Glycopeptide composition of hepatitis B surface antigen.
Three major polypeptides of hepatitis B surface antigen (HBsAg), with mol. wt. 22,000 (p22), 27,000 (p27) and 68,000 (p68), were separated by preparative SDS-PAGE. These three peptides as well as intact HBsAg were found to have almost identical amino acid compositions and carbohydrate was detected in p27 and p68 by PAS staining. Papain treatment of p68 produced two distinct peptides p27 and p22. Moreover, when an artificial mixture of p27 and p22 in a ratio of 1:1 was treated with 0.2 M-periodate for 30 min at 37 degrees C, only p22 was detectable. These results suggest that p68 is composed of p27 and p22, and that p27 is a glycosylated product of p22. Thus, from the evidence obtained, it is possible that p22 (22,000 peptide) is the minimum size of the unique hepatitis B virus (HBV) gene product involved.


MATERIALS SCIENCE: Armenia Wants Second Mideast Synchrotron.
Middle Eastern scientists who for years have been yearning for a synchrotron may wind up with two. Last spring, SESAME (Synchrotron Radiation for Experimental Science and Applications in the Middle East), an 11-nation consortium formed to install and operate a first-generation synchrotron now mothballed in Germany, selected Jordan as the site of the 0.8 giga-electron-volt BESSY-I synchrotron, disappointing Armenian officials who had hoped to snare the prize. But this month Armenia moved to the head of the line for a second, brand-new synchrotron after securing a $15 million down payment from the U.S. Congress as part of a foreign-aid spending bill that would funnel $90 million to the country.


Lean mass declines consistently over 10 years in people living with HIV on antiretroviral therapy, with patterns differing by sex.
The long-term trajectory of and factors affecting lean mass in people living with HIV (PLWH) are incompletely described. PLWH in the Modena HIV Metabolic Cohort underwent dual-energy X-ray absorptiometry (DXA) scans every 6-12 months for up to 10 years (median 4.6 scans). Mixed effect regression modelling in combined and sex-stratified models determined annual rates of and clinical factors significantly associated with appendicular lean mass (ALM). A total of 839 women and 1,759 men contributing ≥2 DXA scans had baseline median age 44 years and 14 years since HIV diagnosis; 76% were virologically suppressed on antiretroviral therapy (ART). Baseline median ALM was 16.9 kg for women and 24.8 kg for men. ALM decreased during the study period, with mean yearly ALM loss of -231 g in women and -322 g in men. Less ALM was associated with female sex, age >50 years, detectable HIV-1 RNA, and tenofovir and integrase inhibitor use. Greater ALM was associated with longer ART duration. In sex-stratified models, relationships between ALM and total ART duration and integrase inhibitor use were not significant for women, but the relationship with tenofovir use persisted. For men, AIDS wasting and CD4+ T-lymphocyte nadir <200 cells/μl were independently associated with lower ALM. ALM steadily declined over time in this cohort of PLWH on ART that included a large number of women. HIV- and ART-specific risk factors emerged that varied by sex. The observed associations between tenofovir or integrase inhibitor use and lower ALM particularly warrant further study.


Diagnostic and Therapeutic Strategy in Anaplastic (Malignant) Meningioma, CNS WHO Grade 3.
Background: Meningiomas are the most common primary central nervous system malignancies accounting for 36% of all intracranial tumors. However, only 1% of meningioma is classified as malignant (anaplastic) meningioma. Due to their rarity, clinical management of these tumors presents several gaps. Methods: We carried out a narrative review aimed to investigate current knowledge of anaplastic meningioma focusing on their pathological and radiological diagnosis, molecular assessment, and loco-regional and systemic management. Results: The most frequent genetic alteration occurring in meningioma is the inactivation in the neurofibromatosis 2 genes (merlin). The accumulation of copy number losses, including 1p, 6p/q, 10q, 14q, and 18p/q, and less frequently 2p/q, 3p, 4p/q, 7p, 8p/q, and 9p, compatible with instability, is restricted to NF2 mutated meningioma. Surgery and different RT approaches represent the milestone of grade 3 meningioma management, while there is a marginal role of systemic therapy. Conclusions: Anaplastic meningiomas are rare tumors, and diagnosis should be suspected and confirmed by trained radiologists and pathologists. Despite the current marginal role of systemic therapy, it is possible that the increasing knowledge of molecular altered pathways of the disease will lead to the development of novel effective systemic treatments.


A new valid Walking Aid Scale better predicts distance walked by prosthesis users than Prosthetic Mobility Questionnaire 2.0 and Activities-Specific Balance Confidence Scale.
The availability of psychometrically-sound and parsimonious outcome measures is key for optimizing decision-making about prosthetic fitting and rehabilitation in lower limb prosthesis users. Despite the increasing clinical use of observational and self-reported scales for assessing mobility and balance, there is currently no scale that accounts for the use of assistive devices while walking under conditions of increasing difficulty. Therefore, the purpose of this study was to develop and validate a Walking Aid Scale (WAS) in a cross-sectional sample of 144 prosthesis users. Specifically, we examined internal consistency and concurrent validity of WAS against two commonly used self-report measures of prosthetic mobility and balance confidence - the Prosthetic Mobility Questionnaire 2.0 (PMQ 2.0) and Activities-Specific Balance Confidence Scale (ABC-5). The predictive value of WAS, in comparison to PMQ 2.0 and ABC-5, was assessed using a 6-Minute Walk Test (6MWT) and participants' characteristics. The WAS showed significant moderate-to-good correlations with PMQ 2.0 and ABC-5, and all scales correlated well with age and 6MWT. Participants who relied less on walking aids reported higher mobility levels, greater balance confidence, and walked longer distances. Age was associated with greater use of walking aids and lower mobility and balance confidence. In the stepwise linear regression analysis, age, amputation level, time since amputation, and WAS predicted about two-thirds of the variability in 6MWT with no significant contribution of PMQ 2.0 and ABC-5. These findings indicate that WAS is a valid instrument and a better predictor of walking distance than PMQ 2.0 and ABC-5 in the lower limb prosthesis users.


Prior pneumococcal vaccination is associated with reduced death, complications, and length of stay among hospitalized adults with community-acquired pneumonia.
Vaccination with pneumococcal polysaccharide reduces the incidence of bacteremic pneumococcal disease in adults. We investigated the impact of prior pneumococcal vaccination on in-hospital mortality and the probability of respiratory failure among hospitalized adults with community-acquired pneumonia. Consecutive individuals hospitalized with community-acquired pneumonia (diagnosed by International Classification of Diseases, Ninth Revision, Clinical Modification codes 480.0-487.0) at 109 community and teaching hospitals in the United States were identified using the Quality and Resource Management System, a database constructed by Tenet HealthCare to improve the quality of patient care. Vaccination status, comorbidities, and outcomes were abstracted by case managers concurrently with patient care. Associations between vaccination, survival, and respiratory failure were defined using multivariable logistic regression models. Of 62,918 adults hospitalized with community-acquired pneumonia between 1999 and 2003, 7390 (12%) had a record of prior pneumococcal vaccination. Vaccine recipients were less likely to die of any cause during hospitalization than were individuals with no record of vaccination (adjusted odds ratio [OR], 0.50; 95% confidence interval [CI], 0.43-0.59), even after adjustment for the presence of comorbid illnesses, age, smoking, and influenza vaccination and under varying assumptions about missing vaccination data. Vaccination also lowered the risk of respiratory failure (adjusted OR, 0.67; 95% CI, 0.59-0.76) and other complications and reduced median length of stay by 2 days, compared with nonvaccination (P<.001). Prior vaccination against pneumococcus is associated with improved survival, decreased chance of respiratory failure or other complications, and decreased length of stay among hospitalized patients with community-acquired pneumonia. These observations reinforce current efforts to improve compliance with existing pneumococcal vaccination recommendations for adults.


Exchange coupling through diamagnetic [Fe(CO)4]2- bridging ligands in a xenophilic cluster.
The electronic structure of so-called 'xenophilic' clusters, which contain both organometallic fragments and Werner-type paramagnetic transition metal centres, presents a challenge to simple theories of bonding. Density functional theory shows clearly that the cluster Mn(2)(thf)(4)(Fe(CO)(4))(2) is best described as an exchange-coupled Mn(II)(2) dimer, the closed-shell organometallic [Fe(CO)(4)](2-) fragments acting simply as bridging ligands. The high-spin configuration of the Mn(II) ions leads to single occupation of the Mn-Fe σ* orbitals and therefore substantially weaker metal-metal bonding than in conventional low-valent organometallic clusters. The transition metal fragments are effective mediators of superexchange (J(calc) = -44 cm(-1)), leading to the measured effective magnetic moment of ~5 μ(B) at 300 K, considerably lower than the limiting value of 8.37 μ(B) for two uncoupled S = 5/2 Mn(II) centres.


Direct ESR detection or peroxynitrite-induced tyrosine-centred protein radicals in human blood plasma.
Peroxynitrite, the reaction product of O2.- and .NO, is a toxic compound involved in several oxidative processes that modify proteins. The mechanisms of these oxidative reactions are not completely understood. In this study, using direct ESR at 37 degrees C, we observed that peroxynitrite induced in human blood plasma a long-lived singlet signal at g = 2.004 arising from proteins. This signal was not due to a specific plasma protein, because several purified proteins were able to form a peroxynitrite-induced g = 2.004 signal, but serum albumin and IgG showed the most intense signals. Hydroxyurea, a tyrosyl radical scavenger, strongly inhibited the signal, and horseradish peroxidase/H2O2, a radical-generating system known to induce tyrosyl radicals, induced a similar signal. Furthermore peptides containing a Tyr in the central portion of the molecule were able to form a stable peroxynitrite-dependent g = 2.004 signal, whereas peptides in which Tyr was substituted with Gly, Trp or Phe and peptides with Tyr at the N-terminus or near the C-terminus did not form radicals that were stable at 37 degrees C. We suggest that Tyr residues are at least the major radical sources of the peroxynitrite-dependent g = 2.004 signal at 37 degrees C in plasma or in isolated proteins. Although significantly enhanced by CO2/bicarbonate, the signal was detectable in whole plasma at relatively high peroxynitrite concentrations (>2 mM) but, after removal of ascorbate or urate or in dialysed plasma, it was detectable at lower concentrations (100-1000 microM). Our results suggest that the major role of ascorbate and urate is to reduce or 'repair' the radical(s) centred on Tyr residues and not to scavenge peroxynitrite (or nitrosoperoxycarbonate, the oxidant formed in CO2-containing fluids). This mechanism of inhibition by plasma antioxidants may be a means of preserving the physiological functions of peroxynitrite.


