Identification of a T cell hybridoma that produces large quantities of macrophage-activating factor.
A murine T cell hybridoma, constructed by fusion of alloantigen-activated T cells with the BW5147 T cell lymphoma, which produces a lymphokine capable of inducing tumoricidal activity in macrophages, has been identified. Lymphokine release could be detected only after mitogen stimulation of the T cell hybridoma culture. Upon cloning of the parental hybridoma, 24 out of 27 clones produced tumoricidal-inducing activity. Seven clones produced more cytocidal-inducing activity than did conventional supernatants, generated by concanavalin A stimulation of normal murine spleen cell cultures, which contained macrophage-activating factor (MAF). The supernatant of hybridoma clone 24/G1 was 25 times more active than conventional MAF preparations. Using supernatants from a variety of clones, the levels of macrophage-activating activity and interleukin 2 were found to vary independently of one another. The lymphokine produced by hybridoma clone 24/G1 appeared to be identical to conventional MAF by a variety of criteria including: (a) a requirement for a second signal for induction of tumoricidal activity in macrophages, (b) inactivation after incubation for 1 h at 65 degrees C, and (c) loss of activity after treatment at pH 4.0 but not at pH 5.0. Like conventional MAF, the hybridoma MAF eluted as a single peak after molecular sieve chromatography on Sephadex G100 and exhibited an apparent molecular weight of 55,000. Although somewhat heterogeneous, the majority of hybridoma 24/G1 MAF displayed an isoelectric point of 5.4 as determined using the chromatofocusing technique. These results thus illustrate the usefulness of T cell hybridomas in distinguishing between various lymphokine activities and indicate that the T cell hybridoma clone 24/G1 will be of particular usefulness in achieving the biochemical purification of substantial quantities of murine MAF.


Circadian rhythm of adrenal glucocorticoid: its regulation and clinical implications.
Glucocorticoid (GC) is an adrenal steroid hormone that controls a variety of physiological processes such as metabolism, immune response, cardiovascular activity, and brain function. In addition to GC induction in response to stress, even in relatively undisturbed states its circulating level is subjected to a robust daily variation with a peak around the onset of the active period of the day. It has long been believed that the synthesis and secretion of GC are primarily regulated by the hypothalamus-pituitary-adrenal (HPA) neuroendocrine axis. However, recent chronobiological research strongly supports the idea that multiple regulatory mechanisms along with the classical HPA neuroendocrine axis underlie the diurnal rhythm of circulating GC. Most notably, recent studies demonstrate that the molecular circadian clockwork is heavily involved in the daily GC rhythm at multiple levels. The daily GC rhythm is implicated in various human diseases accompanied by abnormal GC levels. Patients with such diseases frequently show a blunted GC rhythmicity and, more importantly, circadian rhythm-related symptoms. In this review, we focus on recent advances in the understanding of the circadian regulation of adrenal GC and its implications in human health and disease.


The multifunctional FUS, EWS and TAF15 proto-oncoproteins show cell type-specific expression patterns and involvement in cell spreading and stress response.
FUS, EWS and TAF15 are structurally similar multifunctional proteins that were first discovered upon characterization of fusion oncogenes in human sarcomas and leukemias. The proteins belong to the FET (previously TET) family of RNA-binding proteins and are implicated in central cellular processes such as regulation of gene expression, maintenance of genomic integrity and mRNA/microRNA processing. In the present study, we investigated the expression and cellular localization of FET proteins in multiple human tissues and cell types. FUS, EWS and TAF15 were expressed in both distinct and overlapping patterns in human tissues. The three proteins showed almost ubiquitous nuclear expression and FUS and TAF15 were in addition present in the cytoplasm of most cell types. Cytoplasmic EWS was more rarely detected and seen mainly in secretory cell types. Furthermore, FET expression was downregulated in differentiating human embryonic stem cells, during induced differentiation of neuroblastoma cells and absent in terminally differentiated melanocytes and cardiac muscle cells. The FET proteins were targeted to stress granules induced by heat shock and oxidative stress and FUS required its RNA-binding domain for this translocation. Furthermore, FUS and TAF15 were detected in spreading initiation centers of adhering cells. Our results point to cell-specific expression patterns and functions of the FET proteins rather than the housekeeping roles inferred from earlier studies. The localization of FET proteins to stress granules suggests activities in translational regulation during stress conditions. Roles in central processes such as stress response, translational control and adhesion may explain the FET proteins frequent involvement in human cancer.


The rate of periodontal attachment loss in subjects with established periodontitis.
A stepwise approach to determine attachment level changes was utilized to assess the nature of progression of periodontal disease. Following initial screening, 51 subjects with established periodontitis were monitored quarterly for 9 more months. Probing depth (PD) and relative attachment level (RAL) were recorded using an automated, pressure sensitive probe system. To establish intra-examiner error, repeated measurements were performed for all sites at the final visit. An overall standard deviation (SD) for RAL repeated measurements was initially calculated (0.76 mm) using all 6,935 double measurements. Sites were sorted by factors which contribute to the error of attachment level measurements; i.e., pocket depth (shallow, moderate, deep), tooth type (molar, non-molar) and location (buccal, lingual). Data were sorted by the above 12 groups, and SD for repeated measurements was calculated separately for them. The ratio between these SD and the overall SD served as the corrective factor. Each patient's initial threshold (2 SD) was multiplied by these corrective factors thus resulting in 12 thresholds for each subject. Next, linear, exponential and logarithmic regression models were tested for each site, and the regression model showing the highest R value was chosen for that site. AL changes were tested against the patient's threshold for that site. Sites with attachment loss exceeding the threshold were deemed active. Five hundred eighty-one sites (8.3%) exhibited attachment loss exceeding the various thresholds. Of these, linear progression occurred in 195, logarithmic in 224, and exponential in 162 sites. Individual patient's attachment loss ranged from 0.6 to 19.4% of all sites.(ABSTRACT TRUNCATED AT 250 WORDS)


Variation in SWI/SNF Chromatin Remodeling Complex Proteins is Associated with Alcohol Dependence and Antisocial Behavior in Human Populations.
Testing for direct gene or single nucleotide polymorphism replication of association across studies may not capture the true importance of a candidate locus; rather, we suggest that relevant replication across studies may be found at the level of a biological process. We previously observed that variation in 2 members of the switching defective/sucrose nonfermenting (SWI/SNF) chromatin remodeling complex is associated with alcohol dependence (AD) in the Irish Affected Sib Pair Study for Alcohol Dependence. Here, we tested for association with alcohol-related outcomes using a set of genes functioning in the SWI/SNF complex in 2 independent samples. We used a set-based analysis to examine the 29 genes of the SWI/SNF complex for evidence of association with (i) AD in the adult Collaborative Study on the Genetics of Alcoholism (COGA) case-control sample and (ii) antisocial behavior, hypothesized to be a genetically related developmental precursor, in a younger population sample (Spit for Science [S4S]). We found evidence for association of the SWI/SNF complex with AD in COGA (p = 0.0435) and more general antisocial behavior in S4S (p = 0.00026). The genes that contributed most strongly to the signal in COGA were SS18L1, SMARCD1, BRD7, BCL7B, SMARCB1, and BCL11A. In the S4S sample, ACTB, ARID2, BCL11A, BCL11B, BCL7B, BCL7C, DPF2, and DPF3 all contributed strongly to the signal. We detected associations between the SWI/SNF complex and AD in an adult population selected from treatment-seeking probands and antisocial behavior in an adolescent population sample. This provides strong support for a role for SWI/SNF in the development of alcohol-related problems.


A Chromosome-Scale Genome Assembly of Paper Mulberry (Broussonetia papyrifera) Provides New Insights into Its Forage and Papermaking Usage.
Paper mulberry (Broussonetia papyrifera) is a well-known woody tree historically used for Cai Lun papermaking, one of the four great inventions of ancient China. More recently, Paper mulberry has also been used as forage to address the shortage of feedstuff because of its digestible crude fiber and high protein contents. In this study, we obtained a chromosome-scale genome assembly for Paper mulberry using integrated approaches, including Illumina and PacBio sequencing platform as well as Hi-C, optical, and genetic maps. The assembled Paper mulberry genome consists of 386.83 Mb, which is close to the estimated size, and 99.25% (383.93 Mb) of the assembly was assigned to 13 pseudochromosomes. Comparative genomic analysis revealed the expansion and contraction in the flavonoid and lignin biosynthetic gene families, respectively, accounting for the enhanced flavonoid and decreased lignin biosynthesis in Paper mulberry. Moreover, the increased ratio of syringyl-lignin to guaiacyl-lignin in Paper mulberry underscores its suitability for use in medicine, forage, papermaking, and barkcloth making. We also identified the root-associated microbiota of Paper mulberry and found that Pseudomonas and Rhizobia were enriched in its roots and may provide the source of nitrogen for its stems and leaves via symbiotic nitrogen fixation. Collectively, these results suggest that Paper mulberry might have undergone adaptive evolution and recruited nitrogen-fixing microbes to promote growth by enhancing flavonoid production and altering lignin monomer composition. Our study provides significant insights into genetic basis of the usefulness of Paper mulberry in papermaking and barkcloth making, and as forage. These insights will facilitate further domestication and selection as well as industrial utilization of Paper mulberry worldwide.


Dietary vegetable oils do not alter the intestine transcriptome of gilthead sea bream (Sparus aurata), but modulate the transcriptomic response to infection with Enteromyxum leei.
Studies conducted with gilthead sea bream (Sparus aurata L.) have determined the maximum dietary replacement of fish meal and oil without compromising growth or product quality. The present study aimed to analyze the effect of the nutritional background on fish health and fish fed plant protein-based diets with fish oil (FO diet) or a blend of vegetable oils (66VO diet) were exposed for 102 days to the intestinal myxosporean parasite Enteromyxum leei, and the intestine transcriptome was analyzed with a customized oligo-microarray of 7,500 annotated genes. Infection prevalence was high and similar in the two diet groups, but the outcome of the disease was more pronounced in fish fed the 66VO diet. No differences were found in the transcriptome of both diet control groups, whereas the number of differentially expressed genes in infected groups was considerable. K-means clustering of these differentially expressed genes identified four expression patterns that reflected the progression of the disease with the magnitude of the fold-change being higher in infected 66VO fish. A positive correlation was found between the time of infection and the magnitude of the transcriptional change within the 66VO group, being higher in early infected animals. Within this diet group, a strong up-regulation of many components of the immune specific response was evidenced, whereas other genes related to complement response and xenobiotic metabolism were down-regulated. The high replacement of fish oil by vegetable oils in practical fish feeds did not modify the intestine transcriptome of gilthead sea bream, but important changes were apparent when fish were exposed to the myxosporean E. leei. The detected changes were mostly a consequence rather than a cause of the different disease progression in the two diet groups. Hence, the developed microarray constitutes an excellent diagnostic tool to address changes associated with the action of intestinal pathogens, but lacks a prognostic value to predict in advance the different susceptibility of growing fish to the current pathogen.


