynamics and Arterial Smooth Muscle Cells.
The evolution of the circulatory system from invertebrates to mammals has involved the passage from an open system to a closed in-parallel system via a closed in-series system, accompanying the increasing complexity and efficiency of life's biological functions. The archaic heart enables pulsatile motion waves of hemolymph in invertebrates, and the in-series circulation in fish occurs with only an endothelium, whereas mural smooth muscle cells appear later. The present review focuses on evolution of the circulatory system. In particular, we address how and why this evolution took place from a closed, flowing, longitudinal conductance at low pressure to a flowing, highly pressurized and bifurcating arterial compartment. However, although arterial pressure was the latest acquired hemodynamic variable, the general teleonomy of the evolution of species is the differentiation of individual organ function, supported by specific fueling allowing and favoring partial metabolic autonomy. This was achieved via the establishment of an active contractile tone in resistance arteries, which permitted the regulation of blood supply to specific organ activities via its localized function-dependent inhibition (active vasodilation). The global resistance to viscous blood flow is the peripheral increase in frictional forces caused by the tonic change in arterial and arteriolar radius, which backscatter as systemic arterial blood pressure. Consequently, the arterial pressure gradient from circulating blood to the adventitial interstitium generates the unidirectional outward radial advective conductance of plasma solutes across the wall of conductance arteries. This hemodynamic evolution was accompanied by important changes in arterial wall structure, supported by smooth muscle cell functional plasticity, including contractility, matrix synthesis and proliferation, endocytosis and phagocytosis, etc. These adaptive phenotypic shifts are due to epigenetic regulation, mainly related to mechanotransduction. These paradigms actively participate in cardio-arterial pathologies such as atheroma, valve disease, heart failure, aneurysms, hypertension, and physiological aging.


Honokiol inhibits ultraviolet radiation-induced immunosuppression through inhibition of ultraviolet-induced inflammation and DNA hypermethylation in mouse skin.
Ultraviolet (UV) radiation exposure induces immunosuppression, which contributes to the development of cutaneous malignancies. We investigated the effects of honokiol, a phytochemical found in plants of the genus Magnolia, on UVB-induced immunosuppression using contact hypersensitivity (CHS) as a model in C3H/HeN mice. Topical application of honokiol (0.5 and 1.0 mg/cm2 skin area) had a significant preventive effect on UVB-induced suppression of the CHS response. The inflammatory mediators, COX-2 and PGE2, played a key role in this effect, as indicated by honokiol inhibition of cyclooxygenase-2 (COX-2) expression and PGE2 production in the UVB-exposed skin. Honokiol application also inhibited UVB-induced DNA hypermethylation and its elevation of the levels of TET enzyme, which is responsible for DNA demethylation in UVB-exposed skin. This was consistent with the restoration of the CHS response in mice treated with the DNA demethylating agent, 5-aza-2'-deoxycytidine, after UVB exposure. There was no significant difference in the levels of inhibition of UVB-induced immunosuppression amongst mice that were treated topically with available anti-cancer drugs (imiquimod and 5-fluorouracil). This study is the first to show that honokiol has the ability to inhibit UVB-induced immunosuppression in preclinical model and, thus, has potential for use as a chemopreventive strategy for UVB radiation-induced malignancies.


Outcomes of severe hyperkalemia in cardiopulmonary resuscitation with concomitant hemodialysis.
To investigate the efficacy of hemodialysis during cardiopulmonary resuscitation as an effective adjunct to the treatment of severe hyperkalemia. A prospective study. In hospital dialysis units and intensive care units. Renal failure patients who developed hyperkalemia induced cardiac arrest and failed to recover from conventional cardiopulmonary resuscitation (CPR) were included. Three patients entered into this study: 2 patients with chronic renal failure maintained on regular hemodialysis and one with acute renal failure who suffered from severe hyperkalemia. All three patients developed asystolic cardiac arrest with unrecordable blood pressure due to severe hyperkalemia. Aggressive CPR together with intravenous epinephrine, sodium bicarbonate and calcium chloride were instituted. External cardiac massage with cardiac defibrillation was unable to restore spontaneous heart action. After lack or response to intensive resuscitation, hemodialysis was performed concomitant with CPR to eliminate the potassium load. Sinus rhythm and blood pressure were restored in all 3 patients but one of them eventually succumbed to her underlying disease. Hemodialysis during CPR is probably an effective adjunct to the treatment of severe hyperkalemia in patients with severe hemodynamic compromise and asystolic cardiac arrest.


A beta-cell glycoprotein of Mr 40 000 is the major rat islet cell immunogen following xenogenic immunisation.
An antiserum (R2) was raised in a rabbit against dispersed Sprague Dawley rat islet cells. The R2 antiserum contains islet cell surface antibodies, which mediate complement-dependent cytotoxicity against islet cells resulting in a block of glucose induced insulin release. Immunoprecipitation and gel electrophoretic analysis showed that R2 specifically recognizes an Mr 40 000 glycoprotein present in both rat islet and rat insulinoma cells. This glycoprotein is amphiphilic in character and probably represents a pancreatic beta cell specific plasma membrane component. The results support previous observations in mouse beta cells that a plasma membrane glycoprotein of Mr 40K constitutes a major islet cell immunogen.


Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) shortens the period of neutropenia after autologous bone marrow transplantation in a primate model.
The effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on hematopoietic reconstitution after autologous bone marrow transplantation was evaluated in a primate model. Animals were given a continuous intravenous infusion of recombinant human GM-CSF for several days both before and after transplantation or only after the transplant procedure. Marrow ablation was accomplished by total body irradiation. In both groups of animals, the neutrophil count reached 1,000/mm3 by 8-9 d posttransplant compared with an interval of 17 and 24 d for two concurrent controls. After withdrawal of GM-CSF, neutrophil counts fell to values comparable to those observed in untreated controls. Accelerated recovery of platelet production was also observed in four of the five animals. Two additional animals were initially given GM-CSF several weeks posttransplantation because of inadequate engraftment. Prompt and sustained increases in neutrophil and platelet counts were observed. We conclude that GM-CSF may be useful in accelerating bone marrow reconstitution.


Pseudomonas aeruginosa: arsenal of resistance mechanisms, decades of changing resistance profiles, and future antimicrobial therapies.
Antimicrobial resistance is one of the most serious public health issues facing humans since the discovery of antimicrobial agents. The frequent, prolonged, and uncontrolled use of antimicrobial agents are major factors in the emergence of antimicrobial-resistant bacterial strains, including multidrug-resistant variants. Pseudomonas aeruginosa is a leading cause of nosocomial infections. The abundant data on the increased resistance to antipseudomonal agents support the need for global action. There is a paucity of new classes of antibiotics active against P. aeruginosa. Here, we discuss recent antibacterial resistance profiles and mechanisms of resistance by P. aeruginosa. We also review future potential methods for controlling antibiotic-resistant bacteria, such as phage therapy, nanotechnology and antipseudomonal vaccines.


