Factors that influence exercise among adults with arthritis in three activity levels.
Recent public health objectives emphasize the importance of exercise for reducing disability among people with arthritis. Despite the documented benefits of exercise, people with arthritis are less active than those without arthritis. The purpose of this study was to examine the factors that influence exercise participation among insufficiently active individuals with arthritis and to compare these factors with those identified by nonexercisers and regular exercisers with arthritis. Forty-six individuals with arthritis were recruited from various community-based organizations to participate in seven focus groups segmented by exercise status and education. Trained moderators led each discussion using a standard guide. All focus group discussions were transcribed verbatim and coded. Pain was the most commonly mentioned barrier to exercise and limited exercise participation for nonexercisers and insufficiently active individuals. Paradoxically, insufficiently active individuals also identified exercise-related reductions in pain as a potential motivation for increasing exercise. Likewise, exercise-related reductions in pain were a motivation to continue exercising for the exerciser groups. Nonexercisers expressed that a reduction in pain was a possible outcome of exercise but were skeptical of its occurrence. Receiving tailored advice from a health care provider was consistently identified as an exercise enabler across the groups. Findings from this study indicate that potential strategies for increasing exercise participation include incorporating pain management strategies and coping skills into exercise interventions and ensuring that health care providers provide specific exercise advice to their patients with arthritis.


Extravascular lung water in patients with severe sepsis: a prospective cohort study.
Few investigations have prospectively examined extravascular lung water (EVLW) in patients with severe sepsis. We sought to determine whether EVLW may contribute to lung injury in these patients by quantifying the relationship of EVLW to parameters of lung injury, to determine the effects of chronic alcohol abuse on EVLW, and to determine whether EVLW may be a useful tool in the diagnosis of acute respiratory distress syndrome (ARDS). The present prospective cohort study was conducted in consecutive patients with severe sepsis from a medical intensive care unit in an urban university teaching hospital. In each patient, transpulmonary thermodilution was used to measure cardiovascular hemodynamics and EVLW for 7 days via an arterial catheter placed within 72 hours of meeting criteria for severe sepsis. A total of 29 patients were studied. Twenty-five of the 29 patients (86%) were mechanically ventilated, 15 of the 29 patients (52%) developed ARDS, and overall 28-day mortality was 41%. Eight out of 14 patients (57%) with non-ARDS severe sepsis had high EVLW with significantly greater hypoxemia than did those patient with low EVLW (mean arterial oxygen tension/fractional inspired oxygen ratio 230.7 +/- 36.1 mmHg versus 341.2 +/- 92.8 mmHg; P < 0.001). Four out of 15 patients with severe sepsis with ARDS maintained a low EVLW and had better 28-day survival than did ARDS patients with high EVLW (100% versus 36%; P = 0.03). ARDS patients with a history of chronic alcohol abuse had greater EVLW than did nonalcoholic patients (19.9 ml/kg versus 8.7 ml/kg; P < 0.0001). The arterial oxygen tension/fractional inspired oxygen ratio, lung injury score, and chest radiograph scores correlated with EVLW (r2 = 0.27, r2 = 0.18, and r2 = 0.28, respectively; all P < 0.0001). More than half of the patients with severe sepsis but without ARDS had increased EVLW, possibly representing subclinical lung injury. Chronic alcohol abuse was associated with increased EVLW, whereas lower EVLW was associated with survival. EVLW correlated moderately with the severity of lung injury but did not account for all respiratory derangements. EVLW may improve both risk stratification and management of patients with severe sepsis.


Electronystagmographic analysis of optokinetic and smooth pursuit eye movement disorders in vestibular lesions.
The electronystagmographical analysis of the eye movements is an important method in the evaluation and topical diagnostic procedure of several vestibular lesions. The aim of the study was to compare the electronystagmographical results of the optokinetic and the smooth pursuit eye-movement, and their sensitivity in several vestibular disorders. The patients were divided into five groups: right and left unilateral and bilateral peripheral lesions, central vestibular dysfunction, and normal vestibular function. In patients with normal vestibular system the optokinetic eye movement was pathological in 9.53% of patients, while the smooth pursuit eye movements were pathological in 8.3% of patients with normal vestibular function. In unilateral lesions, 17.42% of the OKNs were pathological, compared with the smooth pursuit test's 20.3% pathological ratio. In the bilateral peripheral vestibular dysfunction the ratio of the pathological eye-movements was 28% equally with to two methods. In central vestibular lesions 22.72% of the patients had abnormal optokinetic eye movements, and the smooth pursuit eye movement was abnormal in 41.6%. Our results show that in the unilateral peripheral vestibular lesions the smooth pursuit eye movement examination seems to be more sensitive than the OKN test, while in central dysfunctions the smooth pursuit eye movement examination is more sensitive than OKN examination.


Dystrophic calcification of the prostate after cryotherapy.
We present a previously undocumented complication of dystrophic calcification of the prostate after cryotherapy. An 87-year-old male presented with recurrent lower urinary tract infections and was found to have an obstructing large calcified mass in the right lobe of the prostate. Subsequently, he underwent transurethral resection of the prostate (TURP) and bladder neck with laser lithotripsy to remove the calculus. We propose that chronic inflammation and necrosis of the prostate from cryotherapy resulted in dystrophic calcification of the prostate. As the use of cryotherapy for the treatment of localized prostate cancer continues to increase, it is important that clinicians be aware of this scenario and the technical challenges it poses.


Simultaneous optimization of percutaneous delivery and adhesion for ketoprofen poultice.
Topical poultices of ketoprofen were prepared using deionized water, propylene glycol (X1), and glycerin (X2) as the vehicle in combination with hydrophilic matrix materials, including gelatin (X3) and sodium polyacrylate. A mixture design was utilized to evaluate the influence of these constituents (X1-X3) on the adhesion of the poultice and the percutaneous penetration of ketoprofen from poultices. The adhesion of the poultice was measured based on the L-Peel test method using a Tensile and Compression Testing Machine. Percutaneous delivery was conducted using nude mouse skin as the barrier. The poultice containing the highest weight fraction of gelatin demonstrated the highest value of peak stress, whereas the poultice containing 0% weight fraction of gelatin showed the smallest value among all formulations. This indicates that gelatin was the main factor determining the adhesion of the poultice. However, the interactive influence of propylene glycol with gelatin on the adhesion of the poultice cannot be ignored. On the contrary, the formulation having the maximal penetration rate was determined to be the vehicle with 0% weight fraction of gelatin and the highest percent weight fraction of glycerin. This indicates that the presence of glycerin in the poultice was able to increase the flux of ketoprofen to some extent. Quantification of individual's effect based on this mixture design resulted in a polynomial equation: Peak stress=0.033X1+0.016X2+0.12X3, flux=1.90X1+4.70X2-6.65X3. Finally, an optimized formulation with acceptable adhesion and a flux comparable to two commercial products was developed in this study.


Mountain ginseng extract exhibits anti-lung cancer activity by inhibiting the nuclear translocation of NF-κB.
Administration of mountain ginseng (MG) extract can restore advanced cancer to a normal state. To elucidate the mechanism by which MG extract prevents the progression of lung cancer, the processes of proliferation and death of lung cancer cells (A549) were examined after treatment with MG extract. Butanol-extracted MG (BX-MG) showed a high inhibitory effect (IC(50) = 2 mg/ml) by attenuating proliferation and inducing apoptosis in lung cancer cells. By HPLC-UV analysis of BX-MG, ginsenosides, Rb1 was identified as the most abundant ginsenoside, followed by Rg1, Re, Rc and Rb2. BX-MG induced caspase-3 dependent apoptosis by inhibiting NF-κB. In addition, BX-MG activated p53 and p21, resulting in the attenuated proliferation of A549 cells. Reduced activity of the NF-κB promoter and increased activity of the p53 promoter indicate that BX-MG regulates apoptosis at the level of transcription in lung cancer cells. Furthermore, BX-MG blocked the nuclear translocation of RelA and the associated reduction in surviving. These results suggest that BX-MG inhibits lung cancer cell growth by activating tumor suppressors and inhibiting nuclear translocation of NF-κB.


Bedside pediatric emergency evaluation through ultrasonography.
Bedside US has emerged as a valuable technology for the emergency department physician. It impacts clinical decision-making and the safety of procedures, and it decreases the time and increases the efficiency for completion of procedures. The portability, accuracy and noninvasive nature of US make it an ideal tool for the trained clinician. Bedside US can improve clinical decision-making for the pediatric patient by helping the clinician to identify critical pathology, direct therapeutic maneuvers and determine the futility of resuscitations. Many pediatric procedures, such as vascular access, lumbar puncture and bladder catheterization, are typically performed blindly. Bedside US enhances the success of procedures, minimizes complications and limits the number of attempts necessary to complete a procedure. Bedside US can be a valuable adjunct for complicated and time-sensitive disease processes such as ectopic pregnancy, testicular torsion and hypovolemia by providing information to guide diagnostic and therapeutic interventions that subsequently improve outcomes.


Prognostic implications of the IDH1 synonymous SNP rs11554137 in pediatric and adult AML: a report from the Children's Oncology Group and SWOG.
IDH1 SNP rs11554137 was recently reported in association with poor prognosis in normal karyotype adult acute myeloid leukemia (AML). We aimed to determine the prevalence, clinical associations, and prognostic significance of SNP rs11554137 in unselected pediatric and adult AML patients. Diagnostic marrow specimens from 527 AML patients treated on the pediatric trial Children's Oncology Group-AAML03P1 (N = 253) or adult SWOG trials (N = 274) were analyzed for the presence of the SNP. SNP rs11554137 was present in 11% of all patients. SNP status had no prognostic impact on survival in pediatric patients. In adult AML, overall survival for SNP-positive patients was 10% versus 18% for SNP-negative patients (P = .44). Among the 142 adults who achieved complete remission, 5-year relapse-free survival was significantly worse for SNP-positive patients (0% vs 25%, P = .0014). However, among adults with normal cytogenetics, FLT3/ITD was present in 90% of SNP-positive patients versus 59% of SNP-negative patients (P = .0053). In multivariate analysis, adjusting for the effects of age, cytogenetics, and FLT3/ITD, the independent prognostic effect of SNP positivity was not statistically significant (hazard ratio = 1.72, P = .18). The clinical profile of SNP-positive patients suggests that SNP rs11554137 may have biologic effects that bear further investigation. The clinical trials in this study are registered at http://www.clinicaltrials.gov as #NCT000707174 and #NCT00899171.