Event-Free Survival, a Prostate-Specific Antigen-Based Composite End Point, Is Not a Surrogate for Overall Survival in Men With Localized Prostate Cancer Treated With Radiation.
Recently, we have shown that metastasis-free survival is a strong surrogate for overall survival (OS) in men with intermediate- and high-risk localized prostate cancer and can accelerate the evaluation of new (neo)adjuvant therapies. Event-free survival (EFS), an earlier prostate-specific antigen (PSA)-based composite end point, may further expedite trial completion. EFS was defined as the time from random assignment to the date of first evidence of disease recurrence, including biochemical failure, local or regional recurrence, distant metastasis, or death from any cause, or was censored at the date of last PSA assessment. Individual patient data from trials within the Intermediate Clinical Endpoints in Cancer of the Prostate-ICECaP-database with evaluable PSA and disease follow-up data were analyzed. We evaluated the surrogacy of EFS for OS using a 2-stage meta-analytic validation model by determining the correlation of EFS with OS (patient level) and the correlation of treatment effects (hazard ratios [HRs]) on both EFS and OS (trial level). A clinically relevant surrogacy was defined a priori as an R2 ≥ 0.7. Data for 10,350 patients were analyzed from 15 radiation therapy-based trials enrolled from 1987 to 2011 with a median follow-up of 10 years. At the patient level, the correlation of EFS with OS was 0.43 (95% CI, 0.42 to 0.44) as measured by Kendall's tau from a copula model. At the trial level, the R2 was 0.35 (95% CI, 0.01 to 0.60) from the weighted linear regression of log(HR)-OS on log(HR)-EFS. EFS is a weak surrogate for OS and is not suitable for use as an intermediate clinical end point to substitute for OS to accelerate phase III (neo)adjuvant trials of prostate cancer therapies for primary radiation therapy-based trials.


Model-Independent 3D Descriptors of Vertebral Cancellous Bone Architecture.
High-resolution micro computed tomography has enabled measurement of bone architecture derived from 3D representations of cancellous bone. Twenty-eight vertebral bodies were obtained from four embalmed male cadavers. From 3D anaglyphs, trabecular rod thickness and length were measured and the trabecular rod Buckling index was calculated. From 3D voxel-based datasets, bone volume density, trabecular thickness, and trabecular separation were measured. Also, trabecular bone pattern factor, structural model index, connectivity density, and degree of anisotropy were calculated. Bone volume density alone explains 59% of the variability in trabecular rod Buckling index. The addition of connectivity density, trabecular separation, and structural model index, in a multiple regression statistical model, improves the explanatory power to 77%. The relationships between measures of cancellous bone architecture and a derived measure of trabecular rod strength were investigated. Morphological descriptors of cancellous bone provide a composite explanatory model of trabecular rod strength.


Evidence for two independent prostate cancer risk-associated loci in the HNF1B gene at 17q12.
We carried out a fine-mapping study in the HNF1B gene at 17q12 in two study populations and identified a second locus associated with prostate cancer risk, approximately 26 kb centromeric to the first known locus (rs4430796); these loci are separated by a recombination hot spot. We confirmed the association with a SNP in the second locus (rs11649743) in five additional populations, with P = 1.7 x 10(-9) for an allelic test of the seven studies combined. The association at each SNP remained significant after adjustment for the other SNP.


Fibroblast growth factor receptors in in vitro and in vivo chondrogenesis: relating tissue engineering using adult mesenchymal stem cells to embryonic development.
Adult mesenchymal stem cells (MSCs) are considered promising candidate cells for therapeutic cartilage and bone regeneration. Because tissue regeneration and embryonic development may involve similar pathways, understanding common pathways may lead to advances in regenerative medicine. In embryonic limb development, fibroblast growth factor receptors (FGFRs) play a role in chondrogenic differentiation. The aim of this study was to investigate and compare FGFR expression in in vivo embryonic limb development and in vitro chondrogenesis of MSCs. Our study showed that in in vitro chondrogenesis of MSCs three sequential stages can be found, as in embryonic limb development. A mesenchymal condensation (indicated by N-cadherin) is followed by chondrogenic differentiation (indicated by collagen II), and hypertrophy (indicated by collagen X). FGFR1-3 are expressed in a stage-dependent pattern during in vitro differentiation and in vivo embryonic limb development. In both models FGFR2 is clearly expressed by cells in the condensation phase. No FGFR expression was observed in differentiating and mature hyaline chondrocytes, whereas hypertrophic chondrocytes stained strongly for all FGFRs. To evaluate whether stage-specific modulation of chondrogenic differentiation in MSCs is possible with different subtypes of FGF, FGF2 and FGF9 were added to the chondrogenic medium during different stages in the culture process (early or late). FGF2 and FGF9 differentially affected the amount of cartilage formed by MSCs depending on the stage in which they were added. These results will help us understand the role of FGF signaling in chondrogenesis and find new tools to monitor and control chondrogenic differentiation.


Thyroid volume measurement by ultrasound in schoolchildren from mildly iodine-deficient area.
Thyroid size was estimated by ultrasound and physical examination in 480 schoolchildren (238 boys and 242 girls), 7-14 years old, living in Tuzla Canton. By physical examination goiter was found in 13.5% (n=65) of subjects. When compared with the upper limits of the reference thyroid volumes reported by WHO and ICCIDD, goiter by ultrasonography was found in 12.9% (n=62) of all subjects. All goitrous children had a diffuse goiter. The differences in mean thyroid volumes between groups with and without goiter detected by physical examination were significant in all age groups (p<0.05). The results of ultrasound examinations correlate well with palpatory findings and show higher values for the thyroid volume in children with goiter. It generally confirms the values of the findings by palpation, even in areas with mild iodine deficiency.


Absence of antineutrophil cytoplasmic antibodies in relatives of UK patients with primary sclerosing cholangitis and ulcerative colitis.
Perinuclear antineutrophil cytoplasmic antibodies (ANCA) have been reported in patients and relatives of patients with ulcerative colitis and primary sclerosing cholangitis, suggesting that ANCA may be a genetic marker of disease susceptibility. The reported frequency of ANCA in relatives has varied greatly, between 0 and 30%. We therefore studied the prevalence of ANCA in unaffected first-degree relatives of British patients with primary sclerosing cholangitis and ulcerative colitis. Thirty-six patients with ulcerative colitis, 33 with primary sclerosing cholangitis and 187 relatives were studied. Ninety-seven relatives were from the primary sclerosing cholangitis proband and 90 were from the ulcerative colitis proband. As an environmental control, 32 spouses were included: 14 from the primary sclerosing cholangitis group and 18 from the ulcerative colitis group. Eighteen healthy volunteers were additional controls. ANCA was detected using immunoalkaline phosphatase method. Only 3 of 97 (3%) of the primary sclerosing cholangitis proband relatives had ANCA. One of these had ulcerative colitis, one had rheumatoid arthritis and the third systemic lupus erythematosus. Both rheumatoid arthritis and system lupus erythematosus are known to exhibit ANCA. All other sera were negative. ANCA was found only in patients with primary cholangitis and ulcerative colitis and not in their healthy first-degree relatives. ANCA is therefore not a genetic marker for increased disease susceptibility to primary sclerosing cholangitis or ulcerative colitis in the British population.


Diversity of lactase persistence alleles in Ethiopia: signature of a soft selective sweep.
The persistent expression of lactase into adulthood in humans is a recent genetic adaptation that allows the consumption of milk from other mammals after weaning. In Europe, a single allele (-13910(∗)T, rs4988235) in an upstream region that acts as an enhancer to the expression of the lactase gene LCT is responsible for lactase persistence and appears to have been under strong directional selection in the last 5,000 years, evidenced by the widespread occurrence of this allele on an extended haplotype. In Africa and the Middle East, the situation is more complicated and at least three other alleles (-13907(∗)G, rs41525747; -13915(∗)G, rs41380347; -14010(∗)C, rs145946881) in the same LCT enhancer region can cause continued lactase expression. Here we examine the LCT enhancer sequence in a large lactose-tolerance-tested Ethiopian cohort of more than 350 individuals. We show that a further SNP, -14009T>G (ss 820486563), is significantly associated with lactose-digester status, and in vitro functional tests confirm that the -14009(∗)G allele also increases expression of an LCT promoter construct. The derived alleles in the LCT enhancer region are spread through several ethnic groups, and we report a greater genetic diversity in lactose digesters than in nondigesters. By examining flanking markers to control for the effects of mutation and demography, we further describe, from empirical evidence, the signature of a soft selective sweep.


Occurrence of graft-versus-host disease increases mortality after umbilical cord blood transplantation for acute myeloid leukaemia: a report from Eurocord and the ALWP of the EBMT.
The efficacy of umbilical cord blood transplantation (UCBT) as treatment for acute myeloid leukaemia (AML) relies on immune-mediated graft-versus-leukaemia effects. Previous studies have suggested a strong association between graft-versus-host disease (GVHD) occurrence and graft-versus-leukaemia effects after allogeneic hematopoietic cell transplantation. Here, we evaluated the kinetics of relapse rate in correlation with GVHD occurrence after UCBT. The kinetics of relapse rate over time in correlation to GVHD occurrence were assessed by calculating the relapse rate per patient-year within sequential 90-day intervals. The impact of GVHD on relapse and mortality was further studied in multivariate Cox models handling GVHD as a time-dependent covariate. The study included data from 1068 patients given single (n = 567) or double (n = 501) UCBT. The proportion of patients with grade II, III and IV acute GVHD was 20%, 7% and 4%, respectively. At 2 years, the cumulative incidence of chronic GVHD was 42%, the cumulative incidence of relapse was 32%, and overall survival was 32% as well. Relapse rates declined gradually over time during the first 30 months after transplantation. There was a possible suggestion that grade II-IV acute (HR = 0.8, P = 0.1) and chronic (HR = 0.65, P = 0.1) GVHD decreased relapse risk. However, grade II-IV acute GVHD significantly increased early (the first 18 months after UCBT) mortality (HR = 1.3, P = 0.02), whilst chronic GVHD increased each early (HR = 2.7, P < 0.001) and late (HR = 4.9, P < 0.001) mortality after UCBT. The occurrence of grade II-IV acute or chronic GVHD each increases overall mortality after UCBT for AML mitigating the possible graft-versus-leukemia effect of GVHD.


