Breast size, thoracic kyphosis & thoracic spine pain - association & relevance of bra fitting in post-menopausal women: a correlational study.
Menopause would seem to exist as a period of accelerated changes for women and their upper torso mechanics. Whether these anthropometric changes reflect changes in pain states remains unclear. Plausible mechanisms of pain exist for the independent and combined effect of increasing breast size and thoracic kyphosis. Bra fit has the potential to change when the anthropometric measures (chest circumference and bust circumference) used to determine bra size change, such as postmenopausally.Identifying an association between breast size, thoracic kyphosis and thoracic spine pain in postmenopausal women and identifying the relevance of bra fit to this association may be of importance to the future management and education of post-menopausal women presenting clinically with thoracic spine pain. A cross-sectional study design. Fifty-one postmenopausal bra-wearing women were recruited. Measures included breast size (Triumph International), thoracic kyphosis (flexible curve), bra fitted (Y/N) and pain (Short Form McGill Pain Questionnaire) and tenderness on palpation (posteroanterior pressure testing). These measures were collected in one session at a physiotherapy clinic. The majority of the women in this study were overweight or obese and wearing an incorrect sized bra. Pain was significantly related to breast size, body weight and BMI at mid thoracic levels (T7-8). In contrast self-reported thoracic pain was not correlated with age or index of kyphosis (thoracic kyphosis). Women with thoracic pain were no more likely to have their bra professionally fitted whereas women with a higher BMI and larger breasts were more likely to have their bra professionally fitted. The findings of this study show that larger breasts and increased BMI are associated with thoracic pain in postmenopausal women. This is unrelated to thoracic kyphosis. Increasing breast size and how a bra is worn may have biomechanical implications for the loaded thoracic spine and surrounding musculature. Post-menopause women present with a spectrum of anthropometrical changes that have the potential to contribute to altered biomechanics and affect pain states in the thoracic spine.


Empirical evaluations of slice-timing, smoothing, and normalization effects in seed-based, resting-state functional magnetic resonance imaging analyses.
Recently, functional connectivity analyses using spontaneous functional magnetic resonance imaging (fMRI) fluctuations have been applied in the context of neurological and psychiatry diseases. In the analyses procedure, preprocessing steps are commonly utilized in exploring functional connectivity, the same strategy as what was conducted in the fMRI process. However, the effectiveness of these preprocessing steps on resting-state fMRI (rs-fMRI) was rarely investigated, and the significance of preprocessing steps on rs-fMRI needs to be studied. Therefore, the main purpose of the current study was to evaluate the effects of multiple preprocessing procedures, including slice-timing correction, smoothing, and spatial normalization, on rs-fMRI signal. Through a seed-based correlation analysis on the motor network, we empirically estimated three indices of spontaneous fMRI fluctuations induced: correlation coefficients (CC), amplitude of low-frequency fluctuations (ALFFs), and fractional ALFF (fALFF), with different strategies of three preprocessing steps. Multiple repetition times (TRs = 2, 3, 4 sec) were also compared to address the issue of temporal mismatch. In the temporal preprocess, we found that the use of slice-timing correction and different TRs had minimal effects on CC and fALFF. However, ALFF was significantly affected using different TR but not affected by slice-timing correction as well. In the spatial preprocess, fALFF was insensitive to both smoothing and normalization. Smoothing consistently increased spatial extents and CC, but suppressed ALFF values. Performing normalization before index calculations provided better spatial sensitivity with larger variability in ALFF, whereas performing normalization after index calculations might preserve the ALFF level as in the unnormalized data. Conclusively, the effects of choosing preprocessing parameters and strategies were presented in the current study, providing practical considerations when conducting rs-fMRI analyses.


