Biocatalytic hydrogen-borrowing cascades.
The exquisite chemoselectivity and the intrinsic compatibility of enzymes have been widely exploited during the past decade for the development of multi-step biocatalytic reactions in one-pot. In this context, hydrogen-borrowing cascades permit to maximise the atom-efficiency through the internal recycling of redox equivalents, which avoids the use of additional oxidants or reductants. Here, we describe the state-of-the-art in the field of biocatalytic hydrogen-borrowing cascades and provide a future perspective for a wider implementation in organic synthesis.


[Comparative analysis of quantifying methods in FDG-PET scans of the brain].
The comparative analysis of three tracer kinetic methods most frequently applied for the quantization of the results of FDG-PET-brain scans was performed. The data of measurements on five healthy patients were evaluated by the most general method developed by Phelps, the Patlak-procedure and the SUV- (standard uptake value) method. It was demonstrated by the aid of correlation analysis that the applicability of the results of the more simple methods to estimate glucose metabolic rate (GMR) as calculated by the Phelps-method depended on the kind of the selected region of the brain. It was shown that the most considerable distortion occurred in the case of the same anatomical regions of the brain with both simplified methods. These regions were located either in the white matter or in the vicinity of larger size blood vessels or they were elements of the base of the skull [gyrus rectus (l. u.), pons, capsula interna (l. u.), cerebellum (l. u.), corpus callosum]. The distorted estimation is explained by the fact that the simpler models neglect dephosphorylation of the FDG-6P, and they also disregard the contribution of the intravascular activity to the tissue radioactivity as determined by the relatively low resolution PET measurement. The correlation coefficient between the GMR as calculated by the Phelps-method and glucose consumption data by the investigated simpler methods had very low values for regions located in the white matter, eventual close to blood vessels or being elements of the base of the skull.


Cancer risks in the optical manufacturing industry.
A mortality odds ratio (MOR) study has been conducted to explore the cancer risks of exposures experienced in the production of optical lenses and metal spectacle frames. Male death certificates were obtained from a Massachusetts town where a large optical industry is located. Craftsmen, foremen, and operatives of non-optical industries, such as woollen textile workers and workers in the optical company with short-term or no exposure, were chosen as reference workers their incomes were similar to those of the exposed workers. Cardiovascular disease (total 714) is chosen as the reference disease to explore cancers (total 232). An excess risk of total cancers observed = 70, expected = 48) has formed among lens workers. The excess may be accounted for mainly by the excess risk of gastrointestinal cancers; the standardised MORs (sMOR) for medium and long-term exposure were 2.2 and 2.5. The excess was especially evident for colorectal cancers; the sMORs for medium and long-term exposures were 3.2 and 2.6. Excess risks of gastrointestinal cancers (sMOR = 2.9) and colorectal cancers (sMOR = 3.4) were found among metal frame workers with long-term (employed for more than 29 years) exposure, but the number of exposed cases was small (9 and 6 respectively). These results suggest that exposure to abrasives or cutting oil mists or both, possibly by ingestion, might increase the risk of gastrointestinal (especially colorectal) cancers among lens and metal spectacle frame manufacturers.


Differential Associations of APOEɛ2 and APOEɛ4 Genotypes with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease in Individuals Without Dementia.
The APOE genotype has emerged as the major genetic factor for AD but differs among different alleles. To investigate the discrepant effects of APOE genotype on AD cerebrospinal fluid (CSF) biomarkers. A total of 989 non-demented ADNI participants were included. The associations of APOEɛ2 and APOEɛ4 with CSF biomarkers were investigated using linear regression models. Interaction and subgroup analyses were used to investigate the effects of sex and age on these associations. Furthermore, we used mediation analyses to assess whether Aβ mediated the associations between APOE genotypes and tau. APOEɛ2 carriers only showed higher Aβ levels (β [95% CI] = 0.07 [0.01, 0.13], p = 0.026). Conversely, APOEɛ4 carriers exhibited lower Aβ concentration (β [95% CI] = -0.27 [-0.31, -0.24], p < 0.001), higher t-Tau (β [95% CI] = 0.25 [0.08, 0.18], p < 0.001) and higher p-Tau (β [95% CI] = 0.31 [0.25, 0.37], p < 0.001). Subgroup analysis showed that APOE ɛ2 was significantly positively associated with Aβ only in females (β [95% CI] = 0.12 [0.04, 0.21], p = 0.005) and older people (β [95% CI] = 0.06 [0.001, 0.12], p = 0.048). But the effects of APOE ɛ4 were independent of gender and age. Besides, the associations of APOE ɛ4 with t-Tau and p-Tau were both mediated by baseline Aβ. Our data suggested that APOEɛ2 could promote Aβ clearance, while the process could be modified by sex and age. However, APOEɛ4 might cause the accumulation of Aβ and tau pathology independent of sex and age.


Spatial accessibility to healthcare facilities in coastal region of Bangladesh.
Though equal and easy accessibility to healthcare facilities are a fundamental right, people of the coastal region often get poor accessibility to healthcare facilities. This research aimed to assess the spatial accessibility to healthcare facilities in the coastal region of Bangladesh. Patuakhali district was selected as the study area. Accessibility to three levels of healthcare facilities: Community Clinic (CC), Upazila Health Complex (UHC) and District Hospital (DH) was measured individually using Geographic Information System (GIS) adopting the simple distance measures. Finally, overall accessibility to healthcare facilities was measured by overlaying accessibility to all three levels of healthcare facilities according to their relative importance. The findings of this study showed that a significant portion (70%) of Patuakhali district had high accessibility to CC; whereas, almost 60% and 40% of the area had poor accessibility to UHC and DH, respectively. Furthermore, 40% and 28% of the area of Patuakhali district had low and high accessibility to overall healthcare facilities, respectively. Furthermore, accessibility to healthcare facilities was found very poor in rural areas, char areas, and seashore. Thereafter, it is recommended to provide an UHC in every upazila and a DH in the southern part of Galachipa upazila to ensure high spatial accessibility of healthcare facilities.


Neoplastic change in chronic leg ulcer.
Seventeen cases of chronic leg ulcers were examined, 12 males and five females, with a mean age of 45 years. The average duration of ulcers was 21 years. Eleven of the cancers arose from ulcers that recurrently healed and broke down. Three arose from ulcers that never healed and three from stable scars. Treatment was by various levels of amputation in nine patients and by excision and skin grafting in one. Histological findings showed 16 cases to be squamous cell carcinoma while one case was sarcomatous in appearance. Most of the cases were poorly differentiated and findings of pseudoepitheliomatous hyperplasia were significant. This was thought to represent earlier stages of fetoplasia which in itself may continue for many years and may be a prelude to frank neoplasia. It was therefore suggested by the authors that the laboratory study of fetal antigens or other fetal markers in these types of lesions may be useful. It was also suggested that careful examination of deeper tissues in lesions where pseudoepitheliomatous hyperplasia has been found is necessary to ascertain that there is no undetected malignancy.


Ruthenium-catalysed Z-selective cross metathesis of allylic-substituted olefins.
The Z-selective cross metathesis of allylic-substituted olefins is explored with recently developed ruthenium-based metathesis catalysts. The reaction proceeds with excellent stereoselectivity for the Z-isomer (typically >95%) and yields of up to 88% for a variety of allylic substituents. This includes the first synthesis of Z-α,β-unsaturated acetals by cross metathesis and their elaboration to Z-α,β-unsaturated aldehydes. In addition, the reaction is tolerant of a variety of cross partners, varying in functionality and steric profile.


Inferring R0 in emerging epidemics-the effect of common population structure is small.
When controlling an emerging outbreak of an infectious disease, it is essential to know the key epidemiological parameters, such as the basic reproduction number R0 and the control effort required to prevent a large outbreak. These parameters are estimated from the observed incidence of new cases and information about the infectious contact structures of the population in which the disease spreads. However, the relevant infectious contact structures for new, emerging infections are often unknown or hard to obtain. Here, we show that, for many common true underlying heterogeneous contact structures, the simplification to neglect such structures and instead assume that all contacts are made homogeneously in the whole population results in conservative estimates for R0 and the required control effort. This means that robust control policies can be planned during the early stages of an outbreak, using such conservative estimates of the required control effort.


Dysregulation of protein trafficking in neurodegeneration.
Intracellular protein trafficking plays an important role in neuronal function and survival. Protein misfolding is a common theme found in many neurodegenerative diseases, and intracellular trafficking machinery contributes to the pathological accumulation and clearance of misfolded proteins. Although neurodegenerative diseases exhibit distinct pathological features, abnormal endocytic trafficking is apparent in several neurodegenerative diseases, such as Alzheimer's disease (AD), Down syndrome (DS) and Parkinson's disease (PD). In this review, we will focus on protein sorting defects in three major neurodegenerative diseases, including AD, DS and PD. An important pathological feature of AD is the presence of extracellular senile plaques in the brain. Senile plaques are composed of β-amyloid (Aβ) peptide aggregates. Multiple lines of evidence demonstrate that over-production/aggregation of Aβ in the brain is a primary cause of AD and attenuation of Aβ generation has become a topic of extreme interest in AD research. Aβ is generated from β-amyloid precursor protein (APP) through sequential cleavage by β-secretase and the γ-secretase complex. Alternatively, APP can be cleaved by α-secretase within the Aβ domain to release soluble APPα which precludes Aβ generation. DS patients display a strikingly similar pathology to AD patients, including the generation of neuronal amyloid plaques. Moreover, all DS patients develop an AD-like neuropathology by their 40 s. Therefore, understanding the metabolism/processing of APP and how these underlying mechanisms may be pathologically compromised is crucial for future AD and DS therapeutic strategies. Evidence accumulated thus far reveals that synaptic vesicle regulation, endocytic trafficking, and lysosome-mediated autophagy are involved in increased susceptibility to PD. Here we review current knowledge of endosomal trafficking regulation in AD, DS and PD.