Rotating bouncing disks, tossing pizza dough, and the behavior of ultrasonic motors.
Pizza tossing and certain forms of standing-wave ultrasonic motors (SWUMs) share a similar process for converting reciprocating input into continuous rotary motion. We show that the key features of this motion conversion process such as collision, separation and friction coupling are captured by the dynamics of a disk bouncing on a vibrating platform. The model shows that the linear or helical hand motions commonly used by pizza chefs and dough-toss performers for single tosses maximize energy efficiency and the dough's airborne rotational speed; on the other hand, the semielliptical hand motions used for multiple tosses make it easier to maintain dough rotation at the maximum speed. The system's bifurcation diagram and basins of attraction also provide a physical basis for understanding the peculiar behavior of SWUMs and provide a means to design them. The model is able to explain the apparently chaotic oscillations that occur in SWUMs and predict the observed trends in steady-state speed and stall torque as preload is increased.


TENS: a treatment option for bladder dysfunction.
To ascertain the mode of action and benefits of transcutaneous electrical nerve stimulation (TENS) in detrusor overactivity, stress incontinence and interstitial cystitis, an English-language literature search using Medline (1984-1995) was undertaken with detrusor instability, incontinence, interstitial cystitis, neuromodulation, transcutaneous electrical nerve stimulation and urodynamics as keywords and the material so identified was reviewed. The mode of action of TENS and optimal stimulation parameters in bladder dysfunction remain unclear. Lack of strict selection criteria and deficient reporting of subjective and objective outcomes precluded full assessment of therapeutic efficacy. A beneficial effect was evident in some studies of detrusor overactivity and interstitial cystitis. A trial of TENS in detrusor overactivity and interstitial cystitis refractory to conventional therapy would seem justified. Continued experimental research and further clinical studies will lead to refinement of the treatment modality.


Function of skin grafts in children following acquired amputation of the lower extremity.
Investigators have recommended aggressive use of skin-grafting in order to preserve length and proximal joint function following an acquired amputation in children. However, there is little objective evidence to either support or refute that recommendation. We performed a retrospective review of the cases of all children for whom a skin graft had been applied to the residual limb following an acquired lower-extremity amputation at our Limb Deficiency Clinic between 1984 and 2002. Skin graft dysfunction, defined as breakdown, contracture, and/or pain, was considered to be clinically relevant if it required the child to discontinue use of the prosthesis for any period of time or if it required revision surgery to facilitate continued prosthetic fitting. Twenty-three children (mean age at amputation, 4.4 years) with a total of thirty-one acquired lower-extremity amputations had been treated with skin-grafting. At a mean of 6.3 years after the operation, sixteen (52%) of the thirty-one extremities had had no episodes of skin graft dysfunction. The remaining fifteen extremities (48%) had had clinically relevant skin graft dysfunction (breakdown in thirteen and contracture and pain in one extremity each). Nine of the ten extensive skin grafts underwent clinically relevant breakdown, as did thirteen of the twenty-four grafts that were located distally on the residual limb. Subsequent surgical revision of the residual limb because of inadequate function of the skin graft was performed on seven extremities (23%), with revision to a more proximal limb-segment level required in five. Focal skin-grafting (involving < or = 25% of the surface area) of partial-thickness soft-tissue defects in order to optimize the length of the residual limb at the time of an amputation is an effective option for children with an acquired lower-extremity amputation. Limited skin-grafting (involving 26% to 50% of the surface area) is more likely to result in skin graft breakdown, particularly when it is done distally. Extensive skin-grafting, while technically possible, frequently requires revision and rarely results in an optimally functioning limb. Alternative treatment strategies should be considered for extremities that would require extensive, distal skin-grafting.


The small FNR regulon of Neisseria gonorrhoeae: comparison with the larger Escherichia coli FNR regulon and interaction with the NarQ-NarP regulon.
Neisseria gonorrhoeae can survive during oxygen starvation by reducing nitrite to nitrous oxide catalysed by the nitrite and nitric oxide reductases, AniA and NorB. The oxygen-sensing transcription factor, FNR, is essential for transcription activation at the aniA promoter, and full activation also requires the two-component regulatory system, NarQ-NarP, and the presence of nitrite. The only other gene known to be activated by the gonococcal FNR is ccp encoding a cytochrome c peroxidase, and no FNR-repressed genes have been reported in the gonococcus. In contrast, FNR acts as both an activator and repressor involved in the control of more than 100 operons in E. coli regulating major changes in the adaptation from aerobic to anaerobic conditions. In this study we have performed a microarray-led investigation of the FNR-mediated responses in N. gonorrhoeae to determine the physiological similarities and differences in the role of FNR in cellular regulation in this species. Microarray experiments show that N. gonorrhoeae FNR controls a much smaller regulon than its E. coli counterpart; it activates transcription of aniA and thirteen other genes, and represses transcription of six genes that include dnrN and norB. Having previously shown that a single amino acid substitution is sufficient to enable the gonococcal FNR to complement an E. coli fnr mutation, we investigated whether the gonococcal NarQ-NarP can substitute for E. coli NarX-NarL or NarQ-NarP. A plasmid expressing gonococcal narQ-narP was unable to complement E. coli narQP or narXL mutants, and was insensitive to nitrate or nitrite. Mutations that progressively changed the periplasmic nitrate sensing region, the P box, of E. coli NarQ to the sequence of the corresponding region of gonococcal NarQ resulted in loss of transcription activation in response to the availability of either nitrate or nitrite. However, the previously reported ligand-insensitive ability of gonococcal NarQ, the "locked on" phenotype, to activate either E. coli NarL or NarP was confirmed. Despite the sequence similarities between transcription activators of E. coli and N. gonorrhoeae, these results emphasise the fundamental differences in transcription regulation between these two types of pathogenic bacteria.


Syphilitic uveitis in human immunodeficiency virus-infected patients.
To document the incidence and clinical features of syphilitic uveitis in patients coinfected with human immunodeficiency virus (HIV). Retrospective chart review. Single tertiary uveitis referral center. The charts of HIV-infected patients with uveitis and a reactive fluorescent treponemal antibody absorption test seen between November 1983 and June 1995 were reviewed. Syphilis was the most common bacterial cause of uveitis in this group. Thirteen patients (0.6% of the 2085 HIV-positive patients seen in the clinic during the study period) were dually infected. Twelve patients were male. Six patients (46%) had previously been treated for syphilis, 4 with intramuscular penicillin G benzathine only. Four patients (31%) had isolated anterior uveitis, 3 patients (23%) had anterior and intermediate uveitis, and 5 patients (38%) had panuveitis. One patient (8%) presented with optic nerve and retinal atrophy. Eight patients were treated with intravenous penicillin, 3 with intravenous and intramuscular penicillin, and 1 with intravenous ceftriaxone sodium. Of the 12 patients for whom follow-up examinations were available after treatment, ocular inflammation decreased in 11 (92%) and visual acuity improved in 8 (67%). Rapid plasma reagin titers decreased a median of 64-fold compared with pretreatment levels, and all patients with reactive cerebrospinal fluid who underwent pretreatment and posttreatment lumbar punctures normalized following therapy with intravenous antibiotics. Syphilis is an uncommon cause of uveitis in HIV-infected patients. Anterior uveitis is the most common ocular manifestation, but panuveitis is more common than isolated anterior uveitis. Intravenous penicillin is effective therapy.


Simvastatin and vitamin E effects on cardiac and hepatic oxidative stress in rats fed on high fat diet.
High fat diet (HFD) is a common cause of metabolic syndrome and type 2 diabetes mellitus. Published data showed that HFD and subsequent dyslipidemia are major triggers for oxidative stress. Forty-eight male Sprague-Dawley rats, weighing 170-200 g, were divided into six groups: control, control with vitamin E (100 mg/kg/day, i.p.), control with simvastatin (SIM) (10 mg/kg of body weight/day), HFD, HFD with vitamin E, and HFD with SIM. Standard and high cholesterol diets were given for 15 weeks and SIM and vitamin E were added in the last 4 weeks. In all rats, serum vitamin E, total cholesterol (TC), triglycerides (TG), low (LDL) and high (HDL) density lipoproteins, alanine (ALT) and aspartate (AST) transaminases, alkaline phosphatase (ALP), and gamma glutamyl transpeptidase (GGT) as well as cardiac and hepatic thiobarbituric acid-reactive substances (TBARS) and antioxidants (reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT)) were measured. Also, electrocardiogram (ECG) was recorded. HFD significantly increased QTc interval, heart rate (HR), serum TC, TG, LDL, ALT, AST, ALP, GGT, liver TG, and cardiac and hepatic TBARS but decreased antioxidants and HDL, while SIM decreased HR, liver TG, serum TC, TG, and LDL and increased HDL in HFD rats. Vitamin E had no effect. Moreover, SIM and vitamin E decreased QTc interval, serum ALT, AST, ALP, GGT, and cardiac and hepatic TBARS and increased antioxidants in HFD rats. Histopathological observations confirm the biochemical parameters. SIM and vitamin E slow progression of hypercholesterolemia-induced oxidative stress in liver and heart and improve their functions.