Directional allosteric regulation of protein filament length.
Cofilin and ADF are cytoskeleton remodeling proteins that cooperatively bind and fragment actin filaments. Bound cofilin molecules do not directly interact with each other, indicating that cooperative binding of cofilin is mediated by the actin filament lattice. Cofilactin is therefore a model system for studying allosteric regulation of self-assembly. How cofilin binding changes structural and mechanical properties of actin filaments is well established. Less is known about the interaction energies and the thermodynamics of filament fragmentation, which describes the collective manner in which the cofilin concentration controls mean actin filament length. Here, we provide a general thermodynamic framework for allosteric regulation of self-assembly, and we use the theory to predict the interaction energies of experimental actin filament length distributions over a broad range of cofilin binding densities and for multiple cofilactin variants. We find that bound cofilin induces changes in nearby actin-actin interactions, and that these allosteric effects are propagated along the filament to affect up to four neighboring cofilin-binding sites (i.e., beyond nearest-neighbor allostery). The model also predicts that cofilin differentially stabilizes and destabilizes longitudinal versus lateral actin-actin interactions, and that the magnitude, range, asymmetry, and even the sign of these interaction energies can be altered using different actin and cofilin mutational variants. These results demonstrate that the theoretical framework presented here can provide quantitative thermodynamic information governing cooperative protein binding and filament length regulation, thus revealing nanometer length-scale interactions from micron length-scale "wet-lab" measurements.


Urinary tract infections in cats with hyperthyroidism, diabetes mellitus and chronic kidney disease.
The prevalence of urinary tract infections (UTIs) in cats with hyperthyroidism (n=90), diabetes mellitus (DM) (n=57) and chronic kidney disease (CKD) (n=77) was evaluated retrospectively. It was found to be 12% in cats with hyperthyroidism and DM, respectively, and 22% in cats with CKD. Associations between UTIs and clinical signs, biochemical markers in serum and urinalyses were investigated. Many of the cats with UTIs had no clinical signs of lower urinary tract disease or changes in their laboratory values indicative of infection. Therefore, a urinalysis alone should not be used to exclude UTIs in these cats. UTIs are relatively common in cats with hyperthyroidism, DM and CKD, and urine cultures are recommended as part of the basic diagnostic plan for cats suspected of suffering from these conditions.


Autologous and allogeneic stem-cell transplantation for transformed follicular lymphoma: a report of the Canadian blood and marrow transplant group.
To determine whether autologous (auto) or allogeneic (allo) stem-cell transplantation (SCT) improves outcome in patients with transformed follicular lymphoma compared with rituximab-containing chemotherapy alone. This was a multicenter cohort study of patients with follicular lymphoma and subsequent biopsy-proven aggressive histology transformation. Patient, treatment, and outcome data were collected from each transplantation center and combined for analysis. A separate control group was composed of patients with transformation treated with rituximab-containing chemotherapy but not SCT. The primary end point was overall survival (OS) after transformation. One hundred seventy-two patients were identified: 22 (13%) treated with alloSCT, 97 (56%) with autoSCT, and 53 (31%) with rituximab-containing chemotherapy. Five-year OS after transformation was 46% for patients treated with alloSCT, 65% with autoSCT, and 61% with rituximab-containing chemotherapy (P = .24). Five-year progression-free survival (PFS) after transformation was 46% for those treated with alloSCT, 55% with autoSCT, and 40% with rituximab-containing chemotherapy (P = .12). In multivariate analysis, patients treated with autoSCT had improved OS compared with those who received rituximab-containing chemotherapy (hazard ratio [HR], 0.13; 95% CI, 0.05 to 0.34; P < .001). On the other hand, there was no OS difference between those treated with alloSCT and rituximab-containing chemotherapy (HR, 0.44; 95% CI, 0.16 to 1.24; P = .12). OS and PFS after SCT were similar between those treated with autoSCT and alloSCT. Five-year transplantation-related mortality was 23% for those treated with alloSCT and 5% for autoSCT. Patients undergoing autoSCT had better outcomes than those treated with rituximab-containing chemotherapy alone. AlloSCT did not improve outcome compared with rituximab-containing chemotherapy and was associated with clinically significant toxicity.


Effect of acupuncture on induction of labor.
The objective of this study is to review the existing scientific evidence on the potential role of acupuncture on induction of labor during pregnancy. The Medline, EMBASE, Cochrane Central Register of Controlled Trials, AMED (Allied and Complementary Medicine), and NCCAM (The National Center for Complementary and Alternative Medicine) databases were searched to identify relevant monographs from 1970 to 2008. These criteria included all available human acupuncture studies on pregnant women carrying a viable fetus due for third trimester induction of labor. These criteria included studies not meeting the inclusion criteria, in languages other than English, or animal studies. Ten (10) studies on labor induction were identified. The duration of labor as a result of acupuncture treatment ranged from 10 hours 20 minutes to 29.1 hours. All of the studies demonstrated labor induction by acupuncture treatment. However, because two randomized controlled trials reported that there was no statistically significant effect of acupuncture, these results are more suggestive than definitive. Furthermore, although the relationship between cervical ripening and interleukin-8 (IL-8), prostaglandin F(2alpha) (PGF(2alpha)), and beta-endorphin is well documented in the literature, there is no evidence to suggest that acupuncture alters these mediators. Serum levels of IL8, beta-endorphin, and PGF(2alpha) were not found to be significantly influenced by acupuncture. Although the definitive role of acupuncture in inducing labor is still yet to be established, the existing studies suggest that acupuncture may be beneficial in labor induction. Further randomized clinical trials are needed to investigate this further.


Embryonic stem-cell-preconditioned microenvironment induces loss of cancer cell properties in human melanoma cells.
The cancer microenvironment affects cancer cell proliferation and growth. Embryonic stem (ES)-preconditioned 3-dimensional (3-D) culture of cancer cells induces cancer cell reprogramming and results in a change in cancer cell properties such as differentiation and migration in skin melanoma. However, the mechanism has not yet been clarified. Using the ES-preconditioned 3-D microenvironment model, we provide evidence showing that the ES microenvironment inhibits proliferation and anchorage-independent growth of SK-MEL-28 melanoma cells. We also found that the ES microenvironment suppresses telomerase activity and thereby induces senescence in SK-MEL-28 cells. Furthermore, we observed that gremlin, an antagonist of BMP4, is secreted from ES cells and plays an important role in cellular senescence. Knocking down gremlin in the ES microenvironment increases proliferation and anchorage-independent growth of SK-MEL-28 melanoma cells. Taken together, these results demonstrated that gremlin is a crucial factor responsible for abrogating melanoma properties in the ES-preconditioned 3-D microenvironment.


Blood flow and ischemia within traumatic cerebral contusions.
To provide evidence of irreversible ischemia in cerebral contusions among patients with severe traumatic brain injuries and to clarify the potential viability of tissue in the pericontusional zone, quantitative regional cerebral blood flow (rCBF) measurements obtained with the xenon-enhanced computed tomographic method were correlated with the areas of contusions, by using image fusion. rCBF measurements obtained during the acute phase (mean, 2 d after injury; range, 0-10 d) were statistically correlated with the extent of tissue necrosis identified as focal atrophy on late follow-up computed tomographic scans (mean time after the xenon-enhanced computed tomographic cerebral blood flow investigation, 265 d; range, 30-1047 d). Seventeen patients exhibited 26 traumatic contusions. All contusions progressed to late focal atrophic areas on the follow-up computed tomographic scans. The rCBF values within the traumatic contusions ranged from 0.5 to 22.0 ml/100 g/min, with a mean of 5.9 +/- 5.9 ml/100 g/min. The contusions exhibited a specific rCBF profile, presenting as a core of severe lethal ischemia surrounded by variable but gradually increasing perfusion with increasing distance from the ischemic core. The ischemic profile of the contusions, with a pericontusional zone of low rCBF, presents the potential risk of secondary ischemic insults, similar to the risk in the ischemic penumbral zones surrounding areas of acute ischemic stroke.


Low Concentrations of Vitamin C Reduce the Synthesis of Extracellular Polymers and Destabilize Bacterial Biofilms.
Extracellular polymeric substances (EPS) produced by bacteria form a matrix supporting the complex three-dimensional architecture of biofilms. This EPS matrix is primarily composed of polysaccharides, proteins and extracellular DNA. In addition to supporting the community structure, the EPS matrix protects bacterial biofilms from the environment. Specifically, it shields the bacterial cells inside the biofilm, by preventing antimicrobial agents from getting in contact with them, thereby reducing their killing effect. New strategies for disrupting the formation of the EPS matrix can therefore lead to a more efficient use of existing antimicrobials. Here we examined the mechanism of the known effect of vitamin C (sodium ascorbate) on enhancing the activity of various antibacterial agents. Our quantitative proteomics analysis shows that non-lethal concentrations of vitamin C inhibit bacterial quorum sensing and other regulatory mechanisms underpinning biofilm development. As a result, the EPS biosynthesis in reduced, and especially the polysaccharide component of the matrix is depleted. Once the EPS content is reduced beyond a critical point, bacterial cells get fully exposed to the medium. At this stage, the cells are more susceptible to killing, either by vitamin C-induced oxidative stress as reported here, or by other antimicrobials or treatments.