Effects of microgravity on cognition: The case of mental imagery.
Human cognitive performance is an important factor for the successful and safe outcome of commercial and non-commercial manned space missions. This article aims to provide a systematic review of studies investigating the effects of microgravity on the cognitive abilities of parabolic or space flight participants due to the absence of the gravito-inertial force. We will focus on mental imagery: one of the best studied cognitive functions. Mental imagery is closely connected to perception and motor behavior. It aids important processes such as perceptual anticipation, problem solving and motor simulation, all of which are critical for space travel. Thirteen studies were identified and classified into the following topics: spatial representations, mental image transformations and motor imagery. While research on spatial representation and mental image transformation continues to grow and specific differences in cognitive functioning between 1 g and 0 g have been observed, motor imagery has thus far received little attention.


A comprehensive assessment of the risk of bone morphogenetic protein use in spinal fusion surgery and postoperative cancer diagnosis.
The risk of postoperative cancer following the use of recombinant human bone morphogenetic protein (BMP)-2 in spinal fusion is one potential complication that has received significant interest. Until recently, there has been little clinical evidence to support the assertion of potential cancer induction after BMP use in spinal surgery. This report aims to summarize the findings from clinical data available to date from the Yale University Open Data Access (YODA) project as well as more recently published large database studies regarding the association of BMP use in spinal fusion and the risk of postoperative cancer. A detailed review was based on online databases, primary studies, FDA reports, and bibliographies of key articles for studies that assessed the efficacy and safety of BMP in spinal fusion. In an analysis of the YODA project, one meta-analysis detected a statistically significant increase in cancer occurrence at 24 months but not at 48 months, and the other meta-analysis did not detect a significant increase in postoperative cancer occurrence. Analysis of 3 large health care data sets (Medicare, MarketScan, and PearlDiver) revealed that none were able to detect a significant increase in risk of malignant cancers when BMP was used compared with controls. The potential risk of postoperative cancer formation following the use of BMP in spinal fusion must be interpreted on an individual basis for each patient by the surgeon. There is no conclusive evidence that application of the common formulations of BMP during spinal surgery results in the formation of cancer locally or at a distant site.


Endoscopic treatment of intranasal abnormalities associated with nasolacrimal duct obstruction.
To report the incidence of intranasal abnormalities in children with nasolacrimal duct (NLD) obstruction and the results of treatment, which included nasal endoscopic removal of abnormal tissue. Nasal endoscopy was performed prospectively in 22 infants with mucoceles; in 97 children > or = 18 months at the time of initial NLD probing; and in 59 children with persistent NLD obstruction after previous probing. Endoscopic removal of abnormal tissue was performed in addition to NLD probing or balloon-catheter dilation. NLD cysts were found in 22 of 22 (100%) infants with mucoceles. Cysts or other abnormalities of the distal duct were found in 6 of 97 (6.2%) children > or = 18 months at the time of initial probing and in 5 of 59 (8.5%) children whose previous NLD probing was unsuccessful. Surgery was successful in 91% of patients. Nasal endoscopy identified intranasal anatomic abnormalities of the distal nasolacrimal duct uniformly in infants with mucoceles and in 6% to 9% of older children with complicated NLD obstruction. Treatment, including endoscopic removal of abnormal tissue, was successful in most patients. The use of nasal endoscopy may improve the treatment of patients with these disorders.


Longitudinal, intermodality registration of quantitative breast PET and MRI data acquired before and during neoadjuvant chemotherapy: preliminary results.
The authors propose a method whereby serially acquired DCE-MRI, DW-MRI, and FDG-PET breast data sets can be spatially and temporally coregistered to enable the comparison of changes in parameter maps at the voxel level. First, the authors aligned the PET and MR images at each time point rigidly and nonrigidly. To register the MR images longitudinally, the authors extended a nonrigid registration algorithm by including a tumor volume-preserving constraint in the cost function. After the PET images were aligned to the MR images at each time point, the authors then used the transformation obtained from the longitudinal registration of the MRI volumes to register the PET images longitudinally. The authors tested this approach on ten breast cancer patients by calculating a modified Dice similarity of tumor size between the PET and MR images as well as the bending energy and changes in the tumor volume after the application of the registration algorithm. The median of the modified Dice in the registered PET and DCE-MRI data was 0.92. For the longitudinal registration, the median tumor volume change was -0.03% for the constrained algorithm, compared to -32.16% for the unconstrained registration algorithms (p = 8 × 10(-6)). The medians of the bending energy were 0.0092 and 0.0001 for the unconstrained and constrained algorithms, respectively (p = 2.84 × 10(-7)). The results indicate that the proposed method can accurately spatially align DCE-MRI, DW-MRI, and FDG-PET breast images acquired at different time points during therapy while preventing the tumor from being substantially distorted or compressed.


Early decrease of XRCC1, a DNA base excision repair protein, may contribute to DNA fragmentation after transient focal cerebral ischemia in mice.
DNA damage and the DNA repair mechanism are known to be involved in ischemia/reperfusion injury in the brain. The x-ray repair cross-complementing group 1 (XRCC1) protein plays a central role in the DNA base excision repair pathway by interacting with DNA ligase III and DNA polymerase beta. The present study examined the protein expression of XRCC1 and DNA fragmentation before and after transient focal cerebral ischemia (FCI). Adult male CD-1 mice were subjected to 60 minutes of FCI by intraluminal blockade of the middle cerebral artery. XRCC1 protein expression was analyzed by immunohistochemistry and Western blot analysis. DNA damage was evaluated by gel electrophoresis and terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling (TUNEL). The spatial relationship between XRCC1 expression and DNA damage was examined by double staining with XRCC1 and TUNEL after FCI. Immunohistochemistry showed the nuclear expression of XRCC1 in all regions of the control brains and that it was predominant in the hippocampus. The XRCC1 level was markedly reduced in the caudate putamen at 10 minutes, further decreased in the entire middle cerebral artery territory at 1 hour, and remained reduced until 4 and 24 hours after FCI. Western blot analysis of the normal control brain showed a characteristic band of 70 kDa, which decreased after FCI. A significant amount of DNA fragmentation was detected by DNA gel electrophoresis 24 hours but not 4 hours after FCI. Double staining showed that the neurons that lost XRCC1 immunoreactivity became TUNEL positive. These results suggest that the early decrease of XRCC1 and the failure of the DNA repair mechanism may contribute, at least in part, to DNA fragmentation after FCI.


A decade review: methods to improve adherence to the treatment regimen among hemodialysis patients.
Hemodialysis patients are asked to adhere to a very difficult treatment regimen consisting of fluid and diet restrictions, many daily medications, and, usually, 3- or 4-hour hemodialysis sessions three times each week. Many hemodialysis patients fail to adhere to their prescribed treatment. Although this regimen is difficult, it is necessary for patients to adhere to the prescribed regimen for optimal health and well-being. It is important for nephrology nurses to know what interventions help patients overcome the barriers that keep them from adhering to the prescribed treatment. The purpose of this paper is to review the literature to examine the research that has been published on methods to improve adherence to the treatment regimen among hemodialysis patients. Behavioral approaches, education, and primary nursing are interventions that have been researched. More research has been reported on the demographics of noncompliant hemodialysis patients than on effective methods that help patients improve adherence to the treatment regimen. Demographic characteristics do not consistently predict compliance for individual patients. Each patient is unique. Research supports the idea that the nephrology nurse should spend time with the patient on a regular basis in order to understand the factors that hinder the individual patient from adhering to the treatment regimen. The nurse who knows the patient well is empowered to develop individualized interventions aimed at reducing barriers that interfere with the patient's ability to adhere the prescribed treatment regimen.


Evolution of the RpoS regulon: origin of RpoS and the conservation of RpoS-dependent regulation in bacteria.
The RpoS sigma factor in proteobacteria regulates genes in stationary phase and in response to stress. Although of conserved function, the RpoS regulon may have different gene composition across species due to high genomic diversity and to known environmental conditions that select for RpoS mutants. In this study, the distribution of RpoS homologs in prokaryotes and the differential dependence of regulon members on RpoS for expression in two gamma-proteobacteria (Escherichia coli and Pseudomonas aeruginosa) were examined. Using a maximum-likelihood phylogeny and reciprocal best hits analysis, we show that the RpoS sigma factor is conserved within gamma-, beta-, and delta-proteobacteria. Annotated RpoS of Borrelia and the enteric RpoS are postulated to have separate evolutionary origins. To determine the conservation of RpoS-dependent gene expression across species, reciprocal best hits analysis was used to identify orthologs of the E. coli RpoS regulon in the RpoS regulon of P. aeruginosa. Of the 186 RpoS-dependent genes of E. coli, 50 proteins have an ortholog within the P. aeruginosa genome. Twelve genes of the 50 orthologs are RpoS-dependent in both species, and at least four genes are regulated by RpoS in other gamma-proteobacteria. Despite RpoS conservation in gamma-, beta-, and delta-proteobacteria, RpoS regulon composition is subject to modification between species. Environmental selection for RpoS mutants likely contributes to the evolutionary divergence and specialization of the RpoS regulon within different bacterial genomes.


Cognitive neuroscience-based approaches to measuring and improving treatment effects on cognition in schizophrenia: the CNTRICS initiative.
The goal of this article is to discuss ways to further improve the search for potentially procognitive agents that could be used to enhance cognition and functional outcome in schizophrenia. In particular, we focus on the potential advantages to this process of using a contemporary, cognitive neuroscience-based approach to measuring cognitive function in clinical trials of procognitive agents in schizophrenia. These tools include computer-administered tasks that measure specific cognitive systems (such as attention, working memory, long-term memory, cognitive control) as well as the component cognitive processes that comprise these more overarching systems. The advantages of using these tools include the ability to identify and use homologous animal and human models in the drug discovery and testing process and the ability to incorporate noninvasive functional imaging measures into clinical trial contexts at several different phases of the drug development process. However, despite the clear potential advantages to using such methods, a number of barriers exist to their translation from basic science tools to tools for drug discovery. We discuss the development and implementation of a new project, Cognitive Neuroscience Treatment to Improve Cognition in Schizophrenia, designed to identify and overcome these barriers to the translation of cognitive neuroscience measures and methods into regular use in the drug discovery and development process of cognition-enhancing agents for use in schizophrenia.