Methamphetamine activates reward circuitry in drug naïve human subjects.
Amphetamines are highly addictive drugs that have pronounced effects on emotional and cognitive behavior in humans. These effects are mediated through their potent dopaminergic agonistic properties. Dopamine has also been implicated in the modulation of responses of the 'reward circuit' in animal and human studies. In this study we use functional magnetic resonance imaging (fMRI) to identify the brain circuitry involved in the psychostimulant effect of methamphetamine in psychostimulant-naïve human subjects. Seven healthy volunteers were scanned in a 3T MR imaging system. They received single-blind intravenous infusions of methamphetamine (0.15 mg/kg), and rated their experience of 'mind-racing' on a button press throughout the experiment. Data were analyzed with statistical parametric mapping methods. Amphetamine administration activated the medial orbitofrontal cortex, the rostral part of the anterior cingulate cortex, and the ventral striatum. Ratings of 'mind-racing' after methamphetamine infusion correlated with activations in the rostral part of the anterior cingulate cortex and in the ventral striatum. In addition, activations in the medial orbitofrontal cortex were independent of motor and related responses involved in making the ratings. These findings indicate that the first administration of a psychostimulant to human subjects activates classical reward circuitry. Our data also support recent hypotheses suggesting a central role for the orbitofrontal cortex in drug reinforcement and the development of addiction.


Experimental evidence for state-dependent nest weight in the blue tit, Cyanistes caeruleus.
Parental investment in reproduction is generally limited by food availability, and so avian life-history research has traditionally focused on the brood rearing phase, when food requirements are greatest. Only relatively recently has the focus extended to the incubation phase, and even more recently to the nest-building phase, where observational and comparative evidence suggest that avian nest building is an energetically expensive and time-consuming activity. We aimed to experimentally test the limitations on this cost in a hole-breeding passerine, the blue tit (Cyanistes caeruleus), by providing supplementary food to experimental pairs during the nest-building period. In comparison with control females, that did not receive supplementary food, experimental females constructed heavier nests, with greater amounts of moss base but similar amounts of cup lining, despite there being no differences in the time taken to build the nest. This study provides empirical support for the hypothesis that avian nest building is a costly behaviour, limited by food availability.


Postexercise hypotension and sympathoinhibition in borderline hypertensive men.
To determine if there would be a decrease in blood pressure after exercise in patients with borderline hypertension and if this decrease would be accompanied by a decrease in sympathetic nerve activity to muscle, we recorded multifiber postganglionic muscle sympathetic activity from the peroneal nerve at rest in nine men with borderline hypertension (age 25 +/- 1 years, mean +/- SEM) before and 60 minutes after 45 minutes of submaximal treadmill exercise. In addition, responses to a cold pressor test, handgrip, and the Valsalva maneuver were recorded before and after exercise. Four subjects were also studied before and after "sham" exercise. Sham exercise had no effect on blood pressure or sympathetic nerve activity whereas resting systolic blood pressure was lower after treadmill exercise in seven subjects (from 136 +/- 4 before to 123 +/- 2 mm Hg 60 minutes after exercise; p less than 0.01). Sixty minutes after exercise, sympathetic nerve activity was lower in all seven subjects (from 19 +/- 2 to 11 +/- 2 bursts/min, p less than 0.015; or from 27 +/- 3 to 14 +/- 2 bursts/100 heartbeats, p less than 0.005) but was slightly increased in the two subjects without postexercise hypotension. Heart rate and pressor and sympathoneural responses to the cold pressor test, handgrip, and the Valsalva maneuver were not altered by prior exercise. When nitroprusside was infused in five subjects to produce a reduction in systolic blood pressure similar to that seen 60 minutes after exercise, this drug increased sympathetic discharge from 37 +/- 6 to 57 +/- 4 bursts/100 heartbeats (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


A comparative study of broccoli sprouts powder and standard triple therapy on cardiovascular risk factors following H.pylori eradication: a randomized clinical trial in patients with type 2 diabetes.
In this clinical trial we compared the effects of broccoli sprouts powder, as an alternative and complementary treatment, to those of standard triple therapy, as a common medical treatment, on cardiovascular risk factors following the H.pylori eradication in patients with type 2 diabetes. Eighty-six type 2 diabetic patients with positive H.pylori stool antigen test (HpSAg) were randomized to receive one of the three following regimens: STT) Standard triple therapy (omeprazole 20 mg, clarithromycin 500 mg, amoxicillin 1000 mg, twice a day for 14 days), BSP) 6 g/d broccoli sprouts powder for 28 days, and combination of these as STT + BSP. After 4 weeks of treatment, H.pylori eradication rates were assessed by HpSAg. Anthropometric measures, blood pressure, serum lipids and lipoproteins as well as serum high sensitive- C reactive protein were also assessed at baseline and at the second examination. Seventy-seven participants completed the study [STT (n = 28), BSP (n = 25), STT + BSP (n = 24)]. The H.pylori eradication rates were 89.3%, 56.0% and 91.7% in STT, BSP and STT + BSP groups, respectively. After the treatment, both systolic and diastolic blood pressure significantly decreased in STT + BSP group (P < 0.05). Serum triglycerides and TG/HDL-C ratio increased in STT patients group (<0.05). Serum hs-CRP levels significantly decreased in the patients who were treated with BSP per se (3.0 ± 2.5 at baseline vs. 2.3 ± 2.1 after the treatment, P < 0.05). Compared to standard triple therapy, BSP regimen in addition to considerable effects on H.pylori eradication had also favorable properties on cardiovascular risk factors following the H.pylori eradication.


Vole population cycles in northern and southern Europe: is there a need for different explanations for single pattern?
1. Students of population cycles in small rodents in Fennoscandia have accumulated support for the predation hypothesis, which states that the gradient in cycle length and amplitude running from southern to northern Fennoscandia reflects the relative influence of specialist and generalist predators on vole dynamics, itself modulated by the presence of snow cover. The hypothesized role of snow cover is to isolate linked specialist predators, primarily the least weasel, Mustela n. nivalis L. and their prey, primarily field voles Microtus agrestis L., from the stabilizing influence of generalist predators. 2. The predation hypothesis does not readily account for the high amplitude and regular 3-year cycles of common voles documented in agricultural areas of western, central and eastern Europe. Such cycles are rarely mentioned in the literature pertaining to Fennoscandian cycles. 3. We consider new data on population cycles and demographic patterns of common voles Microtus arvalis Pallas in south-west France. We show that the patterns are wholly consistent with five of six patterns that characterize rodent cycles in Fennoscandia and that are satisfactorily explained by the predation hypothesis. They include the: (a) existence of cycle; (b) the occurrence of long-term changes in relative abundance and type of dynamics; (c) geographical synchrony over large areas; (d) interspecific synchrony; and (e) voles are large in the increase and peak phase and small in decline and low phase, namely. There is a striking similarity between the patterns shown by common vole populations in south-west France and those from Fennoscandian cyclic rodent populations, although the former are not consistent with a geographical extension of the latitudinal gradient south of Fennoscandia. 4. It is possible that the dominant interaction leading to multiannual rodent oscillations is different in different regions. We argue, however, that advocates of the predation hypothesis should embrace the challenge of developing a widely applicable explanation to population cycles, including justifying any limits to its applicability on ecological and not geographical grounds.


Galectin-3 guides intracellular trafficking of some human serotransferrin glycoforms.
Transferrin internalization via clathrin-mediated endocytosis and subsequent recycling after iron delivery has been extensively studied. Here we demonstrate a previously unrecognized parameter regulating this recycling, the binding of galectin-3 to particular glycoforms of transferrin. Two fractions of transferrin, separated by affinity chromatography based on their binding or not to galectin-3, are targeted to kinetically different endocytic pathways in HFL-1 cells expressing galectin-3 but not in SKBR3 cells lacking galectin-3; the SKBR3 cells, however, can acquire the ability to target these transferrin glycoforms differently after preloading with exogenously added galectin-3. In all, this study provides the first evidence of a functional role for transferrin glycans, in intracellular trafficking after uptake. Moreover, the galectin-3-bound glycoform increased in cancer, suggesting a pathophysiological regulation. These are novel aspects of transferrin cell biology, which has previously considered only a degree of iron loading, but not other forms of heterogeneity.