Calgranulin C has filariacidal and filariastatic activity.
The calgranulins are a family of calcium- and zinc-binding proteins produced by neutrophils, monocytes, and other cells. Calgranulins are released during inflammatory responses and have antimicrobial activity. Recently, one of the calgranulins, human calgranulin C (CaGC), has been implicated as an important component of the host responses that limit the parasite burden during filarial nematode infections. The goal of this work was to test the hypothesis that human CaGC has biologic activity against filarial parasites. Brugia malayi microfilariae and adults were exposed in vitro to 0.75 to 100 nM recombinant human CaGC. Recombinant CaGC affected adult and larval parasites in a dose-dependent fashion. Microfilariae were more sensitive to the action of CaGC than were adult parasites. At high levels, CaGC was both macrofilariacidal and microfilariacidal. At lower levels, the percentage of parasites killed was dependent on the level of CaGC in the culture system. The larvae not killed had limited motility. The filariastatic effect of low-level CaGC was reversed when the CaGC was removed from the culture system. Immunohistochemical analysis demonstrated that human CaGC accumulated in the cells of the hypodermis-lateral chord of adult and larval parasites. The antifilarial activity of CaGC was not due to the sequestration of zinc. Thus, the cellular and molecular mechanisms that result in the production and release of CaGC in humans may play a key role in the regulation of filarial parasite numbers.


Effect of Switching From an Anti-Diabetic Loose Dose Combination to a Fixed Dose Combination Regimen at Equivalent Dosage for 6 Months on Glycemic Control in Japanese Patients With Type 2 Diabetes: A Pilot Study.
Patients with type 2 diabetes mellitus often take multiple anti-diabetic drugs for a long period. Fixed dose combination (FDC) therapy is expected to improve drug adherence for patients with diabetes. The effect of switching from a loose dose combination (LDC) regimen to an FDC regimen at equivalent dosage on glycemic control has not been evaluated fully. Therefore, we investigated the effect of switching from LDC to FDC at equivalent dosage for 6 months on glycemic control in Japanese patients with type 2 diabetes. Thirty-eight Japanese patients with type 2 diabetes who were taking anti-diabetic drugs including pioglitazone + metformin, pioglitazone + alogliptin, or pioglitazone + glimepiride were enrolled. These drugs were switched to an FDC of Metact®, Liobel® or Sonias®, respectively, at equivalent dosage. Other anti-diabetic drugs and units of insulin were not changed during the study if possible. HbA1c and body weight were measured 0, 2, 4 and 6 months after switching from an LDC to FDC. We also conducted a questionnaire survey 2 months after the start of the FDC regimen. HbA1c levels at 2, 4, and 6 months were not significantly changed compared with prior to switching from an LDC to FDC regimen. Moreover, 74.2% of patients considered decreasing the number of drugs to be "very good" or "good". HbA1c levels did not differ between patients receiving LDC and FDC therapy at equivalent dosage in this study.


A cAMP and Ca2+ coincidence detector in support of Ca2+-induced Ca2+ release in mouse pancreatic beta cells.
The blood glucose-lowering hormone glucagon-like peptide-1 (GLP-1) stimulates cAMP production, promotes Ca2+ influx, and mobilizes an intracellular source of Ca2+ in pancreatic beta cells. Here we provide evidence that these actions of GLP-1 are functionally related: they reflect a process of Ca2+-induced Ca2+ release (CICR) that requires activation of protein kinase A (PKA) and the Epac family of cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs). In rat insulin-secreting INS-1 cells or mouse beta cells loaded with caged Ca2+ (NP-EGTA), a GLP-1 receptor agonist (exendin-4) is demonstrated to sensitize intracellular Ca2+ release channels to stimulatory effects of cytosolic Ca2+, thereby allowing CICR to be generated by the uncaging of Ca2+ (UV flash photolysis). This sensitizing action of exendin-4 is diminished by an inhibitor of PKA (H-89) or by overexpression of dominant negative Epac. It is reproduced by cell-permeant cAMP analogues that activate PKA (6-Bnz-cAMP) or Epac (8-pCPT-2'-O-Me-cAMP) selectively. Depletion of Ca2+ stores with thapsigargin abolishes CICR, while inhibitors of Ca2+ release channels (ryanodine and heparin) attenuate CICR in an additive manner. Because the uncaging of Ca2+ fails to stimulate CICR in the absence of cAMP-elevating agents, it is concluded that there exists in beta cells a process of second messenger coincidence detection, whereby intracellular Ca2+ release channels (ryanodine receptors, inositol 1,4,5-trisphosphate (IP3) receptors) monitor a simultaneous increase of cAMP and Ca2+ concentrations. We propose that second messenger coincidence detection of this type may explain how GLP-1 interacts with beta cell glucose metabolism to stimulate insulin secretion.


2015 SCAI/ACC/HFSA/STS Clinical Expert Consensus Statement on the Use of Percutaneous Mechanical Circulatory Support Devices in Cardiovascular Care (Endorsed by the American Heart Association, the Cardiological Society of India, and Sociedad Latino Americana de Cardiología Intervencionista; Affirmation of Value by the Canadian Association of Interventional Cardiology-Association Canadienne de Cardiologie d'intervention).
This article provides a brief summary of the relevant recommendations and references related to percutaneous mechanical circulatory support. The goal was to provide the clinician with concise, evidence-based contemporary recommendations, and the supporting documentation to encourage their application. The full text includes disclosure of all relevant relationships with industry for each writing committee member. A fundamental aspect of all expert consensus statements is that these carefully developed, evidence-based documents can neither encompass all clinical circumstances, nor replace the judgment of individual physicians in management of each patient. The science of medicine is rooted in evidence, and the art of medicine is based on the application of this evidence to the individual patient. This expert consensus statement has adhered to these principles for optimal management of patients requiring percutaneous mechanical circulatory support.


Cloning and characterization of dipeptidyl peptidase 10, a new member of an emerging subgroup of serine proteases.
Two dipeptidyl peptidase IV (DPPIV, DPP4)-related proteins, DPP8 and DPP9, have been identified recently [Abbott, Yu, Woollatt, Sutherland, McCaughan, and Gorrell (2000) Eur. J. Biochem. 267, 6140-6150; Olsen and Wagtmann (2002) Gene 299, 185-193; Qi, Akinsanya, Riviere, and Junien (2002) Patent application WO0231134]. In the present study, we describe the cloning of DPP10, a novel 796-amino-acid protein, with significant sequence identity to DPP4 (32%) and DPP6 (51%) respectively. We propose that DPP10 is a new member of the S9B serine proteases subfamily. The DPP10 gene is located on the long arm of chromosome 2 (2q12.3-2q14.2), close to the DPP4 (2q24.3) and FAP (2q23) genes. The active-site serine residue is replaced by a glycine residue in DPP10, resulting in the loss of DPP activity. The serine residue is also replaced in DPP6, which lacks peptidase activity. DPP8 and DPP9 share an identical active site with DPP4 (Gly-Trp-Ser-Tyr-Gly). In contrast with the previous results suggesting that DPP9 is inactive, we show that DPP9 is a DPP, hydrolysing Ala-Pro-(7-amino-4-methyl-coumarin) with similar pH-specificity and protease-inhibitor-sensitivity to those of DPP4 and DPP8. Northern-blot analysis shows that whereas DPP8 and DPP9 are widely expressed, DPP10 is expressed mainly in the brain and pancreas. DPP6, which has the highest amino acid identity with DPP10, has been shown previously [Nadal, Ozaita, Amarillo, de Miera, Ma, Mo, Goldberg, Misumi, Ikehara, Neubert et al. (2003) Neuron 37, 449-461] to associate with A-type K(+) channel subunits, modulating their transport and function in somatodendritic compartments of neurons. It is possible that DPP10 is involved in similar functions in the brain. Elucidation of the physiological or pathophysiological role of DPP8, DPP9 and DPP10 and characterization of their structure-function relationships will add impetus to the development of inhibitor molecules for pharmacological or therapeutic use.


Diagnosis and management of necrotising fasciitis: a multiparametric approach.
Necrotising fasciitis (NF) is situated with myositis and myonecrosis at the severe end of a spectrum of skin and soft tissue infections but is far removed from erisepelas, impetigo and cellulitis. Inexperienced clinicians are easily misled by the protean manifestations of infection, especially exotoxin or superantigen mediated consequences from streptococcal NF. Early clinical suspicion and surgery are key to improving survival, and patients with NF need integrated multidisciplinary management, adjusted to the infecting organism(s), the site of infection, and the effects from any toxins produced. A multiparametric approach, incorporating various clinical and laboratory parameters, can aid aggressive management. This review describes the diagnosis and management of the major types of NF, emphasising important aetiological clues from the history and the appropriate usage of diagnostic investigations. The potential benefits of controversial therapeutic approaches, including hyperbaric oxygen and intravenous immunoglobulin, are discussed.


The development of gluconeogenesis in rat liver. Effects of glucagon and ether.
1. Administration of glucagon to foetal rats produced a 10-15-fold increase in hepatic phosphoenolpyruvate carboxykinase activity together with a similar increase in the overall pathway of pyruvate conversion into glycogen in liver slices. 2. Glucagon was without effect on gluconeogenesis in vivo, which remained at approx. 0.1% of the incorporation as measured in newborn animals. 3. The apparent discrepancy between these results was due to the ether anaesthesia that was required for experimentation in vivo. Under conditions when minimal ether was used, the rates of labelling of glycogen from [3-(14)C]pyruvate in vivo were increased 10-20-fold and there was an additional stimulus by glucagon. 4. Ether anaesthesia produced a more reduced redox state of the foetal liver cytosol and lowered the ATP/ADP concentration ratio. 5. It is proposed that these effects are significant in the limitation of gluconeogenesis in the foetal rat liver, so that only with high phosphoenolpyruvate carboxykinase activity, high ATP concentration and a relatively oxidized cytosol redox state will a functional gluconeogenic pathway be present.