Isolation of peptides that mimic epitopes on a malarial antigen from random peptide libraries displayed on phage.
The ring-infected erythrocyte surface antigen (RESA) is a dense-granule protein of Plasmodium falciparum which binds to the cytoskeletal structure of the erythrocyte after parasite invasion. It is currently under trial as a vaccine candidate. In an effort to characterize further the antibody responses to this antigen, we have panned two independent libraries of random peptides expressed on the surface of filamentous phage with a monoclonal antibody (MAb 18/2) against RESA. One library consisted of a potentially constrained 17-mer peptide fused with the gpVIII phage coat protein, and the other displayed an unconstrained 15-mer as a fusion with the minor phage coat protein gpIII. Several rounds of biopanning resulted in enrichment from both libraries clones that interacted specifically with MAb 18/2 in protein-blotting and enzyme-linked immunosorbent assay experiments. Nucleotide sequencing of the random oligonucleotide insert revealed a common predominant motif: (S/T)AVDD. Several other clones had related but degenerate motifs. Thus, a monoclonal antibody against a malarial antigen can select common mimotopes from different random peptide libraries. We envisage many uses for this technology in malaria research.


Influence of MTHFR Genetic Background on p16 and MGMT Methylation in Oral Squamous Cell Cancer.
Genetic polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) enzyme may influence DNA methylation. Alterations in DNA methylation patterns of genes involved in the regulation of the cell cycle, DNA repair, cell adherence and metastasis process are known to contribute to cancer development. In this study, the influence of the MTHFR C677T and A1298C gene polymorphisms on global DNA methylation and site-specific methylation on p16 and O⁶-methylguanine-DNA methyltransferase (MGMT) gene promoters was investigated in patients with oral squamous cell cancer (OSCC). To this aim, methylation studies were carried out by using genomic DNA isolated from saliva samples of 58 OSCC patients and 90 healthy controls. The frequency of the CT/AC and TT/AA genotypes was significantly higher in patients than in controls. Whereas no difference in global DNA methylation levels was observed between patients and controls, a higher frequency of methylation at both p16 and MGMT gene promoters was detected in patients compared with controls. A significant association between MTHFR gene polymorphisms and p16 and MGMT gene promoter methylation was found. The frequency of p16 and MGMT methylation was around 60% in patients with either the CT/AC or TT/AA genotype. Our results suggest that hypermethylation of cancer-related genes may be affected by MTHFR polymorphisms.


[Use of photonuclear reactions for studying the biological action of slow heavy ions].
Since ranges of low-energy heavy ions are too little the study of their action on cells is only possible using indirect irradiation, for instance, with neurons which form low--energy heavy ions uniformly inside a cell. In our studies we used photonuclear reactions which occur upon irradiation of a bio-object with high energy bremsstrahlung. The advantage of this method over the method based on the usage of neutrons has been demonstrated. The data are submitted obtained after exposure of yeast cells to photonuclear products.


Engineering threshold-based selection systems.
Using model organisms to identify novel therapeutic targets is frequently constrained by pre-existing genetic toolkits. To expedite positive selection for identification of novel downstream effectors, we engineered conditional expression of activated CED-10/Rac to disrupt Caenorhabditis elegans embryonic morphogenesis, titrated to 100% lethality. The strategy of engineering thresholds for positive selection using experimental animals was validated with pharmacological and genetic suppression and is generalizable to diverse molecular processes and experimental systems.


Influence of luting agent translucency on fiber post retention.
The aim was to assess the influence of cement translucency on the retentive strength of luted fiber posts. Twenty extracted human premolars were randomly divided into four equal groups, based on the combinations of materials to be tested. Two post types of the same size, shape, and chemical composition, but different light-transmission properties [Translucent post (TP) and Opaque post (OP)] were selected. The two post types were luted using the etch-and-rinse, light-curing adhesive in combination with two shades of the same resin cement of markedly different light-transmitting ability [Transparent shade (TS) and Opaque shade (OS)]. Early post retention was assessed using the thin-slice push-out test. Post type did not significantly influence post retention; however, cement translucency emerged as a relevant factor in intraradicular cementation, with the TS achieving higher push-out strengths. The between-factor interaction was also statistically significant; specifically, OP-OS yielded significantly lower retentive strengths than all the other groups. Post translucency did not influence post retention, provided that a highly translucent cement was utilized for luting.


Efficient sensory coding of multidimensional stimuli.
According to the efficient coding hypothesis, sensory systems are adapted to maximize their ability to encode information about the environment. Sensory neurons play a key role in encoding by selectively modulating their firing rate for a subset of all possible stimuli. This pattern of modulation is often summarized via a tuning curve. The optimally efficient distribution of tuning curves has been calculated in variety of ways for one-dimensional (1-D) stimuli. However, many sensory neurons encode multiple stimulus dimensions simultaneously. It remains unclear how applicable existing models of 1-D tuning curves are for neurons tuned across multiple dimensions. We describe a mathematical generalization that builds on prior work in 1-D to predict optimally efficient multidimensional tuning curves. Our results have implications for interpreting observed properties of neuronal populations. For example, our results suggest that not all tuning curve attributes (such as gain and bandwidth) are equally useful for evaluating the encoding efficiency of a population.


Total elbow arthroplasty after resection of tumors at the elbow.
Between 1980 and 1993, 13 patients underwent total elbow arthroplasty at the authors' institution after resection of tumors around the elbow. Arc of elbow motion from extension to flexion improved from a preoperative mean of 29 degrees to a postoperative mean of 73 degrees. Pain scores decreased from a preoperative mean of 3.6 to a postoperative mean of 2.0. Three patients had an excellent, six had a good, two had a fair, and two had a poor result. All seven patients with primary tumors had good or excellent results, compared with only two of six patients with metastatic lesions to the elbow. The data from this study suggest total elbow arthroplasty after resection of tumors provides significant pain relief and improvement in function. Patients with metastatic lesions may be candidates for the procedure, especially if all other methods of palliation have been exhausted. However, the results for patients with metastatic lesions may not be satisfactory.


Analysis of Longissimus thoracis Protein Expression Associated with Variation in Carcass Quality Grade and Marbling of Beef Cattle Raised in the Pacific Northwestern United States.
Longissimus thoracis (LD) samples from 500 cattle were screened for protein expression differences relative to carcass quality grade. The LD of the top 5% (low prime and high choice, HQ) and bottom 5% (low select, LQ) carcasses were analyzed using two-dimensional difference gel electrophoresis and Western blot. Following initial screening, 11 candidate proteins were selected for Western blot analyses. Differentially expressed proteins were clustered into four groups: (1) heat shock proteins and oxidative protection, (2) sarcomeric proteins (muscle maturity and fiber type), (3) metabolism and energetics, and (4) miscellaneous proteins. Proteins from groups 1 and 2 were greater in HQ carcasses. Alternatively, increased quantities of proteins from group 3 were observed in LQ carcasses. Proteomic differences provide insights into pathways contributing to carcass quality grade. A deeper understanding of the physiological pathways involved in carcass quality grade development may allow producers to employ production practices that improve quality grade.


Prostate size in hypogonadal men treated with a nonscrotal permeation-enhanced testosterone transdermal system.
This study examined the effects of testosterone replacement using a nonscrotal testosterone transdermal (TTD) system on prostate size and prostate-specific antigen (PSA) levels in hypogonadal men. As part of an open-label, multicenter study, prostate volume as measured by transrectal ultrasound and PSA were assessed in 29 hypogonadal men during treatment with intramuscular testosterone enanthate (+TE), followed by 8 weeks of androgen withdrawal (-T), and then during 1 year of therapy with Androderm Testosterone Transdermal System, a nonscrotal permeation-enhanced TTD system (+TTD). Mean prostate volume decreased significantly from the +TE period (17 g) compared with the -T period (14 g) (P < 0.001). Prostate volume increased significantly from the -T period compared with the +TTD period (18 g) (P < 0.001). Maximum prostate size, comparable to that measured during +TE (P = 0.125), was reached by month 3 of +TTD therapy; prostate volume did not increase further during the remaining 9 months of +TTD therapy. Prostate volume correlated with age (P < 0.01) during all three periods of observation (+TE: r = 0.69; -T: r = 0.64; and +TTD: r = 0.55). No patient developed symptomatic benign prostatic hyperplasia during the treatment period. PSA levels decreased during androgen withdrawal compared with levels measured during +TE treatment (P < 0.001) and rose with resumption of androgen therapy with TTD (P < 0.006). However, PSA levels during +TTD replacement remained significantly lower (P < 0.001) than during +TE replacement. Physiologic testosterone replacement in hypogonadal men was achieved using the TTD system. Prostate size during therapy with TTD was comparable to that reported for normal men. In these men treated with TTD, PSA levels were also within the normal range.


Direct Feedback Alignment With Sparse Connections for Local Learning.
Recent advances in deep neural networks (DNNs) owe their success to training algorithms that use backpropagation and gradient-descent. Backpropagation, while highly effective on von Neumann architectures, becomes inefficient when scaling to large networks. Commonly referred to as the weight transport problem, each neuron's dependence on the weights and errors located deeper in the network require exhaustive data movement which presents a key problem in enhancing the performance and energy-efficiency of machine-learning hardware. In this work, we propose a bio-plausible alternative to backpropagation drawing from advances in feedback alignment algorithms in which the error computation at a single synapse reduces to the product of three scalar values. Using a sparse feedback matrix, we show that a neuron needs only a fraction of the information previously used by the feedback alignment algorithms. Consequently, memory and compute can be partitioned and distributed whichever way produces the most efficient forward pass so long as a single error can be delivered to each neuron. We evaluate our algorithm using standard datasets, including ImageNet, to address the concern of scaling to challenging problems. Our results show orders of magnitude improvement in data movement and 2× improvement in multiply-and-accumulate operations over backpropagation. Like previous work, we observe that any variant of feedback alignment suffers significant losses in classification accuracy on deep convolutional neural networks. By transferring trained convolutional layers and training the fully connected layers using direct feedback alignment, we demonstrate that direct feedback alignment can obtain results competitive with backpropagation. Furthermore, we observe that using an extremely sparse feedback matrix, rather than a dense one, results in a small accuracy drop while yielding hardware advantages. All the code and results are available under https://github.com/bcrafton/ssdfa.