Use of ejection fraction tests and coronary angiography in patients with heart failure.
To examine the use of tests that measure ejection fraction (EF) and the use of coronary angiography among patients with an initial diagnosis of heart failure (HF). All potential cases of incident HF in Olmsted County, Minnesota, between 1979 and 1999 were identifled. In a random sample of cases validated with the Framingham criteria, we examined the frequency of tests that measure EF (echocardiography, radionuclide ventriculography, and left ventricular angiography) and coronary angiography within 90 days after diagnosis. A total of 655 patients with incident HF were included in the analysis. The use of tests that measure EF and coronary angiography increased early in the study period but stabilized thereafter. In the most recent years (1995-1999), EF was measured in 65% of the patients and coronary angiography performed in 12%. After adjustment for year of diagnosis, body mass index, hypertension, diabetes mellitus, smoking, hyperlipidemia, comorbidity, prior myocardial infarction, and prior angina, men were more likely than women to have EF measured (odds ratio [OR], 1.47; 95% confidence interval [CI], 1.01-2.16) and coronary angiography (OR, 2.61; 95% CI, 1.43-4.76). Increasing age was associated with less use of tests (OR, 0.83; 95% CI, 0.76-0.91; for EF measurement; OR, 0.72; 95% CI, 0.63-0.82; for coronary angiography for every 5-year increase in age). Among patients with HF, tests that measure EF are used substantially less than recommended, and coronary angiograms are used infrequently. Use was particularly low in women and elderly patients. Given the potential benefits of such tests, including more appropriate therapy and more objective monitoring of ventricular function, outcomes in persons with HF may be improved with more consistent use.


Asparaginase dosing for obese patients with acute lymphoblastic leukemia and factors that contribute to outcomes.
Asparaginase in various forms is a standard part of the treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. However, its use is more selective in adults. One of the key reasons is the toxicity observed from this class of agents. In a series of recent post hoc analyses of large prospective studies, obesity has emerged as a key factor that contributes to the challenges with administering regimens that include asparaginase. In this review, the most salient findings are highlighted from these latest publications, both from the pediatric and adult literature. These data are consolidated into recommendations for clinicians who treat adults with ALL, including proposals for how treatment may be modified to try to account for these complications. Lastly, avenues for future investigation are proposed in an attempt to narrow our knowledge gaps in this field, with the goal of safer and more effective treatment for adults with obesity who develop ALL.


[Significance of Tim-3 and Its Ligand Galectin-9 in Th1/Th2 Imbalance in Patients with Multiple Myeloma].
To investigate the significance of Tim-3 and Galectin-9 in Th1/Th2 imbalance in patients with multiple myeloma (MM). 55 newly diagnosed MM patients and 20 healthy controls were included. Flow cytometry was used to detect the expression of Tim-3 on CD4+T cells, the proportion of Th1, Th2, Tim-3+Th1 and Tim-3+Th2 cells in peripheral blood. ELISA was used to detect the levels of cytokines IFN-γ and IL-4 in serum, and PCR was used to detect the level of Galectin-9 mRNA. Then the correlations between Galectin-9 mRNA expression and Th-cell subsets and related cytokine levels, as well as the relationship between Tim-3+Th1/Tim-3+Th2 ratio and corresponding clinical features were analyzed. Compared with the control group, the expression of Tim-3 on CD4+T cells in peripheral blood of MM patients was significantly increased (P<0.05), the proportions of Tim-3+Th1 cells, Tim-3+Th2 cells and Tim-3+Th1/Tim-3+Th2 ratio in MM patients were also increased (P<0.05), while the proportion of Th1 cells and Th1/Th2 ratio in MM patients were significantly decreased (P<0.05). The level of cytokine IFN-γ and IFN-γ/IL-4 ratio in MM patients were significantly decreased (P<0.05), while the level of cytokine IL-4 was increased (P<0.05). The mRNA levels of Galectin-9 in MM patients were significantly increased (P<0.05). The levels of Galectin-9 mRNA were positively correlated with Tim-3+CD4+T cells (r=0.663), Tim-3+Th2 cells (r=0.492) and IL-4 (r=0.470), while negatively correlated with IFN-γ (r=-0.593). The ratios of Tim-3+Th1/Tim-3+Th2 in MM patients were positively correlated with ISS stage (r=0.511), osteolytic damage (r=0.556) and chromosome abnormality (r=0.632). These results suggest that Tim-3 and Galectin-9 are involved in Th1/Th2 imbalance in MM patients, and the high ratio of Tim-3+Th1/Tim-3+Th2 is associated with poor clinical prognosis.