Role of lipid polymorphism in acoustically sensitive liposomes.
Ultrasound (US) triggered drug release is a promising drug delivery method that allows ex vivo modulation of treatment intensity and duration. This method relies on the synergistic interaction between the rupture of sonosensitive particles and enhanced plasma membrane permeability. Conventional liposomal systems where the drug passively diffuses through the membrane show virtually no response to acoustic energy. One method to activate drug transport is to induce a topological restructuring of the lipid membrane (zero intrinsic curvature, H = 0) by puncturing pores (H < 0) through which the drug can readily leak out from the interior of the liposomes. In this work we demonstrate strategies to lower the energy cost of creating such membrane defects by introducing lipid molecules with molecular shapes prone to self-assemble into non-lamellar (negative intrinsic curvature, H < 0) structures. All formulations investigated comprise the relevant components typically required for delivery applications such as stealth moieties, cholesterol, and phospholipids. Small angle X-ray scattering studies of a number of lipid systems at increasing amounts of phosphatidylethanolamine (PE) phospholipids reveal that membranes without PE respond to ultrasound by thinning ca. 10 Å, which concomitantly lowers the bending rigidity quadratically in addition to increasing the passive drug permeability. However, at the appropriate PE content the lipid systems display a classic lamellar structure (H = 0) that undergoes a topological transformation after ultrasound exposure into lipid tubes of the reversed type (H < 0) packed in a 2D hexagonal array. At the dilute regime, Fluorescence Microscopy of giant unilamellar vesicles (GUVs) comprising DOPE also experience ultrasound induced restructuring that can be modulated by DOPE content. In general, smaller vesicles of diverse shape connect and form into a "pearl-necklace" configuration. We argue that the inclusion of DOPE within the GUV membrane may result in curvature-driven lipid sorting, providing the system with local membrane instabilities that drive vesicle pearling when exposed to ultrasound.


Concentration and memory deficits in patients with fibromyalgia syndrome.
The present study compared 30 patients with Fibromyalgia Syndrome (FS) to 30 healthy control subjects matched for age, sex, and estimated intellectual level on standardized measures of attention, concentration, and memory as well as subjective ratings of memory abilities and sleep quality. In addition, in order to investigate the relationship between cognitive functioning and other physical and psychological symptoms, subjects with FS completed psychological measures of pain severity, trait anxiety, and depression. Results indicated that patients with FS performed more poorly on tests of immediate and delayed recall, and sustained auditory concentration, and their ratings of both their memory abilities and sleep quality were lower than those of controls. Furthermore, perceived memory deficits of the FS subjects were disproportionately greater than their objective deficits. Results indicated significant correlations between performance on memory and concentration measures and scores on questionnaires of pain severity and trait anxiety. Implications of these results for multidisciplinary treatment programs are discussed.


[Morals and sex deviations].
Deviance is today more often recognized. It questions norms or established order. Sociology, medicine, law, moral, even if they use the same terms, such as deviance or normality, deal with these realities differentialy. Being more conscious of it allows to define the conditions of a more true and serene dialogue, starting from various disciplines. One wonders more particularly on the specific role of moral. Must the elaboration of moral norms be done in reference to "normality", or do we have to look for lines of sexual humanization?


Long-term treatment with the P2X7 receptor antagonist Brilliant Blue G reduces liver inflammation in a humanized mouse model of graft-versus-host disease.
Allogeneic haematopoietic stem cell transplantation (HSCT) is a frequent curative therapy for numerous haematological malignancies. However, HSCT is limited by the occurrence of graft-versus-host disease (GVHD), with current therapies restricted to general immunosuppression. Activation of the P2X7 receptor by extracellular adenosine triphosphate (ATP) causes inflammation and tissue damage in GVHD. Short-term pharmacological blockade of P2X7 has been shown to reduce clinical disease and/or reduce inflammatory markers in allogeneic and humanized mouse models of GVHD. The current study demonstrates that long-term P2X7 blockade by intra-peritoneal injection of Brilliant Blue G (BBG) thrice weekly for up to 10 weeks did not impact human (h) peripheral blood mononuclear cell (PBMC) engraftment, predominantly T cells, in blood at 3 weeks post-hPBMC injection or in spleens at end-point in humanized mice. Histological analysis demonstrated long-term BBG treatment reduced leukocyte infiltration in the livers of humanized mice. Immunohistochemical analysis demonstrated that BBG treatment reduced liver apoptosis. Long-term BBG treatment did not alter clinical disease, mRNA expression of pro-inflammatory markers in tissues or serum human interferon (IFN)-γ concentrations. Therefore, this study demonstrates that P2X7 activation plays a role in GVHD pathogenesis in the livers of humanized mice, supporting a role for this receptor in GVHD development in HSCT recipients.


Social care and support for elderly men and women in an urban and a rural area of Nepal.
This study has aimed to describe the care and support for urban and rural elderly people of Bhaktapur district, Nepal. Efforts were made to identify the feeling of some features of general well-beings associated to mental health, person responsible for care and support, capability to perform daily routine activities, sources of finance and ownership to the property. More than half of the respondents were found having single or multiple features of loneliness, anxiety, depression and insomnia. The rate of point prevalence loneliness was found higher in the above 80 years of age, urban respondents. Almost 9 in 10 respondents were capable themselves to dress, walk and maintain personal hygiene and majority of them were assisted by spouse, son/daughter-in-laws. Family support was common sources of income and ownership to the property was absolutely high.


Psychological effects of sexual harassment, appraisal of harassment, and organizational climate among U.S. Army soldiers.
This study examines the effects of three types of unwanted sexual experiences in the workplace on the psychological well-being of male and female U.S. Army soldiers, and the mediating or moderating roles of appraisal of sexual harassment, organizational climate, and the sociodemographic profile of victims. A survey was administered to 1,060 male soldiers and 305 female soldiers between May and July, 1995, at three Army posts in the United States. Unwanted sexual experiences were found to be significant predictors of psychological symptoms for male and female soldiers. Certain aspects of organizational climate and appraisal of sexual harassment were also significant predictors of psychological symptoms.


Microsatellite analysis in FVB/N mice.
The purpose of the study reported here was to identify, by size, a set of microsatellite markers for use in diagnostic genetic monitoring of FVB/N mouse colonies. A large panel of microsatellite markers were chosen on the basis oftheir high degree of allelic variability. These markers were then tested for their ability to amplify well under a standard set of polymerase chain reaction analysis conditions and to present an easily identifiable band on an agarose gel. From this panel, we chose at least one marker on each chromosome that amplified well under our standard high-throughput conditions. Using this approach, we identified the allele sizes for 27 microsatellite markers in the FVB/N strain of mice. Each autosomal chromosome and the X chromosome were analyzed using at least one locus marker. We have determined a precise size for FVB/N microsatellite alleles, as opposed to a description of size in relation to that of a known allele.


Measuring cortical thickness on panoramic radiographs: a validation study of the Mental Index.
To validate the Mental Index assessment obtained from panoramic radiographs. Ten dried mandibles were selected, and standardized panoramic radiographs were obtained. The specimens were then perpendicularly sectioned at the mental foramen region, and the inferior mandibular cortical thickness was recorded using a digital caliper. Measurements of panoramic radiographs were compared with the dried mandibles. Four observers carried out twice the measurements for the panoramic radiographs. Two observers performed twice the measurements of the dried mandibles. Reliability was assessed by duplicate measurements. Agreement between the actual mandible measurements and the radiographic assessment was moderate for the noncorrected measurements. Agreement between anatomic and radiographic measurements improved remarkably after standard correction for magnification. Bone status reports based on measuring cortical thickness of the lower border of the mandible at the mental foramen based on panoramic radiographs, i.e., Mental Index, are accurate. Compensation for magnification, however, is necessary.


The minimally important difference (MID) for patient-reported outcomes including pain, fatigue, sleep and the health assessment questionnaire disability index (HAQ-DI) in primary Sjögren's syndrome.
We wanted to determine the MID for the HAQ, pain, fatigue, sleep and global VAS (0-100mm) in Sjögren's syndrome (SS) using a patient-reported overall health status anchor. Patients with a diagnosis of primary Sjögren's syndrome (pSS) who had answered a standardised questionnaire at two consecutive visits including an overall health status question: 'How would you describe your overall status since your last visit: much better, better, the same, worse, much worse?' were included. The MID was calculated as the mean change between visits for those who rated their disease as better or worse. Scales on VAS were from 0 (best) to 100 (worst). Forty patients met the inclusion criteria (97% female, mean age 58 years, mean disease duration 10 years). The mean baseline HAQ was 0.68. Ten rated their status as better and 14 as worse than the previous visit. MID estimates for improvemenT/worsening (SD) respectively were: -7.4 (27.8) / 20.7 (20.0) for pain VAS, -6.2 (28.3) / 15.2 (21.8) for fatigue VAS, -24.0 (24.0) / 15.2 (28.0) for sleep VAS, -0.18 (0.23) / 0.14 (0.30) for HAQ and -23.1 (21.6) / 16.4 (20.9) for global VAS. Spearman's rho correlation coefficients for the patient-reported outcomes were 0.38 (pain VAS), 0.54 (fatigue VAS), 0.55 (sleep VAS), 0.39 (HAQ), and 0.57 (global VAS), p<0.05. The MID for pain and fatigue are greater for worsening than improvement. A small change in the HAQ is detected as a change in status by the patient. This knowledge may aid those who treat SS and in designing intervention studies.


Assessing brain free fraction in early drug discovery.
The incorporation of brain tissue binding routinely in CNS drug discovery screening strategies has markedly changed the way CNS drug discovery is performed and is proving to be a valuable tool in identifying new therapies for CNS diseases. For many years emphasis has been placed on the magnitude of the brain to blood ratio, the bigger the better, even though, in many cases, brain total concentration (C(brain)) has no or, at best, poor correlation with receptor occupancy/pharmacodynamic readout. Today, C(brain) values measured during in vivo experiments are corrected for the fraction unbound measured through in vitro experiments using brain tissue homogenate or brain tissue slice to obtain an estimate of the brain unbound concentration (C(u,brain)), and this has been demonstrated across a range of CNS targets to give a much better correlation with receptor occupancy/pharmacodynamic readout. This apparently simple change in CNS lead optimisation strategy has de facto revolutionised the vision of the brain penetration concepts. This review will provide an overview of the use and applications of assessing brain free fraction to determine C(u,brain). Assessing brain free fraction to determine C(u,brain) in CNS lead optimisation strategies is the surrogate of choice for rapidly assessing biophase concentration for the majority of CNS targets.


Dermatophytes isolated from superficial fungal infections in Krakow, Poland, between 1995 and 2010.
Superficial fungal infections due to dermatophytes are common over the world and their frequency is constantly increasing. The aim of our study was to discuss fungal infections with frequency of occurrence, clinical stages and aetiology in patients admitted to dermatological ward and microbiological laboratory of the specialist hospital in Krakow. Investigations performed between 1995 and 2010 included the group of 5333 individuals. Dermatophyte infections, confirmed by culture, were revealed in 1007 subjects (18.9%), i.e. in 553 males and 454 females. The most frequent clinical forms of infections were tinea unguium and tinea pedis, caused mainly by Trichophyton rubrum and by Trichophyton mentagrophytes. Tinea corporis, tinea manuum, tinea capitis and tinea cruris constituted a small percentage of infections and the main aetiological factors of these dermatomycoses were also T. rubrum and T. mentagrophytes. Between 1995 and 2000 there were stated small differences in the number of isolated strains of dermatophytes in comparison with the number of examined patients. Since 2006 there has been observed a decrease in number of patients in our hospital with suspected fungal infections, but per cent of positive cultures has remained unchanged in comparison with earlier period.