Psychosocial Treatments for Schizophrenia: An Evaluation of Theoretically Divergent Treatment Paradigms, and Their Efficacy.
General Purpose: This paper chronologically examines four theoretically divergent psychosocial treatments for schizophrenia, each intended to augment pharmacological treatment. The goal is to familiarize readers with a sample of well-established psychosocial treatments to provide an enhanced perspective on newer and future psychosocial treatments for schizophrenia. Clinical implications and future research directions are discussed. Social skills training, cognitive behavioral therapy, cognitive remediation, and social cognitive training therapy paradigms were searched and the extant literature is summarized for each, with particular focus on: 1) the rationale for treatment methodology; 2) particular methods of treatment; and, 3) meta-analytic data regarding their efficacy and/or effectiveness. Each of the four treatment methodologies discussed evinces particular strengths and specific weaknesses for clinical practice, with no clear superior methodology across all clinical populations/situations. Future research must continue to examine social cognitive treatments, as well as the effects of combined psychosocial treatments.


Wound healing in hemophilia B mice and low tissue factor mice.
Wound healing involves a number of physiologic mechanisms including coagulation, inflammation, formation of granulation tissue, and tissue remodeling. Coagulation with robust thrombin generation leading to fibrin formation is necessary for wound healing. It is less clear if there is a requirement for ongoing coagulation to support tissue remodeling. We have studied wound healing in mice with defects in both the initiation (low tissue factor) and propagation (hemophilia B) phases. In hemophilia B mice, dermal wound healing is delayed; this delay is associated with bleeding into the granulation tissue. Mice can be treated with replacement therapy (factor IX) or bypassing agents (factor VIIa) to restore thrombin generation. If treated just prior to wound placement, mice will have normal hemostasis in the first day of wound healing. As the therapeutic agents clear, the mice will revert to hemophilic state. If the primary role of coagulation in wound healing is to provide a stable platelet/fibrin plug that is loaded with thrombin, then treating hemophilic animals just prior to wound placement should restore normal wound healing. The results from this study did not support that hypothesis. Instead the results show that restoring thrombin generation only at the time of wound placement did not improve the delayed wound healing. In preliminary studies on low tissue factor mice, there also appears to be a delay in wound healing with evidence of bleeding into the granulation tissue. The current data suggests that ongoing coagulation function needs to be maintained to support a normal wound healing process.


Three-dimensional in vivo mapping of brain lesions in humans.
We describe a multistep technique for three-dimensional reconstruction and analysis of brain lesions in vivo, based on the manipulation of magnetic resonance raw data obtained with a special protocol. The technique permits the direct visual identification of neuroanatomical landmarks in each brain specimen and eliminates the need to rely on averaged templates of human brain sections, which can be a source of lesion localization error. The technique also allows for the bidirectional cross-reference between data points in two-dimensional slices and in volume reconstruction and for the projection of subcortical structures onto the three-dimensional cortical surface. The three-dimensional lesion mapping technique can be applied to research with the lesion method in both human and nonhuman primates, to the planning of neurosurgical lesion approach, and to the teaching of neuroanatomy.


Ehrlichia chaffeensis co-opts phagocytic hemocytes for systemic dissemination in the Lone Star tick, Amblyomma americanum.
Hematophagous arthropods can acquire and transmit several pathogens of medical importance. In ticks, the innate immune system is crucial in the outcome between vector-pathogen interaction and overall vector competence. However, the specific immune response(s) elicited by the immune cells known as hemocytes remains largely undefined in Ehrlichi a chaffeensis and its competent tick vector, Amblyomma americanum . Here, we show that granulocytes, professional phagocytic cells, are integral in eliciting immune responses against commensal and pathogen infection. The chemical depletion of granulocytes led to decreased phagocytic efficiency of tissues-associated hemocytes. We demonstrate E. chaffeensis can infect circulating hemocytes, and both cell-free plasma and hemocytes from E. chaffeensis- infected ticks can establish Ehrlichia infection in recipient ticks. Lastly, we provide evidence to show granulocytes play a dual role in E. chaffeensis infection. Depleting granulocytic hemocytes increased Ehrlichia load in the salivary gland and midgut tissues. In contrast, granulocyte depletion led to a reduced systemic load of Ehrlichia . This study has identified multiple roles for granulocytic hemocytes in the control and systemic dissemination of E. chaffeensis infection.


ABCA1- and ABCG1-mediated cholesterol efflux capacity of cerebrospinal fluid is impaired in Alzheimer's disease.
HDL-like particles in human cerebrospinal fluid (CSF) promote the efflux of cholesterol from astrocytes toward the neurons that rely on this supply for their functions. We evaluated whether cell cholesterol efflux capacity of CSF (CSF-CEC) is impaired in Alzheimer's disease (AD) by analyzing AD (n = 37) patients, non-AD dementia (non-AD DEM; n = 16) patients, and control subjects (n = 39). As expected, AD patients showed reduced CSF Aβ 1-42, increased total and phosphorylated tau, and a higher frequency of the apoε4 genotype. ABCA1- and ABCG1-mediated CSF-CEC was markedly reduced in AD (-73% and -33%, respectively) but not in non-AD DEM patients, in which a reduced passive diffusion CEC (-40%) was observed. Non-AD DEM patients displayed lower CSF apoE concentrations (-24%) compared with controls, while apoA-I levels were similar among groups. No differences in CSF-CEC were found by stratifying subjects for apoε4 status. ABCG1 CSF-CEC positively correlated with Aβ 1-42 (r = 0.305, P = 0.025), while ABCA1 CSF-CEC inversely correlated with total and phosphorylated tau (r = -0.348, P = 0.018 and r = -0.294, P = 0.048, respectively). The CSF-CEC impairment and the correlation with the neurobiochemical markers suggest a pathophysiological link between CSF HDL-like particle dysfunction and neurodegeneration in AD.


Ultrasound assisted low-temperature drying of kiwifruit: Effects on drying kinetics, bioactive compounds and antioxidant activity.
Low-temperature drying is considered to be a promising technique for food processing. It preserves thermolabile compounds and might be intensified by acoustic assistance. The effect of acoustic assistance (20.5 kW m-3 ) during low-temperature drying of kiwifruit (at 5, 10 and 15 °C, and 1 m s-1 ) on drying kinetics, bioactive compounds (such as ascorbic acid, vitamin E, and total polyphenols), and antioxidant activity was studied. Drying time was shortened by 55-65% when using power ultrasound. A diffusion model was used to evaluate the drying kinetics. The effective diffusion coefficient increased by 154 ± 30% and the external mass transfer coefficient increased by 158 ± 66% when ultrasound was applied during drying, compared with drying without ultrasound application. With regard to bioactive compounds and antioxidant activity, although samples dried at 15 °C presented significantly higher (P < 0.05) losses (39-54% and 57-69%, respectively) than samples dried at 5 °C (14-43% and 23-50%, respectively) when ultrasound was not applied, the application of ultrasound during drying at 15 °C significantly reduced (P < 0.05) those losses in all quality parameters (15-47% and 47-58%, respectively). Overall, low-temperature drying of kiwifruit was enhanced by acoustic assistance preserving bioactive compounds and antioxidant activity, especially at 15 °C. © 2018 Society of Chemical Industry.


Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer's brain.
The primary structure of canonical amyloid-β-protein was elucidated more than 30 years ago, yet the forms of amyloid-β that play a role in Alzheimer's disease pathogenesis remain poorly defined. Studies of Alzheimer's disease brain extracts suggest that amyloid-β, which migrates on sodium dodecyl sulphate polyacrylamide gel electrophoresis with a molecular weight of ∼7 kDa (7kDa-Aβ), is particularly toxic; however, the nature of this species has been controversial. Using sophisticated mass spectrometry and sensitive assays of disease-relevant toxicity we show that brain-derived bioactive 7kDa-Aβ contains a heterogeneous mixture of covalently cross-linked dimers in the absence of any other detectable proteins. The identification of amyloid-β dimers may open a new phase of Alzheimer's research and allow a better understanding of Alzheimer's disease, and how to monitor and treat this devastating disorder. Future studies investigating the bioactivity of individual dimers cross-linked at known sites will be critical to this effort.


Effect of estrogen (Premarin) replacement therapy on serum level of total estrogen and urinary excretion of calcium and hydroxyproline in postmenopausal Chinese women.
The study subjects included a total of 30 postmenopausal Chinese women, including 14 natural menopausal women, 13 castrated menopausal women and 3 post-irradiated menopausal women. Premarin 1.25 mg/day was given orally for 3 weeks and off one week, repeated for 6 cycles. Fasting morning urine and blood samples were collected before hormone treatment and at the end of 3 weeks, 11 weeks, and 23 weeks of Premarin therapy. Serum total estrogen level was measured by radioimmunoassay. Urinary calcium and creatinine were measured by atomic absorption and Jeffe's reaction, respectively. The concentration of urinary hydroxyproline was determined by Kivirikko's method. After Premarin therapy, the mean concentration of serum total estrogen increased 3 to 4 times from the pretreatment level of 71.7 pg/ml. On the other hand, the mean value of calcium/creatinine (Ca/Cr) molar ratio dropped down from 0.249 to 0.098. The mean value of hydroxyproline/creatinine (HOPr/Cr) molar ratio was reduced from 0.028 to 0.012. In view of the hormonal and biochemical changes after Premarin therapy, it is concluded that estrogen (Premarin) replacement should be effective in the treatment of enhanced bone loss or osteoporosis in postmenopausal women. The relationship of estrogen and calcitonin in the regulation of bone metabolism is also discussed.


Application of a sub-0.1-mm3 implantable mote for in vivo real-time wireless temperature sensing.
There has been increasing interest in wireless, miniaturized implantable medical devices for in vivo and in situ physiological monitoring. Here, we present such an implant that uses a conventional ultrasound imager for wireless powering and data communication and acts as a probe for real-time temperature sensing, including the monitoring of body temperature and temperature changes resulting from therapeutic application of ultrasound. The sub-0.1-mm3, sub-1-nW device, referred to as a mote, achieves aggressive miniaturization through the monolithic integration of a custom low-power temperature sensor chip with a microscale piezoelectric transducer fabricated on top of the chip. The small displaced volume of these motes allows them to be implanted or injected using minimally invasive techniques with improved biocompatibility. We demonstrate their sensing functionality in vivo for an ultrasound neurostimulation procedure in mice. Our motes have the potential to be adapted to the distributed and localized sensing of other clinically relevant physiological parameters.