Impact of changes in television viewing time and physical activity on longevity: a prospective cohort study.
Television viewing is a highly prevalent sedentary behavior among older adults, yet the mortality risks associated with hours of daily viewing over many years and whether increasing or decreasing viewing time affects mortality is unclear. This study examined: 1) the long-term association between mortality and daily viewing time; 2) the influence of reducing and increasing in television viewing time on longevity and 3) combined effects of television viewing and moderate-to-vigorous physical activity (MVPA) on longevity. Participants included 165,087 adults in the NIH-AARP Diet and Health (aged 50-71 yrs) who completed questionnaires at two-time-points (Time 1: 1994-1996, and Time 2: 2004-2006) and were followed until death or December 31, 2011. Multivariable-adjusted Cox proportional hazards regression was used to estimate Hazard Ratios and 95% confidence intervals (CI) with self-reported television viewing and MVPA and all-cause mortality. Over 6.6 years of follow-up, there were 20,104 deaths. Compared to adults who watched < 3 h/day of television at both time points, mortality risk was 28% greater (CI:1.21,1.34) those who watched 5+ h/day at both time-points. Decreasing television viewing from 5 + h/day to 3-4 h/d was associated with a 15% reduction in mortality risk (CI:0.80, 0.91) and decreasing to <3 h/day resulted in an 12% lower risk (CI:0.79, 0.97). Conversely, adults who increased their viewing time to 3-4 h/day had an 17% greater mortality risk (CI:1.10, 1.24) and those who increased to 5+ h/day had a 45% greater risk (CI:1.32, 1.58), compared to those who consistently watched <3 h/day. The lowest mortality risk was observed in those who were consistently active and watched < 3 h/day of television. We confirm that prolonged television viewing time was associated with greater mortality in older adults and demonstrate for the first time that individuals who reduced the amount of time they spent watching television had lower mortality. Our findings provide new evidence to support behavioral interventions that seek to reduce sedentary television viewing in favor of more physically active pursuits, preferably MVPA. Given the high prevalence of physical inactivity and prolonged television viewing in older adults, favorable changes in these two modifiable behaviors could have substantial public health impact. ClinicalTrials.gov number, NCT00340015.


Health Impact of PM10, PM2.5 and Black Carbon Exposure Due to Different Source Sectors in Stockholm, Gothenburg and Umea, Sweden.
The most important anthropogenic sources of primary particulate matter (PM) in ambient air in Europe are exhaust and non-exhaust emissions from road traffic and combustion of solid biomass. There is convincing evidence that PM, almost regardless of source, has detrimental health effects. An important issue in health impact assessments is what metric, indicator and exposure-response function to use for different types of PM. The aim of this study is to describe sectorial contributions to PM exposure and related premature mortality for three Swedish cities: Gothenburg, Stockholm and Umea. Exposure is calculated with high spatial resolution using atmospheric dispersion models. Attributed premature mortality is calculated separately for the main local sources and the contribution from long-range transport (LRT), applying different relative risks. In general, the main part of the exposure is due to LRT, while for black carbon, the local sources are equally or more important. The major part of the premature deaths is in our assessment related to local emissions, with road traffic and residential wood combustion having the largest impact. This emphasizes the importance to resolve within-city concentration gradients when assessing exposure. It also implies that control actions on local PM emissions have a strong potential in abatement strategies.


A Development of Nucleic Chromatin Measurements as a New Prognostic Marker for Severe Chronic Heart Failure.
Accurate prediction of both mortality and morbidity is of significant importance, but it is challenging in patients with severe heart failure. It is especially difficult to detect the optimal time for implanting mechanical circulatory support devices in such patients. We aimed to analyze the morphometric ultrastructure of nuclear chromatin in cardiomyocytes by developing an original clinical histopathological method. Using this method, we developed a biomarker to predict poor outcome in patients with dilated cardiomyopathy (DCM). As a part of their diagnostic evaluation, 171 patients underwent endomyocardial biopsy (EMB). Of these, 63 patients diagnosed with DCM were included in this study. We used electron microscopic imaging of cardiomyocyte nuclei and an automated image analysis software program to assess whether it was possible to detect discontinuity of the nuclear periphery. Twelve months after EMB, all patients with a discontinuous nuclear periphery (Group A, n = 11) died from heart failure or underwent left ventricular assist device (VAD) implantation. In contrast, in patients with a continuous nuclear periphery (Group N, n = 52) only 7 patients (13%) underwent VAD implantation and there were no deaths (p<0.01). We then evaluated chromatin particle density (Nuc-CS) and chromatin thickness in the nuclear periphery (Per-CS) in Group N patients; these new parameters were able to identify patients with poor prognosis. We developed novel morphometric methods based on cardiomyocyte nuclear chromatin that may provide pivotal information for early prediction of poor prognosis in patients with DCM.


Osteology of a slave burial population from Barbados, West Indies.
A unique seventeenth-nineteenth century slave cemetery population from Newton plantation, Barbados, allows examination of craniodental characters in relation to ethnohistorical data. Age-at-death estimates suggest life expectancy at birth of 29 years and low infant mortality; historical demography, however, suggests life expectancy of 20 years and very high infant mortality. Tooth decay, bilateral tooth loss, periodontal disease, root hypercementosis, and severe enamel hypoplasia are high in frequency. The teeth yield evidence of such cultural practices as pipe-smoking and incisor mutilation. Several skeletal features reflect periodic near-starvation. Directional and fluctuating dental asymmetry, relative tooth size, and hypoplasia distribution suggest slaves experienced considerable weaning trauma; metabolic stress at this time exceeded that of prenatal and immediate postnatal periods. Odontometrics and dental and cranial nonmetric traits indicate that modern Blacks are intermediate between the ancestral slaves and modern Whites but more similar to the latter, suggesting effects of environmental covariance exceed those of genetic admixture. Nonmetric trait distributions show nonrandom patterns according to area of burial in the cemetery, a possible result of family segregation.


Vaccine development to prevent cytomegalovirus disease: report from the National Vaccine Advisory Committee.
Cytomegalovirus (CMV) infection is the most common intrauterine infection in the United States, and it exacts a heavy toll when it infects children and immunocompromised individuals. A CMV vaccine was assigned the highest priority by the Institute of Medicine in its 1999 assessment of targets for vaccine development. The priority was based on the cost and human suffering that would be alleviated by reducing the disease burden of congenital CMV infection. The National Vaccine Advisory Committee and invited experts examined the prospects for a CMV vaccine and the actions needed to bring about successful vaccine development at a National Vaccine Program Office workshop in October 2000. This article summarizes information about the changing epidemiology of CMV and immune responses to infection and immunity, and it reviews the current status of several vaccine candidates. Support of government agencies for CMV vaccine research and development is critical to address this need.


Effects of venlafaxine extended release on resilience in posttraumatic stress disorder: an item analysis of the Connor-Davidson Resilience Scale.
The aim was to evaluate the efficacy of venlafaxine extended release (ER) on characteristics of resilience, measured by the Connor-Davidson Resilience Scale, in patients with posttraumatic stress disorder (PTSD). Data were evaluated from a randomized, 6-month, international, multicenter study of adult outpatients with a primary diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition PTSD for >or=6 months, and 17-item Clinician-Administered PTSD Scale score >or=60. Patients were assigned randomly to treatment with flexible-dose venlafaxine ER (37.5-300 mg/day) or placebo. Changes from baseline scores and effect sizes of response to treatment with venlafaxine ER compared with placebo were computed for each item, as well as for the newly developed 2-item and 10-item subscales. Effect sizes across items ranged from 0.41 (moderate) to 0.08 (very weak). The effect size for the Resilience Scale-2 (2-item subscale) was 0.32, which was comparable to the effect sizes of 0.35 for the 25-item full scale and 0.34 for the 10-item subscale. Venlafaxine ER improved resilience on individual Connor-Davidson Resilience Scale items that reflect four factors (hardiness, persistence/tenacity, social support, and faith in a benevolent or meaningful world), to varying degrees in patients with PTSD. The findings suggest that assessment of treatment response might be enhanced by routine evaluation of resilience.