High voltage atmospheric cold air plasma control of bacterial biofilms on fresh produce.
Atmospheric cold plasma (ACP) offers great potential for decontamination of food borne pathogens. This study examined the antimicrobial efficacy of ACP against a range of pathogens of concern to fresh produce comparing planktonic cultures, monoculture biofilms (Escherichia coli, Salmonella enterica, Listeria monocytogenes, Pseudomonas fluorescens) and mixed culture biofilms (Listeria monocytogenes and Pseudomonas fluorescens). Biotic and abiotic surfaces commonly occurring in the fresh food industry were investigated. Microorganisms showed varying susceptibility to ACP treatment depending on target and process factors. Bacterial biofilm populations treated with high voltage (80 kV) ACP were reduced significantly (p < 0.05) in both mono- and mixed species biofilms after 60 s of treatment and yielded non-detectable levels after extending treatment time to 120 s. However, an extended time was required to reduce the challenge mixed culture biofilm of L. monocytogenes and P. fluorescens inoculated on lettuce, which was dependent on biofilm formation conditions and substrate. Contained treatment for 120 s reduced L. monocytogenes and P. fluorescens inoculated as mixed cultures on lettuce (p < 0.05) by 2.2 and 4.2 Log10 CFU/ml respectively. When biofilms were grown at 4 °C on lettuce, there was an increased resistance to ACP treatment by comparison with biofilm grown at temperature abuse conditions of 15 °C. Similarly, L. monocytogenes and P. fluorescens exposed to cold stress (4 °C) for 1 h demonstrated increased tolerance to ACP treatment compared to non-stressed cells. These finding demonstrates that bacterial form, mono versus mixed challenges as well as environmental stress conditions play an important role in ACP inactivation efficacy.


Feasibility of a Digital Intervention to Promote Healthy Weight Management among Postpartum African American/Black Women.
The study aim was to implement and evaluate the feasibility of a culturally informed ("BeFAB") app for African American/Black women to address postpartum weight. Women (n = 136; mean age = 27.8 ± 5.4; mean BMI = 32.5 ± 4.3) were recruited from postpartum units, and randomly assigned to receive BeFAB (n = 65) or usual care (n = 71) for 12 weeks. App content included didactic lessons delivered via a virtual coach, app-based messages, goal setting and tracking, and edutainment videos. Feasibility outcomes included recruitment, retention and engagement, and self-reported acceptability. Behavioral (i.e., diet, physical activity), psychosocial (i.e., stress, coping, support, self-efficacy) and weight outcomes were also examined. Recruitment goals were met, but attrition was high, with 56% retention at 12 weeks. Approximately half of participants accessed the app and set a goal ≥one time, but <10% reported achieving a nutrition or activity goal. Among study completers, ≥60% found the app content at least somewhat helpful. Within-group changes for BeFAB among completers were found for increased moderate-to-vigorous physical activity and decreased fruit/vegetable intake and weight. Findings indicate initial feasibility of recruiting postpartum women to participate in a digital healthy body weight program but limited use, reflecting low acceptability and challenges in engagement and retention. Future research is needed on strategies to engage and retain participants in postpartum interventions.


Experimental glaucoma and cell size, density, and number in the primate lateral geniculate nucleus.
To examine the effects that elevated intraocular pressure (IOP), a glaucoma risk factor, has on the size, density, and number of neurons in the primate lateral geniculate nucleus (LGN). The monkey model of experimental glaucoma was combined with standard histologic staining and analysis techniques. Fourteen animals were examined. Mean IOPs higher than 40 mm Hg for 2.5, 4, 8, and 24 weeks resulted in reductions of 10% to 58% in the cross-sectional areas of LGN neurons receiving input from the glaucomatous eye. Reductions for animals with lower mean IOPs (37 and 28 mm Hg) for 16 and 27 weeks were 16% and 30%, respectively. Neurons receiving input from the normal eye also were reduced in size (4 -26%). No differential effect in cell size was seen for magnocellular versus parvocellular neurons. Elevation of IOP resulted in an increase in cell density in all layers of the LGN. The increase was approximately two times greater in parvocellular (59%) than magnocellular (31%) layers. When corrected for volumetric shrinkage of the LGN, the estimated loss of neurons was approximately four times greater in the magnocellular than parvocellular layers (38% versus 10%). Elevation of IOP affects the size, density, and number of neurons in the LGN, and the volume of the nucleus itself. Although higher mean pressures (more than 40 mm Hg) reduce the period during which these changes occur, comparable damage can be achieved by even moderate (28 -37 mm Hg) levels of elevated IOP. On the basis of cell loss, elevation of IOP appears to have a more profound degenerative effect on the magnocellular than on the parvocellular regions of the LGN.


Collagen-Based Fillers as Alternatives to Cyanoacrylate Glue for the Sealing of Large Corneal Perforations.
To describe the use of collagen-based alternatives to cyanoacrylate glue for the sealing of acute corneal perforations. A collagen analog comprising a collagen-like peptide conjugated to polyethylene glycol (CLP-PEG) and its chemical crosslinker were tested for biocompatibility. These CLP-PEG hydrogels, which are designed to act as a framework for corneal tissue regeneration, were then tested as potential fillers in ex vivo human corneas with surgically created full-thickness perforations. Bursting pressures were measured in each of 3 methods (n = 10 for each condition) of applying a seal: 1) cyanoacrylate glue with a polyethylene patch applied ab externo (gold standard); 2) a 100-μm thick collagen hydrogel patch applied ab interno, and 3) the same collagen hydrogel patch applied ab interno supplemented with CLP-PEG hydrogel molded in situ to fill the remaining corneal stromal defect. Cyanoacrylate gluing achieved a mean bursting pressure of 325.9 mm Hg, significantly higher than the ab interno patch alone (46.3 mm Hg) and the ab interno patch with the CLP-PEG filler (86.6 mm Hg). All experimental perforations were sealed effectively using 100 μm hydrogel sheets as an ab interno patch, whereas conventional ab externo patching with cyanoacrylate glue failed to provide a seal in 30% (3/10) cases. An ab interno patch system using CLP-PEG hydrogels designed to promote corneal tissue regeneration may be a viable alternative to conventional cyanoacrylate glue patching for the treatment of corneal perforation. Further experimentation and material refinement is required in advance of clinical trials.


STAY-GREEN and chlorophyll catabolic enzymes interact at light-harvesting complex II for chlorophyll detoxification during leaf senescence in Arabidopsis.
During leaf senescence, plants degrade chlorophyll to colorless linear tetrapyrroles that are stored in the vacuole of senescing cells. The early steps of chlorophyll breakdown occur in plastids. To date, five chlorophyll catabolic enzymes (CCEs), NONYELLOW COLORING1 (NYC1), NYC1-LIKE, pheophytinase, pheophorbide a oxygenase (PAO), and red chlorophyll catabolite reductase, have been identified; these enzymes catalyze the stepwise degradation of chlorophyll to a fluorescent intermediate, pFCC, which is then exported from the plastid. In addition, STAY-GREEN (SGR), Mendel's green cotyledon gene encoding a chloroplast protein, is required for the initiation of chlorophyll breakdown in plastids. Senescence-induced SGR binds to light-harvesting complex II (LHCII), but its exact role remains elusive. Here, we show that all five CCEs also specifically interact with LHCII. In addition, SGR and CCEs interact directly or indirectly with each other at LHCII, and SGR is essential for recruiting CCEs in senescing chloroplasts. PAO, which had been attributed to the inner envelope, is found to localize in the thylakoid membrane. These data indicate a predominant role for the SGR-CCE-LHCII protein interaction in the breakdown of LHCII-located chlorophyll, likely to allow metabolic channeling of phototoxic chlorophyll breakdown intermediates upstream of nontoxic pFCC.


Assessment of higher order cognitive skills in undergraduate education: modified essay or multiple choice questions? Research paper.
Reliable and valid written tests of higher cognitive function are difficult to produce, particularly for the assessment of clinical problem solving. Modified Essay Questions (MEQs) are often used to assess these higher order abilities in preference to other forms of assessment, including multiple-choice questions (MCQs). MEQs often form a vital component of end-of-course assessments in higher education. It is not clear how effectively these questions assess higher order cognitive skills. This study was designed to assess the effectiveness of the MEQ to measure higher-order cognitive skills in an undergraduate institution. An analysis of multiple-choice questions and modified essay questions (MEQs) used for summative assessment in a clinical undergraduate curriculum was undertaken. A total of 50 MCQs and 139 stages of MEQs were examined, which came from three exams run over two years. The effectiveness of the questions was determined by two assessors and was defined by the questions ability to measure higher cognitive skills, as determined by a modification of Bloom's taxonomy, and its quality as determined by the presence of item writing flaws. Over 50% of all of the MEQs tested factual recall. This was similar to the percentage of MCQs testing factual recall. The modified essay question failed in its role of consistently assessing higher cognitive skills whereas the MCQ frequently tested more than mere recall of knowledge. Construction of MEQs, which will assess higher order cognitive skills cannot be assumed to be a simple task. Well-constructed MCQs should be considered a satisfactory replacement for MEQs if the MEQs cannot be designed to adequately test higher order skills. Such MCQs are capable of withstanding the intellectual and statistical scrutiny imposed by a high stakes exit examination.


Risk of squamous cell carcinoma and adenocarcinoma of the lung in relation to lifetime filter cigarette smoking.
Over the past few decades, the incidence of adenocarcinoma (AC) of the lung increased much more rapidly than that of squamous cell carcinoma (SCC) in men and women. During this time period, filter cigarettes with substantially reduced "tar" and nicotine yields in the smoke came to dominate the market. The risk of SCC and AC in lifelong smokers of filter cigarettes relative to lifelong nonfilter cigarette smokers was assessed in a case-control study performed between 1977 and 1995 with 2292 lung carcinoma patients and 1343 hospital controls who were current smokers. Odds ratios (OR) for SCC in male and female subjects who had smoked filter cigarettes exclusively during their lives were slightly reduced relative to lifetime nonfilter cigarette smokers in men (OR = 0.8; 95% confidence interval [CI], 0.5-1.2), and significantly reduced in women (OR = 0.4; 95% CI, 0.2-0.8). No reduction in risk was observed for AC of the lung in men or women. Evidence that the increasing predominance of AC over SCC may be due in part to the reduced risk of SCC (but not AC) associated with lifelong filter cigarette smoking is strongest in women; for men, further studies that include larger numbers of lifetime filter smokers are needed to confirm this finding. A lack of protection against AC from low yield filter cigarettes may result from smokers' "compensating" with deeper and more frequent inhalation, thereby increasing delivery of carcinogens to the peripheral lung. The smoke of modern cigarettes also contains higher concentrations of nitrosamines that primarily produce AC.