Development of eating behaviors among children and adolescents.
The prevalence of obesity among children is high and is increasing. We know that obesity runs in families, with children of obese parents at greater risk of developing obesity than children of thin parents. Research on genetic factors in obesity has provided us with estimates of the proportion of the variance in a population accounted for by genetic factors. However, this research does not provide information regarding individual development. To design effective preventive interventions, research is needed to delineate how genetics and environmental factors interact in the etiology of childhood obesity. Addressing this question is especially challenging because parents provide both genes and environment for children. An enormous amount of learning about food and eating occurs during the transition from the exclusive milk diet of infancy to the omnivore's diet consumed by early childhood. This early learning is constrained by children's genetic predispositions, which include the unlearned preference for sweet tastes, salty tastes, and the rejection of sour and bitter tastes. Children also are predisposed to reject new foods and to learn associations between foods' flavors and the postingestive consequences of eating. Evidence suggests that children can respond to the energy density of the diet and that although intake at individual meals is erratic, 24-hour energy intake is relatively well regulated. There are individual differences in the regulation of energy intake as early as the preschool period. These individual differences in self-regulation are associated with differences in child-feeding practices and with children's adiposity. This suggests that child-feeding practices have the potential to affect children's energy balance via altering patterns of intake. Initial evidence indicates that imposition of stringent parental controls can potentiate preferences for high-fat, energy-dense foods, limit children's acceptance of a variety of foods, and disrupt children's regulation of energy intake by altering children's responsiveness to internal cues of hunger and satiety. This can occur when well-intended but concerned parents assume that children need help in determining what, when, and how much to eat and when parents impose child-feeding practices that provide children with few opportunities for self-control. Implications of these findings for preventive interventions are discussed.


Differentiation of Benign Fluid Collections from Soft-Tissue Sarcomas on FDG-PET/CT.
To assess the diagnostic performance of (18)F-FDG PET-CT in differentiating soft tissue sarcomas (STSs) from benign fluid collections (BFs). Four readers independently reviewed 100 lesions on (18)F-FDG PET-CT and subjectively classified each lesion as an STS or BF and scored the spatial pattern of (18)F-FDG avidity (SP) of each on a 4-point ordered scale (thin, moderate, thick, solid). Subjective assessment by readers allowed sensitive (91%-98%) differentiation of STSs from BFs, with lower specificity (59%-91%). The STSs had significantly higher SUVmax (median 10.7, range: 2.0-33.7) than BFs (median 2.8, range: 1.1-12.3). Reader agreement in assessment of SP had average κ = 0.61 (range 0.46-0.70). Classification of thick or solid SP as STS yielded an inter-reader averaged sensitivity and specificity of 69% and 98%, respectively. The presence of thick or solid SP resulted in 14.1-fold increase in partial odds of STS. Each unit increase in SUVmax resulted in 1.35-fold increase in partial odds of STS. The receiver operating characteristic (ROC) curves and 95% intervals for SUVmax alone and SUVmax + SP overlapped. The average subjective assessments for the four readers and estimated performance of using SP alone were both contained within the 95% intervals of the two ROC curves. (18)F-FDG PET-CT is a sensitive modality for differentiating STSs from BFs. SUVmax and SP are significantly associated with STS. Classification schemes based upon SUVmax alone or augmented with SP can be useful for distinguishing STS from BF.


Is Internet Addiction a Clinical Symptom or a Psychiatric Disorder? A Comparison With Bipolar Disorder.
The general purpose of this review is to present an updated literature overview of neurobiological/clinical aspects of Internet addiction (IA), particularly of overlaps and differences with bipolar affective disorder (BPAD). Articles with clinical/neurobiological aspects of IA or similarities/differences with BPAD as main topics, from 1990 to present and written in English language, were included. Comorbidity between IA and other psychiatric disorders, including BPAD, is common. Dysfunctions in dopaminergic pathways have been found both in IA and in mood disorders. Most of investigations in IA support a chronic hypodopaminergic dysfunctional state in brain reward circuit and an excessive reward experience during mood elevation. Neuroimaging studies show prefrontal cortex abnormalities shared between addictive and bipolar patients. BPAD and IA present numerous overlaps, such as polymorphisms in nicotinic receptors genes, anterior cingulate/prefrontal cortex abnormalities, serotonin/dopamine dysfunctions, and good response to mood stabilizers. The future is to clarify diagnostic criteria to better define the IA/BPAD relationship.


Plasma Exchange as an Adjunctive Therapy for Crescentic IgA Nephropathy.
Crescentic IgA nephropathy (CreIgAN) has a poor prognosis despite aggressive immunosuppressive therapy. The efficacy of plasma exchange (PE) in CreIgAN is not well defined. Twelve patients with severe CreIgAN who received PE as addition to routine immunosuppressive therapy, followed for more than 6 months, were involved. Twelve matched historical controls who received immunosuppressive therapy alone were selected by propensity score matching. Renal survival, plasma IgA-IgG complex and active complement products were assessed. Nine men and 3 women received a median of 7 PE courses (range 5-10). Their baseline urine protein excretion rate was 5.8 (4.5-8.7) g/day, and their serum creatinine level was 705.3 ± 296.4 μmol/l. During a mean follow-up of 15.6 months (6-51 months), 6 of the 12 PE group patients were free of dialysis, while all the control patients were dialysis dependent (6 of 12 vs. 0 of 12, p = 0.014). In the PE group, dialysis had to be restarted for 1 patient owing to the development of severe pneumonia and pulmonary failure. PE was associated with a higher kidney survival rate (log rank test, p = 0.026) during follow-up. It also significantly decreased plasma IgA-IgG complex levels (pre-PE: 85.3 ± 25.9% vs. post-PE: 38.4 ± 12.4%, p < 0.001) and plasma and urinary active complement product levels, including C3a, C5a and soluble C5b-9. The latter levels remained low until the last follow-up. This study indicated that PE could increase renal recovery rates in severe CreIgAN.


The development of zebrafish tendon and ligament progenitors.
Despite the importance of tendons and ligaments for transmitting movement and providing stability to the musculoskeletal system, their development is considerably less well understood than that of the tissues they serve to connect. Zebrafish have been widely used to address questions in muscle and skeletal development, yet few studies describe their tendon and ligament tissues. We have analyzed in zebrafish the expression of several genes known to be enriched in mammalian tendons and ligaments, including scleraxis (scx), collagen 1a2 (col1a2) and tenomodulin (tnmd), or in the tendon-like myosepta of the zebrafish (xirp2a). Co-expression studies with muscle and cartilage markers demonstrate the presence of scxa, col1a2 and tnmd at sites between the developing muscle and cartilage, and xirp2a at the myotendinous junctions. We determined that the zebrafish craniofacial tendon and ligament progenitors are neural crest derived, as in mammals. Cranial and fin tendon progenitors can be induced in the absence of differentiated muscle or cartilage, although neighboring muscle and cartilage are required for tendon cell maintenance and organization, respectively. By contrast, myoseptal scxa expression requires muscle for its initiation. Together, these data suggest a conserved role for muscle in tendon development. Based on the similarities in gene expression, morphology, collagen ultrastructural arrangement and developmental regulation with that of mammalian tendons, we conclude that the zebrafish tendon populations are homologous to their force-transmitting counterparts in higher vertebrates. Within this context, the zebrafish model can be used to provide new avenues for studying tendon biology in a vertebrate genetic system.


Identifying functional gene sets from hierarchically clustered expression data: map of abiotic stress regulated genes in Arabidopsis thaliana.
We present MultiGO, a web-enabled tool for the identification of biologically relevant gene sets from hierarchically clustered gene expression trees (http://ekhidna.biocenter.helsinki.fi/poxo/multigo). High-throughput gene expression measuring techniques, such as microarrays, are nowadays often used to monitor the expression of thousands of genes. Since these experiments can produce overwhelming amounts of data, computational methods that assist the data analysis and interpretation are essential. MultiGO is a tool that automatically extracts the biological information for multiple clusters and determines their biological relevance, and hence facilitates the interpretation of the data. Since the entire expression tree is analysed, MultiGO is guaranteed to report all clusters that share a common enriched biological function, as defined by Gene Ontology annotations. The tool also identifies a plausible cluster set, which represents the key biological functions affected by the experiment. The performance is demonstrated by analysing drought-, cold- and abscisic acid-related expression data sets from Arabidopsis thaliana. The analysis not only identified known biological functions, but also brought into focus the less established connections to defense-related gene clusters. Thus, in comparison to analyses of manually selected gene lists, the systematic analysis of every cluster can reveal unexpected biological phenomena and produce much more comprehensive biological insights to the experiment of interest.


Crystal structure of the pregnane X receptor-estradiol complex provides insights into endobiotic recognition.
The human nuclear pregnane X receptor (PXR) responds to a wide variety of xenobiotic and endobiotic compounds, including pregnanes, progesterones, corticosterones, lithocholic acids, and 17beta-estradiol. In response to these ligands, the receptor controls the expression of genes central to the metabolism and excretion of potentially harmful chemicals from both exogenous and endogenous sources. Although the structural basis of PXR's interaction with small and large xenobiotics has been examined, the detailed nature of its binding to endobiotics, including steroid-like ligands, remains unclear. We report the crystal structure of the human PXR ligand-binding domain (LBD) in complex with 17beta-estradiol, a representative steroid ligand, at 2.65 A resolution. Estradiol is found to occupy only one region of PXR's expansive ligand-binding pocket, leaving a notable 1000 A3 of space unoccupied, and to bridge between the key polar residues Ser-247 and Arg-410 in the PXR LBD. Positioning the steroid scaffold in this way allows it to make several direct contacts to alphaAF of the receptor's AF-2 region. The PXR-estradiol complex was compared with that of other nuclear receptors, including the estrogen receptor, in complexes with analogous ligands. It was found that PXR's placement of the steroid is remarkably distinct relative to other members of the nuclear receptor superfamily. Using the PXR-estradiol complex as a guide, the binding of other steroid- and cholesterol-like molecules was then considered. The results provide detailed insights into the manner in which human PXR responds to a wide range of endobiotic compounds.


A family physician's journey in exploring sexual health perceptions and needs in a boarding school community.
Sexual health in schools is neglected in most developing countries,[1] however, it is emerging as a major need of the hour. This article captures the author's experience as a family physician in a boarding school setting in India highlighting the need and possible solutions pertaining to sexual health in the school community. An international boarding school in India with approximately 600 students, 500 teachers, and administrators who lived on the school campus and 500 support staff who lived off-campus. Three events prodded the author to explore perceptions and needs pertaining to sexual health in the school community. Being a difficult area of inquiry, this was done as informal qualitative research by dialoguing with six groups of people in the school community: School counselors, parents, student supervisors such as teachers, advisors and dorm parents, school administrators, support staff, and the students and the responses were collated. A mere 17.9% of grade 5 to 12 students, of age-groups 10 to 19 never had a conversation with their parents about sexuality. Students were largely ignorant or misinformed on most sexuality-related issues but engaged well when offered anonymity or safe space. Though all stakeholders in the school agreed that students needed an age-appropriate, gender and culture-sensitive, scientific and comprehensive sex education, parental responses were mixed. The author's journey as a family physician in a school setting has prompted exploration of a wholistic model for the provision of comprehensive sexual health in schools and the emerging role of a family physician in schools.