Identification of increased amounts of eppin protein complex components in sperm cells of diabetic and obese individuals by difference gel electrophoresis.
Metabolic disorders like diabetes mellitus and obesity may compromise the fertility of men and women. To unveil disease-associated proteomic changes potentially affecting male fertility, the proteomes of sperm cells from type-1 diabetic, type-2 diabetic, non-diabetic obese and clinically healthy individuals were comparatively analyzed by difference gel electrophoresis. The adaptation of a general protein extraction procedure to the solubilization of proteins from sperm cells allowed for the resolution of 3187 fluorescent spots in the difference gel electrophoresis image of the master gel, which contained the entirety of solubilized sperm proteins. Comparison of the pathological and reference proteomes by applying an average abundance ratio setting of 1.6 and a p ≤ 0.05 criterion resulted in the identification of 79 fluorescent spots containing proteins that were present at significantly changed levels in the sperm cells. Biometric evaluation of the fluorescence data followed by mass spectrometric protein identification revealed altered levels of 12, 71, and 13 protein species in the proteomes of the type-1 diabetic, type-2 diabetic, and non-diabetic obese patients, respectively, with considerably enhanced amounts of the same set of one molecular form of semenogelin-1, one form of clusterin, and two forms of lactotransferrin in each group of pathologic samples. Remarkably, β-galactosidase-1-like protein was the only protein that was detected at decreased levels in all three pathologic situations. The former three proteins are part of the eppin (epididymal proteinase inhibitor) protein complex, which is thought to fulfill fertilization-related functions, such as ejaculate sperm protection, motility regulation and gain of competence for acrosome reaction, whereas the putative role of the latter protein to function as a glycosyl hydrolase during sperm maturation remains to be explored at the protein/enzyme level. The strikingly similar differences detected in the three groups of pathological sperm proteomes reflect a disease-associated enhanced formation of predominantly proteolytically modified forms of three eppin protein complex components, possibly as a response to enduring hyperglycemia and enhanced oxidative stress.


[Late replicating human X-chromosome in the early S-period].
The early S-period in cultured human lymphocytes was studied using the premature chromosome condensation technique. In the lymphocytes, isolated from females but not from males, one uncondensed G1-chromosome was detected among "pulverized" chromosomes which remained unlabeled with H3-thymidine. This chromosome is regarded as an inactivated X-chromosome. The data obtained are in agreement with the phenomenon of the delayed onset of DNA replication in the inactivated X-chromosomes.


Attitudes of physical therapist students toward physical therapist assistants before and after full-time clinical internships.
Development of attitudes of physical therapists (PTs) toward physical therapist assistants (PTAs) begins during their professional education, and attitudes are influenced further by clinical experiences. The purpose of this study was to understand attitudes of student PTs toward PTAs. We surveyed 66 clinical intern students enrolled in an entry-level master of physical therapy program. PT students received the same survey before and after their full-time clinical internship. Eleven Likert scale items were used to assess students' attitudes toward PTAs in the areas of competence, financial remuneration, and job security. One item was designed to determine whether PT students' level of contact with PTAs influenced attitudes. A random sample of 13 (20.9%) students who returned surveys were asked to participate in a telephone interview designed to enrich the quantitative data. After item analysis, five of the scale items were eliminated from the analyses due to poor internal consistency. Cronbach's alpha of the remaining six scale items was 0.75. Survey results reveal that PT students maintain an overall positive attitude toward PTAs before and after full-time clinical internship. Qualitative interview data support this finding. Students' attitudes in specific areas of PTA competence were negative and positive, however. The negative attitude may have been based on the students' beliefs that PTAs are not competent to perform physical therapy in situations that are changing or unpredictable. Positive attitudes may have been reflective of the students' beliefs that PTAs are competent to implement established plans of care. Student ranking of four professional issues showed a significant difference before and after full-time clinical internships.


Maintenance care in chiropractic--what do we know?
Back problems are often recurring or chronic. It is therefore not surprising that chiropractors wish to prevent their return or reduce their impact. This is often attempted with a long-term treatment strategy, commonly called maintenance care. However, some aspects of maintenance care are considered controversial. It is therefore relevant to investigate the scientific evidence forming the basis for its use. A review of the literature was performed in order to obtain answers to the following questions: What is the exact definition of maintenance care, what are its indications for use, and how is it practised? How common is it that chiropractors support the concept of maintenance care, and how well accepted is it by patients? How frequently is maintenance care used, and what factors are associated with its use? Is maintenance care a clinically valid method of approach, and is it cost-effective for the patient? Thirteen original studies were found, in which maintenance care was investigated. The relative paucity of studies, the obvious bias in many of these, the lack of exhaustive information, and the diversity of findings made it impossible to answer any of the questions. There is no evidence-based definition of maintenance care and the indications for and nature of its use remains to be clearly stated. It is likely that many chiropractors believe in the usefulness of maintenance care but it seems to be less well accepted by their patients. The prevalence with which maintenance care is used has not been established. Efficacy and cost-effectiveness of maintenance care for various types of conditions are unknown. Therefore, our conclusion is identical to that of a similar review published in 1996, namely that maintenance care is not well researched and that it needs to be investigated from several angles before the method is subjected to a multi-centre trial.


Estimates of drowning morbidity and mortality adjusted for exposure to risk.
To estimate the rate of unintentional drowning mortality and hospitalised morbidity using population-based, population-risk and person-time denominator data and to compare the estimates obtained. To then compare exposure-based rates for drowning with road traffic death rates. Retrospective analysis of unintentional drowning mortality and hospitalised morbidity of New South Wales (NSW, Australia) residents 16+ years of age during 1 January to 31 December 2005. Information on population-risk and person-time risk was obtained from the 2005 NSW Population Health Survey. Analysis of road traffic death data from NSW and population and person-time risk estimates from the Survey of Vehicle Use, Household Travel Surveys and Roads and Traffic Authority Speed Surveys in 2005. Estimated drowning mortality and hospitalised morbidity rates for adults were higher using population-risk and person-time risk exposures compared to a population-based exposure. Population-based estimates of road traffic mortality were four times higher than drowning mortality rates. In contrast, exposure adjusted person-time estimates for drowning were 200 times higher than road traffic fatalities. Many injury risks are underestimated when the total age-specific population is used to calculate an injury rate instead of actual population-risk or person-time exposure. This can result in the identification of misleading priorities for injury prevention. Drowning risk is strikingly higher than previously thought based on population-based estimates. This information is important for decision-making and policy development as it provides a basis for comparing the inherent risk in exposure to hazards with potential to cause injury.


Child health care uptake among low-income and immigrant families in a Swedish county.
To study the uptake of child health care among low-income and immigrant families in the county of Uppsala, Sweden, to investigate whether these families received extra attention as proposed in the Swedish Child Health Services (CHS) state-of-the-art consensus document from the year 2000. Data were collected for 25,024 infants born 1998-2006 from the database of statistics of the Child Health Care Unit in Uppsala and socio-demographic indicators from Swedish national registers. Disposable income was divided into quartiles. Country of birth of the mother was categorized into four regions with two subgroups each, mothers with or without a Swedish-born partner. Analysis was conducted by Cox regression and linear regression models. Small differences between Swedish vs. immigrant and high vs. low-income families were detected. Low-income mothers (RR 0.78) as well as mothers born in all country of birth regions with an immigrant partner (RR 0.28-0.95) had lower rates of participation in parental groups. The CHS provided basic child health care to almost all infants including children in immigrant and low-income Swedish families. However, the results did not indicate that disadvantaged families received the extra attention proposed in the consensus document.


Long-range migration of centrioles to the apical surface of the olfactory epithelium.
Olfactory sensory neurons (OSNs) in vertebrates detect odorants using multiple cilia, which protrude from the end of the dendrite and require centrioles for their formation. In mouse olfactory epithelium, the centrioles originate in progenitor cells near the basal lamina, often 50-100 μm from the apical surface. It is unknown how centrioles traverse this distance or mature to form cilia. Using high-resolution expansion microscopy, we found that centrioles migrate together, with multiple centrioles per group and multiple groups per OSN, during dendrite outgrowth. Centrioles were found by live imaging to migrate slowly, with a maximum rate of 0.18 µm/minute. Centrioles in migrating groups were associated with microtubule nucleation factors, but acquired rootletin and appendages only in mature OSNs. The parental centriole had preexisting appendages, formed a single cilium before other centrioles, and retained its unique appendage configuration in the mature OSN. We developed an air-liquid interface explant culture system for OSNs and used it to show that centriole migration can be perturbed ex vivo by stabilizing microtubules. We consider these results in the context of a comprehensive model for centriole formation, migration, and maturation in this important sensory cell type.


[Adolescent idiopathic scoliosis : diagnostic criteria and management].
The rapid growth of the spine during the pubertal spurt requires greater vigilance for the pediatrician at the annual check during this period to detect the occurrence of scoliosis. Before confirming the diagnosis of idiopathic scoliosis, it is imperative to exclude a secondary cause with appropriate history and clinical examination, and in selective cases with additional testing. Any scoliosis detected during growth should be considered potentially progressive and sent to a specialist if it is equal to or exceeds 20° on the X-rays. Radiological changes of more than 5° during a 6 months interval must also motivate an appointment with a specialist. Regular clinical and radiological surveillance, every 6 months, remains imperative to confirm or deny this risk of progression and decide on treatment.


Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: The role of thymic stromal lymphopoietin.
Type 2 innate lymphoid cells (ILC2s) represent an important type 2 immune cell. Glucocorticoid regulation of human ILC2s is largely unknown. We sought to assess steroid resistance of human blood and airway ILC2s from asthmatic patients and to examine its mechanism of induction. We studied human blood and lung ILC2s from asthmatic patients and control subjects using flow cytometry and ELISA. Dexamethasone inhibited (P = .04) chemoattractant receptor-homologous molecule expressed on TH2 lymphocytes and type 2 cytokine expression by blood ILC2s stimulated with IL-25 and IL-33. However, it did not do so when ILC2s were stimulated with IL-7 and thymic stromal lymphopoietin (TSLP), 2 ligands of IL-7 receptor α. Unlike blood ILC2s, bronchoalveolar lavage (BAL) fluid ILC2s from asthmatic patients were resistant to dexamethasone. BAL fluid from asthmatic patients had increased TSLP but not IL-7 levels. BAL fluid TSLP levels correlated (r = 0.74) with steroid resistance of ILC2s. TSLP was synergistically induced in epithelial cells by IL-13 and human rhinovirus. Mechanistically, dexamethasone upregulated ILC2 expression of IL-7 receptor α, which augmented and sustained signal transducer and activator of transcription (STAT) 5 signaling by TSLP. TSLP induced mitogen-activated protein kinase kinase (MEK), c-Fos, inhibitor of DNA binding 3, phosphorylated signal transducer and activator of transcription (pSTAT) 3, and pSTAT5, molecules linked to steroid resistance. Dexamethasone inhibited c-Fos, inhibitor of DNA binding 3, and pSTAT3 but not pSTAT5 and MEK. The MEK inhibitor trametinib, the Janus kinase-STAT inhibitor tofacitinib, and the STAT5 inhibitor pimozide reversed steroid resistance of BAL ILC2s. Dexamethasone inhibited type 2 cytokine production by blood ILC2s. IL-7 and TSLP abrogated this inhibition and induced steroid resistance of ILC2s in a MEK- and STAT5-dependent manner. BAL fluid ILC2s from asthmatic patients with increased TSLP levels were steroid resistant, which was reversed by clinically available inhibitors of MEK and STAT5.


Hemagglutinin variants of reovirus type 3 have altered central nervous system tropism.
Variants of the Dearing strain of reovirus type 3 with antigenically altered hemagglutinin proteins are much less neurovirulent than the parental virus. When injected intracerebrally into mice these variants infected a subset of the brain neurons that were infected by the parental virus. When injected intraperitoneally, the variants did not spread to the brain. These results indicate that minor modifications of the reovirus hemagglutinin dramatically alter the ability of the virus to spread into and injure the central nervous system.


Relation between income inequality and mortality: empirical demonstration.
To assess the extent to which observed associations at population level between income inequality and mortality are statistical artefacts. Indirect "what if" simulation by using observed risks of mortality at individual level as a function of income to construct hypothetical state level mortality specific for age and sex as if the statistical artefact argument were 100% correct. Data from the 1990 census for the 50 US states plus Washington, DC, were used for population distributions by age, sex, state, and income range; data disaggregated by age, sex, and state from the Centers for Disease Control and Prevention were used for mortality; and regressions from the national longitudinal mortality study were used for the individual level relation between income and risk of mortality. Hypothetical mortality, while correlated with inequality (as implied by the logic of the statistical artefact argument), showed a weaker association with states' levels of income inequality than the observed mortality. The observed associations in the United States at the state level between income inequality and mortality cannot be entirely or substantially explained as statistical artefacts of an underlying individual level relation between income and mortality. There remains an important association between income inequality and mortality at state level over and above anything that could be accounted for by any statistical artefact. This result reinforces the need to consider a broad range of factors, including the social milieu, as fundamental determinants of health.


Intima media thickness of common carotids and abdominal aorta in children and adolescents with congenital adrenal hyperplasia due to 21-hydroxylase deficiency in relation to their genotypes.
Patients with congenital adrenal hyperplasia (CAH) are at risk of vascular and metabolic complications due to steroid therapy and increased adrenal androgens exposure. of the study was to evaluate the relation between patient's genotype and (1) intima media thickness of abdominal aorta (AIMT) and common carotid arteries (CIMT) and (2) metabolic profile. In 71 patients (27 boys) aged from 1.5 to 17.9 years, with 21-hydroxylase deficiency (21OHD) CAH: 9 with nonclassic (NC) CAH, 62 with classic CAH: 10 with simple virilising (SV) and 52 with salt wasting (SW) CAH (13-Del/Del, 8-Del/I2G, 7-I2G/I2G and 24-other genotypes), and in 77 lean and 36 normotensive obese, age and gender matched controls, assessment of CIMT and AIMT as well as hormonal and biochemical evaluation were performed. The highest AIMT was observed in SW Del/Del and I2G/I2G groups and the highest CIMT in SV CAH subgroup. CIMT and AIMT correlated significantly with testosterone and free androgen index (FAI), and were significantly higher in patients with advanced bone age and obesity independent. Significantly higher HOMA, testosterone and FAI values were found in SV CAH. In CAH patients CIMT and AIMT are influenced by androgens and obesity independent. In the examined group vascular and metabolic abnormalities are pronounced more in certain subgroups of CAH (SV and SW: Del/Del) and in patients with advanced bone age.


Acute myeloid leukemia with cryptic CBFB-MYH11 type D.
A 77 year-old female was found with FAB M4Eo acute myeloid leukemia. Although CBFB-MYH11 mRNA was detected in RT-PCR, the conventional cytogenetic analysis failed to reveal inv(16). Fluorescence in situ hybridization (FISH) and the sequence analysis revealed a fusion between the exon 5 of CBFB and the exon 8 of MYH11, resulting in a minor variant fusion product previously reported as type D. In order to detect the cryptic inv(16) type D, both FISH and RT-PCR are required, and furthermore, the primers for the sequence analysis needs to be selected for the proper diagnosis.


Effect of Cadmium and Copper Exposure on Growth, Secondary Metabolites and Antioxidant Activity in the Medicinal Plant Sambung Nyawa (Gynura procumbens (Lour.) Merr).
A randomized complete block (RCBD) study was designed to investigate the effects of cadmium (Cd) and copper (Cu) on the growth, bioaccumulation of the two heavy metals, metabolite content and antibacterial activities in Gyanura procumbens (Lour.) Merr. Nine treatments including (1) control (no Cd and Cu); (2) Cd 2 = cadmium 2 mg/L; (3) Cd 4 = cadmium 4 mg/L; (4) Cu 70 = copper 70 mg/L; (5) Cu 140 = copper 140 mg/L); (6) Cd 2 + Cu 70 = cadmium 2 mg/L + copper 70 mg/L); (7) Cd 2 + Cu 140 = cadmium 2 mg/L + copper 70 mg/L); (8) Cd 4 + Cu 70 = cadmium 4 mg/L+ copper 70 mg/L and (9) Cd 4 + Cu 140 = cadmium 4 mg/L + copper 140 mg/L) were evaluated in this experiment. It was found that the growth parameters (plant dry weight, total leaf area and basal diameter) were reduced with the exposure to increased concentrations of Cd and Cu and further decreased under interaction between Cd and Cu. Production of total phenolics, flavonoids and saponin was observed to be reduced under combined Cd and Cu treatment. The reduction in the production of plant secondary metabolites might be due to lower phenyl alanine lyase (PAL) activity under these conditions. Due to that, the 1,1-diphenyl-2-picrylhydrazyl (DPPH), ferric reducing antioxidant potential (FRAP) and antibacterial activities was also found to be reduced by the combined treatments. The current experiments show that the medicinal properties of G. procumbens are reduced by cadmium and copper contamination. The accumulation of heavy metal also was found to be higher than the safety level recommended by the WHO in the single and combined treatments of Cd and Cu. These results indicate that exposure of G. procumbens to Cd and Cu contaminated soil may potentially harm consumers due to bioaccumulation of metals and reduced efficacy of the herbal product.


Coping skills of olympic developmental soccer athletes.
Athletes at Olympic Developmental Program (ODP) camps experience unusually high levels of expectations and inherent mental and physical challenges within such a short span of time. With the increasing emphasis on talent development, there has been consensus by the ODP staff to more clearly define present levels of coping skills, in order to enhance athletic prediction, maximize training efforts, identify the predisposition to injury, and focus on areas pertinent to successful performance. This study examined athletic and pain coping skills of U. S. ODP soccer athletes not previously investigated. Following written informed consent, 70 males completed the Athletic Coping Skills Inventory and the Sports Inventory for Pain. Data were analyzed by competitive level (U-14, U-15), and skill position (goalkeeper/defense, midfield/foward). MANOVA indicated a significant main effect across competitive level (Wilks' Lambda F(12,57) = 2.27; p = 0.02; n-beta = 0.915) but no significant effect by skill position (Wilks' Lambda F(12,57) = 0.931; p = 0.523; n-beta = 0.457). Post hoc analyses indicated that U-15 athletes scored significantly higher in concentration (p = 0.01) and body awareness (p = 0.03), but lower in avoidance (p = 0.01) than U-14 competitors. In conclusion, older, more experienced athletes revealed more positive athletic and pain coping skills than younger, less experienced athletes, although athletes in skill positions requiring spontaneous decision-making skills and split-second adjustment in a constantly changing sport environment (forwards, midfielders) did not exhibit more positive athletic and pain coping skills than those positions requiring reaction and protection (defenders, goalkeepers).


Secondary Cutaneous Dissemination of Peripheral T-Cell Lymphoma With T-Follicular Helper Phenotype as a Patient's Fourth Primary Malignancy.
Peripheral T-cell lymphomas expressing follicular helper T-cell (TFH) markers have recently been identified. Although this type of lymphomas consist of malignant proliferation of T-cells, they may also exhibit B-cell clonality. We report a case of a 72-year-old woman with multiple erythematous to violaceous nonscaling plaques and tumors on her trunk. Histopathological analysis revealed a dense infiltration of medium-to-large-sized atypical cells throughout the entire dermis. The result of immunohistochemical analysis showed that the infiltrating T-cells expressed programmed death-1 (PD-1), CD10, Bcl-6, CD3, CD4, CD2, and CD5. The infiltrate also contained scattered atypical large B-cells. Based on the clinical appearance and the histopathological findings, we diagnosed the patient with secondary cutaneous dissemination of peripheral T-cell lymphoma with expression of a T-follicular helper phenotype.