Adjusting for confounding by neighborhood using generalized linear mixed models and complex survey data.
When investigating health disparities, it can be of interest to explore whether adjustment for socioeconomic factors at the neighborhood level can account for, or even reverse, an unadjusted difference. Recently, we proposed new methods to adjust the effect of an individual-level covariate for confounding by unmeasured neighborhood-level covariates using complex survey data and a generalization of conditional likelihood methods. Generalized linear mixed models (GLMMs) are a popular alternative to conditional likelihood methods in many circumstances. Therefore, in the present article, we propose and investigate a new adaptation of GLMMs for complex survey data that achieves the same goal of adjusting for confounding by unmeasured neighborhood-level covariates. With the new GLMM approach, one must correctly model the expectation of the unmeasured neighborhood-level effect as a function of the individual-level covariates. We demonstrate using simulations that even if that model is correct, census data on the individual-level covariates are sometimes required for consistent estimation of the effect of the individual-level covariate. We apply the new methods to investigate disparities in recency of dental cleaning, treated as an ordinal outcome, using data from the 2008 Florida Behavioral Risk Factor Surveillance System (BRFSS) survey. We operationalize neighborhood as zip code and merge the BRFSS data with census data on ZIP Code Tabulated Areas to incorporate census data on the individual-level covariates. We compare the new results to our previous analysis, which used conditional likelihood methods. We find that the results are qualitatively similar.


Development of the neurons controlling fertility in humans: new insights from 3D imaging and transparent fetal brains.
Fertility in mammals is controlled by hypothalamic neurons that secrete gonadotropin-releasing hormone (GnRH). These neurons differentiate in the olfactory placodes during embryogenesis and migrate from the nose to the hypothalamus before birth. Information regarding this process in humans is sparse. Here, we adapted new tissue-clearing and whole-mount immunohistochemical techniques to entire human embryos/fetuses to meticulously study this system during the first trimester of gestation in the largest series of human fetuses examined to date. Combining these cutting-edge techniques with conventional immunohistochemistry, we provide the first chronological and quantitative analysis of GnRH neuron origins, differentiation and migration, as well as a 3D atlas of their distribution in the fetal brain. We reveal not only that the number of GnRH-immunoreactive neurons in humans is significantly higher than previously thought, but that GnRH cells migrate into several extrahypothalamic brain regions in addition to the hypothalamus. Their presence in these areas raises the possibility that GnRH has non-reproductive roles, creating new avenues for research on GnRH functions in cognitive, behavioral and physiological processes.


Autosomal dominant cortical tremor, myoclonus and epilepsy.
The term 'cortical tremor' was first introduced by Ikeda and colleagues to indicate a postural and action-induced shivering movement of the hands which mimics essential tremor, but presents with the electrophysiological findings of cortical reflex myoclonus. The association between autosomal dominant cortical tremor, myoclonus and epilepsy (ADCME) was first recognized in Japanese families and is now increasingly reported worldwide, although it is described using different acronyms (BAFME, FAME, FEME, FCTE and others). The disease usually takes a benign course, although drug-resistant focal seizures or slight intellectual disability occur in some cases. Moreover, a worsening of cortical tremor and myoclonus is common in advanced age. Although not yet recognized by the International League Against Epilepsy (ILAE), this is a well-delineated epilepsy syndrome with remarkable features that clearly distinguishes it from other myoclonus epilepsies. Moreover, genetic studies of these families show heterogeneity and different susceptible chromosomal loci have been identified.


Oral versus Intravenous Antibiotics for Bone and Joint Infection.
The management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. We investigated whether oral antibiotic therapy is noninferior to intravenous antibiotic therapy for this indication. We enrolled adults who were being treated for bone or joint infection at 26 U.K. centers. Within 7 days after surgery (or, if the infection was being managed without surgery, within 7 days after the start of antibiotic treatment), participants were randomly assigned to receive either intravenous or oral antibiotics to complete the first 6 weeks of therapy. Follow-on oral antibiotics were permitted in both groups. The primary end point was definitive treatment failure within 1 year after randomization. In the analysis of the risk of the primary end point, the noninferiority margin was 7.5 percentage points. Among the 1054 participants (527 in each group), end-point data were available for 1015 (96.3%). Treatment failure occurred in 74 of 506 participants (14.6%) in the intravenous group and 67 of 509 participants (13.2%) in the oral group. Missing end-point data (39 participants, 3.7%) were imputed. The intention-to-treat analysis showed a difference in the risk of definitive treatment failure (oral group vs. intravenous group) of -1.4 percentage points (90% confidence interval [CI], -4.9 to 2.2; 95% CI, -5.6 to 2.9), indicating noninferiority. Complete-case, per-protocol, and sensitivity analyses supported this result. The between-group difference in the incidence of serious adverse events was not significant (146 of 527 participants [27.7%] in the intravenous group and 138 of 527 [26.2%] in the oral group; P=0.58). Catheter complications, analyzed as a secondary end point, were more common in the intravenous group (9.4% vs. 1.0%). Oral antibiotic therapy was noninferior to intravenous antibiotic therapy when used during the first 6 weeks for complex orthopedic infection, as assessed by treatment failure at 1 year. (Funded by the National Institute for Health Research; OVIVA Current Controlled Trials number, ISRCTN91566927 .).


Enhanced mitochondrial superoxide scavenging does not improve muscle insulin action in the high fat-fed mouse.
Improving mitochondrial oxidant scavenging may be a viable strategy for the treatment of insulin resistance and diabetes. Mice overexpressing the mitochondrial matrix isoform of superoxide dismutase (sod2(tg) mice) and/or transgenically expressing catalase within the mitochondrial matrix (mcat(tg) mice) have increased scavenging of O2(˙-) and H2O2, respectively. Furthermore, muscle insulin action is partially preserved in high fat (HF)-fed mcat(tg) mice. The goal of the current study was to test the hypothesis that increased O2(˙-) scavenging alone or in combination with increased H2O2 scavenging (mtAO mice) enhances in vivo muscle insulin action in the HF-fed mouse. Insulin action was examined in conscious, unrestrained and unstressed wild type (WT), sod2(tg), mcat(tg) and mtAO mice using hyperinsulinemic-euglycemic clamps (insulin clamps) combined with radioactive glucose tracers following sixteen weeks of normal chow or HF (60% calories from fat) feeding. Glucose infusion rates, whole body glucose disappearance, and muscle glucose uptake during the insulin clamp were similar in chow- and HF-fed WT and sod2(tg) mice. Consistent with our previous work, HF-fed mcat(tg) mice had improved muscle insulin action, however, an additive effect was not seen in mtAO mice. Insulin-stimulated Akt phosphorylation in muscle from clamped mice was consistent with glucose flux measurements. These results demonstrate that increased O2(˙-) scavenging does not improve muscle insulin action in the HF-fed mouse alone or when coupled to increased H2O2 scavenging.


Dissection of autophagosome biogenesis into distinct nucleation and expansion steps.
Rapamycin, an antifungal macrolide antibiotic, mimics starvation conditions in Saccharomyces cerevisiae through activation of a general G(0) program that includes widespread effects on translation and transcription. Macroautophagy, a catabolic membrane trafficking phenomenon, is a prominent part of this response. Two views of the induction of autophagy may be considered. In one, up-regulation of proteins involved in autophagy causes its induction, implying that autophagy is the result of a signal transduction mechanism leading from Tor to the transcriptional and translational machinery. An alternative hypothesis postulates the existence of a dedicated signal transduction mechanism that induces autophagy directly. We tested these possibilities by assaying the effects of cycloheximide and specific mutations on the induction of autophagy. We find that induction of autophagy takes place in the absence of de novo protein synthesis, including that of specific autophagy-related proteins that are up-regulated in response to rapamycin. We also find that dephosphorylation of Apg13p, a signal transduction event that correlates with the onset of autophagy, is also independent of new protein synthesis. Finally, our data indicate that autophagosomes that form in the absence of protein synthesis are significantly smaller than normal, indicating a role for de novo protein synthesis in the regulation of autophagosome expansion. Our results define the existence of a signal transduction-dependent nucleation step and a separate autophagosome expansion step that together coordinate autophagosome biogenesis.


A Rapid Review of Environmental Health Gaps in Antimicrobial Resistance and Water-Related Research from 1990-2020.
Antimicrobial resistance (AMR) is a pervasive global health threat linked to human antimicrobial misuse and abuse, food production, and broader environmental contamination. While global agencies promote a multi-sectoral One Health system approach to equitably combat human, animal, and environmental health AMR risks, it is widely acknowledged that the human and animal sectors dominate discussions. Given this disproportionate focus, identification of critical research gaps is needed to develop stewardship plans that equitably address One Health AMR threats. This review used natural language processing and term frequency algorithms to classify 12,638 records from 1990-2020 thematically in order to highlight sectoral prioritization and gaps. It also specifically assessed water-related gaps as water is recognized as both a primary environmental dissemination pathway and key means of intervention. Drawing from systemic health and integrated water management lenses, this review found that themes related to plant, wildlife, and environmental-related AMR threats-in particular, the role that environmental (ambient) waters play in AMR development, transmission, and spread-are under-prioritized as compared to human and food animal health concerns regardless of geographic region or income level. Further prioritization of these themes is needed to strengthen the environmental dimension of One Health AMR responses and systemically protect global health.