Distraction osteogenesis following low-dose hyperfractionated irradiation in the rat mandible.
The investigators hypothesized that low-dose hyperfractionated radiation would impair mandibular distraction osteogenesis (DO) in a murine mandibular model. Male Sprague-Dawley rats underwent fractionated radiation (30 Gy) of the left mandible. After a 2-week recovery period, an external frame distractor was applied and gradual distraction of the mandible was performed. Tissue was harvested after a 28-day consolidation period. Gross, radiologic, and histologic evaluations were undertaken. Control animals underwent surgery for an identical time frame without preoperative radiation. Animals subjected to preoperative radiation (n = 10) showed suboptimal bone formation, including bone atrophy, incomplete bridging of the distraction gap, and gross bony defects or nonunion, compared with controls (n = 10). Although physical lengthening was achieved, irradiation consistently led to a detrimental effect on the normal process of DO. This set of experiments establishes a valuable rodent model to evaluate the effects of radiation on DO and may help to formulate strategies to optimize DO before it is widely applied in oncologic reconstruction.


Single-Item, Self-Rated Health is a Useful Indicator of Health in Myofascial Temporomandibular Disorders.
To (1) examine differences in self-rated health (SRH) between a group of women with myofascial temporomandibular disorders (mTMD) and controls; (2) determine the extent to which pain, mental health, and physical function mediate these differences; and (3) explore specific mTMD symptoms and impairments explaining SRH among mTMD cases. An existing dataset of a sample of women with mTMD (n = 125) and a group of demographically similar controls (n = 49) was used. SRH was measured via a single item with 5 answer options ranging from poor (SRH = 1) to excellent (SRH = 5). Bodily pain, mental health, and physical function were measured with the Short-Form Health Survey. Regression analyses with SRH as the outcome were conducted. mTMD cases reported poorer SRH compared to controls, and bodily pain score fully mediated these lower scores. Physical function partially mediated the association between mTMD and SRH, while mental health did not explain much of the variance in SRH. This pattern held in case-only analyses. The association was not explained by mTMD-specific symptoms or by localized mTMD pain severity, although mTMD disability was independently associated with lower SRH. SRH is a simple and useful tool to consider in mTMD research, as it discriminates between cases and controls based on pain and physical function and is associated with mTMD disability.


Therapeutic intent of proton pump inhibitor prescription among elderly nonsteroidal anti-inflammatory drug users.
Prescription of proton pump inhibitors (PPIs) has increased dramatically. To assess therapeutic intent of PPI prescription among elderly veterans prescribed nonsteroidal anti-inflammatory drugs. Medical-record abstraction identified therapeutic intent of PPI prescription. An 'appropriate therapeutic intent' was defined as symptomatic gastro-oesophageal reflux disease or endoscopic oesophagitis, Zollinger-Ellison disease, dyspepsia, upper gastrointestinal event, Helicobacter pylori infection or nonsteroidal anti-inflammatory drug gastroprotection. Logistic regression predicted the outcome while adjusting for clinical characteristics. Of 1491 patients [mean 73 years (s.d. 5.6), 73% white and 99.8% men], among those charts which did document a therapeutic indication, 88.8% were appropriate. Prior gastroscopy was predictive of an appropriate therapeutic intent (OR 2.7; 95% CI: 1.9-3.7). Prescription to patients who used VA pharmacy services only, to in-patients, or by a cardiologist or an otolaryngologist were less likely to be appropriate. Gastroprotection was poorly recognized as an indication for PPI prescription, except by rheumatologists (OR 46.7; 95% CI: 15.9-136.9), or among highly co-morbid patients (OR 1.8; 95% CI: 1.1-2.9). Among in-patients, 45% of PPI prescriptions were initiated for unknown or inappropriate reasons. Type of provider predicts appropriate PPI use. In-patient prescription is associated with poor recognition of necessary gastroprotection and unknown therapeutic intent.


The involvement of the thalamus in semantic retrieval: a clinical group study.
There is increasing attention about the role of the thalamus in high cognitive functions, including memory. Although the bulk of the evidence refers to episodic memory, it was recently proposed that the mediodorsal (MD) and the centromedian-parafascicular (CM-Pf) nuclei of the thalamus may process general operations supporting memory performance, not only episodic memory. This perspective agrees with other recent fMRI findings on semantic retrieval in healthy participants. It can therefore be hypothesized that lesions to the MD and the CM-Pf impair semantic retrieval. In this study, 10 patients with focal ischemic lesions in the medial thalamus and 10 healthy controls matched for age, education, and verbal IQ performed a verbal semantic retrieval task. Patients were assigned to a target clinical group and a control clinical group based on lesion localization. Patients did not suffer from aphasia and performed in the range of controls in a categorization and a semantic association task. However, target patients performed poorer than healthy controls on semantic retrieval. The deficit was not because of higher distractibility but of an increased rate of false recall and, in some patients, of a considerably increased rate of misses. The latter deficit yielded a striking difference between the target and the control clinical groups and is consistent with anomia. Follow-up high-resolution structural scanning session in a subsample of patients revealed that lesions in the CM-Pf and MD were primarily associated with semantic retrieval deficits. We conclude that integrity of the MD and the CM-Pf is required for semantic retrieval, possibly because of their role in the activation of phonological representations.


Parental smoking, maternal alcohol, coffee and tea consumption during pregnancy, and childhood acute leukemia: the ESTELLE study.
To investigate the role of parental smoking during pre-conception and pregnancy, maternal beverage consumption (alcohol, coffee and tea) during pregnancy and their possible interactions, in the etiology of childhood acute leukemia (CL). The ESTELLE study included 747 cases of CL [636 cases of acute lymphoblastic leukemia (ALL) and 100 cases of acute myeloblastic leukemia (AML)] diagnosed in France in 2010-2011 and 1,421 population controls frequency-matched with the cases on age and gender. Data were obtained from structured telephone questionnaires administered to the mothers. The odds ratios (OR) and their 95 % confidence intervals were estimated using unconditional logistic regression models adjusted for potential confounders. AML, but not ALL, was non-significantly associated with alcohol drinking during pregnancy [OR = 1.3 (0.8-2.0)] with a significant positive dose-response trend (p-trend = 0.02). Pre-conception paternal smoking was significantly associated with ALL [OR = 1.2 (1.1-1.5)] and AML [OR = 1.5 (1.0-2.3)]. CL was not associated with maternal smoking [OR = 1.0 (0.8-1.2)], or maternal coffee [OR = 0.9 (0.8-1.1)] or tea drinking [OR = 0.9 (0.8-1.1)] during pregnancy. However, a high consumption of coffee (>2 cups/day) was significantly associated with ALL [OR = 1.3 (1.0-1.8)]. The findings constitute additional evidence that maternal alcohol drinking during pregnancy may be involved in AML, and that paternal smoking before pregnancy may be a risk factor for CL. The role of maternal coffee drinking in CL remains unclear and should be investigated further in consortium analyses and in large birth cohort studies with exposure assessment more contemporaneous with the exposure, before the occurrence of the disease.