Haptoglobin alters oxygenation and oxidation of hemoglobin and decreases propagation of peroxide-induced oxidative reactions.
We compared oxygenation and anaerobic oxidation reactions of a purified complex of human hemoglobin (Hb) and haptoglobin (Hb-Hp) to those of uncomplexed Hb. Under equilibrium conditions, Hb-Hp exhibited active-site heterogeneity and noncooperative, high-affinity O(2) binding (n(1/2)=0.88, P(1/2)=0.33 mm Hg in inorganic phosphate buffer at pH 7 and 25 °C). Rapid-reaction kinetics also exhibited active-site heterogeneity, with a slower process of O(2) dissociation and a faster process of CO binding relative to uncomplexed Hb. Deoxygenated Hb-Hp had significantly reduced absorption at the λ(max) of 430 nm relative to uncomplexed Hb, as occurs for isolated Hb subunits that lack T-state stabilization. Under comparable experimental conditions, the redox potential (E(1/2)) of Hb-Hp was found to be +54 mV, showing that it is much more easily oxidized than uncomplexed Hb (E(1/2)=+125 mV). The Nernst plots for Hb-Hp oxidation showed no cooperativity and slopes less than unity indicated active-site heterogeneity. The redox potential of Hb-Hp was unchanged by pH over the range of 6.4-8.3. Exposure of Hb-Hp to excess hydrogen peroxide (H(2)O(2)) produced ferryl heme, which was found to be more kinetically inert in the Hb-Hp complex than in uncomplexed Hb. The negative shift in the redox potential of Hb-Hp and its stabilized ferryl state may be central elements in the protection against Hb-induced oxidative damage afforded by formation of the Hb-Hp complex.


[Functional assessment of stress and resistance of the body of soldiers on the stages of an emergency service].
Service in the armed forces takes place on the background of tension of different systems of the body and the level of stress depends on the stage of passage performance. The highest level of stress is voltage observed at the initial stage, which affects the general state of health of the soldier, his successful performance of professional duties and, consequently, reducing the overall resistance of the organism. The results obtained indicate a high "energy" cost of passing military performance.


Reconstructing Harry: a genealogical study of a colonial family 'inside' and 'outside' the Grahamstown Asylum, 1888-1918.
Recent scholarship has explored the dynamics between families and colonial lunatic asylums in the late nineteenth century, where families actively participated in the processes of custodial care, committal, treatment and release of their relatives. This paper works in this historical field, but with some methodological and theoretical differences. The Foucauldian study is anchored to a single case and family as an illness narrative that moves cross-referentially between bureaucratic state archival material, psychiatric case records, and intergenerational family-storytelling and family photographs. Following headaches and seizures, Harry Walter Wilbraham was medically boarded from his position as Postmaster in the Cape of Good Hope Colony of South Africa with a 'permanent disease of the brain', and was committed to the Grahamstown Asylum in 1910, where he died the following year, aged 40 years. In contrast to writings about colonial asylums that usually describe several patient cases and thematic patterns in archival material over time and place, this study's genealogical lens examines one white settler male patient's experiences within mental health care in South Africa between 1908 and 1911. The construction of Harry's 'case' interweaves archival sources and reminiscences inside and outside the asylum, and places it within psychiatric discourse of the time, and family dynamics in the years that followed. Thus, this case study maps the constitution of 'patient' and 'family' in colonial life, c.1888-1918, and considers the calamity, uncertainty, stigma and silences of mental illness.


Reducing stock-outs of essential tuberculosis medicines: a system dynamics modelling approach to supply chain management.
The under-performance of supply chains presents a significant hindrance to disease control in developing countries. Stock-outs of essential medicines lead to treatment interruption which can force changes in patient drug regimens, drive drug resistance and increase mortality. This study is one of few to quantitatively evaluate the effectiveness of supply chain policies in reducing shortages and costs. This study develops a systems dynamics simulation model of the downstream supply chain for amikacin, a second-line tuberculosis drug using 10 years of South African data. We evaluate current supply chain performance in terms of reliability, responsiveness and agility, following the widely-used Supply Chain Operation Reference framework. We simulate 141 scenarios that represent different combinations of supplier characteristics, inventory management strategies and demand forecasting methods to identify the Pareto optimal set of management policies that jointly minimize the number of shortages and total cost. Despite long supplier lead times and unpredictable demand, the amikacin supply chain is 98% reliable and agile enough to accommodate a 20% increase in demand without a shortage. However, this is accomplished by overstocking amikacin by 167%, which incurs high holding costs. The responsiveness of suppliers is low: only 57% of orders are delivered to the central provincial drug depot within one month. We identify three Pareto optimal safety stock management policies. Short supplier lead time can produce Pareto optimal outcomes even in the absence of other optimal policies. This study produces concrete, actionable guidelines to cost-effectively reduce stock-outs by implementing optimal supply chain policies. Preferentially selecting drug suppliers with short lead times accommodates unexpected changes in demand. Optimal supply chain management should be an essential component of national policy to reduce the mortality rate.


Evaluation of the standardized assessment of concussion in a pediatric emergency department.
The Standardized Assessment of Concussion (SAC) is a validated tool for identifying the effects of mild traumatic brain injury (mTBI). Previous research focused on sport-related sideline evaluation of adolescents and adults. Our goal was to evaluate performance of the SAC among subjects with and without head injury in a pediatric emergency department (ED). This was an observational study of children 6 to 18 years of age who presented to an ED with blunt head injury (case-patients) or minor extremity injury (controls). SAC and graded-symptom-checklist scores were compared. American Academy of Neurology concussion grades, presence of loss of consciousness and posttraumatic amnesia were also compared with SAC and graded-symptom-checklist scores among case-patients. Three hundred forty-eight children were enrolled. SAC scores trended lower (greater cognitive deficits) for case-patients compared with controls but did not reach significance. Graded-symptom-checklist scores were significantly higher among case-patients. Presence of altered mental status magnified this effect. There was no correlation between SAC scores and other indicators of mTBI. There was a positive correlation between graded-symptom-checklist scores and posttraumatic amnesia and American Academy of Neurology concussion grade. The graded symptom checklist reliably identified mTBI symptoms for all children aged 6 years and older. SAC scores tended to be lower for case-patients compared with controls but did not reach significance. Patients with altered mental status at the time of injury manifest an increased number and severity of symptoms. Additional research into strategies to identify cognitive deficits related to mTBI and classify mTBI severity in children is needed.


Composition and geographic variation of the bacterial microbiota associated with the coelomic fluid of the sea urchin Paracentrotus lividus.
In the present work, culture-based and culture-independent investigations were performed to determine the microbiota structure of the coelomic fluid of Mediterranean sea urchin Paracentrotus lividus individuals collected from two distinct geographical sites neighboring a high-density population bay and a nature reserve, respectively. Next Generation Sequencing analysis of 16S rRNA gene (rDNA) showed that members of the Proteobacteria, Bacteroidetes and Fusobacteria phyla, which have been previously reported to be commonly retrieved from marine invertebrates, dominate the overall population of microorganisms colonizing this liquid tissue, with minority bacterial genera exhibiting remarkable differences among individuals. Our results showed that there is a correlation between microbiota structure and geographical location of the echinoderm collection site, highlighting over-representation of metagenomic functions related to amino acid and bioactive peptides metabolism in specimens inhabiting the nature reserve. Finally, we also described the developmental delay and aberrations exhibited by sea urchin embryos exposed to distinct bacterial isolates, and showed that these defects rely upon hydrophilic compound(s) synthesized by the bacterial strains assayed. Altogether, our findings lay the groundwork to decipher the relationships of bacteria with sea urchins in their aquatic environment, also providing an additional layer of information to understand the biological roles of the coelomic fluid.


[Must we justify our medical decisions?].
To provide an equal or better health care with limited resources, is an inescapable constraint for health care providers. Every physician and clinical decision maker must now account for economical and technical resources that are to be invested in diagnostic and therapeutic procedures, in public as well as in private medical practice. Every medical decision must be endorsed in relation with the expected benefits and risks for the patient and/or the society. Methods and protocols must provide a definite efficiency and rely on a better management of resources allowed to health services and facilities. Words, concepts and basic principles of medical decision analysis are inescapable tools to cope with uncertainty, to evaluate medical decisions according to their expected consequences, objective and subjective, for a definite patient in a bedside situation, as for a larger community. In a context of economic constraint, rational decision analysis is a prerequisite for a better quality of care, optimizing expected results, personal preferences and expenses of financial, technical and human resources in order to save time, risks and suffering.


Comparison of Wooden and Polyethylene Cutting Boards: Potential for the Attachment and Removal of Bacteria from Ground Beef †.
The potentials for removal of beef bacterial microflora from unscored polyethylene and hardwood cutting boards were compared. Ground beef was placed for 0 to 90 min onto cutting boards at room temperature and then removed; the surfaces were swabbed and the bacteria were enumerated. The boards were cleaned with various cleaning agents and then analyzed for bacterial removal. In addition, aqueous extracts from eight hardwoods were incubated with Escherichia coli O157:H7 for 0 to 30 h at 37°C to determine their inhibitory potential. Differences between the bacterial levels on wooden and plastic boards were not significant regardless of contact time. Washing with any cleaner, including water, removed most bacteria from either type of board. White ash extracts reduced E. coli O157:H7 levels to undetectable within 24 h; black cherry and red oak exhibited low inhibitory activity. Slight growth was observed in extracts from all other hardwoods, including hard maple, suggesting that aqueous extractable agents that are active against E. coli O157:H7 are not generally present in hardwoods. This study demonstrates the need to control cutting board sanitation regardless of composition.