Respiratory disorders in aluminium potroom workers.
Epidemiological studies of aluminum potroom workers have been in progress in Norway since 1986. The occurrence of work-related asthmatic symptoms and their determinants were studied. Work-related asthmatic symptoms and airflow limitation were closely associated with duration of potroom employment. A significant relationship between current fluoride exposure and work-related asthmatic symptoms was observed in a smaller, cross-sectional population where a detailed exposure classification was carried out. A similar association and also a dose-response gradient was found in a longitudinal study of new employees. The existence of occupational asthma in aluminium potroom workers was confirmed by characteristic patterns of repeated peak flow measurements supported by changes in methacholine responsiveness in workers with suspected work-related asthma. Current smoking as a risk factor for work-related asthmatic symptoms was observed both in cross-sectional and in longitudinal investigations. Similarly to current fluoride exposure, a dose-response gradient was demonstrated in the association between work-related asthmatic symptoms and current amount of tobacco smoked. Allergy was not shown to be a determinant of work-related asthmatic symptoms in any part of the investigation. A family history of asthma and previous occupational exposure may have had some influence on the risk of developing symptoms but the findings were inconsistent and probably of minor importance. Methacholine challenge seemed inappropriate for the screening of aluminium potroom workers in order to detect work-related asthmatic symptoms, but was closely correlated to the severity of symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparison of neurological outcome between tracheal intubation and supraglottic airway device insertion of out-of-hospital cardiac arrest patients: a nationwide, population-based, observational study.
The effect of prehospital use of supraglottic airway devices as an alternative to tracheal intubation on long-term outcomes of patients with out-of-hospital cardiac arrest is unclear. We compared the neurological outcomes of patients who underwent supraglottic airway device insertion with those who underwent tracheal intubation. We conducted a nationwide population-based observational study using a national database containing all out-of-hospital cardiac arrest cases in Japan over a 3-year period (2005-2007). The rates of neurologically favorable 1-month survival (primary outcome) and of 1-month survival and return of spontaneous circulation before hospital arrival (secondary outcomes) were examined. Multiple logistic regression analyses were performed to adjust for potential confounders. Advanced airway devices were used in 138,248 of 318,141 patients, including an endotracheal tube (ETT) in 16,054 patients (12%), a laryngeal mask airway (LMA) in 34,125 patients (25%), and an esophageal obturator airway (EOA) in 88,069 patients (63%). The overall rate of neurologically favorable 1-month survival was 1.03% (1426/137,880). The rates of neurologically favorable 1-month survival were 1.14% (183/16,028) in the ETT group, 0.98% (333/34,059) in the LMA group, and 1.04% (910/87,793) in the EOA group. Compared with the ETT group, the rates were significantly lower in the LMA group (adjusted odds ratio 0.77, 95% confidence interval [CI] 0.64-0.94) and EOA group (adjusted odds ratio 0.81, 95% CI 0.68-0.96). Prehospital use of supraglottic airway devices was associated with slightly, but significantly, poorer neurological outcomes compared with tracheal intubation, but neurological outcomes remained poor overall.


Chemokine-mediated angiogenesis: an essential link in the evolution of airway fibrosis?
Angiogenesis may be an important factor in the development of fibrotic lung disease. Prior studies have strongly suggested a role for angiogenic vascular remodeling in pulmonary fibrosis, and emerging evidence indicates that new vessel formation is critical in airway fibrosis. Bronchiolitis obliterans syndrome is a fibrotic occlusion of distal airways that is largely responsible for the morbidity and mortality of patients after lung transplantation. In this issue, Belperio et al. demonstrate a role for CXC chemokine receptor 2 in the regulation of angiogenesis-mediated airway fibroproliferation. By integrating an understanding of neovascularization into the study of events that occur between inflammation and fibrosis, it becomes increasingly possible to rationally design therapies that can halt conditions of maladaptive fibrosis.


Changes in automatic threat processing precede and predict clinical changes with exposure-based cognitive-behavior therapy for panic disorder.
Cognitive behavioral therapy (CBT) is an effective treatment for emotional disorders such as anxiety or depression, but the mechanisms underlying successful intervention are far from understood. Although it has been a long-held view that psychopharmacological approaches work by directly targeting automatic emotional information processing in the brain, it is usually postulated that psychological treatments affect these processes only over time, through changes in more conscious thought cycles. This study explored the role of early changes in emotional information processing in CBT action. Twenty-eight untreated patients with panic disorder were randomized to a single session of exposure-based CBT or waiting group. Emotional information processing was measured on the day after intervention with an attentional visual probe task, and clinical symptoms were assessed on the day after intervention and at 4-week follow-up. Vigilance for threat information was decreased in the treated group, compared with the waiting group, the day after intervention, before reductions in clinical symptoms. The magnitude of this early effect on threat vigilance predicted therapeutic response after 4 weeks. Cognitive behavioral therapy rapidly affects automatic processing, and these early effects are predictive of later therapeutic change. Such results suggest very fast action on automatic processes mediating threat sensitivity, and they provide an early marker of treatment response. Furthermore, these findings challenge the notion that psychological treatments work directly on conscious thought processes before automatic information processing and imply a greater similarity between early effects of pharmacological and psychological treatments for anxiety than previously thought.


Measuring resident physicians' performance of preventive care. Comparing chart review with patient survey.
The Accreditation Council for Graduate Medical Education has suggested various methods for evaluation of practice-based learning and improvement competency, but data on implementation of these methods are limited. To compare medical record review and patient surveys on evaluating physician performance in preventive services in an outpatient resident clinic. Within an ongoing quality improvement project, we collected baseline performance data on preventive services provided for patients at the University of Alabama at Birmingham (UAB) Internal Medicine Residents' ambulatory clinic. Seventy internal medicine and medicine-pediatrics residents from the UAB Internal Medicine Residency program. Resident- and clinic-level comparisons of aggregated patient survey and chart documentation rates of (1) screening for smoking status, (2) advising smokers to quit, (3) cholesterol screening, (4) mammography screening, and (5) pneumonia vaccination. Six hundred and fifty-nine patient surveys and 761 charts were abstracted. At the clinic level, rates for screening of smoking status, recommending mammogram, and for cholesterol screening were similar (difference <5%) between the 2 methods. Higher rates for pneumonia vaccination (76% vs 67%) and advice to quit smoking (66% vs 52%) were seen on medical record review versus patient surveys. However, within-resident (N=70) comparison of 2 methods of estimating screening rates contained significant variability. The cost of medical record review was substantially higher ($107 vs $17/physician). Medical record review and patient surveys provided similar rates for selected preventive health measures at the clinic level, with the exception of pneumonia vaccination and advising to quit smoking. A large variation among individual resident providers was noted.


Hox/Pbx and Brn binding sites mediate Pax3 expression in vitro and in vivo.
Pax3 is a paired-homeodomain class transcription factor that serves a role in dorsal-ventral and medial-lateral patterning during vertebrate embryogenesis. Its expression is localized to dorsal domains within the developing neural tube and lateral domains within the developing somite. Additionally, modulation of its expression occurs along the rostral-caudal axis. Previous studies [Development 124 (1997) 617] have localized sequence elements required for expression of Pax3 in the neural tube and neural crest to a 1.6 kbp promoter fragment. In the present study, four discrete DNA elements within the 1.6 kbp promoter fragment are shown by electrophoretic mobility shift assays (EMSA) to exhibit sequence specific interactions with proteins present in nuclear extracts from P19 EC cells induced to express Pax3 by treatment with retinoic acid (RA). Proteins interacting at each of these elements are identified based on biochemical purification using DNA affinity chromatography or a candidate approach. These identifications were confirmed by the ability of specific antibodies to super-shift DNA-protein complexes in EMSA. Two of the four DNA sequence elements are shown to interact with the neural specific Pou-domain class III transcription factors Brn1 and Brn2. The remaining sites contain either consensus binding elements for heterodimers of Pbx and an anterior set of Hox family members, from paralogous groups 1-5, or monomeric Meis and are shown to interact with members of the Pbx and Meis families. Ectopic expression of Brn2 plus HoxA1 but not either factor alone, is sufficient to induce efficient expression from the endogenous Pax3 promoter in P19 EC stem cells under conditions where they would not otherwise express Pax3. Finally, in transgenic mice, mutation of either of the Pou-domain protein binding sites results in reduced expression throughout the neural tube while mutation of the Pbx/Hox binding site results in loss of expression in the anterior domain in which Hox family members from paralogous groups 1-5 are expressed. These observations demonstrate that binding elements for both neural and anterior-posterior position specific transcription factors mediate domains of Pax3 expression.


Calcium effects on life-history traits in a wild population of the great tit (Parus major): analysis of long-term data at several spatial scales.
Calcium is an essential micronutrient for birds during egg formation and for skeletal development in nestlings. Habitat level studies suggest that birds breeding in low-calcium areas may be limited in the size or number of eggs they lay and in the quality of their nestlings. However, as birds forage non-randomly and may travel considerable distances to acquire calcium, describing different breeding environments in terms of their calcium availability is problematic. Here we explore the spatial relationships between 300-fold variation in soil calcium and the life-history traits of ca. 6,000 pairs of great tits breeding in a single continuous woodland over 41 years. Controlling for other habitat differences, we found strong positive associations between soil calcium, clutch size and recruitment at spatial scales of over 300 m from each nestbox, suggesting that females may have been travelling inter-territorially to acquire calcium during egg formation. Soil calcium near each nestbox (mean distance = 58 m) was a strong positive predictor of mean fledgling mass, suggesting that local calcium was more important during nestling stages. We found no effect of soil calcium on lay-date or egg mass. This study is the first to provide evidence that small woodland passerines are limited by calcium availability at several different spatial scales. However, experimental work is necessary to test the causality of these spatial patterns.


Fiber plucking by molecular motors yields large emergent contractility in stiff biopolymer networks.
The mechanical properties of the cell depend crucially on the tension of its cytoskeleton, a biopolymer network that is put under stress by active motor proteins. While the fibrous nature of the network is known to strongly affect the transmission of these forces to the cellular scale, our understanding of this process remains incomplete. Here we investigate the transmission of forces through the network at the individual filament level, and show that active forces can be geometrically amplified as a transverse motor-generated force "plucks" the fiber and induces a nonlinear tension. In stiff and densely connected networks, this tension results in large network-wide tensile stresses that far exceed the expectation drawn from a linear elastic theory. This amplification mechanism competes with a recently characterized network-level amplification due to fiber buckling, suggesting that that fiber networks provide several distinct pathways for living systems to amplify their molecular forces.


Comparison of transvaginal sonography, saline infusion sonography, and hysteroscopy in premenopausal women with abnormal uterine bleeding.
Saline infusion sonography (SIS) is a relatively new technique in the evaluation of abnormal uterine bleeding. We compared the diagnostic accuracy of SIS with that of transvaginal sonography (TVS) in the detection of intracavitary abnormalities in premenopausal women with abnormal uterine bleeding. In this prospective study, consecutive premenopausal women who underwent a hysteroscopy for abnormal uterine bleeding also underwent TVS and SIS. The findings at TVS and SIS were compared with the hysteroscopic and histologic findings. Sensitivity, specificity, and likelihood ratios were calculated. Receiver operating characteristic curves were constructed to assess the performance of endometrial thickness measured using TVS. Sixty-two patients were included in the study. TVS demonstrated 60% sensitivity in directly visualizing intracavitary abnormalities and 93% specificity. The likelihood ratio of the presence of an intracavitary abnormality was 8, and the likelihood ratio of the absence of an intracavitary abnormality was 0.43. Defining an abnormality at TVS as direct visualization of an intracavitary abnormality or an endometrial thickness greater than 5 mm, TVS had an 85% sensitivity and a 21% specificity, with corresponding likelihood ratios of 1.1 and 0.71, respectively. For SIS, the sensitivity, specificity, and likelihood ratios of the presence and absence of intracavitary abnormalities were 88%, 95%, 10, and 0.13, respectively. SIS is more accurate in the diagnosis of intracavitary abnormalities in premenopausal women than is TVS. An approach using endometrial thickness measurement by TVS and reserving SIS for patients who have an endometrial thickness greater than 5 mm or an intracavitary abnormality visualized by TVS would be the most effective method to reduce the number of hysteroscopies.