Modeling developmental transitions in adaptive resonance theory.
Neural networks are applied to a theoretical subject in developmental psychology: modeling developmental transitions. Two issues that are involved will be discussed: discontinuities and acquiring qualitatively new knowledge. We will argue that by the appearance of a bifurcation, a neural network can show discontinuities and may acquire qualitatively new knowledge. First, it is shown that biological principles of neurite outgrowth result in self-organization in a neural network, which is strongly dependent on a bifurcation in the activity dynamics. Second, the effect of a bifurcation due to morphological change is investigated in an Adaptive Resonance Theory (ART) network. Exact ART networks with quantitative differences in network structure at the category level show qualitatively different dynamical regimes, which are separated by bifurcations. These qualitative differences in dynamics affect the cognitive function of Exact ART: Representations of learned categories are local or distributed.


Iron: an essential micronutrient for the legume-rhizobium symbiosis.
Legumes, which develop a symbiosis with nitrogen-fixing bacteria, have an increased demand for iron. Iron is required for the synthesis of iron-containing proteins in the host, including the highly abundant leghemoglobin, and in bacteroids for nitrogenase and cytochromes of the electron transport chain. Deficiencies in iron can affect initiation and development of the nodule. Within root cells, iron is chelated with organic acids such as citrate and nicotianamine and distributed to other parts of the plant. Transport to the nitrogen-fixing bacteroids in infected cells of nodules is more complicated. Formation of the symbiosis results in bacteroids internalized within root cortical cells of the legume where they are surrounded by a plant-derived membrane termed the symbiosome membrane (SM). This membrane forms an interface that regulates nutrient supply to the bacteroid. Consequently, iron must cross this membrane before being supplied to the bacteroid. Iron is transported across the SM as both ferric and ferrous iron. However, uptake of Fe(II) by both the symbiosome and bacteroid is faster than Fe(III) uptake. Members of more than one protein family may be responsible for Fe(II) transport across the SM. The only Fe(II) transporter in nodules characterized to date is GmDMT1 (Glycine max divalent metal transporter 1), which is located on the SM in soybean. Like the root plasma membrane, the SM has ferric iron reductase activity. The protein responsible has not been identified but is predicted to reduce ferric iron accumulated in the symbiosome space prior to uptake by the bacteroid. With the recent publication of a number of legume genomes including Medicago truncatula and G. max, a large number of additional candidate transport proteins have been identified. Members of the NRAMP (natural resistance-associated macrophage protein), YSL (yellow stripe-like), VIT (vacuolar iron transporter), and ZIP (Zrt-, Irt-like protein) transport families show enhanced expression in nodules and are expected to play a role in the transport of iron and other metals across symbiotic membranes.


Vasoactive Intestinal Peptide Deficiency Is Associated With Altered Gut Microbiota Communities in Male and Female C57BL/6 Mice.
Vasoactive intestinal peptide (VIP) is crucial for gastrointestinal tract (GIT) health. VIP sustains GIT homeostasis through maintenance of the intestinal epithelial barrier and acts as a potent anti-inflammatory mediator that contributes to gut bacterial tolerance. Based on these biological functions by VIP, we hypothesized that its deficiency would alter gut microbial ecology. To this end, fecal samples from male and female VIP+/+, VIP+/-, and VIP-/- littermates (n = 47) were collected and 16S rRNA sequencing was conducted. Our data revealed significant changes in bacterial composition, biodiversity, and weight loss from VIP-/- mice compared to VIP+/+ and VIP+/- littermates, irrespective of sex. The gut bacteria compositional changes observed in VIP-/- mice was consistent with gut microbial structure changes reported for certain inflammatory and autoimmune disorders. Moreover, predicted functional changes by PICRUSt software suggested an energy surplus within the altered microbiota from VIP-/- mice. These data support that VIP plays an important role in maintaining microbiota balance, biodiversity, and GIT function, and its genetic removal results in significant gut microbiota restructuring and weight loss.


Cost of cervical cancer treatment: implications for providing coverage to low-income women under the Medicaid expansion for cancer care.
To date, no study has reported on the cost of treating cervical cancer among Medicaid beneficiaries younger than 65 years of age. This information is essential for assessing the cost effectiveness of screening interventions for low-income women and the funding required for treatment programs established by the Breast and Cervical Cancer Prevention and Treatment Act of 2000. Administrative data from the North Carolina Medicaid program linked with cancer registry data were used to analyze total Medicaid costs for these patients and the incremental costs of cervical cancer care at 6 and 12 months from diagnosis. We compared 207 beneficiaries diagnosed with cancer during the years 2002 to 2004 with 414 controls. Total Medicaid costs at 6 months after diagnosis were $3,807, $23,187, $35,853, and $45,028 for in situ, local, regional, and distant cancers, respectively. The incremental cost of cancer treatment for local and regional cancers was $13,935 and $26,174 and by 12 months increased to $15,868 and $30,917, respectively. Medicaid coverage may be required for many months after diagnosis to ensure the provision of comprehensive care, especially for women with late-stage cancers. Given the great differences in cost of early versus late-stage cancers, interventions aimed at increasing screening among low-income women are likely to be cost effective.


Comparison of the Z and W sex chromosomal architectures in elegant crested tinamou (Eudromia elegans) and ostrich (Struthio camelus) and the process of sex chromosome differentiation in palaeognathous birds.
To clarify the process of avian sex chromosome differentiation in palaeognathous birds, we performed molecular and cytogenetic characterization of W chromosome-specific repetitive DNA sequences for elegant crested tinamou (Eudromia elegans, Tinamiformes) and constructed comparative cytogenetic maps of the Z and W chromosomes with nine chicken Z-linked gene homologues for E. elegans and ostrich (Struthio camelus, Struthioniformes). A novel family of W-specific repetitive sequences isolated from E. elegans was found to be composed of guanine- and cytosine-rich 293-bp elements that were tandemly arrayed in the genome as satellite DNA. No nucleotide sequence homologies were found for the Struthioniformes and neognathous birds. The comparative cytogenetic maps of the Z and W chromosomes of E. elegans and S. camelus revealed that there are partial deletions in the proximal regions of the W chromosomes in the two species, and the W chromosome is more differentiated in E. elegans than in S. camelus. These results suggest that a deletion firstly occurred in the proximal region close to the centromere of the acrocentric proto-W chromosome and advanced toward the distal region. In E. elegans, the W-specific repeated sequence elements were amplified site-specifically after deletion of a large part of the W chromosome occurred.


Enhanced extinction of cocaine seeking in brain-derived neurotrophic factor Val66Met knock-in mice.
The Val66Met polymorphism in the brain-derived neurotropic factor (BDNF) gene results in alterations in fear extinction behavior in both human populations and mouse models. However, it is not clear whether this polymorphism plays a similar role in extinction of appetitive behaviors. Therefore, we examined operant learning and extinction of both food and cocaine self-administration behavior in an inbred genetic knock-in mouse strain expressing the variant Bdnf. These mice provide a unique opportunity to relate alterations in aversive and appetitive extinction learning as well as provide insight into how human genetic variation can lead to differences in behavior. BDNF(Met/Met) mice exhibited a severe deficit in operant learning as demonstrated by an inability to learn the food self-administration task. Therefore, extinction experiments were performed comparing wildtype (BDNF(Val/Val) ) animals to mice heterozygous for the Met allele (BDNF(Val/Met) ), which did not differ in food or cocaine self-administration behavior. In contrast to the deficit in fear extinction previously demonstrated in these mice, we found that BDNF(Val/Met) mice exhibited more rapid extinction of cocaine responding compared to wildtype mice. No differences were found between the genotypes in the extinction of food self-administration behavior or the reinstatement of cocaine seeking, indicating that the effect is specific to extinction of cocaine responding. These results suggest that the molecular mechanisms underlying aversive and appetitive extinction are distinct from one another and BDNF may play opposing roles in the two phenomena.