[Lamivudine for the treatment of patients with chronic hepatitis with negative hepatitis B AgHbe].
It is estimated that chronic hepatitis B affects to than 350 million people around the world. Patients with AgHB- minus account, in some areas, for between 50-80% of the total of the population with chronic hepatitis B. Spontaneous clearance is rare within these patients, the response to interferon is low and the probability of developing cirrhosis and hepatocarcinoma is higher than in the wild type. To analyze the response to lamivudine treatment in patients with chronic hepatitis B which are AgHB negative. Seven of the 9 patients which were treated in our department for more than 3 months were AgHB negative. Six of them responded to the treatment in an average time of 3.5 months (range 1-6 months). There were two patients that relapsed at 18 and 24 months and they were treated with adefovir. Four patients remained DNA negative and had normal aminotransferases values after an average treatment time of 25 months. In our series, the majority of the patients (77.7%) were AgHB negative at the beginning of treatment. The efficacy of the treatment with lamivudine in these cases is high (85.7%) and with an early response (average 3.5 months). One third of patients treated relapsed after one and a half years of treatment.


Factors that accelerate or retard red blood cell senescence.
This article explores information concerning alterations in the time of age-related red blood cell (rbc) death (rbc senescence) in experimental animals and humans. Those factors that accelerate or retard the mean time for senescent death [the mean potential rbc life-span, (T)] are discussed; specifically excluded are conditions in which rbc survival is shortened due to an increase in the rate of age-independent [random hemolysis, (k)]rbc death. The factors prolonging senescence are reduction in metabolic rate through hibernation, reduced environmental temperature, hypophysectomy and thyroidectomy, and splenectomy. In general, these processes prolong rbc senescence by about 10%-15% in the models studied to date. The failure of splenectomy to prolong rbc senescence to any physiologically meaningful extent casts serious doubt on the concept that splenic processes are a major factor in the senescence process. Rbcs made under conditions of increased erythropoiesis and/or increased metabolic rate show acceleration of senescence. Thus, rbcs of animals treated with thyroxine show a 15% acceleration of senescence. "Stress reticulocytes" and normal full-term human newborn rbc may show up to 25% reduction in (T). The maximum acceleration seen to date is 50%-90%, as seen in the rbcs of the fetal and newborn rat. rbc senescence is not accelerated in rats with splenomegaly and increased rates of random hemolysis, again casting strong doubts on the spleen's ability to alter rbc senescence by progressively modifying the rbc during successive passages through that organ. It is postulated that rbc senescence is mainly a function of the red cell's initial endowment, particularly in the dynamic ability of that cell (and its membrane) to adapt to cumulative stresses that exist during its circulation through the body.


Do "Moderate" Drinkers Have Reduced Mortality Risk? A Systematic Review and Meta-Analysis of Alcohol Consumption and All-Cause Mortality.
Previous meta-analyses of cohort studies indicate a J-shaped relationship between alcohol consumption and allcause mortality, with reduced risk for low-volume drinkers. However, low-volume drinkers may appear healthy only because the "abstainers" with whom they are compared are biased toward ill health. The purpose of this study was to determine whether misclassifying former and occasional drinkers as abstainers and other potentially confounding study characteristics underlie observed positive health outcomes for lowvolume drinkers in prospective studies of all-cause mortality. A systematic review and meta-regression analysis of studies investigating alcohol use and mortality risk after controlling for quality-related study characteristics was conducted in a population of 3,998,626 individuals, among whom 367,103 deaths were recorded. Without adjustment, meta-analysis of all 87 included studies replicated the classic J-shaped curve, with low-volume drinkers (1.3-24.9 g ethanol per day) having reduced mortality risk (RR = 0.86, 95% CI [0.83, 0.90]). Occasional drinkers (<1.3 g per day) had similar mortality risk (RR = 0.84, 95% CI [0.79, 0.89]), and former drinkers had elevated risk (RR = 1.22, 95% CI [1.14, 1.31]). After adjustment for abstainer biases and quality-related study characteristics, no significant reduction in mortality risk was observed for low-volume drinkers (RR = 0.97, 95% CI [0.88, 1.07]). Analyses of higher-quality bias-free studies also failed to find reduced mortality risk for low-volume alcohol drinkers. Risk estimates for occasional drinkers were similar to those for low- and medium-volume drinkers. Estimates of mortality risk from alcohol are significantly altered by study design and characteristics. Meta-analyses adjusting for these factors find that low-volume alcohol consumption has no net mortality benefit compared with lifetime abstention or occasional drinking. These findings have implications for public policy, the formulation of low-risk drinking guidelines, and future research on alcohol and health.