The redusome hypothesis of aging and the control of biological time during individual development.
The redusome hypothesis of aging and the control of biological time in individual development is proposed. Redusomes are hypothetical perichromosomal particles arising in differentiation events during morphogenesis of an organism. The linear molecule of DNA covered with proteins in the redusome is assumed to be a copy of a segment of chromosomal DNA. Redusomes are located mainly in subtelomeric regions of chromosomes. The redusome does not leave the body of a chromosome even in the course of cellular divisions, being kept in its chromosomal nest. Like telomeric DNA, redusome linear DNA is shortened step by step. Thus, tiny redusomes progressively decrease in size; it is from here their name originates. Together with loss of the length of DNA in a redusome, the number of different genes contained in it also decreases. Shortening of the redusomal DNA molecules (and, coupled to it, changes of the sets of genes in redusomes) is responsible for age-dependent shifts in the level of expression of different chromosomal genes. Owing to this, redusome DNA shortening serves as a key means of measuring biological time in individual development. The main part of DNA of most redusomes is postulated to be occupied by noncoding genes. Low-molecular-weight RNAs (micro RNAs and fountain RNAs, or fRNAs) are assumed to be transcribed from them. These RNAs are involved in regulation of various chromatin repackings that are specific to certain differentiations, while others modulate the levels of expression of chromosomal genes. Hypothetical fountain RNAs can quantitatively regulate the expression levels of chromosomal genes, forming specific complexes with fions. Fions are suggested to be specific sites of a chromosomal DNA which are complementary to different fRNAs. Fions reside in the vicinity of usual chromosomal genes. A complex of the fRNA-fion, specifically interacting with a closed gate of the corresponding ion channel of the internal nuclear membrane, initiates the opening of the gate for a very short time, thus organizing activity of an ion fountain which appears to be automatically aimed at the chromosomal gene nearest to the fion involved. The ion fountain creates, depending on specificity of matching fRNA, fion, and ion channel, a distinctive ionic environment near certain structural genes. Ion fountains exert their action on the configuration of corresponding segments of chromatin and on the transcriptional efficiency of chromosomal genes in a topographically specific manner. Hence, the fountain system of the nucleus is able to regulate the quantitative traits both of cells and organism; it can control dominance of alleles and plays a role in individual development. Significant and escalating truncation of the redusome DNA causes cell aging due to an arising and increasing deficit of fRNAs and, for this reason, the lack of required ions near certain structural genes. Progressive shortening of DNA of redusomes is proposed to result in cellular aging because of a constantly growing shortage of low-molecular-weight RNAs transcribed from redusomal genes. Two types of redusomes are postulated: chronosomes and printosomes. Linear molecules of DNA in these two types of redusomes are called chronomeres and printomeres, respectively. Chronosomes are responsible for measurement of biological time in nondividing cells of the CNS. Printosomes remember positions of cells in the course of interpretation of the positional information in morphogenesis. In accordance with the position of a cell in a morphogenetic field, printomeres do change cellular properties and remember the change made (this is a so-called printomere mechanism of interpretation of positional information). Besides, printomeres participate in maintaining the achieved state of cellular differentiation. Normally, the chronomere is shortened only on the maximum of infradian hormonal rhythm (T-rhythm) which initiates the act of a superhigh velocity of its transcription that is finished with truncation of the end of a chronomere (an effect called scrupting). Theprintomere can be shortened due to the effect of DNA end underreplication and owing to scrupting. The effect of the end underreplication of DNA in doubling cells occurs simultaneously both in printomeres and telomeres. Shortening of telomeres is just a bystander process of aging of cells, whereas the true cause of biological aging is only the shortening of redusome DNA. Processing of certain redusomes in terminally differentiating cells is a cause of a proliferation arrest. Linkage of genes in a eukaryotic chromosome is determined by the distances between genes and redusomes.


Fragmentation of functional resting state brain networks in a transgenic mouse model of tau pathology: A metabolic connectivity study using [18F]FDG-PET.
In a previous study, regional reductions in cerebral glucose metabolism have been demonstrated in the tauopathy mouse model rTg4510 (Endepols et al., 2022). Notably, glucose hypometabolism was present in some brain regions without co-localized synaptic degeneration measured with [18F]UCB-H. We hypothesized that in those regions hypometabolism may reflect reduced functional connectivity rather than synaptic damage. To test this hypothesis, we performed seed-based metabolic connectivity analyses using [18F]FDG-PET data in this mouse model. Eight rTg4510 mice at the age of seven months and 8 non-transgenic littermates were injected intraperitoneally with 11.1 ± 0.8 MBq [18F]FDG and spent a 35-min uptake period awake in single cages. Subsequently, they were anesthetized and measured in a small animal PET scanner for 30 min. Three seed-based connectivity analyses were performed per group. Seeds were selected for apparent mismatch between [18F]FDG and [18F]UCB-H. A seed was placed either in the medial orbitofrontal cortex, dorsal hippocampus or dorsal thalamus, and correlated with all other voxels of the brain across animals. In the control group, the emerging correlative pattern was strongly overlapping for all three seed locations, indicating a uniform fronto-thalamo-hippocampal resting state network. In contrast, rTg4510 mice showed three distinct networks with minimal overlap. Frontal and thalamic networks were greatly diminished. The hippocampus, however, formed a new network with the whole parietal cortex. We conclude that resting-state functional networks are fragmented in the brain of rTg4510 mice. Thus, hypometabolism can be explained by reduced functional connectivity of brain areas devoid of tau-related pathology, such as the thalamus.


Meta-analysis for rare events.
Meta-analysis provides a useful framework for combining information across related studies and has been widely utilized to combine data from clinical studies in order to evaluate treatment efficacy. More recently, meta-analysis has also been used to assess drug safety. However, because adverse events are typically rare, standard methods may not work well in this setting. Most popular methods use fixed or random effects models to combine effect estimates obtained separately for each individual study. In the context of very rare outcomes, effect estimates from individual studies may be unstable or even undefined. We propose alternative approaches based on Poisson random effects models to make inference about the relative risk between two treatment groups. Simulation studies show that the proposed methods perform well when the underlying event rates are low. The methods are illustrated using data from a recent meta-analysis (N. Engl. J. Med. 2007; 356(24):2457-2471) of 48 comparative trials involving rosiglitazone, a type 2 diabetes drug, with respect to its possible cardiovascular toxicity.


Role of humic-bound iron as an electron transfer agent in dissimilatory Fe(III) reduction.
The dissimilatory Fe(III) reducer Geobacter metallireducens reduced Fe(III) bound in humic substances, but the concentrations of Fe(III) in a wide range of highly purified humic substances were too low to account for a significant portion of the electron-accepting capacities of the humic substances. Furthermore, once reduced, the iron in humic substances could not transfer electrons to Fe(III) oxide. These results suggest that other electron-accepting moieties in humic substances, such as quinones, are the important electron-accepting and shuttling agents under Fe(III)-reducing conditions.


Multispectral scanning time-resolved fluorescence spectroscopy (TRFS) technique for intravascular diagnosis.
This study describes a scanning time-resolved fluorescence spectroscopy (TRFS) system designed to continuously acquire fluorescence emission and to reconstruct fluorescence lifetime images (FLIM) from a luminal surface by using a catheter-based optical probe with rotary joint and pull-back device. The ability of the system to temporally and spectrally resolve the fluorescence emission from tissue was validated using standard dyes and tissue phantoms (e.g., ex vivo pig aorta phantom). Current results demonstrate that this system is capable to reliably resolve the fluorescence emission of multiple fluorophores located in the lumen; and suggest its potential for intravascular detection of distinct biochemical features of atherosclerotic plaques.


[Effects of polyene antibiotics on the membranes of dog kidney isolated nuclei].
The effects of amphotericin B and nistatin on the membranes of dog kidney isolated nuclei after their incubation with the antibiotics in question, have been studied. It is found that the polyene antibiotics, though they are superficially-active compounds, have no solubilizing effect on nuclear membranes and do not change their chemical composition. Electrophoretic study has revealed that nuclear membrane proteins, besides high- and low-molecular protein components, also contain a large amount of histones. The incubation of the nuclei with the polyene antibiotics results in marked changes in the fractional composition of nuclear membrane proteins, the most significant changes being induced by amphotericin B. It is assumed that polyene antibiotics induce proteolytic degradation of nuclear membrane proteins.


Aldosterone Predicts Cardiovascular, Renal, and Metabolic Disease in the General Community: A 4-Year Follow-Up.
We recently reported that normal aldosterone levels are associated with cardiovascular, renal, and metabolic disease in a sample of the US general community (Visit 1). For the current analyses we used the same cohort in a new 4-year follow-up study (Visit 2). We measured aldosterone at Visit 1 and analyzed its predictive role for new diseases at Visit 2 (n=1140). We measured aldosterone at Visit 2 and investigated its associations with disease at Visit 2 (n=1368). We analyzed aldosterone continuously and we also dichotomized the variable as whether subjects were in the third tertile versus second and first tertiles. As continuous variable at Visit 1, aldosterone predicted new onset hypertension (HTN) (OR=1.36, CI=1.13-1.63, P=0.001), central obesity (OR=1.36, CI=1.07-1.73, P=0.011), and use of lipid-lowering drugs (OR=1.25, CI=1.05-1.48, P=0.012) at Visit 2, after adjustment for age, sex, and body mass index. When in the third tertile (8.5-88.6 ng/dL), aldosterone predicted type 2 diabetes (T2DM, OR=1.96, CI=1.03-3.70, P=0.039). At Visit 2, aldosterone remained associated with HTN, obesity, and chronic kidney disease (CKD), as reported for Visit 1. However, aldosterone was not associated with heart failure (HF) at Visit 1 and 2, nor was aldosterone a predictor of HF between visits. Aldosterone predicts new HTN, central obesity, T2DM, and use of lipid-lowering drugs in the general community and remains associated with HTN, obesity, and CKD over 4 years. Aldosterone is not associated nor predicts HF. Further studies are warranted to evaluate aldosterone as therapeutic target in the general community.


Effects of endurance training on standard and signal-averaged electrocardiograms of sled dogs.
To determine the effect of endurance training on QRS duration, QRS-wave amplitude, and QT interval. 100 sled dogs in Alaska. Dogs were examined in early September (before training) and late March (after training). During the interim, dogs trained by pulling a sled with a musher (mean, 20 km/d). Standard and signal-averaged ECG were obtained before and after training. Endurance training significantly increased mean QRS duration by 4.4 milliseconds for standard ECG (mean +/- SEM; 62.3 +/- 0.7 to 66.7 +/- 0.6 milliseconds) and 4.3 milliseconds for signal-averaged ECG (51.5 +/- 0.7 to 55.8 +/- 0.6 milliseconds) without changing body weight. Increase in QRS duration corresponded to a calculated increase in heart weight (standard ECG, 23%; signal-averaged ECG, 27%). Signal-averaged QRS duration was correlated with echocardiographically determined left ventricular diastolic diameter for the X orthogonal lead (r = +0.41), Y orthogonal lead (r = +0.33), and vector (r = +0.35). Training also increased QT interval (234 +/- 2 to 249 +/- 2 milliseconds) and R-wave amplitude in leads II and rV2, increased peak-to-peak voltage and S-wave amplitude in the Y orthogonal lead, and decreased Q-wave amplitude in the Y orthogonal lead. Electrocardiographic changes reflected physiologic cardiac hypertrophy in these canine athletes in response to repetitive endurance exercise. The QRS duration increases in response to endurance exercise training and, therefore, may be of use in predicting performance in endurance activities.