Cholecystokinin and somatostatin in Alzheimer's disease postmortem cerebral cortex.
The neuropeptides cholecystokinin (CCK) and somatostatin are synthesized in separate, but morphologically similar, populations of locally projecting neurons in cerebral cortex. Concentrations of somatostatin are markedly diminished in Alzheimer's disease (AD), suggesting possible dysfunction of the intrinsic cortical neurons in which it is produced. We determined whether cortical levels of CCK might be similarly affected in AD by dissecting postmortem brain samples from 14 histologically confirmed cases of AD and 17 age-matched controls and measuring CCK and somatostatin by radioimmunoassay. CCK-like immunoreactivity was significantly reduced in the AD brains by 24 to 38% in five of the 11 cortical areas examined but was normal in the remaining regions. Somatostatin concentrations measured in the same tissue extracts were consistently decreased by 45 to 65%. These results indicate that (1) CCK-immunoreactive neurons in cortex are affected by the AD process, and (2) the changes in levels of CCK are less dramatic than the reductions of somatostatin immunoreactivity.


Genotype and risk of major bleeding during warfarin treatment.
To determine whether genetic variants associated with warfarin dose variability were associated with increased risk of major bleeding during warfarin therapy. Using Vanderbilt's DNA biobank we compared the prevalence of CYP2C9, VKORC1 and CYP4F2 variants in 250 cases with major bleeding and 259 controls during warfarin therapy. CYP2C9*3 was the only allele that differed significantly among cases (14.2%) and controls (7.8%; p = 0.022). In the 214 (85.6%) cases with a major bleed 30 or more days after warfarin initiation, CYP2C9*3 was the only variant associated with bleeding (adjusted odds ratio: 2.05; 95% CI: 1.04, 4.04). The CYP2C9*3 allele may double the risk of major bleeding among patients taking warfarin for 30 or more days.


Use of proton pump inhibitors and risk of hip/femur fracture: a population-based case-control study.
Previous studies evaluated the association between proton pump inhibitor (PPI) use and subsequent fracture risk, but they showed ambiguous results. Therefore, the objective was to evaluate this association in a different study population. Our findings show that there is probably no causal relationship between PPI use and hip fracture risk. Previous studies evaluated the association between PPI use and subsequent fracture risk, but they showed ambiguous results. To further test these conflicting results, the objective of this study was to evaluate the association between the use of PPIs and the risk of hip/femur fracture in a different study population. A case-control study was conducted using data from the Dutch PHARMO record linkage system. The study population included 6,763 cases aged 18 years and older with a first hip/femur fracture during enrollment and 26,341 age-, gender- and region-matched controls. Current users of PPIs had an increased risk of hip/femur fracture yielding an adjusted odds ratio (AOR) of 1.20 (95% CI 1.04-1.40). Fracture risk attenuated with increasing durations of use, resulting in AORs of 1.26 (95% CI 0.94-1.68) in the first 3 months, 1.31 (95% CI 0.97-1.75) between 3 and 12 months, 1.18 (95% CI 0.92-1.52) between 13 and 36 months and 1.09 (95% CI 0.81-1.47) for use longer than 36 months. Our findings show that there is probably no causal relationship between PPI use and hip fracture risk. The observed association may be the result of unmeasured distortions: although current use of PPIs was associated with a 1.2-fold increased risk of hip/femur fracture, the positive association was attenuated with longer durations of continuous use. Our findings do not support that discontinuation of PPIs decreases risk of hip fracture in elderly patients.


Directed enzymatic activation of 1-D DNA tiles.
The tile assembly model is a Turing universal model of self-assembly where a set of square shaped tiles with programmable sticky sides undergo coordinated self-assembly to form arbitrary shapes, thereby computing arbitrary functions. Activatable tiles are a theoretical extension to the Tile assembly model that enhances its robustness by protecting the sticky sides of tiles until a tile is partially incorporated into a growing assembly. In this article, we experimentally demonstrate a simplified version of the Activatable tile assembly model. In particular, we demonstrate the simultaneous assembly of protected DNA tiles where a set of inert tiles are activated via a DNA polymerase to undergo linear assembly. We then demonstrate stepwise activated assembly where a set of inert tiles are activated sequentially one after another as a result of attachment to a growing 1-D assembly. We hope that these results will pave the way for more sophisticated demonstrations of activated assemblies.


Estimating home-range size: when to include a third dimension?
Most studies dealing with home ranges consider the study areas as if they were totally flat, working only in two dimensions, when in reality they are irregular surfaces displayed in three dimensions. By disregarding the third dimension (i.e., topography), the size of home ranges underestimates the surface actually occupied by the animal, potentially leading to misinterpretations of the animals' ecological needs. We explored the influence of considering the third dimension in the estimation of home-range size by modeling the variation between the planimetric and topographic estimates at several spatial scales. Our results revealed that planimetric approaches underestimate home-range size estimations, which range from nearly zero up to 22%. The difference between planimetric and topographic estimates of home-ranges sizes produced highly robust models using the average slope as the sole independent factor. Moreover, our models suggest that planimetric estimates in areas with an average slope of 16.3° (±0.4) or more will incur in errors ≥5%. Alternatively, the altitudinal range can be used as an indicator of the need to include topography in home-range estimates. Our results confirmed that home-range estimates could be significantly biased when topography is disregarded. We suggest that study areas where home-range studies will be performed should firstly be scoped for its altitudinal range, which can serve as an indicator for the need for posterior use of average slope values to model the surface area used and/or available for the studied animals.


Investigation of DMSO-induced conformational transitions in human serum albumin using two-dimensional raman optical activity spectroscopy.
Recent Raman and Raman optical activity (ROA) results have demonstrated that dimethyl sulfoxide (DMSO) induces the selective conversion of α-helix motifs into the poly(L-proline) II (PPII) helix conformation in an array of proteins, while β-sheets remain mostly unaffected. Human serum albumin (HSA), a highly α-helical protein, underwent the most dramatic changes and, therefore, was selected as a model for further investigations into the mechanism of this conformational change. Herein we report the use of two-dimensional ROA correlation analysis applying synchronous, autocorrelation, and moving windows approaches in order to understand the conformational transitions in HSA as a function of DMSO concentration. Our results indicate that the destabilization of native α-helix starts at DMSO concentrations as little as 20% in water (v/v), with the transition to PPII helix being complete at ~80% DMSO. These results clearly indicate that any protein preparation containing relatively low concentrations of DMSO should consider possible disruptions in α-helical domains.