The FAO/WHO International Food Safety Authorities Network in Review, 2004-2018: Learning from the Past and Looking to the Future.
Contemporary patterns of global food trade necessitate cross-border communication between government authorities when unsafe food enters international commerce. The Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) International Food Safety Authorities Network (INFOSAN), established in 2004, facilitates urgent communication between >600 members from 188 of the 194 FAO and WHO Member States around the world and supports the strengthening of food safety systems in an effort to mitigate the global burden of foodborne disease. For nearly 15 years, INFOSAN has been operating as a global, virtual community of practice (CoP), fostering knowledge transfer and exchange between members, and enabling crucial international communication during food safety emergencies. During this time, a number of important partnerships have been forged, including with other networks like PulseNet International. Complementarity, and cooperation between global networks like INFOSAN and PulseNet is vital to improve the efficiency and effectiveness of global efforts to curb foodborne illness. Since 2011, detailed data related to the patterns of information exchange during 293 food safety emergencies communicated through INFOSAN have been documented systematically. An analysis of these data reveals that a relatively limited number of active members from a select group of Member States contribute the majority of information exchanged through the network. For example, nine (5%) Member States were each involved in 24 or more food safety events communicated through INFOSAN between 2011 and 2017, whereas 123 (65%) Member States were involved in three events or less, including 36 (19%) involved in none. These data also demonstrate that although the overall responsiveness of members during emergencies has improved in recent years, impediments to rapid and efficient information sharing still persist. A number of potential barriers to active participation in INFOSAN have been hypothesized, but members themselves have not been conferred with on their relative importance. As a member-driven network, future research to investigate the experiences of INFOSAN members in a rigorous and systematic manner is recommended. Such work could illuminate the specific areas in which to introduce operational shifts by the INFOSAN Secretariat, to strengthen the global CoP, increase the value of INFOSAN among members, and have a robust and meaningful impact at country level to reduce the burden of foodborne disease globally.


Menstrual and premenstrual issues in female military cadets: a unique population with significant concerns.
There is a strong need to determine what effect, if any, menstruation has on the performance of duty as a Cadet at the United States Military Academy (USMA) at West Point, and to determine what impact, if any, the USMA environment has on the menstrual cycle. To study menstrual function and premenstrual symptoms in a structured, rigorous military environment; determine the perceived impact of menstrual and premenstrual symptoms on academic, physical, and military activities; and evaluate the difficulties inherent to menstruation in a military setting. A survey about high school menstrual and premenstrual function, and the Premenstrual Assessment Form (PAF), were completed by all 158 freshman female Cadets in July 1991. In May 1992, 83 participants completed a survey assessing menstrual and premenstrual symptoms, including interference with activities during the year. Menstrual regularity, premenstrual symptoms, interference with activities. Participants reported menstrual patterns and premenstrual symptoms in high school similar to other females their age. Most (62%) predicted a change in menstruation at the USMA, half were worried that physical symptoms would interfere with activities, one-fourth were worried that premenstrual symptoms would interfere with activities, and one-fourth were worried that obtaining and changing menstrual materials would interfere with activities. Almost all respondents (91%) reported changes in menstruation during the year, most commonly less regular, less frequent, shorter, lighter, and less crampy periods. Menstrual and premenstrual symptoms interfered with physical activities (66.2%, 61.4% respectively) more so than academic (50.6%, 45.7% respectively) or military activities (39.8%, 47.0% respectively). Female Cadets described significant difficulties with changing (62.6%), obtaining (51.8%), and disposing of (38.5%) menstrual materials. The data demonstrate major changes in menstrual function in over 90% of female Cadets; a significant perceived impact of menstrual and premenstrual symptoms on academic, physical, and military activities; and difficulties in obtaining, changing, and disposing of menstrual materials in a military setting. These findings have implications for females in the military, as well as for young women generally.


Age-related decline in urine concentration may not be universal: Comparative study from the U.S. and two small-scale societies.
Evidence from industrialized populations suggests that urine concentrating ability declines with age. However, lifestyle factors including episodic protein intake and low hypertension may help explain differences between populations. Whether this age-related decline occurs among small-scale populations with active lifestyles and non-Western diets is unknown. We test the universality of age-related urine concentration decline. We used urine specific gravity (Usg) and urine osmolality (Uosm) data from 15,055 U.S. nonpregnant adults without kidney failure aged 18-80 in 2007-2012 participating in the National Health and Nutrition Examination Survey (NHANES). We tested the relationship of age on urine concentration biomarkers with multiple linear regressions using survey commands. We compared results to longitudinal data on Usg from 116 Tsimane' forager-horticulturalists (266 observations) adults aged 18-83 in 2013-2014 from Lowland Bolivia, and to 38 Hadza hunter-gatherers (156 observations) aged 18-75 in 2010-2015 from Tanzania using random-effects panel linear regressions. Among U.S. adults, age was significantly negatively associated with Usg (Adjusted beta [B] = -0.0009 g/mL/10 years; SE = 0.0001; p < 0.001) and Uosm (B = -28.1 mOsm/kg/10 yr; SE = 2.4; p < 0.001). In contrast, among Tsimane' (B = 0.0003 g/mL/10 yr; SE = 0.0002; p = 0.16) and Hadza (B = -0.0004 g/mL/10 yr; SE = 0.0004; p = 0.29) age was not associated with Usg. Older Tsimane' and Hadza exhibited similar within-individual variability in Usg equivalent to younger adults. While U.S. adults exhibited age-related declines in urine concentration, Tsimane' and Hadza adults did not exhibit the same statistical decline in Usg. Mismatches between evolved physiology and modern environments in lifestyle may affect kidney physiology and disease risk.


Spatial distribution and sources of dissolved trace metals in surface water of the Wei River, China.
For this study, 34 water samples were collected along the Wei River and its tributaries. Multivariate statistical analyses were employed to interpret the environmental data and to identify the natural and anthropogenic trace metal inputs to the surface waters of the river. Our results revealed that Zn, Se, B, Ba, Fe, Mn, Mo, Ni and V were all detected in the Wei River. Compared to drinking water guidelines, the primary trace metal pollution components (B, Ni, Zn and Mn) exceeded drinking water standard levels by 47.1, 50.0, 44.1 and 26.5%, respectively. Inter-element relationships and landscape features of trace metals conducted by hierarchical cluster analysis (HCA) identified a uniform source of trace metals for all sampling sites, excluding one site that exhibited anomalous concentrations. Based on the patterns of relative loadings of individual metals calculated by principal component analysis (PCA), the primary trace metal sources were associated with natural/geogenic contributions, agro-chemical processes and discharge from local industrial sources. These results demonstrated the impact of human activities on metal concentrations in the Wei River.


Six Degrees of Epistasis: Statistical Network Models for GWAS.
There is growing evidence that much more of the genome than previously thought is required to explain the heritability of complex phenotypes. Recent studies have demonstrated that numerous common variants from across the genome explain portions of genetic variability, spawning various avenues of research directed at explaining the remaining heritability. This polygenic structure is also the motivation for the growing application of pathway and gene set enrichment techniques, which have yielded promising results. These findings suggest that the coordination of genes in pathways that are known to occur at the gene regulatory level also can be detected at the population level. Although genes in these networks interact in complex ways, most population studies have focused on the additive contribution of common variants and the potential of rare variants to explain additional variation. In this brief review, we discuss the potential to explain additional genetic variation through the agglomeration of multiple gene-gene interactions as well as main effects of common variants in terms of a network paradigm. Just as is the case for single-locus contributions, we expect each gene-gene interaction edge in the network to have a small effect, but these effects may be reinforced through hubs and other connectivity structures in the network. We discuss some of the opportunities and challenges of network methods for analyzing genome-wide association studies (GWAS) such as the study of hubs and motifs, and integrating other types of variation and environmental interactions. Such network approaches may unveil hidden variation in GWAS, improve understanding of mechanisms of disease, and possibly fit into a network paradigm of evolutionary genetics.


An evaluation of the aboistop citronella-spray collar as a treatment for barking of domestic dogs.
The aim of our study was to investigate whether citronella-spray collars offer a humane alternative to electric-shock collars to reduce the barking of domestic dogs. The Aboistop collar was applied to seven dogs with problematic barking behaviour by the dogs' owners in a series of case studies concurrently run. Vocalisation of the dogs was recorded in the problem context under baseline conditions, inactive collar conditions, and active collar conditions. The Aboistop collar was effective at reducing problem vocalization for only three of seven dogs and appeared to be most effective for dogs whose problem barking had developed more recently. The collar may be more humane than other punishment methods, but it did produce stress reactions which varied in severity across the dogs. Clinical Relevance. In our study, the collar was applied by the dogs' owners in order to test whether the collar would be effective when used by members of the public. While the results here are preliminary, they suggest that the collar may be effective for some dogs, but not for others, when applied by dog owners for the treatment of problem vocalisation. Further research is required to determine whether the collar could be effective when administered by a trained professional.