Specialized function of carbonic anhydrase-rich and granular cells of turtle bladder.
The mucosal surface of the turtle bladder consists of two major cell types, carbonic anhydrase-rich (CA) and granular (G) cells. These cells types may have specific transport functions. To separate and study these cells, they were removed from the bladder by collagenase digestion and then separated into two distant subpopulations by Ficoll discontinuous density-gradient centrifugation. By morphological criteria the lighter subpopulation (band II) consists primarily of CA cells and the denser population (band III) G cells. The distribution of two enzymes important for H+ transport, CA and glucose-6-phosphate dehydrogenase (G-6-PD), and the effect of specific transport inhibitors, acetazolamide and ouabain, on O2 consumption of these cells was examined. The CA activity of band II cells was 4.5 times greater than that of band III cells. The G-6-PD activity of band II cells was 2.2 times greater than that of band III cells. The rate of O2 consumption of band II cells, 4.73 microliters.mg protein-1.h-1, was reduced 40% by 5 X 10(-5) M acetazolamide but not by ouabain. Band III O2 consumption, 3.43 microliters.mg protein-1.h-1, was reduced 30% by 10(-4) M ouabain but not by acetazolamide. On the basis of the distribution of CA and G-6-PD and the effect of acetazolamide and ouabain on O2 consumption, we propose that CA cells are primarily responsible for H+ transport and G cells for Na+ transport.


5-methoxyuridine: a new minor constituent located in the first position of the anticodon of tRNAAla, tRNAThr, and tRNAVal from Bacillus subtilis.
The sequences of the anticodon of tRNAAla, tRNAThr, and tRNAVal from Bacillus subtilis W 168 were N-G-C, N-G-U, and N-A-C, respectively. A new minor constituent, N, occupied the first position of the anticodon of each tRNA. N was indentified as 5-methoxyuridine (mo5U, Figure 1) by comparison of its UV absorption spectra, Rf values in thin-layer chromatography using several solvent systems and mass spectra with those of chemically synthesized specimen.


The Molecular Mechanisms Employed by the Parasite Myxobolus bejeranoi (Cnidaria: Myxozoa) from Invasion through Sporulation for Successful Proliferation in Its Fish Host.
Myxozoa is a unique group of obligate endoparasites in the phylum Cnidaria that can cause emerging diseases in wild and cultured fish populations. Recently, we identified a new myxozoan species, Myxobolus bejeranoi, which infects the gills of cultured tilapia while suppressing host immunity. To uncover the molecular mechanisms underlying this successful parasitic strategy, we conducted transcriptomics analysis of M. bejeranoi throughout the infection. Our results show that histones, which are essential for accelerated cell division, are highly expressed even one day after invasion. As the infection progressed, conserved parasitic genes that are known to modulate the host immune reaction in different parasitic taxa were upregulated. These genes included energy-related glycolytic enzymes, as well as calreticulin, proteases, and miRNA biogenesis proteins. Interestingly, myxozoan calreticulin formed a distinct phylogenetic clade apart from other cnidarians, suggesting a possible function in parasite pathogenesis. Sporogenesis was in its final stages 20 days post-exposure, as spore-specific markers were highly expressed. Lastly, we provide the first catalog of transcription factors in a Myxozoa species, which is minimized compared to free-living cnidarians and is dominated by homeodomain types. Overall, these molecular insights into myxozoan infection support the concept that parasitic strategies are a result of convergent evolution.