Mixed-model reanalysis of primate data suggests tissue and species biases in oligonucleotide-based gene expression profiles.
An emerging issue in evolutionary genetics is whether it is possible to use gene expression profiling to identify genes that are associated with morphological, physiological, or behavioral divergence between species and whether these genes have undergone positive selection. Some of these questions were addressed in a recent study (Enard et al. 2002) of the difference in gene expression among human, chimp, and orangutan, which suggested an accelerated rate of divergence in gene expression in the human brain relative to liver. Reanalysis of the Affymetrix data set using analysis of variance methods to quantify the contributions of individuals and species to variation in expression of 12,600 genes indicates that as much as one-quarter of the genome shows divergent expression between primate species at the 5% level. The magnitude of fold change ranges from 1.2-fold up to 8-fold. Similar conclusions apply to reanalysis of Enard et al. 2002 parallel murine data set. However, biases inherent to short oligonucleotide microarray technology may account for some of the tissue and species effects. At high significance levels, more differences were observed in the liver than in the brain in each of the pairwise species comparisons, so it is not clear that expression divergence is accelerated in the human brain. Further, there is an apparent bias toward upregulation of gene expression in the brain in both primates and mice, whereas genes are equally likely to be up- or downregulated in the liver when these species diverge. A small subset of genes that are candidates for adaptive divergence may be identified on the basis of a high ratio of interspecific to intraspecific divergence.


Detection of artificial changes in mole size by skin self-examination.
The efficacy of the skin self-examination (SSE) to detect artificial changes in the size of nevi has not been evaluated in a controlled setting. Our purpose was to determine the sensitivity and specificity of the SSE in detecting artificial changes in mole size in patients at high risk for melanoma. In a single-center, single-blinded cross-over study, patients who had been performing the SSE confidently for at least 1 year examined their backs after the diameter of an existing mole was increased artificially in random order by 0, 2, or 4 mm. The specificity of the SSE was 62% (95% confidence interval [CI], 53%-72%) (N = 103). The sensitivity of the 2 mm change was 58% (95% CI, 49%-68%) and that of the 4 mm change was 75% (95% CI, 66%-83%). SSE performance was not related to perceived risk, number of moles, gender, age, or frequency of self-examination. Even in our highly motivated and selected group of high-risk patients, 25% could not detect an obvious increase in the diameter of an existing nevus, whereas 38% incorrectly identified a change when none was made. The SSE is only a moderately effective tool for the detection of acute, large, changes in mole size. The usefulness of the SSE in detection of new lesions or changes in existing lesions is likely due to a combination of factors or due to factors other than size, such as color, border irregularity, and texture, among others.


Mathematical properties of the JPEG2000 wavelet filters.
The LeGall 5/3 and Daubechies 9/7 filters have risen to special prominence because they were selected for inclusion in the JPEG2000 standard. We determine their key mathematical features: Riesz bounds, order of approximation, and regularity (Hölder and Sobolev). We give approximation theoretic quantities such as the asymptotic constant for the L2 error and the angle between the analysis and synthesis spaces which characterizes the loss of performance with respect to an orthogonal projection. We also derive new asymptotic error formulae that exhibit bound constants that are proportional to the magnitude of the first nonvanishing moment of the wavelet. The Daubechies 9/7 stands out because it is very close to orthonormal, but this turns out to be slightly detrimental to its asymptotic performance when compared to other wavelets with four vanishing moments.


Infectivity with human ascariasis in Ibadan Oyo State, Nigeria.
Some of the common foodstuffs that assist in the transmission of ascariasis in Ibadan have been determined. The frequency of recovery of Ascaris ova in the different food samples examined varied from 9.6% in tomatoes to 25.6% in lettuce leaves. The indiscriminate pollution of Ibadan environment with human faeces enables the foodstuff consumed raw to serve as effective sources of heavy Ascaris infection which lead to other medical complications. The strategies for the control of Ascaris infection in Ibadan were discussed.


Association Between the Order of Macrolide and Cephalosporin Treatment and Outcomes of Pneumonia.
Many patients hospitalized with pneumonia are treated with combination macrolide/cephalosporin therapy. Macrolides have immunomodulatory effects and do not directly cause bacterial lysis. These effects suggest the possibility that initial treatment with a macrolide before a cephalosporin could improve patient outcomes by preventing the inflammatory response to rapid bacterial lysis that can be caused by cephalosporin treatment. This study explores whether initial treatment for pneumonia with a macrolide before a cephalosporin is associated with better patient outcomes than treatment with a cephalosporin before a macrolide. This is a retrospective cohort study using a clinically rich database derived from electronic health records of 71 hospitals. We compared outcomes for pneumonia patients who received intravenous treatment with a macrolide at least 1 hour before a cephalosporin, versus patients who received a cephalosporin at least 1 hour before a macrolide. Propensity matching was performed for 527 patients in each group. Among the propensity-matched cohorts, for the macrolide first group, in-hospital mortality was 4.2% vs 5.5% for the cephalosporin first group (P = .31), combined in-hospital mortality/hospice discharge was 6.3% vs 9.3% (P = .06), median hospital length of stay was 101.5 hours vs 109.5 hours (P = .09), and 30-day readmission was 12.9% vs 10.6% (P = .27). Treatment of pneumonia with a macrolide before a cephalosporin was not associated with significantly improved outcomes when compared with treatment with a cephalosporin first; however, the lower rate of mortality/discharge to hospice and the large confidence intervals allow for the possibility of a clinically significant benefit.


Large-scale studies of the association between variation at the TNF/LTA locus and susceptibility to type 2 diabetes.
The proinflammatory cytokine TNF-alpha has been implicated in the pathogenesis of insulin resistance and type 2 diabetes, and variation in the gene encoding TNF-alpha (TNF) has shown inconsistent associations with susceptibility to both conditions. Additionally, the coding non-synonymous variant T60N in the neighbouring LTA gene has been reported to be associated with type 2 diabetes. The present study aimed to obtain a robust assessment of the role of variation in the tightly linked TNF/LTA region in diabetes susceptibility by genotyping TNF and LTA variants in large case-control resources. The G-308A and G-238A TNF promoter variants and the LTA T60N polymorphism were genotyped in two UK case samples that were ascertained for positive family history and/or early onset of type 2 diabetes (combined n=858) and in 1,257 ethnically matched controls. There were no significant associations between the T60N, G-308A or G-238A genotype and type 2 diabetes in the combined analysis (exact Cochran-Mantel-Haenszel statistic for ordered genotypes for T60N, p=0.69; for G-308A, p=0.51; for G-238A, p=0.16). The present study, one of the largest association analyses yet reported at this locus, provides no evidence that the specific TNF or LTA variants examined influence susceptibility to type 2 diabetes. More comprehensive studies of the TNF/LTA locus in substantially larger sample sets are required to establish whether genome sequence variation at this locus truly influences susceptibility to type 2 diabetes.


Attitudes towards body weight dissatisfaction associated with adolescents' perceived health and sleep (PeNSE 2015).
This study aimed to investigate whether attitudes towards body weight dissatisfaction is associated with perceived health and impairments in sleep among a national population-based sample of Brazilian adolescents. This is a cross-sectional data from the 2015 National School-Based Health Survey (PeNSE). A total of 100.182 students (70.8% were between 14 to 15) in ninth-grade, enrolled in public and private schools were eligible for data analysis. Variables were measured using a questionnaire and binary logistic regression was used. There was association between attitudes towards body weight dissatisfaction and perceived health (not controlling weight = OR: 2.19, 95%CI: 2.00-2.40; trying to lose = OR: 1.90, 95%CI: 1.75-2.05; gain = OR: 2.22, 95%CI: 2.01-2.46; maintain = OR: 1.81, 95%CI: 1.54-2.14). Adolescents were also more likely to present impairments in sleep (not controlling weight = OR: 1.21, 95%CI: 1.11-1.32; trying to lose = OR: 1.16, 95%CI: 1.08-1.25; gain = OR: 1.43, 95%CI: 1.28-1.61; maintain = OR: 1.43, 95%CI: 1.22-2.68). Dissatisfaction is an additional concern in the daily life of adolescents, which is associated to depreciation of the quality of sleep and decrement of psychological well-being.


The Effect of Health Literacy Counselling on Self-Care in Women after Mastectomy: a Randomized Clinical Trial.
Introduction: Breast cancer has a high prevalence, constituting a major cause of mortality in women around the world. Health literacy has a vital role in the self-care of chronic diseases such as cancer and is an essential element in the ability of each person to engage with health promotion. The aim of this study was to determine effect of health literacy counselling on self-care in women after mastectomy. Methods: This study is a randomized, controlled, clinical trial carried out on 72 women with breast cancer after mastectomy in Fars province. The eligible women entered the study using convenience sampling and were then divided into an intervention and a control group through randomized blocks of four. Health literacy questionnaire and self-care questionnaire were distributed among the participants before, immediately after and three weeks following the intervention. Data analysis was performed in SPSS ver.13. Results: The results showed no significant differences between the two groups in terms of their health literacy and self-care scores before the intervention (P=0.299 and 0.059). A comparison of the mean values showed a greater increase in the mean score of health literacy and score of self-care immediately and three weeks after the intervention in the intervention group compared to the control group. Also, the mean score of the dimensions of self-care in chemotherapy increased over time in the intervention group. Conclusion: The findings of this study confirm the higher effectiveness of counseling with a health literacy approach on overall self-care in chemotherapy and all its dimensions.


The effects of vasoactive intestinal peptide on dura mater nitric oxide levels and vessel-contraction responses in sympathectomized rats.
Nitric oxide (NO) and neurogenic inflammation in dura mater due to nociceptor activation has been implicated for pathophysiology of primary headache disorders. Development of migraine has also been observed in patients treated with ganglion blockage for sympathetic reflex dystrophy. Vasoactive intestinal peptide (VIP) is an antioxidant, anti-inflammatory, and neuroprotective neuropeptide. This study is intended to investigate the effects of VIP on dura mater NO levels and vessel-contraction responses in sympathectomized rats. In the experiments, 30 male rats in five groups were used. Group 1 sympathectomized: under anesthesia, superior cervical sympathetic ganglion was removed via incision at the center line in the neck area. Group 2 sympathectomized + VIP: postoperative VIP of 25 ng/kg/day (0.2 ml) intraperitoneally administered to the rats exposed to the same operations for 5 days. Group 3 sham: ganglia and nerves were exposed but not dissected. Group 4 control: no treatment was done. Group 5 VIP: only VIP was administered for 5 days. Sympathectomy induced a significant increase in dura mater NO levels and VIP decreased NO to control levels and increased the norepinephrine vessel-contraction responses of sympathectomized rats. VIP is an efficient NO modulator in superior cervical ganglionectomized rats.