GLI3 repressor controls nephron number via regulation of Wnt11 and Ret in ureteric tip cells.
Truncating GLI3 mutations in Pallister-Hall Syndrome with renal malformation suggests a requirement for Hedgehog signaling during renal development. HH-dependent signaling increases levels of GLI transcriptional activators and decreases processing of GLI3 to a shorter transcriptional repressor. Previously, we showed that Shh-deficiency interrupts early inductive events during renal development in a manner dependent on GLI3 repressor. Here we identify a novel function for GLI3 repressor in controlling nephron number. During renal morphogenesis, HH signaling activity, assayed by expression of Ptc1-lacZ, is localized to ureteric cells of the medulla, but is undetectable in the cortex. Targeted inactivation of Smo, the HH effector, in the ureteric cell lineage causes no detectable abnormality in renal morphogenesis. The functional significance of absent HH signaling activity in cortical ureteric cells was determined by targeted deletion of Ptc1, the SMO inhibitor, in the ureteric cell lineage. Ptc1(-/-UB) mice demonstrate ectopic Ptc1-lacZ expression in ureteric branch tips and renal hypoplasia characterized by reduced kidney size and a paucity of mature and intermediate nephrogenic structures. Ureteric tip cells are remarkable for abnormal morphology and impaired expression of Ret and Wnt11, markers of tip cell differentiation. A finding of renal hypoplasia in Gli3(-/-) mice suggests a pathogenic role for reduced GLI3 repressor in the Ptc1(-/-UB) mice. Indeed, constitutive expression of GLI3 repressor via the Gli3(Delta699) allele in Ptc1(-/-UB) mice restores the normal pattern of HH signaling, and expression of Ret and Wnt11 and rescued the renal phenotype. Thus, GLI3 repressor controls nephron number by regulating ureteric tip cell expression of Wnt11 and Ret.


Medical residents' perceptions of end-of-life care training in a large urban teaching hospital.
Contemporary medicine has begun to reemphasize the importance of palliative and end-of-life-care. This shift requires a commensurate change in physician education to provide adequate palliative care training. The present research assessed medical residents' perceptions of their clinical and educational experiences in palliative care training as provided by a large urban teaching hospital. All graduating third-year residents in internal medicine, family medicine, and social pediatrics at Montefiore Medical Center were asked to participate in a brief telephone survey. The survey assessed residents' experiences in caring for patients who were dying or had died, and their evaluation of faculty supervision, clinical rotations, and academic activities. Fifty-five residents (90%) were surveyed. They reported caring for few patients at the end of life over their 3 years of training (median of 10 inpatients who died, one outpatient who died, and three outpatients who were potentially terminally ill). Furthermore, the majority of residents gave poor ratings to clinical supervision and to clinical rotations where they were likely to evaluate dying patients (intensive care units and oncology), with only 16% of residents reporting that they had received very good or outstanding palliative care training. In order to provide adequate palliative care education to future physicians, residency programs must strategically target hospital training units, enhance the quality of palliative care supervision and training that residents receive, and increase the number of dying patients they care for in ambulatory care and nonhospital settings. Recommendations for change are discussed.


On random generation and the central executive of working memory.
Four experiments explore participants' attempts to generate random sequences. Experiment 1 showed that oral random number generation is strongly affected by both response speed and response set size, in contrast to a random key-pressing task in Expt 2. Expt 3 confirmed differences between output modalities in the set size effect, and Expt 4 indicated that an important source of difficulty in producing random numbers orally lies in the requirement to represent candidate choices. Across experiments, data show a strong tendency on the part of participants to suppress response repetitions, an effect which decays over intervening responses. Whilst consistent with the possibility that random generation taps some executive functions, findings suggest the need to expand current models of attentional control in working memory to account for distinct constraints.


Diastolic (dys-)function and electrophysiology.
Cross-talk between cardiac electrical and mechanical function is a bidirectional process: The origin and spread of electric excitation govern cardiac contraction and relaxation, while the mechanic environment provides feedback information to the heart's electric behavior. The latter tends to be unduly disregarded by the medical community. This article reviews experimental findings on the effects of diastolic mechanics on cardiac electrophysiology, and describes physiological correlates, clinical manifestations, and therapeutic utility of cardiac mechanic stimulation in humans.


A Wearable Microfluidic Sensing Patch for Dynamic Sweat Secretion Analysis.
Wearable sweat sensing is a rapidly rising research area driven by its promising potential in health, fitness, and diagnostic applications. Despite the growth in the field, major challenges in relation to sweat metrics remain to be addressed. These challenges include sweat rate monitoring for its complex relation with sweat compositions and sweat sampling for sweat dynamics studies. In this work, we present a flexible microfluidic sweat sensing patch that enhances real-time electrochemical sensing and sweat rate analysis via sweat sampling. The device contains a spiral-patterned microfluidic component that is embedded with ion-selective sensors and an electrical impedance-based sweat rate sensor on a flexible plastic substrate. The patch is enabled to autonomously perform sweat analysis by interfacing the sensing component with a printed circuit board that is capable of on-site signal conditioning, analysis, and transmission. Progressive sweat flow in the microfluidic device, governed by the pressure induced by the secreted sweat, enhances sweat sampling and electrochemical detection via a defined sweat collection chamber and a directed sweat route. The characteristic of the sweat rate sensor is validated through a theoretical simulation, and the precision and accuracy of the flow rate is verified with a commercial syringe pump and a Macroduct sweat collector. On-body simultaneous monitoring of ion (H+, Na+, K+, Cl-) concentration and sweat rate is also demonstrated for sensor functionality. This sweat sensing patch provides an integrated platform for a comprehensive sweat secretion analysis and facilitates physiological and clinical investigations by closely monitoring interrelated sweat parameters.


Constraints on the Metabolic Activity of Microorganisms in Atacama Surface Soils Inferred from Refractory Biomarkers: Implications for Martian Habitability and Biomarker Detection.
Dryness is one of the main environmental challenges to microbial survival. Understanding the threshold of microbial tolerance to extreme dryness is relevant to better constrain the environmental limits of life on Earth and critically evaluate long-term habitability models of Mars. Biomolecular proxies for microbial adaptation and growth were measured in Mars-like hyperarid surface soils in the Atacama Desert that experience only a few millimeters of precipitation per decade, and in biologically active soils a few hundred kilometers away that experience two- to fivefold more precipitation. Diversity and abundance of lipids and other biomolecules decreased with increasing dryness. Cyclopropane fatty acids (CFAs), which are indicative of adaptive response to environmental stress and growth in bacteria, were only detected in the wetter surface soils. The ratio of trans to cis isomers of an unsaturated fatty acid, another bacterial stress indicator, decreased with increasingly dry conditions. Aspartic acid racemization ratios increased from 0.01 in the wetter soils to 0.1 in the driest soils, which is indicative of racemization rates comparable to de novo biosynthesis over long timescales (∼10,000 years). The content and integrity of stress proteins profiled by immunoassays were additional indicators that biomass in the driest soils is not recycled at significant levels. Together, our results point to minimal or no in situ microbial growth in the driest surface soils of the Atacama, and any metabolic activity is likely to be basal for cellular repair and maintenance only. Our data add to a growing body of evidence that the driest Atacama surface soils represent a threshold for long-term habitability (i.e., growth and reproduction). These results place constraints on the potential for extant life on the surface of Mars, which is 100-1000 times drier than the driest regions in the Atacama. Key Words: Atacama Desert-Dryness-Growth-Habitability-Biomarker-Mars. Astrobiology 18, 955-966.


Effect of ethanolic extract of leaves of Paederia foetida Linn. on acetic acid induced colitis in albino rats.
To evaluate the effect of ethanolic extract of leaves of Paederia foetida on acetic acid induced colitis in albino rats. Ethanolic extract of Paederia foetida (EEPF) was prepared by percolation method. Acute toxicity test was done by using Organization for Economic Cooperation and Development guidelines. Albino rats were divided into four groups of five animals each. Groups A and B received 3% gum acacia. Groups C and D received EEPF 500 mg/kg body weight (BW) and 5-aminosalisylic acid 100 mg/kg BW respectively. Colitis was induced by transrectal administration of 4% acetic acid on 5(th) day. All animals were sacrificed after 48 h of colitis induction and distal 10 cm of the colon was dissected. Colon was weighed for disease activity index (DAI) and scored macroscopically and microscopically. Biochemical assessment of tissue myeloperoxidase (MPO), catalase (CAT) and superoxide dismutase (SOD) was done in colonic tissue homogenate and malondialdehyde (MDA) was estimated in serum. P. foetida showed significant (P < 0.05) reduction in DAI, macroscopic and microscopic lesion score as well as significant (P < 0.05) improvement in MPO, MDA, CAT, and SOD level as compared to Group B. The ethanolic extract of leaves of P. foetida showed significant amelioration of experimentally induced colitis, which may be attributed to its anti-inflammatory and antioxidant property.


Effective connectivity during processing of facial affect: evidence for multiple parallel pathways.
The perception of facial affect engages a distributed cortical network. We used functional magnetic resonance imaging and dynamic causal modeling to characterize effective connectivity during explicit (conscious) categorization of affective stimuli in the human brain. Specifically, we examined the modulation of connectivity from posterior regions of the face-processing network to the lateral ventral prefrontal cortex (VPFC) during affective categorization and we tested for a potential role of the amygdala (AMG) in mediating this modulation. We found that explicit processing of facial affect led to prominent modulation (increase) in the effective connectivity from the inferior occipital gyrus (IOG) to the VPFC, while there was less evidence for modulation of the afferent connections from fusiform gyrus and AMG to VPFC. More specifically, the forward connection from IOG to the VPFC exhibited a selective increase under anger (as opposed to fear or sadness). Furthermore, Bayesian model comparison suggested that the modulation of afferent connections to the VPFC was mediated directly by facial affect, as opposed to an indirect modulation mediated by the AMG. Our results thus suggest that affective information is conveyed to the VPFC along multiple parallel pathways and that AMG activity is not sufficient to account for the gating of information transfer to the VPFC during explicit emotional processing.