Physical-property comparison of a chairside- or laboratory-polymerized permanent soft-liner during 1 year.
This investigation examined the influence of polymerization mode and water storage duration on the Shore A hardness, water sorption, resin solubility, and glass transition temperature of Permasoft, a commercial soft denture liner that is polymerized either chairside or in the laboratory. Specimen disks (31-mm diameter x 10 mm thick) and bars (44 x 8.5 x 1.2 mm) were polymerized following manufacturer's recommendations. The chairside polymerization process was simulated by pouring the mixed components into a mold and processing at 70 degrees C for 15 minutes under 2-psi pressure. Laboratory-polymerized specimens of the same dimensions were fabricated by processing under 500-psi pressure at 100 degrees C for 45 minutes. Specimens were stored in distilled water at 37 degrees C for 1, 7, and 30 days, and 6 and 12 months. Specimens were tested for Shore A hardness, water sorption, resin solubility, and glass transition temperature after the prescribed interval. To determine the effects of polymerization mode and storage time on material properties, a repeated-measures ANOVA (hardness data) and a two-way ANOVA (sorption and solubility data) with appropriate post-hoc tests were used. Shore A hardness values increased from a low of 9.4 (+/- 0.5) units immediately after fabrication to a maximum of 15.9 (+/- 1.1) units after 1 year. Mode of polymerization did not influence hardness (p = .9851). Water-sorption values ranged from 4.2 (+/- 0.2%) of dry weight to 14.7 (+/- 2.5%) after 1 year. Resin solubility varied from 10.3 (+/- 0.6%) of preimmersion weight to 15.4 (+/- 1.1%), and immersion duration had no effect on solubility. In addition, after 1 year of storage, no difference in resin solubility or water sorption was found with respect to cure mode. The glass transition temperature for chairside-polymerized samples approximated -10 degrees C, while that for labpolymerized samples approximated -15 degrees C. With regard to the material properties evaluated in this study, clinically processed Permasoft liner was equivalent to the laboratory-processed material.


Vocal training, levodopa, and environment effects on ultrasonic vocalizations in a rat neurotoxin model of Parkinson disease.
Levodopa does not improve dysarthria in patients with Parkinson Disease (PD), although vocal exercise therapy, such as "LSVT/LOUD(®)", does improve vocal communication. Most patients receive vocal exercise therapy while concurrently being treated with levodopa, although the interaction between levodopa and vocal exercise therapy on communication in PD is relatively unknown. Further, carryover of vocal exercise therapy to novel situations is critical for successful outcomes, but the influence of novel situations on rehabilitated vocal communication is not well understood. To address the influence of exercise, medications, and environment on vocal communication with precise experimental control, we employed the widely used 6-OHDA rat neurotoxin model of PD (infusion to the medial forebrain bundle), and assessed ultrasonic vocalizations after: vocal exercise, vocal exercise with levodopa, levodopa alone, and control conditions. We tested USVs in the familiar training environment of the home cage and a novel cage. We hypothesized that parkinsonian rats that undergo vocal exercise would demonstrate significant improvement of ultrasonic vocalization (USV) acoustic parameters as compared to the control exercise and levodopa-only treatment groups. We further hypothesized that vocal exercise in combination with levodopa administration, similar to what is common in humans, would lead to improvement in USV outcomes, particularly when tested in a familiar versus a novel environment. We found that the combination of exercise and levodopa lead to some improvement in USV acoustic parameters and these effects were stronger in a familiar vs. a novel environment. Our results suggest that although treatment can improve aspects of communication, environment can influence the benefits of these effects.


Two new species of Plectranthias (Teleostei, Serranidae, Anthiadinae) from mesophotic coral ecosystems in the tropical Central Pacific.
Two new species of Plectranthias perchlets are described, collected from mesophotic coral ecosystems in French Polynesia and the Republic of the Marshall Islands, in the tropical Central Pacific. Plectranthias polygonius sp. nov. was collected at a depth of 105 m in Tahiti, French Polynesia, and 120 m in Maloelap Atoll, Republic of the Marshall Islands. It was also observed in Moorea and Rangiroa (French Polynesia), and at Majuro and Erikub Atolls, Republic of the Marshall Islands. Plectranthias hinano sp. nov. was collected at a depth of 90-98 m in Tahiti, French Polynesia, and observed in Moorea. The barcode fragment of the cytochrome oxidase I gene of Plectranthias polygonius sp. nov. does not closely match any published sequence of Plectranthias, with approximately 15% uncorrected divergence from several species. Plectranthias polygonius sp. nov. can be distinguished from all of its congeners by coloration and morphology. The barcode fragment of the COI gene of Plectranthias hinano sp. nov. is closest to Plectranthias bennetti, with 5.4% uncorrected divergence. Plectranthias hinano sp. nov. is also distinguished from all of its congeners by morphology, and a coloration that includes two indistinct black spots along the base of the dorsal-fin, and transparent yellow dorsal and anal fin membranes. With this publication, the genus Plectranthias now comprises 58 valid species, with representatives from tropical to temperate waters of the Atlantic, Pacific, and Indian oceans. These two new discoveries add to the growing body of research highlighting the rich biodiversity of mesophotic ecosystems.


Role of UTS2 gene in the genetic susceptibility to atrial fibrillation in the Chinese population.
Atrial fibrosis plays a key role in the inducibility and persistence of atrial fibrillation. Urotensin II (U-II/UTS2) induces cardiac fibrosis by increasing fibroblast collagen synthesis and increased U-II plasma levels have been reported in patients with atrial fibrosis. Our objective was therefore to evaluate the possible role of the UTS2 gene polymorphisms Thr21Met and Ser89Asn in the genetic susceptibility to atrial fibrillation in a Chinese population. A case-control study was designed to compare the distribution of alleles and genotypes between controls (n=197) and patients with AF (n=197). The detection of UTS2 gene polymorphisms was undertaken using the PCR-restriction fragment length polymorphism technique. We identified statistically significant differences between the atrial fibrillation and control groups with regard to the frequency of genotype variant GA at the Ser89Asn locus (OR 1.955, 95% CI 1.071 to 3.566, p=0.029). When stratified by sex, differences in genotype distribution of polymorphism Ser89Asn was only seen in men in the additive tested inheritance model (OR 2.843, 95% CI 1.273 to 6.348, p=0.011). There was a statistical difference in Met21Met, implying a potential beneficial role for atrial fibrillation in the recessive tested inheritance model among men (OR 0.260, 95% CI 0.075 to 0.89, p=0.033; AA vs GA-GG). For subjects with atrial fibrillation, the Met21Met genotype was associated with a larger anteroposterior left atrial diameter (AA vs GG, 4.12±0.62 vs 3.86±0.51, p=0.028) and a smaller left ventricular end-diastolic diameter (AA vs GG, 4.50±0.48 vs 4.78±0.49, p=0.039). Ser89Asn polymorphisms of the UTS2 gene are significantly associated with atrial fibrillation in the Chinese population. Additionally, we demonstrated that genotype Met21Met may have a potential beneficial role in atrial fibrillation.


Treatment of neck pain: injections and surgical interventions: results of the Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders.
Best evidence synthesis. To identify, critically appraise, and synthesize literature from 1980 through 2006 on surgical interventions for neck pain alone or with radicular pain in the absence of serious pathologic disease. There have been no comprehensive systematic literature or evidence-based reviews published on this topic. We systematically searched Medline for literature published from 1980 to 2006 on percutaneous and open surgical interventions for neck pain. Publications on the topic were also solicited from experts in the field. Consensus decisions were made about the scientific merit of each article; those judged to have adequate internal validity were included in our Best Evidence Synthesis. Of the 31,878 articles screened, 1203 studies were relevant to the Neck Pain Task Force mandate and of these, 31 regarding treatment by surgery or injections were accepted as scientifically admissible. Radiofrequency neurotomy, cervical facet injections, cervical fusion and cervical arthroplasty for neck pain without radiculopathy are not supported by current evidence. We found there is support for short-term symptomatic improvement of radicular symptoms with epidural corticosteroids. It is not clear from the evidence that long-term outcomes are improved with the surgical treatment of cervical radiculopathy compared to nonoperative measures. However, relatively rapid and substantial symptomatic relief after surgical treatment seems to be reliably achieved. It is not evident that one open surgical technique is clearly superior to others for radiculopathy. Cervical foramenal or epidural injections are associated with relatively frequent minor adverse events (5%-20%); however, serious adverse events are very uncommon (<1%). After open surgical procedures on the cervical spine, potentially serious acute complications are seen in approximately 4% of patients. Surgical treatment and limited injection procedures for cervical radicular symptoms may be reasonably considered in patients with severe impairments. Percutaneous and open surgical treatment for neck pain alone, without radicular symptoms or clear serious pathology, seems to lack scientific support.


Topological phase transition and texture inversion in a tunable topological insulator.
The recently discovered three-dimensional or bulk topological insulators are expected to exhibit exotic quantum phenomena. It is believed that a trivial insulator can be twisted into a topological state by modulating the spin-orbit interaction or the crystal lattice, driving the system through a topological quantum phase transition. By directly measuring the topological quantum numbers and invariants, we report the observation of a phase transition in a tunable spin-orbit system, BiTl(S(1-δ)Se(δ))(2), in which the topological state formation is visualized. In the topological state, vortex-like polarization states are observed to exhibit three-dimensional vectorial textures, which collectively feature a chirality transition as the spin momentum-locked electrons on the surface go through the zero carrier density point. Such phase transition and texture inversion can be the physical basis for observing fractional charge (±e/2) and other fractional topological phenomena.