The primary structure of the beta-subunit of the cell surface adhesion glycoproteins LFA-1, CR3 and p150,95 and its relationship to the fibronectin receptor.
The lymphocyte-function-associated antigen-1 (LFA-1), the complement receptor type 3 (CR3) and the antigen p150,95 are cell-surface glycoproteins. They are heterodimeric complexes, each containing a unique alpha-subunit noncovalently associated with a common beta-subunit. We have purified the beta-subunit from human spleen and obtained limited peptide sequences. What appears to be the complete primary structure for the fully processed beta-subunit was obtained by cDNA sequencing of clones from a phorbol ester (PMA) stimulated U937 cDNA library. There are five possible glycosylation sites and a transmembrane segment. The sequence contains a high level of cysteine (7.6%), with 24 of the 57 cysteine residues being found in three repeating units each with eight residues. The entire primary structure has 47% identity to a subunit of a fibronectin binding protein from chicken fibroblasts. It seems that LFA-1, CR3 and p150,95 antigens may belong to an extended family of cell surface molecules including the fibronectin binding protein.


Verifiable soil organic carbon modelling to facilitate regional reporting of cropland carbon change: A test case in the Czech Republic.
Regional monitoring, reporting and verification of soil organic carbon change occurring in managed cropland are indispensable to support carbon-related policies. Rapidly evolving gridded agronomic models can facilitate these efforts throughout Europe. However, their performance in modelling soil carbon dynamics at regional scale is yet unexplored. Importantly, as such models are often driven by large-scale inputs, they need to be benchmarked against field experiments. We elucidate the level of detail that needs to be incorporated in gridded models to robustly estimate regional soil carbon dynamics in managed cropland, testing the approach for regions in the Czech Republic. We first calibrated the biogeochemical Environmental Policy Integrated Climate (EPIC) model against long-term experiments. Subsequently, we examined the EPIC model within a top-down gridded modelling framework constructed for European agricultural soils from Europe-wide datasets and regional land-use statistics. We explored the top-down, as opposed to a bottom-up, modelling approach for reporting agronomically relevant and verifiable soil carbon dynamics. In comparison with a no-input baseline, the regional EPIC model suggested soil carbon changes (~0.1-0.5 Mg C ha-1 y-1) consistent with empirical-based studies for all studied agricultural practices. However, inaccurate soil information, crop management inputs, or inappropriate model calibration may undermine regional modelling of cropland management effect on carbon since each of the three components carry uncertainty (~0.5-1.5 Mg C ha-1 y-1) that is substantially larger than the actual effect of agricultural practices relative to the no-input baseline. Besides, inaccurate soil data obtained from the background datasets biased the simulated carbon trends compared to observations, thus hampering the model's verifiability at the locations of field experiments. Encouragingly, the top-down agricultural management derived from regional land-use statistics proved suitable for the estimation of soil carbon dynamics consistently with actual field practices. Despite sensitivity to biophysical parameters, we found a robust scalability of the soil organic carbon routine for various climatic regions and soil types represented in the Czech experiments. The model performed better than the tier 1 methodology of the Intergovernmental Panel on Climate Change, which indicates a great potential for improved carbon change modelling over larger political regions.


Severe hypernatremia in deceased liver donors does not impact early transplant outcome.
There may be an increased risk of primary nonfunction in livers procured from donors with hypernatremia. The purported mechanism for this effect is undefined. This study analyzes early graft function for donor livers procured from patients with severe hypernatremia. The organ procurement records for 1013 consecutive deceased liver donors between 2001 and 2008 were reviewed. Both peak and terminal serum sodium levels were categorized as (1) severe for a level 170 mEq/L or higher, (2) moderate for 160 to 169 mEq/L, and (3) normal for less than 160 mEq/L. Outcomes included 30-day posttransplant alanine aminotransferase and total bilirubin, primary nonfunction, and 30-day and 1-year graft survival. Within the severe hypernatremia group, there were 142 (peak) and 50 (terminal) donors, whereas the moderate group had 233 (peak) and 162 (terminal) donors. The study groups did not differ in recipient age, model for end-stage liver disease score, steatosis, and ischemia times for the peak or terminal serum sodium groups. The differing levels of hypernatremia severity did not differ importantly, for peak or terminal serum sodium, in posttransplant alanine aminotransferase or total bilirubin, or the risk of intraoperative death and primary nonfunction. Thirty-day and 1-year graft survival did not demonstrate a negative impact from donor hypernatremia. Posttransplant measures of early liver function and risk of failure, up to 1-year posttransplant, did not differ significantly based on peak or terminal donor serum sodium levels. These results suggest that donor serum sodium level likely has little clinical impact on posttransplant liver function.


Effect of estrogen and progesterone priming on the uptake and release of serotonin and noradrenaline from the ventromedial hypothalamus.
Estradiol benzoate (EB) or EB plus progesterone (P) were administered to chronic ovariectomized rats in doses which are known to induce sexual receptivity. P was injected 48 hr after EB and the animals were decapitated 54 hr after E.B. The ventromedial hypothalamus (VMH) (excluding the arcuate-median eminence region) was dissected out and used to determine 3H-noradrenaline (3H-NA) and 3H-serotonin (3H-5-HT) uptake and release induced by high potassium concentration. Animals injected with oil were used as controls. VMH from EB (10 micrograms/kg) plus P (2 mg/kg) primed animals had higher release of 3H-NE than controls; uptake and release of 3H-5-HT was also augmented in these animals. EB (100 micrograms/kg) priming alone did not induce significant variations. The increase in 3H-NA release is interpreted as evidence of incremented activity in a 3H-NA system, facilitating sexual receptivity. The change in 3H-5-HT uptake and release is discussed in respect to the existence of an inhibitory serotonergic system modulating sexual behavior.


Expression of p34(cdc2) and cyclins A and B compared to other proliferative features of non-Hodgkin's lymphomas: a multivariate cluster analysis.
In view of recent knowledge on proteins regulating the cell cycle, we re-evaluated proliferative features of 98 diffusely growing non-Hodgkin's lymphomas. The combined use of 5 proliferation-associated variables (mitotic indices and percentages of Ki-67(+), p34(cdc2+), cyclin A(+) and cyclin B(+) cells) and their entry into a multivariate cluster analysis separated, without overlaps, the entire cohort into 3 groups (clusters) with (1) low, (2) intermediate and (3) high proliferative activity. Conversely, bivariate plots exposed considerable cluster overlaps. Multivariate stepwise discriminant analysis of all cases revealed a decreasing order of discriminant power for % Ki-67(+) cells > % p34(cdc2+) cells > mitotic index > % cyclin A(+) cells > % cyclin B(+) cells. The combined use of 2 variables only, mitotic index and % p34(cdc2+) cells, allowed a clear-cut separation of clusters 2 and 3. In bivariate plots, correlations were best between % Ki-67(+) cells and % cyclin A(+) cells and between mitotic indices and % cyclin B(+) cells. Except for chronic lymphocytic leukemias, immunocytomas and marginal zone lymphomas (all in cluster 1), individual lymphoma entities were distributed among at least 2 clusters. There was, however, a marked preponderance of mantle cell lymphomas and diffuse follicular center lymphomas in cluster 1 and of diffuse large B-cell lymphomas and peripheral T-cell lymphomas in cluster 2. Anaplastic large-cell lymphomas predominated in cluster 3 and responded best to therapy.


A dual mechanism underlying retroactive shifts of auditory spatial attention: dissociating target- and distractor-related modulations of alpha lateralization.
Attention can be allocated to mental representations to select information from working memory. To date, it remains ambiguous whether such retroactive shifts of attention involve the inhibition of irrelevant information or the prioritization of relevant information. Investigating asymmetries in posterior alpha-band oscillations during an auditory retroactive cueing task, we aimed at differentiating those mechanisms. Participants were cued to attend two out of three sounds in an upcoming sound array. Importantly, the resulting working memory representation contained one laterally and one centrally presented item. A centrally presented retro-cue then indicated the lateral, the central, or both items as further relevant for the task (comparing the cued item(s) to a memory probe). Time-frequency analysis revealed opposing patterns of alpha lateralization depending on target eccentricity: A contralateral decrease in alpha power in target lateral trials indicated the involvement of target prioritization. A contralateral increase in alpha power when the central item remained relevant (distractor lateral trials) suggested the de-prioritization of irrelevant information. No lateralization was observed when both items remained relevant, supporting the notion that auditory alpha lateralization is restricted to situations in which spatial information is task-relevant. Altogether, the data demonstrate that retroactive attentional deployment involves excitatory and inhibitory control mechanisms.


Development of an abbreviated version of the delirium motor subtyping scale (DMSS-4).
Delirium is a common neuropsychiatric syndrome with considerable heterogeneity in clinical profile. Identification of clinical subtypes can allow for more targeted clinical and research efforts. We sought to develop a brief method for clinical subtyping in clinical and research settings. A multi-site database, including motor symptom assessments conducted in 487 patients from palliative care, adult and old age consultation-liaison psychiatry services was used to document motor activity disturbances as per the Delirium Motor Checklist (DMC). Latent class analysis (LCA) was used to identify the class structure underpinning DMC data and also items for a brief subtyping scale. The concordance of the abbreviated scale was then compared with the original Delirium Motor Subtype Scale (DMSS) in 375 patients having delirium as per the American Psychiatric Association's Diagnostic and Statistical Manual (4th edition) criteria. Latent class analysis identified four classes that corresponded closely with the four recognized motor subtypes of delirium. Further, LCA of items (n = 15) that loaded >60% to the model identified four features that reliably identified the classes/subtypes, and these were combined as a brief motor subtyping scale (DMSS-4). There was good concordance for subtype attribution between the original DMSS and the DMSS-4 (κ = 0.63). The DMSS-4 allows for rapid assessment of clinical subtypes in delirium and has high concordance with the longer and well-validated DMSS. More consistent clinical subtyping in delirium can facilitate better delirium management and more focused research effort.