Implementation of case management to reduce cardiovascular disease risk in the Stanford and San Mateo Heart to Heart randomized controlled trial: study protocol and baseline characteristics.
Case management has emerged as a promising alternative approach to supplement traditional one-on-one sessions between patients and doctors for improving the quality of care in chronic diseases such as coronary heart disease (CHD). However, data are lacking in terms of its efficacy and cost-effectiveness when implemented in ethnic and low-income populations. The Stanford and San Mateo Heart to Heart (HTH) project is a randomized controlled clinical trial designed to rigorously evaluate the efficacy and cost-effectiveness of a multi-risk cardiovascular case management program in low-income, primarily ethnic minority patients served by a local county health care system in California. Randomization occurred at the patient level. The primary outcome measure is the absolute CHD risk over 10 years. Secondary outcome measures include adherence to guidelines on CHD prevention practice. We documented the study design, methodology, and baseline sociodemographic, clinical and lifestyle characteristics of 419 participants. We achieved equal distributions of the sociodemographic, biophysical and lifestyle characteristics between the two randomization groups. HTH participants had a mean age of 56 years, 63% were Latinos/Hispanics, 65% female, 61% less educated, and 62% were not employed. Twenty percent of participants reported having a prior cardiovascular event. 10-year CHD risk averaged 18% in men and 13% in women despite a modest low-density lipoprotein cholesterol level and a high on-treatment percentage at baseline. Sixty-three percent of participants were diagnosed with diabetes and an additional 22% had metabolic syndrome. In addition, many participants had depressed high-density lipoprotein (HDL) cholesterol levels and elevated values of total cholesterol-to-HDL ratio, triglycerides, triglyceride-to-HDL ratio, and blood pressure. Furthermore, nearly 70% of participants were obese, 45% had a family history of CHD or stroke, and 16% were current smokers. We have recruited an ethnically diverse, low-income cohort in which to implement a case management approach and test its efficacy and cost-effectiveness. HTH will advance the scientific understanding of better strategies for CHD prevention among these priority subpopulations and aid in guiding future practice that will reduce health disparities.


Hydrogen sensing with diameter- and chirality-sorted carbon nanotubes.
The work function of palladium is known to be sensitive to hydrogen by the formation of a surface dipole layer or Pd hydride. One approach to detect such a change in the work function can be based on the formation of a Schottky barrier between the palladium metal and a semiconductor. Here, we study the hydrogen sensitivity of Schottky barrier field-effect transistors made for the first time from diameter- and chirality-sorted semiconducting single-walled carbon nanotubes (s-SWNTs) in contact with Pd electrodes. We observe an unrivaled 100-fold change in the on-state conductance at 100 ppm H2 compared to air for devices with s-SWNT and diameters between 1 and 1.6 nm. Hydrogen sensing is not observed for devices of Pd-contacted few-layer graphene (FLG), as expected due to the absence of a significant Schottky barrier. Unexpectedly, we observe also a vanishing sensitivity for small-diameter SWNTs. We explain this observation by changes in the nanotube work function caused by spillover and chemisorption of atomic hydrogen onto small-diameter nanotubes. We also observe that long-term sensing stability is only achieved if the gate voltage is inverted periodically. Under constant gate bias, the sensitivity reduces with time, which we relate to gate screening by accumulated charges in the substrate.


The Importance of Computer Science for Public Health Training: An Opportunity and Call to Action.
A century ago, the Welch-Rose Report established a public health education system in the United States. Since then, the system has evolved to address emerging health needs and integrate new technologies. Today, personalized health technologies generate large amounts of data. Emerging computer science techniques, such as machine learning, present an opportunity to extract insights from these data that could help identify high-risk individuals and tailor health interventions and recommendations. As these technologies play a larger role in health promotion, collaboration between the public health and technology communities will become the norm. Offering public health trainees coursework in computer science alongside traditional public health disciplines will facilitate this evolution, improving public health's capacity to harness these technologies to improve population health.


Sliding friction at soft micropatterned elastomer interfaces.
In this paper, we present an experimental study of the friction between a smooth elastomer lens and an elastomer substrate micropatterned with hexagonal arrays of cylindrical pillars. Depending on the normal load, the surfaces can be in top or mixed contact. The friction force can be interpreted in terms of friction stresses in the full contact and top contact zones. The latter is higher than that on smooth surfaces evidencing the role of the elastic deformations of the surfaces in the dissipation processes.


Impact of Frailty on Clinical and Financial Outcomes Following Minor Lower Extremity Amputation: A Nationwide Analysis.
Frailty has been shown to portend worse outcomes in surgical patients. Our goal was to identify the impact of frailty on outcomes and resource utilization among patients undergoing minor lower extremity amputation in the United States. Using the Nationwide Readmission Database, we identified all adults undergoing a minor amputation between 2010 and 2015, and assessed 90-day outcomes, including readmission, reamputation, mortality, and cumulative hospitalization costs. Frailty was defined by International Classification of Diseases codes consistent with the ten frailty clusters as defined by the Johns Hopkins Adjusted Clinical Group System. Multivariable regression models were developed for risk adjustment. An estimated 302 798 patients (mean age = 61.8 years) were identified, of which 15.2% were categorized as Frail. Before adjustment, frailty was associated with increased rates of readmission (44% vs. 36%, P < .001) and in-hospital mortality (4% vs. 2%, P < .001). Frailty was also associated with increased cumulative costs of care ($39 417 vs. $27 244, P < .001). After risk adjustment, frailty remained an independent predictor of readmission (Adjusted odds ratio [AOR] 1.18, CI 1.14-1.23), in-hospital mortality (AOR 1.48, CI 1.34-1.65), and incremental costs (+$7 646, CI $6927-$8365). Frailty is an independent marker of worse outcomes following minor foot amputation, and may be utilized to direct quality improvement efforts.


Alternative Donor Transplantation with High-Dose Post-Transplantation Cyclophosphamide for Refractory Severe Aplastic Anemia.
Severe aplastic anemia (SAA) is a life-threatening hematopoietic stem cell disorder that is treated with bone marrow transplantation (BMT) or immunosuppressive therapy (IST). The management of patients with refractory SAA after IST is a major challenge. Alternative donor BMT is the best chance for cure in refractory SAA, but morbidity and mortality from graft failure and complications of graft-versus-host disease (GVHD) have limited enthusiasm for this approach. Here, we employed post-transplantation high-dose cyclophosphamide in an effort to safely expand the donor pool in 16 consecutive patients with refractory SAA who did not have a matched sibling donor. Between July 2011 and August 2016, 16 patients underwent allogeneic (allo) BMT for refractory SAA from 13 haploidentical donors and 3 unrelated donors. The nonmyeloablative conditioning regimen consisted of antithymocyte globulin, fludarabine, low-dose cyclophosphamide, and total body irradiation. Post-transplantation cyclophosphamide 50 mg/kg/day i.v. on days +3 and +4 was administered for GVHD prophylaxis. Additionally, patients received mycophenolate mofetil on days +5 through 35 and tacrolimus from day +5 through 1 year. The median age of the patients at the time of transplantation was 30 (range, 11 to 69) years. The median time to neutrophil recovery over 1000 × 103/mm3 for 3 consecutive days was 19 (range, 16 to 27) days, to red cell engraftment was 25 (range, 2 to 58) days, and to last platelet transfusion to keep platelets counts over 50 × 103/mm3 was 27.5 (range, 22 to 108) days. Graft failure, primary or secondary, was not seen in any of the patients. All 16 patients are alive, transfusion independent, and without evidence of clonality. The median follow-up is 21 (range, 3 to 64) months. Two patients had grade 1 or 2 skin-only acute GVHD. These same 2 also had mild chronic GVHD of the skin/mouth requiring systemic steroids. One of these GVHD patients was able to come off all IST by 15 months and the other by 17 months. All other patients stopped IST at 1 year. Nonmyeloablative alloBMT using post-transplantation cyclophosphamide allowed for safe expansion of the donor pool to include HLA-haploidentical donors. This approach appears promising in refractory SAA patients. Importantly, engraftment was 100%, pre-existing clonal disease was eradicated, and the risk of GVHD was low.


RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection.
Innate immune signaling in the central nervous system (CNS) exhibits many remarkable specializations that vary across cell types and CNS regions. In the setting of neuroinvasive flavivirus infection, neurons employ the immunologic kinase receptor-interacting kinase 3 (RIPK3) to promote an antiviral transcriptional program, independently of the traditional function of this enzyme in promoting necroptotic cell death. However, while recent work has established roles for neuronal RIPK3 signaling in controlling mosquito-borne flavivirus infections, including West Nile virus and Zika virus, functions for RIPK3 signaling in the CNS during tick-borne flavivirus infection have not yet been explored. Here, we use a model of Langat virus (LGTV) encephalitis to show that RIPK3 signaling is specifically required in neurons of the cerebellum to control LGTV replication and restrict disease pathogenesis. This effect did not require the necroptotic executioner molecule mixed lineage kinase domain like protein (MLKL), a finding similar to previous observations in models of mosquito-borne flavivirus infection. However, control of LGTV infection required a unique, region-specific dependence on RIPK3 to promote expression of key antiviral interferon-stimulated genes (ISG) in the cerebellum. This RIPK3-mediated potentiation of ISG expression was associated with robust cell-intrinsic restriction of LGTV replication in cerebellar granule cell neurons. These findings further illuminate the complex roles of RIPK3 signaling in the coordination of neuroimmune responses to viral infection, as well as provide new insight into the mechanisms of region-specific innate immune signaling in the CNS.


Food engorgement in 35 dogs (2009-2013) compared with 36 dogs with gastric dilation and volvulus.
The clinical features and management of food engorgement (FE) in dogs have not been previously described. This retrospective observational study describes characteristics and outcome of 35 dogs with FE, and compares features on presentation to 36 dogs with gastric dilation and volvulus (GDV). Cases were retrospectively reviewed for history, clinical findings and outcome. Gastric distension was measured by caudal gastric margin (CGM), level with lumbar vertebrae, on a lateral abdominal radiograph. Frequent characteristics of dogs with FE included tachycardia, tachypnoea, hyperproteinaemia, increased base excess (BE), mild hypernatraemia and hyperlactataemia. There was overlap in CGM between dogs with GDV (CGM range L3 to >L6) and dogs with FE (CGM range <L2 to L5-L6). In contrast to dogs with GDV, lactate concentration in dogs with FE was not associated with CGM or BE. Dogs with FE mostly received medical intervention consisting of fluid therapy and analgesia, and all dogs survived to discharge. In conclusion, dogs with FE frequently presented with acid-base and electrolyte derangements, including hyperlactataemia. While dogs with FE can have gastric distension as severe as that seen with GDV, outcome with supportive care only is excellent.


Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG.
To combat the emergence of drug-resistant strains of Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening of a library of 594 hit compounds uncovered two leads that were active against M. tuberculosis in its replicating, non-replicating, and intracellular states: compounds 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide). Mutants resistant to both compounds harbored mutations in ethA (rv3854c), the gene encoding the monooxygenase EthA, and/or in pyrG (rv1699) coding for the CTP synthetase, PyrG. Biochemical investigations demonstrated that EthA is responsible for the activation of the compounds, and by mass spectrometry we identified the active metabolite of 7947882, which directly inhibits PyrG activity. Metabolomic studies revealed that pharmacological inhibition of PyrG strongly perturbs DNA and RNA biosynthesis, and other metabolic processes requiring nucleotides. Finally, the crystal structure of PyrG was solved, paving the way for rational drug design with this newly validated drug target.


CCSVI and MS: no meaning, no fact.
A condition called "chronic cerebrospinal venous insufficiency" (CCSVI) has been postulated to play a role in the pathogenesis of multiple sclerosis (MS). This hypothesis implies that a complex pattern of extracranial venous stenosis determines a venous reflux into the brain of MS patients, followed by increased intravenous pressure, blood-brain barrier breakdown and iron deposition into the brain parenchyma, thus triggering a local inflammatory response. In this review, we critically analyze the scientific basis of CCSVI, the current literature on the relationship between CCSVI and MS, as well as the ultrasound methodology that has been claimed to provide evidence of impaired cerebral venous drainage. We show that no piece of the CCSVI theory has a solid supportive scientific evidence. The CCSVI appears to be a rather alien condition and its existence should be definitely questioned. Finally, no proven (i.e., based on strict scientific methodology and on the rules of evidence-based medicine) therapeutic effect of the "liberation" procedure (unblocking the extracranial venous obstruction using angioplasty) has been shown up to date.


'Return to home cage' as a reward for maze learning in young and old genetically heterogeneous mice.
Recent studies have shown that 'return to home cage' can serve as a reward for maze learning in adult male mice. The present study examined whether the same reward is an effective motivator of learning in young and old mice and included females in the study design. We tested 25- and 65-d-old HS mice and 85- and 800-d-old B6D2F2 mice in a Lashley III maze. Return to home cage motivated maze acquisition in all groups. Compared with 65-d-old HS mice, 25-d-olds acquired the maze more slowly, took longer to achieve the test criterion, and showed increased latency to reach the goal box. There was no difference between 85- and 800-d-old B6D2F2 mice in rate of acquisition. This reward procedure may reduce the potentially confounding effects of deprivation or aversive stimuli on maze performance and may be suitable as a motivational procedure for a wide range of subject groups.


Emergent properties in small-scale societies.
A multi-agent simulation is used to explore the relationship between the micro and the macro levels in small-scale societies. The simulation demonstrates, using an African hunter-gatherer group (the !Kung san) as a case study, the way in which population stability may arise from culturally framed, micro-level decision making by women about spacing of births. According to the simulation, population stability as an emergent property has different implications, depending on resource density. Data on Australian hunter-gatherer groups are presented that support the implications of the simulation. !Kung san micro-level cultural rules on incestuous marriages are shown to have macro-level consequences in the form of marriages between residential camps. Between-camp marriages have significant implications for access to resources and thereby for population dynamics of the group as a whole.


Tissue-type plasminogen activator-plasmin-BDNF modulate glutamate-induced phase-shifts of the mouse suprachiasmatic circadian clock in vitro.
The mammalian circadian clock in the suprachiasmatic nucleus (SCN) maintains environmental synchrony through light signals transmitted by glutamate released from retinal ganglion terminals. Brain-derived neurotrophic factor (BDNF) is required for light/glutamate to reset the clock. In the hippocampus, BDNF is activated by the extracellular protease, plasmin, which is produced from plasminogen by tissue-type plasminogen activator (tPA). We provide data showing expression of proteins from the plasminogen activation cascade in the SCN and their involvement in circadian clock phase-resetting. Early night glutamate application to SCN-containing brain slices resets the circadian clock. Plasminogen activator inhibitor-1 (PAI-1) blocked these shifts in slices from wild-type mice but not mice lacking its stabilizing protein, vitronectin (VN). Plasmin, but not plasminogen, prevented inhibition by PAI-1. Both plasmin and active BDNF reversed alpha(2)-antiplasmin inhibition of glutamate-induced shifts. alpha(2)-Antiplasmin decreased the conversion of inactive to active BDNF in the SCN. Finally, both tPA and BDNF allowed daytime glutamate-induced phase-resetting. Together, these data are the first to demonstrate expression of these proteases in the SCN, their involvement in modulating photic phase-shifts, and their activation of BDNF in the SCN, a potential 'gating' mechanism for photic phase-resetting. These data also demonstrate a functional interaction between PAI-1 and VN in adult brain. Given the usual association of these proteins with the extracellular matrix, these data suggest new lines of investigation into the locations and processes modulating mammalian circadian clock phase-resetting.


Oxidation of aquatic pollutants by ferrous-oxalate complexes under dark aerobic conditions.
This study evaluates the ability of Fe(II)-oxalate complexes for the generation of OH through oxygen reduction and the oxidative degradation of aquatic pollutants under dark aerobic conditions (i.e., with oxygen but without light). The degradation of 4-chlorophenol (4-CP) was rapid in the mixture of Fe(2+) and oxalate prepared using ultrapure water, but was absent without either Fe(2+) or oxalate. The formation of Fe(II)-oxalate complexes enables two-electron reduction of oxygen to generate H2O2 and subsequent production of OH. The significant inhibition of 4-CP degradation in the presence of H2O2 and OH scavenger confirms such mechanisms. The degradation experiments with varying [Fe(2+)], [oxalate], and initial pH demonstrated that the degradation rate depends on [Fe(II)(Ox)2(2-)], but the degree of degradation is primarily determined by [Fe(II)(Ox)2(2-)]+[Fe(II)(Ox)(0)]. Efficient degradation of diverse aquatic pollutants, especially phenolic pollutants, was observed in the Fe(II)-oxalate complexes system, wherein the oxidation efficacy was primarily correlated with the reaction rate constant between pollutant and OH. The effect of various organic ligands (oxalate, citrate, EDTA, malonate, and acetate) on the degradation kinetics of 4-CP was investigated. The highest efficiency of oxalate for the oxidative degradation is attributed to its high capability to enhance the reducing power and low reactivity with OH.


Highly Sensitive Pulsed Digital Holography for Built-in Defect Analysis with a Laser Excitation.
A highly sensitive method is presented for noninvasive defect analysis on thin structures with a Q-switched double-pulsed ruby laser with frequency doubling (347 nm). In our research we feature an all-optical arrangement, where a focused laser pulse derived from the same ruby laser (694 nm) acts as a built-in synchronous excitation source for digital holographic interferometry. The recordings are made with a CCD camera for capturing two holograms (two states of the specimen) corresponding to the two UV laser pulses with a short time separation (10-50 mus). Subtraction of the phase distribution in two digital holograms gives a fringe phase map that shows the change in deformation of the specimen between the recordings. The advantage of the proposed method is two fold. First, the use of a shorter wavelength results in a higher sensitivity. Second, owing to the induced synchronous built-in optical excitation, the specimen is not subjected to any external physical excitation devices. Experimental results are presented on identification and evaluation of defects in thin metal sheets.


Socioeconomic inequalities in health during the Great Recession: A scoping review of the research literature.
Aims: The so-called 'Great Recession' in Europe triggered widespread concerns about population health, as reflected by an upsurge in empirical research on the health impacts of the economic crisis. A growing body of empirical studies has also been devoted to socioeconomic inequalities in health during the Great Recession. The aim of the current study is to summarise this health inequality literature by means of a scoping review. Methods: We have performed a scoping review of the research literature (English language) published in the years 2012-2017. Only empirical papers with (a) health status measured on the individual level, (b) information on socioeconomic position (i.e. employment status, educational level, income/wealth, and/or occupational class), and (c) data from European countries in both pre- and post-crisis years were considered relevant. In total, 49 empirical studies fulfilled these inclusion criteria. Results: The empirical findings in the 49 included studies predominantly show that socioeconomic inequalities in health either increased or remained stable from pre- to post-crisis years. Two-thirds (65%) of the studies found evidence of either increasing or partially increasing health inequalities. Thus, people in lower socioeconomic strata fared worse overall in terms of health during the Great Recession, compared to people with higher socioeconomic status. Conclusions: The Great Recession in Europe tends to be followed by increasing socioeconomic inequalities in health. Policymakers should take note of this finding. Widening socioeconomic inequalities in health is a major cause of concern, in particular if health deterioration among 'vulnerable groups' is caused by accelerating cumulative disadvantages.


Replication and meta-analysis of GWAS identified susceptibility loci in Kawasaki disease confirm the importance of B lymphoid tyrosine kinase (BLK) in disease susceptibility.
The BLK and CD40 loci have been associated with Kawasaki disease (KD) in two genome-wide association studies (GWAS) conducted in a Taiwanese population of Han Chinese ancestry (Taiwanese) and in Japanese cohorts. Here we build on these findings with replication studies of the BLK and CD40 loci in populations of Korean and European descent. The BLK region was significantly associated with KD susceptibility in both populations. Within the BLK gene the rs2736340-located linkage disequilibrium (LD ) comprising the promoter and first intron was strongly associated with KD, with the combined results of Asian studies including Taiwanese, Japanese, and Korean populations (2,539 KD patients and 7,021 controls) providing very compelling evidence of association (rs2736340, OR = 1.498, 1.354-1.657; P = 4.74×10(-31)). We determined the percentage of B cells present in the peripheral blood mononuclear cell (PBMC) population and the expression of BLK in the peripheral blood leukocytes (leukocytes) of KD patients during the acute and convalescent stages. The percentage of B cells in the PBMC population and the expression of BLK in leukocytes were induced in patients in the acute stage of KD. In B cell lines derived from KD patients, and in purified B cells from KD patients obtained during the acute stage, those with the risk allele of rs2736340 expressed significantly lower levels of BLK. These results suggest that peripheral B cells play a pathogenic role during the acute stage of KD. Decreased BLK expression in peripheral blood B cells may alter B cell function and predispose individuals to KD. These associative data suggest a role for B cells during acute KD. Understanding the functional implications may facilitate the development of B cell-mediated therapy for KD.