Innovative Use of Thighplasty to Improve Prosthesis Fit and Function in a Transfemoral Amputee.
Excess residual limb fat is a common problem that can impair prosthesis control and negatively impact gait. In the general population, thighplasty and liposuction are commonly performed for cosmetic reasons but not specifically to improve function in amputees. The objective of this study was to determine if these procedures could enhance prosthesis fit and function in an overweight above-knee amputee. We evaluated the use of these techniques on a 50-year-old transfemoral amputee who was overweight. The patient underwent presurgical imaging and tests to measure her residual limb tissue distribution, socket-limb interface stiffness, residual femur orientation, lower-extremity function, and prosthesis satisfaction. A medial thighplasty procedure with circumferential liposuction was performed, during which 2,812 g (6.2 lbs.) of subcutaneous fat and skin was removed from her residual limb. Imaging was repeated 5 months postsurgery; functional assessments were repeated 9 months postsurgery. The patient demonstrated notable improvements in socket fit and in performing most functional and walking tests. Her comfortable walking speed increased 13.3%, and her scores for the Sit-to-Stand and Four Square Step tests improved over 20%. Femur alignment in her socket changed from 8.13 to 4.14 degrees, and analysis showed a marked increase in the socket-limb interface stiffness. This study demonstrates the potential of using a routine plastic surgery procedure to modify the intrinsic properties of the limb and to improve functional outcomes in overweight or obese transfemoral amputees. This technique is a potentially attractive option compared with multiple reiterations of sockets, which can be time-consuming and costly.


Automated detection of instantaneous gait events using time frequency analysis and manifold embedding.
Accelerometry is a widely used sensing modality in human biomechanics due to its portability, non-invasiveness, and accuracy. However, difficulties lie in signal variability and interpretation in relation to biomechanical events. In walking, heel strike and toe off are primary gait events where robust and accurate detection is essential for gait-related applications. This paper describes a novel and generic event detection algorithm applicable to signals from tri-axial accelerometers placed on the foot, ankle, shank or waist. Data from healthy subjects undergoing multiple walking trials on flat and inclined, as well as smooth and tactile paving surfaces is acquired for experimentation. The benchmark timings at which heel strike and toe off occur, are determined using kinematic data recorded from a motion capture system. The algorithm extracts features from each of the acceleration signals using a continuous wavelet transform over a wide range of scales. A locality preserving embedding method is then applied to reduce the high dimensionality caused by the multiple scales while preserving salient features for classification. A simple Gaussian mixture model is then trained to classify each of the time samples into heel strike, toe off or no event categories. Results show good detection and temporal accuracies for different sensor locations and different walking terrains.


Clinical follow-up of children with high vitamin B12 values: should we worry?
Requests of Vitamin B12 test increased with the widespread use of autoanalysers. Although the cause of requests was deficiency suspicions, an important ratio of high levels of Vitamin B12 were reported to physicians by laboratory. Ratios of values of high Vitamin B12 among test request in adults are reported as 14- 20% in present three monocentre studies and one multicentre study. There is no report on children with high vitamin B12 for both ratio in lab requests or clinical follow up. We evaluated the records of 40 children (23 male /17 female) with high B12 values ( > 1000 pg/ ml) retrospectively. Children were otherwise healthy children and were seen at outpatient pediatric clinics. Additionally, vitamin B12 values of 13 acute lymphoblastic leukemia patients at diagnosis time were retrieved to enlighten possible role of lymphocytes. Children did not have any malign or chronic diseases causing the high Vitamin B12 values. Holotranscobalamin levels were normal or slightly above. Two patients did develop leukemia later. Our follow up showed that high vitamin B12 values slightly decreased at 3 months and then remained unchanged later. The high numbers of T and B cells are not the source of vitamin B12 elevation. Our study suggests that high-vitamin B12 values are usually benign in children but some patients may develop leukemia later. We suggest that patients should be followed up for some time after testing for severe hematological diseases.


Virtual sensors for on-line wheel wear and part roughness measurement in the grinding process.
Grinding is an advanced machining process for the manufacturing of valuable complex and accurate parts for high added value sectors such as aerospace, wind generation, etc. Due to the extremely severe conditions inside grinding machines, critical process variables such as part surface finish or grinding wheel wear cannot be easily and cheaply measured on-line. In this paper a virtual sensor for on-line monitoring of those variables is presented. The sensor is based on the modelling ability of Artificial Neural Networks (ANNs) for stochastic and non-linear processes such as grinding; the selected architecture is the Layer-Recurrent neural network. The sensor makes use of the relation between the variables to be measured and power consumption in the wheel spindle, which can be easily measured. A sensor calibration methodology is presented, and the levels of error that can be expected are discussed. Validation of the new sensor is carried out by comparing the sensor's results with actual measurements carried out in an industrial grinding machine. Results show excellent estimation performance for both wheel wear and surface roughness. In the case of wheel wear, the absolute error is within the range of microns (average value 32 μm). In the case of surface finish, the absolute error is well below Ra 1 μm (average value 0.32 μm). The present approach can be easily generalized to other grinding operations.


[Relationship between health care insurance and Papanicolaou exam: a propensity score application using a complex sample inquiry].
Cervical uterine cancer is the second most common malignancy affecting women worldwide. Papanicolaou smear is a simple screening test that can detect the disease at an early and curable stage. Although indicated to every adult woman, Pap smear screening covers less than 70% of Brazilian women. This study aimed to evaluate if private health care insurance coverage was associated with Papanicolaou smear screening. We analyzed data from 6,299 women aged 35 years or older, resident in Rio de Janeiro state, who had been interviewed in the National Household Sample Survey (PNAD) in 2003. In order to minimize the occurrence of biases, we utilized the propensity score matching method, considering all information from sample design in the scores estimation (sample weights, strata and primary sampling units). A sub-sample of 2,348 women was then obtained, with socioeconomic and biological covariates equally distributed between the groups with and without private health insurance coverage (1,174 pairs). Logistic regression model was then used and the results showed that the chance of Papanicolaou smear screening is 26.1% higher (OR=1.261; p=0,096; CI 95%= [0.96;1.66]) for women with health insurance coverage when compared to women without health insurance coverage at 10% of significance. The results indicate the need of extending periodic cervical cancer screening for all women, reducing the inequalities still present nowadays.


Vitamin D and fertility: a systematic review.
Vitamin D has been well-known for its function in maintaining calcium and phosphorus homeostasis and promoting bone mineralization. There is some evidence that in addition to sex steroid hormones, the classic regulators of human reproduction, vitamin D also modulates reproductive processes in women and men. The aim of this review was to assess the studies that evaluated the relationship between vitamin D and fertility in women and men as well as in animals. We performed a systematic literature search in Pubmed for relevant English language publications published until October 2011. The vitamin D receptor (VDR) and vitamin D metabolizing enzymes are found in reproductive tissues of women and men. Vdr knockout mice have significant gonadal insufficiency, decreased sperm count and motility, and histological abnormalities of testis, ovary and uterus. Moreover, we present evidence that vitamin D is involved in female reproduction including IVF outcome (clinical pregnancy rates) and polycystic ovary syndrome (PCOS). In PCOS women, low 25-hydroxyvitamin D (25(OH)D) levels are associated with obesity, metabolic, and endocrine disturbances and vitamin D supplementation might improve menstrual frequency and metabolic disturbances in those women. Moreover, vitamin D might influence steroidogenesis of sex hormones (estradiol and progesterone) in healthy women and high 25(OH)D levels might be associated with endometriosis. In men, vitamin D is positively associated with semen quality and androgen status. Moreover, vitamin D treatment might increase testosterone levels. Testiculopathic men show low CYP21R expression, low 25(OH)D levels, and osteoporosis despite normal testosterone levels.


Atomic layer MoS2-graphene van der Waals heterostructure nanomechanical resonators.
Heterostructures play significant roles in modern semiconductor devices and micro/nanosystems in a plethora of applications in electronics, optoelectronics, and transducers. While state-of-the-art heterostructures often involve stacks of crystalline epi-layers each down to a few nanometers thick, the intriguing limit would be hetero-atomic-layer structures. Here we report the first experimental demonstration of freestanding van der Waals heterostructures and their functional nanomechanical devices. By stacking single-layer (1L) MoS2 on top of suspended single-, bi-, tri- and four-layer (1L to 4L) graphene sheets, we realize an array of MoS2-graphene heterostructures with varying thickness and size. These heterostructures all exhibit robust nanomechanical resonances in the very high frequency (VHF) band (up to ∼100 MHz). We observe that fundamental-mode resonance frequencies of the heterostructure devices fall between the values of graphene and MoS2 devices. Quality (Q) factors of heterostructure resonators are lower than those of graphene but comparable to those of MoS2 devices, suggesting interface damping related to interlayer interactions in the van der Waals heterostructures. This study validates suspended atomic layer heterostructures as an effective device platform and provides opportunities for exploiting mechanically coupled effects and interlayer interactions in such devices.


A prospective comparative study of gentamicin- and amikacin-induced nephrotoxicity in patients with normal baseline renal function.
The aim of this study was to compare the nephrotoxic potential of amikacin (AK) and gentamicin (GM) in patients with normal baseline renal function. This study was a 1-year, non-interventional prospective study of patients administered either GM or AK. The study was carried out at the internal medicine department of Al-Watani governmental study. Nephrotoxicity was defined as a serum creatinine (SCr) increase of >or=0.5 mg/dL from the basal (normal) SCr level. The two groups (GM, n = 45 and AK, n = 49) were similar in population composition, and underlying pathological and infectious processes requiring antimicrobials. No significant difference in age was found between patients in the GM and AK groups, P = 0.83. Patients in the GM group received comparatively lower doses than those in the AK group (mean = 2.5 mg/kg/day and 14.4 mg/kg/day, respectively) but the duration of treatment was similar. Sixteen of 45 patients receiving GM (35.6%) and eight of 49 patients receiving AK (16.3%) developed nephrotoxicity, P = 0.033. Single daily dosing with GM, regardless of the total daily dose, produced less nephrotoxicity than multiple dosing. In contrast, AK given at a total dose of 1 g daily, showed no benefit of single dosing compared with multiple dosing. In patients with initial normal renal function, GM was significantly more nephrotoxic than AK. Multiple dosing of GM was more nephrotoxic than single dosing. AK-induced nephrotoxicity was not significantly dependent on dosing frequency.