Natural language processing.
Natural language processing (NLP) is the study of mathematical and computational modeling of various aspects of language and the development of a wide range of systems. These include spoken language systems that integrate speech and natural language; cooperative interfaces to databases and knowledge bases that model aspects of human-human interaction; multilingual interfaces; machine translation; and message-understanding systems, among others. Research in NLP is highly interdisciplinary, involving concepts in computer science, linguistics, logic, and psychology. NLP has a special role in computer science because many aspects of the field deal with linguistic features of computation and NLP seeks to model language computationally.


Anti-virulence activities of biflavonoids from Mesua ferrea L. flower.
Based on the anti-virulence activity on Salmonella, the ethyl acetate extract (EAE) of Mesua ferrea flower was investigated for its chemical constituents. Ten purified compounds were identified and assayed for their inhibitory activity against Type III secretion system (T3SS) by polyacrylamide gel electrophoresis (SDS-PAGE) and Western blots experiments. We found the biflavonoids, rhusflavanone and mesuaferrone B, exhibited inhibitory effects on the secretion of Salmonella pathogenicity island 1 (SPI-1) effector proteins (SipA, B, C and D) without effecting the bacterial growth. In addition, 5, 6, 6'-trihydroxy-[1,1'-biphenyl]-3,3'-dicarboxylic acid (6) is a new natural product from M. ferrea flower.


FODMAP intake in children with coeliac disease influences diet quality and health-related quality of life and has no impact on gastrointestinal symptoms.
Children with coeliac disease (CD) following the gluten-free diet may experience ongoing gastrointestinal symptoms despite strict adherence. The study objective was to evaluate the association between foods high in fermentable oligo/di/monosaccharides, and polyols (FODMAP) and gastrointestinal symptoms, and the potential implications to diet quality and health-related quality of life in CD children. Dietary intake was studied in age-sex matched children 5-18 years (CD, n = 46; non-coeliac mild chronic gastrointestinal complaints [GIC], n = 46; healthy controls [HC], n = 46). CD children consumed fewer foods high in FODMAPs compared to GIC and HC (p < .0001). FODMAP intake was not related to gastrointestinal symptoms in CD children (p > 0.05) but was positively associated with child health-related quality of life (p < 0.05). FODMAP intake from fruits and vegetables was positively associated with diet adequacy and total diet quality in CD children (p < 0.05). FODMAP intake may influence diet quality and health-related quality of life but has no impact on gastrointestinal symptoms in CD children.


Lymphatic vessels in the colonic mucosa in ulcerative colitis.
In the normal colonic mucosa, lymphatics are found only in a narrow band associated with the muscularis mucosae and are absent from the rest of the mucosa. This study examined whether this arrangement of lymphatics is also valid in ulcerative colitis. Histological sections of colon from 15 long-standing cases were investigated with antibodies against CD 34 (negative for lymphatics; positive for blood vessel endothelium) and, in selected cases, podoplanin (positive for lymphatic endothelium; negative for blood vessel endothelium). Whereas inflammation of the mucosa was not associated with changes in lymphatics, an increase in intramucosal lymphatics was seen when the pathological changes included widening of the muscularis mucosae or penetration of the mucosa by muscle fibers, filiform changes in the mucosa, and hyperplasia of the mucosa-associated lymphoid tissue (MALT). In specimens with epithelial dysplasia, an association between the dysplastic epithelium and ectatic and quantitatively increased lymphatics was observed. With superimposed carcinoma, no relationship between the malignant tumor and lymphatics was identifiable. Nevertheless, pre-existing lymphatics in the muscularis mucosae were involved in lymphatic tumor spread. The immunohistochemical findings demonstrated that lymphatics occurred in all areas of the mucosa in ulcerative colitis (or, in effect, at sites which were not normally found under physiological conditions) and in regions that favored lymphatic tumor dissemination. Whether these lymphatics were actually involved in metastasis remains to be defined.


Most older women recover baseline functional status following pelvic organ prolapse surgery.
To evaluate postoperative functional status changes in older women undergoing pelvic organ prolapse (POP) surgery and determine predictors for nonrecovery of baseline status. We enrolled women ≥ 65 years in whom POP surgery was planned and measured functional status using the Katz Activities of Daily Living (ADL) and Lawton Instrumental Activities of Daily Living (IADL) scales at baseline, 1 week, 2 weeks, and 3 months postoperatively. We used logistic regression modeling to identify predictors of postoperative nonrecovery of functional status (score < baseline) and calculated score change over time. Sixty-six women were enrolled and 3-month data were complete for 53. Subjects had a mean age of 72 ± 5 years, were all Caucasian, and had predominantly undergone vaginal surgery (70 %). At baseline 31% were ADL-dependent and 12% were IADL-dependent. Both ADL and IADL scores changed significantly over time (p <0.001). At 3 months postoperatively, 19% of women failed to return to baseline ADLs and 25% failed to return to baseline IADLs. At all time points ADL dependence was almost entirely attributable to lack of continence, while IADL dependence was commonly due to the inability to independently perform activities outside the home. Age, number of comorbidities, depression, and baseline functional status were not significant predictors of IADL nonrecovery. In a model controlling for baseline IADL status, age, and BMI, higher baseline Colorectal-Anal Distress Inventory (CRADI) score significantly predicted IADL nonrecovery (AOR 1.13, 95% CI 1.00,1.27, p = 0.04). Most older women with baseline functional status independence undergoing POP surgery can expect to regain independence by 3 months postoperatively.


Interval mapping of QTLs controlling yield-related traits and seed protein content in Pisum sativum.
A linkage map of garden pea was constructed on the basis of 114 plants (F2 generation) derived from a cross combination Wt10245 x Wt11238. The map, consisting of 204 morphological, isozyme, AFLP, ISSR, STS, CAPS and RAPD markers, was used for interval mapping of quantitative trait loci (QTLs) controlling seed number, pod number, 1000-seed weight, 1000-yield, and seed protein content. Characterization of each QTL included identification of QTL position with reference to the flanking markers, estimation of the part of variance explained by this QTL, and determination of its gene action. The yield-related traits were measured in F2 plants and in F4 recombinant inbred lines (RILs). The interval mapping revealed two to six QTLs per trait, demonstrating linkage to seven pea chromosomes. A total of 37 detected QTLs accounted for 9.1-55.9% of the trait's phenotypic variation and showed different types of gene action. As many as eight and ten QTLs influencing the analysed traits were mapped in linkage groups III and V, respectively, indicating an important role of these regions of the pea genome in the control of yield and seed protein content.


Prognostic significance of atypical papillary urothelial hyperplasia.
Typical papillary hyperplasia, a recently recognized precursor lesion to low-grade papillary urothelial neoplasms, consists of undulating folds of cytologically benign urothelium. Well-developed, branching fibrovascular cores of a papillary neoplasm are not evident. We have noted lesions with the architectural pattern of papillary hyperplasia; however, the overlying urothelium demonstrated varying degrees of cytologic atypia. We identified 15 cases of atypical papillary hyperplasia (13 males, 2 females, age 55 to 92) with overlying urothelium showing cytologic atypia. Of these cases, 8 (53%) were received in consultation. Of the 15 cases, 8 exhibited overlying flat carcinoma in situ (CIS), 4 had overlying dysplasia, and 3 were transitional between papillary hyperplasia with atypia and the earliest lesions of papillary neoplasia. Of these cases, 5 patients had multiple specimens with atypical papillary hyperplasia (range, 2 to 8) over time. Concurrent to the diagnosis of atypical papillary hyperplasia, there were 25 different urothelial lesions: CIS (n = 11), papilloma (n = 1), papillary neoplasm of low malignant potential with CIS (n = 1), high-grade papillary urothelial carcinoma (n = 10; 3 with CIS), small-cell carcinoma (n = 1), and infiltrating urothelial carcinoma (n = 1). Of 11 patients with known prior history, 2 had 12 prior urothelial neoplasms (9 low-grade papillary neoplasms, 2 papillary urothelial neoplasms of low malignant potential, and 1 high-grade papillary cancer). Of 10 patients with atypical papillary hyperplasia and a minimum of 1 year of follow-up, 9 had 19 recurrences: CIS (n = 4), papilloma (n = 1), papillary neoplasm of low malignant potential (n = 1), infiltrating urothelial carcinoma (n = 3; 1 with CIS), and high-grade papillary urothelial carcinoma (n = 10; 5 with invasion and 2 with CIS). Whether the papillary hyperplasia had overlying CIS or dysplasia did not affect the correlation with urothelial neoplasms. Immunohistochemical analysis of p53 and Ki-67 expression in 8 cases demonstrated overexpression of p53 (n = 2; 1 with overlying dysplasia and 1 with overlying CIS), and Ki-67 (n = 5; 2 with overlying dysplasia and 3 with overlying CIS). Taken together, these results suggest that atypical papillary hyperplasia is most frequently associated with CIS and high-grade papillary cancer. In some cases, CIS or dysplasia may evolve into atypical papillary hyperplasia, with further progression to high-grade papillary cancer. This process may be analogous to papillary hyperplasia without cytologic atypia progressing to low-grade papillary urothelial neoplasms.


Decreased expression of Freud-1/CC2D1A, a transcriptional repressor of the 5-HT1A receptor, in the prefrontal cortex of subjects with major depression.
Serotonin1A (5-HT(1A)) receptors are reported altered in the brain of subjects with major depressive disorder (MDD). Recent studies have identified transcriptional regulators of the 5-HT(1A) receptor and have documented gender-specific alterations in 5-HT(1A) transcription factor and 5-HT(1A) receptors in female MDD subjects. The 5' repressor element under dual repression binding protein-1 (Freud-1) is a calcium-regulated repressor that negatively regulates the 5-HT(1A) receptor gene. This study documented the cellular expression of Freud-1 in the human prefrontal cortex (PFC) and quantified Freud-1 protein in the PFC of MDD and control subjects as well as in the PFC of rhesus monkeys chronically treated with fluoxetine. Freud-1 immunoreactivity was present in neurons and glia and was co-localized with 5-HT(1A) receptors. Freud-1 protein level was significantly decreased in the PFC of male MDD subjects (37%, p=0.02) relative to gender-matched control subjects. Freud-1 protein was also reduced in the PFC of female MDD subjects (36%, p=0.18) but was not statistically significant. When the data was combined across genders and analysed by age, the decrease in Freud-1 protein level was greater in the younger MDD subjects (48%, p=0.01) relative to age-matched controls as opposed to older depressed subjects. Similarly, 5-HT(1A) receptor protein was significantly reduced in the PFC of the younger MDD subjects (48%, p=0.01) relative to age-matched controls. Adult male rhesus monkeys administered fluoxetine daily for 39 wk revealed no significant change in cortical Freud-1 or 5-HT(1A) receptor proteins compared to vehicle-treated control monkeys. Reduced protein expression of Freud-1 in MDD subjects may reflect dysregulation of this transcription factor, which may contribute to the altered regulation of 5-HT(1A) receptors observed in subjects with MDD. These data may also suggest that reductions in Freud-1 protein expression in the PFC may be associated with early onset of MDD.