Anti-EGFR Agents: Current Status, Forecasts and Future Directions.
The epidermal growth factor receptor (EGFR) is one of the most important and attractive targets for specific anticancer therapies. It is a robust regulator of pathways involved in cancer pathogenesis and progression. Thus far, clinical trials have demonstrated the benefits of monoclonal antibodies and synthetic tyrosine kinase inhibitors in targeting this receptor; however, novel strategies are still being developed. This article reviews the current state of efforts in targeting the EGFR in cancer therapy. Following a brief characterization of EGFR, we will present a complete list of anti-EGFR agents that are already approved, and available in clinical practice. Aside from the indications, we will present the sales forecasts and expiry dates of product patents for the selected agents. Finally, we discuss the novel anti-EGFR strategies that are currently in preclinical development.


Epidemiology of blindness and visual impairment in the kingdom of Tonga.
Data on the prevalence and causes of blindness and visual impairment in Polynesians are not readily available nor are they population based. This survey was designed to obtain an accurate estimate of blindness and its causes in Tonga. A sample of 4056 persons, aged 20 years and over, was selected by stratified cluster sampling. Participants received a screening, visual acuity examination, and, if visually impaired, were referred for detailed ophthalmic examination to determine the cause. The prevalence of bilateral blindness in the study population was 0.47% and all affected were aged over 50 years. It is estimated that the national prevalence of bilateral blindness, adjusted for the sample weight applied in the selection procedure, is 0.56% (95% confidence interval 0-1.13). Monocular blindness was three times more frequent. Cataract was responsible for 68.4% of bilateral and 30.3% of monocular blindness. Risk factors for life time experience of cataract included age and diabetes (self-reported). Neither smoking nor the presence of pterygium were independently associated with cataract. Increasing years of education were protective against cataract for women, but not men. Corneal opacity from infection or trauma, and diabetes were responsible for most of the remaining visual impairment. While these results do not represent a significant public health problem by world standards they do provide a basis for planning blindness prevention programmes in the region.


Do spiritual patients want spiritual interventions?: A qualitative exploration of underserved cancer patients' perspectives on religion and spirituality.
This study examines religion and spirituality among advanced cancer patients from an underserved, ethnically-diverse population by exploring patient conceptualizations of religion and spirituality, the role of religion and spirituality in coping with cancer, and patient interest in spiritual support. Qualitative semi-structured interviews were conducted with patients who had participated in a study of a "mind-body" support group for patients with all cancer types. Analysis based on grounded theory was utilized to identify themes and theoretical constructs. With regard to patient conceptualizations of religion and spirituality, three categories emerged: (1) Spirituality is intertwined with organized religion; (2) Religion is one manifestation of the broader construct of spirituality; (3) Religion and spirituality are completely independent, with spirituality being desirable and religion not. Religion and spirituality played a central role in patients' coping with cancer, providing comfort, hope, and meaning. Patients diverged when it came to spiritual support, with some enthusiastic about interventions incorporating their spiritual values and others stating that they already get this support through religious communities. Spirituality plays a central role in the cancer experience of this underserved ethnically-diverse population. While spirituality seems to be a universal concern in advanced cancer patients, the meaning of spirituality differs across individuals, with some equating it with organized religion and others taking a more individualized approach. It is important that psychosocial interventions are developed to address this concern. Future research is needed to further explore the different ways that patients conceptualize spirituality and to develop spiritually-based treatments that are not "one size fits all."


Serum Thyrotropin Concentrations Are Not Associated with the Ankle-Brachial Index: Results from Three Population-Based Studies.
There is only limited data on the potential association between thyroid dysfunction and peripheral arterial disease (PAD). The aim of our study was to investigate the potential association of thyroid function, as defined by serum concentrations of the clinically used primary thyroid function marker thyrotropin [i.e. thyroid-stimulating hormone (TSH)] and 3,5-diiodothyronine (3,5-T2), with the ankle-brachial index (ABI) as a marker of PAD. We used data from 5,818 individuals from three cross-sectional population-based studies conducted in Northeast (SHIP-2 and SHIP-TREND) and Central Germany (CARLA). Measurement of serum TSH concentrations was conducted in one central laboratory for all three studies. In a randomly selected subpopulation of 750 individuals of SHIP-TREND, serum 3,5-T2 concentrations were measured with a recently developed immunoassay. ABI was measured either by a hand-held Doppler ultrasound using the Huntleigh Dopplex D900 or palpatorily by the OMRON HEM-705CP device. Serum TSH concentrations were not significantly associated with ABI values in any of the three studies. Likewise, groups of individuals with a TSH <0.3 mIU/l or with a TSH ≥3.0 mIU/l had no significantly different ABI values in comparison with individuals with a TSH in the reference range. Analyses regarding TSH within the reference range or serum 3,5-T2 concentrations did not reveal consistent significant associations with the ABI. No sex-specific associations were detected. The results of our study do not substantiate evidence for an association between thyroid function and PAD, but further studies are needed to investigate the associations of overt forms of thyroid dysfunction with PAD.


Ovarian steroids influence cell proliferation in the dentate gyrus of the adult female rat in a dose- and time-dependent manner.
In previous work, we have demonstrated that cell proliferation in the adult hippocampal formation is regulated by estrogen under both natural and experimental conditions. To determine the extent to which this regulation is affected by the dose or schedule of hormone treatment, or progesterone administration, we examined the impact of different acute and chronic ovarian hormone replacement regimens on cell production using the S-phase marker bromodeoxyuridine. Additionally, we investigated the long-term impact of surgical ovarian hormone depletion on the capacity of estrogen to stimulate cell proliferation and the production of new cells that express either TuJ1 (a marker of neuronal phenotype) or glial fibrillary acidic protein (GFAP; a marker of astroglial phenotype). Acute treatment with a moderate, but not a low or a high, dose of estrogen rapidly increased cell proliferation in ovariectomized (OVX) animals, an effect that was reversed by the administration of progesterone. In contrast, OVX animals that were chronically replaced with either estrogen alone (continuous or cyclic) or estrogen plus progesterone (cyclic) did not exhibit an estrogen-induced increase in cell proliferation 3 weeks following the onset of hormone replacement. In animals that were subjected to a prolonged absence of ovarian hormones, acute treatment with the moderate dose of estrogen failed to stimulate cell proliferation, and a decrease in the number of new cells expressing a neuronal phenotype was evident. Collectively, these results indicate that a prolonged reduction in ovarian hormones results in 1) a diminished responsiveness to estrogen over time in this system and 2) a decrease in neuron production that is unlikely to be reversible by standard regimens of hormone replacement.


Sexually explicit media exposure as a sexual milestone among gay, bisexual, and other men who have sex with men.
Gay, bisexual, and other men who have sex with men (GBMSM) remain at high risk of HIV infection via condomless anal sex. Sexually explicit media (SEM) likely influences GBMSM's sexual behavior and has been associated with condomless anal sex. SEM messages may be especially potent during formative developmental periods. We examined the association between age of first SEM exposure and condomless anal sex in a sample of adult GBMSM (N = 1,114) recruited using the Internet. Every 1-year delay in age of first SEM exposure resulted in a 3% decrease in the odds of engaging in condomless anal sex as an adult (odds ratio = .97, 95% CI [.95, .99], p = .01). This association remained significant in 3 separate multivariable models that controlled for age of sexual debut, age of anal sex debut, and current age, respectively. This association was moderated by ethnicity such that the effect was stronger among Latino men. GBMSM who were exposed to SEM earlier in their lives report more sexual risk behavior as adults. SEM exposure in GBMSM is an important sexual development milestone deserving further research. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Aberrant p53 alters DNA damage checkpoints in response to cisplatin: downregulation of CDK expression and activity.
The p53 tumor suppressor protein is a critical mediator of cell cycle arrest and apoptosis in response to genotoxic stress. Abrogation of p53 function is a major feature of tumor development and may result in a compromised DNA-damage response. In our study, we examined the effect of expressing a human p53 cDNA, encoding a histidine to leucine amino acid substitution at codon 179 (H179L), on the ability of wild-type p53-containing NIH3T3 cells to respond to treatment with the chemotherapeutic cisplatin. After 72 hr of cisplatin treatment control cells underwent apoptosis preceded by a combination of S- and G(2) arrest, as judged by flow cytometry of propidium iodide-stained cells, and TUNEL and caspase-3 assays. This correlated with increased expression of the pro-apoptotic protein Bax. In contrast, cells stably expressing H179L-p53 arrested in S-phase following cisplatin treatment, which correlated with a marked decrease in the expression of cdc2, cyclin B1 and cyclin A, and a decrease in CDK2 and cyclin A-associated kinase activity. Interestingly, H179L p53 expressing cells underwent apoptosis earlier than control cells, indicating that this aberrant p53 may enhance cisplatin chemosensitivity. These data suggest that dominant-negative p53 can influence the expression and activity of CDK complexes, thereby modifying cell behavior following cisplatin-induced genotoxicity.


Extensive adaptive changes occur in the transcriptome of Streptococcus agalactiae (group B streptococcus) in response to incubation with human blood.
To enhance understanding of how Streptococcus agalactiae (group B streptococcus, GBS) adapts during invasive infection, we performed a whole-genome transcriptome analysis after incubation with whole human blood. Global changes occurred in the GBS transcriptome rapidly in response to blood contact following shift from growth in a rich laboratory medium. Most (83%) of the significantly altered transcripts were down-regulated after 30 minutes of incubation in blood, and all functional categories of genes were abundantly represented. We observed complex dynamic changes in the expression of transcriptional regulators and stress response genes that allow GBS to rapidly adapt to blood. The transcripts of relatively few proven virulence genes were up-regulated during the first 90 minutes. However, a key discovery was that genes encoding proteins involved in interaction with the host coagulation/fibrinolysis system and bacterial-host interactions were rapidly up-regulated. Extensive transcript changes also occurred for genes involved in carbohydrate metabolism, including multi-functional proteins and regulators putatively involved in pathogenesis. Finally, we discovered that an incubation temperature closer to that occurring in patients with severe infection and high fever (40 degrees C) induced additional differences in the GBS transcriptome relative to normal body temperature (37 degrees C). Taken together, the data provide extensive new information about transcriptional adaptation of GBS exposed to human blood, a crucial step during GBS pathogenesis in invasive diseases, and identify many new leads for molecular pathogenesis research.