Testes and brain gene expression in precocious male and adult maturing Atlantic salmon (Salmo salar).
The male Atlantic salmon generally matures in fresh water upon returning after one or several years at sea. Some fast-growing male parr develop an alternative life strategy where they sexually mature before migrating to the oceans. These so called 'precocious' parr or 'sneakers' can successfully fertilise adult female eggs and so perpetuate their line. We have used a custom-built cDNA microarray to investigate gene expression changes occurring in the salmon gonad and brain associated with precocious maturation. The microarray has been populated with genes selected specifically for involvement in sexual maturation (precocious and adult) and in the parr-smolt transformation. Immature and mature parr collected from a hatchery-reared stock in January were significantly different in weight, length and condition factor. Changes in brain expression were small - never more than 2-fold on the microarray, and down-regulation of genes was much more pronounced than up-regulation. Significantly changing genes included isotocin, vasotocin, cathepsin D, anamorsin and apolipoprotein E. Much greater changes in expression were seen in the testes. Among those genes in the testis with the most significant changes in expression were anti-Mullerian hormone, collagen 1A, and zinc finger protein (Zic1), which were down-regulated in precocity and apolipoproteins E and C-1, lipoprotein lipase and anti-leukoproteinase precursor which were up-regulated in precocity. Expression changes of several genes were confirmed in individual fish by quantitative PCR and several genes (anti-Mullerian hormone, collagen 1A, beta-globin and guanine nucleotide binding protein (G protein) beta polypeptide 2-like 1 (GNB2L1) were also examined in adult maturing testes. Down-regulation of anti-Mullerian hormone was judged to be greater than 160-fold for precocious males and greater than 230-fold for November adult testes in comparison to July testes by this method. For anti-Mullerian hormone and guanine nucleotide binding protein beta polypeptide 2-like 1 expression changes in precocious males mirrored mature adults (November) but for collagen 1A and beta-globin the pattern was more complex. Expression changes in the fish brain during the process of precocious sexual maturation were small compared to those in the testes. Microarray analysis suggested down-regulation of housekeeping functions and up-regulation of a small number of specific processes. Transcriptional changes in the testes were much more pronounced with anti-Mullerian hormone playing a major role. Expression profiles for mature parr and maturing adult testes indicate subtle differences in gene expression between these two related groups.


Pharmacological interventions for somatoform disorders in adults.
Somatoform disorders are characterised by chronic, medically unexplained physical symptoms (MUPS). Although different medications are part of treatment routines for people with somatoform disorders in clinics and private practices, there exists no systematic review or meta-analysis on the efficacy and tolerability of these medications. We aimed to synthesise to improve optimal treatment decisions. To assess the effects of pharmacological interventions for somatoform disorders (specifically somatisation disorder, undifferentiated somatoform disorder, somatoform autonomic dysfunction, and pain disorder) in adults. We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR) (to 17 January 2014). This register includes relevant randomised controlled trials (RCTs) from The Cochrane Library (all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). To identify ongoing trials, we searched ClinicalTrials.gov, Current Controlled Trials metaRegister, the World Health Organization International Clinical Trials Registry Platform, and the Chinese Clinical Trials Registry. For grey literature, we searched ProQuest Dissertation & Theses Database, OpenGrey, and BIOSIS Previews. We handsearched conference proceedings and reference lists of potentially relevant papers and systematic reviews and contacted experts in the field. We selected RCTs or cluster RCTs of pharmacological interventions versus placebo, treatment as usual, another medication, or a combination of different medications for somatoform disorders in adults. We included people fulfilling standardised diagnostic criteria for somatisation disorder, undifferentiated somatoform disorder, somatoform autonomic dysfunction, or somatoform pain disorder. One review author and one research assistant independently extracted data and assessed risk of bias. Primary outcomes included the severity of MUPS on a continuous measure, and acceptability of treatment. We included 26 RCTs (33 reports), with 2159 participants, in the review. They examined the efficacy of different types of antidepressants, the combination of an antidepressant and an antipsychotic, antipsychotics alone, or natural products (NPs). The duration of the studies ranged between two and 12 weeks.One meta-analysis of placebo-controlled studies showed no clear evidence of a significant difference between tricyclic antidepressants (TCAs) and placebo for the outcome severity of MUPS (SMD -0.13; 95% CI -0.39 to 0.13; 2 studies, 239 participants; I(2) = 2%; low-quality evidence). For new-generation antidepressants (NGAs), there was very low-quality evidence showing they were effective in reducing the severity of MUPS (SMD -0.91; 95% CI -1.36 to -0.46; 3 studies, 243 participants; I(2) = 63%). For NPs there was low-quality evidence that they were effective in reducing the severity of MUPS (SMD -0.74; 95% CI -0.97 to -0.51; 2 studies, 322 participants; I(2) = 0%).One meta-analysis showed no clear evidence of a difference between TCAs and NGAs for severity of MUPS (SMD -0.16; 95% CI -0.55 to 0.23; 3 studies, 177 participants; I(2) = 42%; low-quality evidence). There was also no difference between NGAs and other NGAs for severity of MUPS (SMD -0.16; 95% CI -0.45 to 0.14; 4 studies, 182 participants; I(2) = 0%).Finally, one meta-analysis comparing selective serotonin reuptake inhibitors (SSRIs) with a combination of SSRIs and antipsychotics showed low-quality evidence in favour of combined treatment for severity of MUPS (SMD 0.77; 95% CI 0.32 to 1.22; 2 studies, 107 participants; I(2) = 23%).Differences regarding the acceptability of the treatment (rate of all-cause drop-outs) were neither found between NGAs and placebo (RR 1.01, 95% CI 0.64 to 1.61; 2 studies, 163 participants; I(2) = 0%; low-quality evidence) or NPs and placebo (RR 0.85, 95% CI 0.40 to 1.78; 3 studies, 506 participants; I(2) = 0%; low-quality evidence); nor between TCAs and other medication (RR 1.48, 95% CI 0.59 to 3.72; 8 studies, 556 participants; I(2) =14%; low-quality evidence); nor between antidepressants and the combination of an antidepressant and an antipsychotic (RR 0.80, 95% CI 0.25 to 2.52; 2 studies, 118 participants; I(2) = 0%; low-quality evidence). Percental attrition rates due to adverse effects were high in all antidepressant treatments (0% to 32%), but low for NPs (0% to 1.7%).The risk of bias was high in many domains across studies. Seventeen trials (65.4%) gave no information about random sequence generation and only two (7.7%) provided information about allocation concealment. Eighteen studies (69.2%) revealed a high or unclear risk in blinding participants and study personnel; 23 studies had high risk of bias relating to blinding assessors. For the comparison NGA versus placebo, there was relatively high imprecision and heterogeneity due to one outlier study. Although we identified 26 studies, each comparison only contained a few studies and small numbers of participants so the results were imprecise. The current review found very low-quality evidence for NGAs and low-quality evidence for NPs being effective in treating somatoform symptoms in adults when compared with placebo. There was some evidence that different classes of antidepressants did not differ in efficacy; however, this was limited and of low to very low quality. These results had serious shortcomings such as the high risk of bias, strong heterogeneity in the data, and small sample sizes. Furthermore, the significant effects of antidepressant treatment have to be balanced against the relatively high rates of adverse effects. Adverse effects produced by medication can have amplifying effects on symptom perceptions, particularly in people focusing on somatic symptoms without medical causes. We can only draw conclusions about short-term efficacy of the pharmacological interventions because no trial included follow-up assessments. For each of the comparisons where there were available data on acceptability rates (NGAs versus placebo, NPs versus placebo, TCAs versus other medication, and antidepressants versus a combination of an antidepressant and an antipsychotic), no clear differences between the intervention and comparator were found.Future high-quality research should be carried out to determine the effectiveness of medications other than antidepressants, to compare antidepressants more thoroughly, and to follow-up participants over longer periods (the longest follow up was just 12 weeks). Another idea for future research would be to include other outcomes such as functional impairment or dysfunctional behaviours and cognitions as well as the classical outcomes such as symptom severity, depression, or anxiety.