Combining electrospinning with hot drawing process to fabricate high performance poly (L-lactic acid) nanofiber yarns for advanced nanostructured bio-textiles.
Fiber constructed yarns are the elementary building blocks for the generation of implantable biotextiles, and there are always needs for designing and developing new types of yarns to improve the properties of biotextile implants. In the present study, we aim to develop novel nanofiber yarns (NYs) by combining nanostructure that more closely mimic the extracellular matrix fibrils of native tissues with biodegradability, strong mechanical properties and great textile processibility. A novel electrospinning system which integrates yarn formation with hot drawing process was developed to fabricate poly(L-lactic acid) (PLLA) NYs. Compared to the PLLA NYs without hot drawing, the thermally drawn PLLA NYs presented superbly-orientated fibrous structure and notably enhanced crystallinity. Importantly, they possessed admirable mechanical performances, which matched and even exceeded the commercial PLLA microfiber yarns (MYs). The thermally drawn PLLA NYs were also demonstrated to notably promote the adhesion, alignment, proliferation, and tenogenic differentiation of human adipose derived mesenchymal stem cells (hADMSCs) compared to the PLLA NYs without hot drawing. The thermally drawn PLLA NYs were further processed into various nanofibrous tissue scaffolds with defined structures and adjustable mechanical and biological properties using textile braiding and weaving technologies, demonstrating the feasibility and versatility of thermally drawn PLLA NYs for textile-forming utilization. The hADMSCs cultured on PLLA NY-based textiles presented enhanced attachment and proliferation capacities than those cultured on PLLA MY-based textiles. This work presents a facile technique to manufacture high performance PLLA NYs, which opens up opportunities to generate advanced nanostructured biotextiles for surgical implant applications.


Influence of stress and health-behaviour on miRNA expression.
Psychological stress is correlated with and may even cause DNA damage, which contributes to the etiology of various diseases. Recent studies point to the role of micro-RNA (miRNA), small molecules that regulate gene expression, in health and disease. This study investigated the relationship between transient stress and two cancer-related miRNAs, and determined whether health-behaviour moderated these relationships. Using a pre-post design, 37 German students completed measures on health-behaviour and perceived stress, the latter after a study break (low stress) and after an exam (high stress). On both occasions, students underwent blood tests to determine the expression of let-7b and miR-21, two miRNAs recently found to be related to cancer. The students reported significantly higher stress after the exam than in the study break period. The levels of let-7b and miR-21 expression significantly declined from low- to high-stress periods. Importantly, baseline health-behaviour interacted with time in relation to miR-21, such that the expression of this marker decreased only in students with inadequate health-behaviour, while it did not change in students with adequate health-behaviour. This is the first study showing that brief academic stress can alter the expression of two cancer-related miRNA molecules, and that health-behaviour may moderate these effects for miR-21.


Timely and spatially regulated maturation of B and T cell repertoire during human fetal development.
Insights into the ontogeny of the human fetal adaptive immune system are of great value for understanding immunocompetence of the developing fetus. However, to date, this has remained largely uncharted territory, in large part because blood samples from healthy, early gestation fetuses have been hard to come by. In a comprehensive study, we analyzed levels of T cell receptor excision circles (TRECs), signal-joint κ receptor excision circles (sjKRECs), and intron recombination signal sequence-K-deleting element (iRSS-Kde) rearrangement, and T and B lymphocyte repertoire clonality in human fetuses from 12 to 26 weeks of gestational age. Using next-generation sequencing, we analyzed the diversity and complexity of T cell receptor β (TRB) and immunoglobulin heavy chain (IGH) repertoires in four fetuses at 12, 13, 22, and 26 weeks of gestation and in healthy full-term infants. We report the progressive increase of TREC, sjKREC, and iRSS-Kde levels over time and confirm that B cell development precedes T cell development in the human fetus. Temporally and spatially regulated maturation of B and T cell repertoire diversity and complexity during human fetal development was observed, including evidence that immunoglobulin somatic hypermutation and class switch recombination occur already during intrauterine life. Our results help define physiological levels of immunodeficiency in premature infants and may serve as a reference for future studies aimed at investigating the impact of intrauterine pathologies on fetal immune development and function.


Elucidating Events within the Black Box of Enzyme Catalysis in Energy Metabolism: Insights into the Molecular Mechanism of ATP Hydrolysis by F1-ATPase.
Oxygen exchange reactions occurring at β-catalytic sites of the FOF1-ATP synthase/F1-ATPase imprint a unique record of molecular events during the catalytic cycle of ATP synthesis/hydrolysis. This work presents a new theory of oxygen exchange and tests it on oxygen exchange data recorded on ATP hydrolysis by mitochondrial F1-ATPase (MF1). The apparent rate constant of oxygen exchange governing the intermediate Pi-HOH exchange accompanying ATP hydrolysis is determined by kinetic analysis over a ~50,000-fold range of substrate ATP concentration (0.1-5000 μM) and a corresponding ~200-fold range of reaction velocity (3.5-650 [moles of Pi/{moles of F1-ATPase}-1 s-1]). Isotopomer distributions of [18O]Pi species containing 0, 1, 2, and 3 labeled oxygen atoms predicted by the theory have been quantified and shown to be in perfect agreement with the experimental distributions over the entire range of medium ATP concentrations without employing adjustable parameters. A novel molecular mechanism of steady-state multisite ATP hydrolysis by the F1-ATPase has been proposed. Our results show that steady-state ATP hydrolysis by F1-ATPase occurs with all three sites occupied by Mg-nucleotide. The various implications arising from models of energy coupling in ATP synthesis/hydrolysis by the ATP synthase/F1-ATPase have been discussed. Current models of ATP hydrolysis by F1-ATPase, including those postulated from single-molecule data, are shown to be effectively bisite models that contradict the data. The trisite catalysis formulated by Nath's torsional mechanism of energy transduction and ATP synthesis/hydrolysis since its first appearance 25 years ago is shown to be in better accord with the experimental record. The total biochemical information on ATP hydrolysis is integrated into a consistent model by the torsional mechanism of ATP synthesis/hydrolysis and shown to elucidate the elementary chemical and mechanical events within the black box of enzyme catalysis in energy metabolism by F1-ATPase.


Gemmae: a role in sexual reproduction in the fern genus vittaria.
Gemmae are generally defined as vegetative propagules. In the shoestring ferns, Vittaria, gemmae grown in the presence of mature gametophyte plants or on medium containing gibberellic acid produce antheridia in lieu of vegetative growth. This suggests that antheridial differentiation in Vittaria is controlled by a chemical antheridogen system similar to those described in other fern genera. In natural populations of Vittaria gametophytes composed primarily of long-lived individuals, gemmae may provide the only source of tissue susceptible to antheridogen action and may have evolved in response to that condition.


Rationale, Design and Baseline Characteristics of Participants in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) Trial.
Long-term aspirin prevents vascular events but is only modestly effective. Rivaroxaban alone or in combination with aspirin might be more effective than aspirin alone for vascular prevention in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD). Rivaroxaban as well as aspirin increase upper gastrointestinal (GI) bleeding and this might be prevented by proton pump inhibitor therapy. Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) is a double-blind superiority trial comparing rivaroxaban 2.5 mg twice daily combined with aspirin 100 mg once daily or rivaroxaban 5 mg twice daily vs aspirin 100 mg once daily for prevention of myocardial infarction, stroke, or cardiovascular death in patients with stable CAD or PAD. Patients not taking a proton pump inhibitor were also randomized, using a partial factorial design, to pantoprazole 40 mg once daily or placebo. The trial was designed to have at least 90% power to detect a 20% reduction in each of the rivaroxaban treatment arms compared with aspirin and to detect a 50% reduction in upper GI complications with pantoprazole compared with placebo. Between February 2013 and May 2016, we recruited 27,395 participants from 602 centres in 33 countries; 17,598 participants were included in the pantoprazole vs placebo comparison. At baseline, the mean age was 68.2 years, 22.0% were female, 90.6% had CAD, and 27.3% had PAD. COMPASS will provide information on the efficacy and safety of rivaroxaban, alone or in combination with aspirin, in the long-term management of patients with stable CAD or PAD, and on the efficacy and safety of pantoprazole in preventing upper GI complications in patients receiving antithrombotic therapy.


Assessing the welfare of kennelled dogs-A review of animal-based measures.
Hundreds of thousands of dogs are housed in kennels worldwide, yet there are no standard protocols for assessing the welfare of dogs in these environments. Animal science is focusing increasingly on the importance of animal-based measures for determining welfare states, and those measures that have been used with kennelled dogs are reviewed in this paper with particular focus on their validity and practicality. From a physiological standpoint, studies using cortisol, heart rate and heart rate variability, temperature changes, and immune function are discussed. Behavioural measures are also of great relevance when addressing canine welfare, thus studies on fear and anxiety behaviours, abnormal behaviours like stereotypies, as well as responses to strangers and novel objects are reviewed. Finally, a limited number of studies attempting to use cognitive bias and learning ability are also mentioned as cognitive measures. The literature to date provides a strong background for which measures may be useful in determining the welfare of kennelled canines, however more research is needed to further assess the value of using these methods, particularly in regard to the large degree of individual differences that exist between dogs.


Comparison of neuromuscular adjustments associated with sustained isometric contractions of four different muscle groups.
The extent and characteristics of muscle fatigue of different muscle groups when subjected to a similar fatiguing task may differ. Thirteen healthy young men performed sustained contractions at 50% maximal voluntary contraction (MVC) force until task failure, with four different muscle groups, over two sessions. Per session, one upper limb and one lower limb muscle group were tested (knee extensors and thumb adductor, or plantar and elbow flexors). Changes in voluntary activation level and contractile properties were derived from doublet responses evoked during and after MVCs before and after exercise. Time to task failure differed (P < 0.05) between muscle groups (220 ± 64 s for plantar flexors, 114 ± 27 s for thumb adductor, 77 ± 25 s for knee extensors, and 72 ± 14 s for elbow flexors). MVC force loss immediately after voluntary task failure was similar (-30 ± 11% for plantar flexors, -37 ± 13% for thumb adductor, -34 ± 15% for knee extensors, and -40 ± 12% for elbow flexors, P > 0.05). Voluntary activation was decreased for plantar flexors only (from 95 ± 5% to 82 ± 9%, P < 0.05). Potentiated evoked doublet amplitude was more depressed for upper limb muscles (-59.3 ± 14.7% for elbow flexors and -60.1 ± 24.1% for thumb adductor, P < 0.05) than for knee extensors (-28 ± 15%, P < 0.05); no reduction was found in plantar flexors (-7 ± 12%, P > 0.05). In conclusion, despite different times to task failure when sustaining an isometric contraction at 50% MVC force for as long as possible, diverse muscle groups present similar loss of MVC force after task failure. Thus the extent of muscle fatigue is not affected by time to task failure, whereas this latter determines the etiology of fatigue.


Dual labeling with 5-aminolevulinic acid and fluorescein in high-grade glioma surgery with a prototype filter system built into a neurosurgical microscope: technical note.
Recent efforts to improve visualization of 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PPIX) fluorescence resulted in a dual-labeling technique, combining it with fluorescein sodium in a prototype setup. Fluorescein identifies regions with blood-brain barrier breakdown in gliomas. However, normally perfused and edematous brain fluoresces unselectively, with strong background enhancement. The aim of this study was to test the feasibility of a novel, integrated filter combination using porphyrins for selective tumor identification and fluorescein for background enhancement. A microscope with a novel built-in filter system (YB 475) for visualizing both fluorescein and 5-ALA-induced porphyrins was used. Resection limits were identified with the conventional BLUE 400 filter system. Six patients harboring contrast ring-enhancing lesions were analyzed. The complete surgical field could now be illuminated. Fluorescein was helpful for improving background visualization, and enhancing dura, edematous tissue, and cortex. Overlapping regions with both fluorophores harbored merged orange fluorescence. PPIX fluorescence was better visualized, even in areas beyond a normal working distance of approximately 25 cm, where the BLUE 400 filters recognized no or weak fluorescence. The novel filter system improved general tissue brightness and background visualization, enhancing fluorescence-guided tumor resection. Furthermore, it appears promising from a scientific perspective, enabling the simultaneous and direct observation of areas with blood-brain barrier breakdown and PPIX fluorescence.


Transcranial magnetic stimulation can measure and modulate learning and memory.
The potential uses for Transcranial Magnetic Stimulation (TMS) in the study of learning and memory range from a method to map the topography and intensity of motor output maps during visuomotor learning to inducing reversible lesions that allow for the precise temporal and spatial dissection of the brain processes underlying learning and remembering. Single-pulse TMS appears to be adequate to examine motor output maps but repetitive TMS (rTMS) appears necessary to affect most cognitive processes in measurable ways. The results we have reviewed in this article indicate that rTMS may have a potential clinical application in patients with epilepsy in whom it is important to identify the lateralization of verbal memory. Single-pulse TMS can help identify changes in motor output maps during training, that may indicate improved or diminished learning and memory processes following a stroke or other neurological insult. Other evidence indicates that rTMS may even have the capability of facilitating various aspects of memory performance. From a research perspective. rTMS has demonstrated site- and time-specific effects primarily in interfering with explicit retrieval of episodic information from long-term memory. rTMS may also be able to modulate retrieval from semantic memory as evidenced by response-time and accuracy changes after rTMS. All these findings suggest that the use of transcranial magnetic stimulation in the study of learning and memory will increase in the future and that it is already a valuable tool in the cognitive neuroscientists' belt.


Increased protein oxidation and loss of protein-bound sialic acid in hepatic tissues of D-galactose induced aged rats.
A redox basis of the increased oxidative protein damage and free radical-mediated desialylation have not been fully elucidated in aging. It is well known that the incidence of several liver diseases increase with age. This original research focuses on protein oxidation mechanisms and protein-bound sialic acid levels in liver tissue of the mimetic aging rats. Injection of D-galactose (60 mg/kg/day) for six weeks to male Sprague-Dawley rats (20-week-old) used to establish mimetic aging model. We investigated the tissue levels of various protein oxidation markers such as protein carbonyl groups, suitable advanced oxidation protein products and protein thiol groups. Our study also covered protein-bound sialic acid in liver tissue of D-galactose-induced aging rats. PCO (Protein Carbonyl Groups), P-OOH (Protein Hydroperoxides) and AOPP (Advanced Oxidation Protein Products) levels in aging rats were significantly higher compared to young control groups. On the other hand, P-SH (Protein Thiol Groups) levels were not found to be different between two groups. SA (Sialic Acid) levels in D-galactose-induced aging rats were significantly lower compared to control groups. Our results demonstrated greater susceptibility to hepatic oxidative protein damage and desialylation of hepatocellular proteins in Dgalactose- induced aging rats. These molecular mechanisms may be operative in the many age-related liver diseases, which are pertinent to increased oxidative stress and altered redox homeostasis.


A homozygous missense mutation in the ciliary gene TTC21B causes familial FSGS.
Several genes, mainly involved in podocyte cytoskeleton regulation, have been implicated in familial forms of primary FSGS. We identified a homozygous missense mutation (p.P209L) in the TTC21B gene in seven families with FSGS. Mutations in this ciliary gene were previously reported to cause nephronophthisis, a chronic tubulointerstitial nephropathy. Notably, tubular basement membrane thickening reminiscent of that observed in nephronophthisis was present in patients with FSGS and the p.P209L mutation. We demonstrated that the TTC21B gene product IFT139, an intraflagellar transport-A component, mainly localizes at the base of the primary cilium in developing podocytes from human fetal tissue and in undifferentiated cultured podocytes. In contrast, in nonciliated adult podocytes and differentiated cultured cells, IFT139 relocalized along the extended microtubule network. We further showed that knockdown of IFT139 in podocytes leads to primary cilia defects, abnormal cell migration, and cytoskeleton alterations, which can be partially rescued by p.P209L overexpression, indicating its hypomorphic effect. Our results demonstrate the involvement of a ciliary gene in a glomerular disorder and point to a critical function of IFT139 in podocytes. Altogether, these data suggest that this homozygous TTC21B p.P209L mutation leads to a novel hereditary kidney disorder with both glomerular and tubulointerstitial damages.


Exploring the genetic basis of human population differences in DNA methylation and their causal impact on immune gene regulation.
DNA methylation is influenced by both environmental and genetic factors and is increasingly thought to affect variation in complex traits and diseases. Yet, the extent of ancestry-related differences in DNA methylation, their genetic determinants, and their respective causal impact on immune gene regulation remain elusive. We report extensive population differences in DNA methylation between 156 individuals of African and European descent, detected in primary monocytes that are used as a model of a major innate immunity cell type. Most of these differences (~ 70%) are driven by DNA sequence variants nearby CpG sites, which account for ~ 60% of the variance in DNA methylation. We also identify several master regulators of DNA methylation variation in trans, including a regulatory hub nearby the transcription factor-encoding CTCF gene, which contributes markedly to ancestry-related differences in DNA methylation. Furthermore, we establish that variation in DNA methylation is associated with varying gene expression levels following mostly, but not exclusively, a canonical model of negative associations, particularly in enhancer regions. Specifically, we find that DNA methylation highly correlates with transcriptional activity of 811 and 230 genes, at the basal state and upon immune stimulation, respectively. Finally, using a Bayesian approach, we estimate causal mediation effects of DNA methylation on gene expression in ~ 20% of the studied cases, indicating that DNA methylation can play an active role in immune gene regulation. Using a system-level approach, our study reveals substantial ancestry-related differences in DNA methylation and provides evidence for their causal impact on immune gene regulation.


An MND/ALS phenotype associated with C9orf72 repeat expansion: abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline.
The transactive response DNA binding protein (TDP-43) proteinopathies describe a clinico-pathological spectrum of multi-system neurodegeneration that spans motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) and frontotemporal lobar degeneration (FTLD). We have identified four male patients who presented with the clinical features of a pure MND/ALS phenotype (without dementia) but who had distinctive cortical and cerebellar pathology that was different from other TDP-43 proteinopathies. All patients initially presented with weakness of limbs and respiratory muscles and had a family history of MND/ALS. None had clinically identified cognitive decline or dementia during life and they died between 11 and 32 months after symptom onset. Neuropathological investigation revealed lower motor neuron involvement with TDP-43-positive inclusions typical of MND/ALS. In contrast, the cerebral pathology was atypical, with abundant star-shaped p62-immunoreactive neuronal cytoplasmic inclusions in the cerebral cortex, basal ganglia and hippocampus, while TDP-43-positive inclusions were sparse. This pattern was also seen in the cerebellum where p62-positive, TDP-43-negative inclusions were frequent in granular cells. Western blots of cortical lysates, in contrast to those of sporadic MND/ALS and FTLD-TDP, showed high p62 levels and low TDP-43 levels with no high molecular weight smearing. MND/ALS-associated SOD1, FUS and TARDBP gene mutations were excluded; however, further investigations revealed that all four of the cases did show a repeat expansion of C9orf72, the recently reported cause of chromosome 9-linked MND/ALS and FTLD. We conclude that these chromosome 9-linked MND/ALS cases represent a pathological sub-group with abundant p62 pathology in the cerebral cortex, hippocampus and cerebellum but with no significant associated cognitive decline.


Oblique lateral impact biofidelity deflection corridors from Post Mortem Human Surrogates.
The objective of the study was to determine the thorax and abdomen deflection-time corridors in oblique side impacts. Data were analyzed from Post Mortem Human Surrogate (PMHS) sled tests, certain aspects of which were previously published. A modular and scalable anthropometry-specific segmented load-wall system was fixed to the platform of the sled. Region-specific forces were recorded from load cells attached to the load-wall plates. The thorax and abdomen regions were instrumented with chestbands, and deflection contours were obtained. Biomechanical responses were processed using the impulse-momentum normalization method and scaled to the mid-size male mass, 76-kg. The individual effective masses of the thorax and abdomen were used to determine the scale factors in each sled test, thus using the response from each experiment. The maximum deflections and their times of attainments were obtained, and mean and plus minus one standard deviation corridors were derived. Test-by-test thorax and abdomen force-time histories are given. Deflection-time histories for each specimen for the two body regions and corridors are presented. The mean maximum deflections for the thorax and abdomen body regions were 68.41 ± 16.1 and 68.98 ± 12.69 mm, respectively. Deflections were greater in oblique than pure lateral loading tests for both body regions, indicating the increased sensitivity of oblique side impact vector to the human response. The mean and one standard deviation responses of the thorax and abdomen serve as biofidelity corridors under oblique loading. Because modern instrumentation techniques can accommodate deflection sensors in the thorax and abdomen in devices such as WorldSID, and computer finite element models are flexible enough to extract regional and local deformation fields, the present data can be used to evaluate dummy biofidelity and validate and verify numerical models. They can be used to advance injury assessment reference values in oblique impacts.