Optogenetic activation of CA1 pyramidal neurons at the dorsal and ventral hippocampus evokes distinct brain-wide responses revealed by mouse fMRI.
The dorsal and ventral hippocampal regions (dHP and vHP) are proposed to have distinct functions. Electrophysiological studies have revealed intra-hippocampal variances along the dorsoventral axis. Nevertheless, the extra-hippocampal influences of dHP and vHP activities remain unclear. In this study, we compared the spatial distribution of brain-wide responses upon dHP or vHP activation and further estimate connection strengths between the dHP and the vHP with corresponding extra-hippocampal areas. To achieve this, we first investigated responses of local field potential (LFP) and multi unit activities (MUA) upon light stimulation in the hippocampus of an anesthetized transgenic mouse, whose CA1 pyramidal neurons expressed a step-function opsin variant of channelrhodopsin-2 (ChR2). Optogenetic stimulation increased hippocampal LFP power at theta, gamma, and ultra-fast frequency bands, and augmented MUA, indicating light-induced activation of CA1 pyramidal neurons. Brain-wide responses examined using fMRI revealed that optogenetic activation at the dHP or vHP caused blood oxygenation level-dependent (BOLD) fMRI signals in situ. Although activation at the dHP induced BOLD responses at the vHP, the opposite was not observed. Outside the hippocampal formation, activation at the dHP, but not the vHP, evoked BOLD responses at the retrosplenial cortex (RSP), which is in line with anatomical evidence. In contrast, BOLD responses at the lateral septum (LS) were induced only upon vHP activation, even though both dHP and vHP send axonal fibers to the LS. Our findings suggest that the primary targets of dHP and vHP activation are distinct, which concurs with attributed functions of the dHP and RSP in spatial memory, as well as of the vHP and LS in emotional responses.


AKAP5 signaling complexes: focal points and functional properties.
Kinase Anchoring Proteins (AKAPs) have evolved to regulate the spatial and temporal organization of cellular signal transduction. As a typical member, AKAP5 which consisting of three orthologues: bovine AKAP75, rodent AKAP150 and human AKAP79, is the best known model in the anchoring and targeting properties. It is shown that AKAP5 can bind β2-adrenergic receptor, which is a member of GPCR superfamily, and orchestrate the interactions of various protein kinases, protein phosphatases and cytoskeletal element. AKAP5 is originally identified as a component of the postsynaptic density in neurons and plays a vital role in modulating neuronal activities. Subsequently, the AKAP5 complexes are also detected in other tissues and participated in various processes.


Delivering the Multisensory Experience of Dining-Out, for Those Dining-In, During the Covid Pandemic.
In many parts of the world, restaurants have been forced to close in unprecedented numbers during the various Covid-19 pandemic lockdowns that have paralyzed the hospitality industry globally. This highly-challenging operating environment has led to a rapid expansion in the number of high-end restaurants offering take-away food, or home-delivery meal kits, simply in order to survive. While the market for the home delivery of food was already expanding rapidly prior to the emergence of the Covid pandemic, the explosive recent growth seen in this sector has thrown up some intriguing issues and challenges. For instance, concerns have been raised over where many of the meals that are being delivered are being prepared, given the rise of so-called "dark kitchens." Furthermore, figuring out which elements of the high-end, fine-dining experience, and of the increasingly-popular multisensory experiential dining, can be captured by those diners who may be eating and drinking in the comfort of their own homes represents an intriguing challenge for the emerging field of gastrophysics research; one that the chefs, restaurateurs, restaurant groups, and even the food delivery companies concerned are only just beginning to get to grips with. By analyzing a number of the high-end fine-dining home food delivery options that have been offered (in the UK and in the US) in this narrative review, we highlight a number of promising directions for those wanting to optimize the at-home multisensory dining experience, wherever in the world they might be.


A propidium monoazide-quantitative PCR method for the detection and quantification of viable Enterococcus faecalis in large-volume samples of marine waters.
The development of rapid detection assays of cell viability is essential for monitoring the microbiological quality of water systems. Coupling propidium monoazide with quantitative PCR (PMA-qPCR) has been successfully applied in different studies for the detection and quantification of viable cells in small-volume samples (0.25-1.00 mL), but it has not been evaluated sufficiently in marine environments or in large-volume samples. In this study, we successfully integrated blue light-emitting diodes for photoactivating PMA and membrane filtration into the PMA-qPCR assay for the rapid detection and quantification of viable Enterococcus faecalis cells in 10-mL samples of marine waters. The assay was optimized in phosphate-buffered saline and seawater, reducing the qPCR signal of heat-killed E. faecalis cells by 4 log10 and 3 log10 units, respectively. Results suggest that high total dissolved solid concentration (32 g/L) in seawater can reduce PMA activity. Optimal PMA-qPCR standard curves with a 6-log dynamic range and detection limit of 10(2) cells/mL were generated for quantifying viable E. faecalis cells in marine waters. The developed assay was compared with the standard membrane filter (MF) method by quantifying viable E. faecalis cells in seawater samples exposed to solar radiation. The results of the developed PMA-qPCR assay did not match that of the standard MF method. This difference in the results reflects the different physiological states of E. faecalis cells in seawater. In conclusion, the developed assay is a rapid (∼5 h) method for the quantification of viable E. faecalis cells in marine recreational waters, which should be further improved and tested in different seawater settings.


Perception of professional ethics by Iranian occupational therapists working with children.
Ethics are related to the structure and culture of the society. In addition to specialized ethics for every profession, individuals also hold their own personal beliefs and values. This study aimed to investigate Iranian occupational therapists' perception of ethical practice when working with children. For this purpose, qualitative content analysis was used and semi-structured interviews were conducted with ten occupational therapists in their convenient place and time. Each interview was transcribed and double-checked by the research team. Units of meaning were extracted from each transcription and then coded and categorized accordingly. The main categories of ethical practice when working with children included personal attributes, responsibility toward clients, and professional responsibility. Personal attributes included four subcategories: veracity, altruism, empathy, and competence. Responsibility toward clients consisted of six subcategories: equality, autonomy, respect for clients, confidentiality, beneficence, and non-maleficence. Professional responsibility included three subcategories: fidelity, development of professional knowledge, and promotion and growth of the profession. Findings of this study indicated that in Iran, occupational therapists' perception of autonomy, beneficence, non-maleficence, fidelity and competence is different from Western countries, which may be due to a lower knowledge of ethics and other factors such as culture. The results of this study may be used to develop ethical codes for Iranian occupational therapists both during training and on the job.


Protein sequence requirements for function of the human T-cell leukemia virus type 1 Rex nuclear export signal delineated by a novel in vivo randomization-selection assay.
The Rex protein of human T-cell leukemia virus type 1, like the functionally equivalent Rev protein of human immunodeficiency virus type 1, contains a leucine-rich activation domain that specifically interacts with the human nucleoporin-like Rab/hRIP cofactor. Here, this Rex sequence is shown to function also as a protein nuclear export signal (NES). Rex sequence libraries containing randomized forms of the activation domain/NES were screened for retention of the ability to bind Rab/hRIP by using the yeast two-hybrid assay. While the selected sequences differed widely in primary sequence, all were functional as Rex activation domains. In contrast, randomized sequences that failed to bind Rab/hRIP lacked Rex activity. The selected sequences included one with homology to the Rev activation domain/NES and a second that was similar to the NES found in the cellular protein kinase inhibitor alpha. A highly variant, yet fully active, activation domain sequence selected on the basis of Rab/hRIP binding retained full NES function even though this sequence preserved only a single leucine residue. In contrast, nonfunctional activation domain mutants that were unable to bind Rab/hRIP had also lost NES function. These data demonstrate that NES activity is a defining characteristic of the activation domains found in the Rev/Rex class of retroviral regulatory proteins and strongly support the hypothesis that the Rab/hRIP cofactor plays a critical role in mediating the biological activity of these NESs. In addition, these data suggest a consensus sequence for NESs of the Rev/Rex class.