Phenolic fraction of tobacco smoke inhibits BPDE-induced apoptosis response and potentiates cell transformation: role of attenuation of p53 response.
Polynuclear aromatic hydrocarbons (PAHs) present in tobacco smoke are regarded as chemical carcinogens. Previously, we observed that a weakly acidic phenolic fraction of tobacco smoke condensate (TSCPhFr), which is devoid of PAHs, significantly potentiates (±)-anti-BP-7,8-diol-9,10-epoxide (BPDE)-induced anchorage-independent cell growth of promotion-sensitive JB6 cell, indicating its tumor-promoting potential. In the present article, we report that further fractionation of phenolic components from TSCPhFr did not show any significant potentiation of BPDE-induced cell transformation by any of the HPLC-purified phenolic fractions, indicating several phenolic components as a whole are needed for observed activity. Although the tumor-promoting activity of weakly acidic phenolic fraction of tobacco smoke had been indicated long before, no studies have been pursued to understand the mechanism(s) underlying the tumor-promoting activity of TSCPhFr. We observed that BPDE, an ultimate carcinogenic metabolite of tobacco smoke carcinogen benzo[a]pyrene, elicits apoptosis induction, which is significantly inhibited by TSCPhFr. Increased cell transformation and decreased apoptosis by TSCPhFr were associated with attenuation of BPDE-induced p53 accumulation. JB6 cells transfected with p53 siRNA showed significantly less apoptosis induction by BPDE as compared to control cells. In p53 impaired cells (which are observed to have a faster growth rate as compared to normal cells), TSCPhFr has a practically negligible effect on apoptosis induction in response to BPDE. Also, in p53 null HCT116 p53(-/-) cells, BPDE-induced apoptosis is unresponsive to TSCPhFr. Inhibition of BPDE-induced NF-κB activation was also observed by us previously. Interestingly, treatment of cells with NF-κB-specific inhibitor IKK-NBD peptide showed no effect on BPDE-induced apoptosis, whereas TSCPhFr showed moderate inhibition of apoptosis in NF-κB inhibited cells as compared to control cells. Our observations indicate that attenuation of BPDE-induced p53 response has a role in apoptosis inhibition and increased cell transformation by TSCPhFr. These findings have implication with regard to the underlying mechanism of tumor-promoting activity of TSCPhFr in PAH-induced carcinogenesis. Although p53-mediated NF-κB activation has a role in apoptosis induction, the role of NF-κB in TSCPhFr-mediated potentiation of PAH-induced cell transformation is not clear from our studies.


Differential patterns of memory loss among patients with Alzheimer's disease, Huntington's disease, and alcoholic Korsakoff's syndrome.
Patients with Huntington's disease (HD), alcoholic Korsakoff's syndrome (KS), and Alzheimer's disease (AD) were compared with normal control subjects on a task designed to assess recognition memory for different classes of stimuli: spatial, verbal, color, pattern, and facial. In addition, recall of verbal stimuli was assessed at two delay intervals. On recognition testing, AD and KS patients were impaired on each of the five stimulus conditions. However, HD patients, though impaired on four of the recognition conditions, were unimpaired when verbal stimuli were used. On recall testing, the AD, HD, and KS groups were equally impaired at the shorter delay (15 s). However, at the longer delay (two minutes), the KS and HD patients, though still impaired relative to the normal control group, performed significantly better than the AD group.


Cardiac allograft vasculopathy after heart transplantation: risk factors and management.
Cardiovascular disease post-transplant, particularly ischemic heart disease, is a significant problem for all transplant recipients. The major risk factors-smoking, obesity, diabetes, dyslipidemia and hypertension-are often more prevalent in heart transplant populations than in the general population. One of the main risk factors influencing graft loss and patient survival is cardiac allograft vasculopathy (CAV). Because CAV affects between 30% and 60% of cardiac transplant recipients within 5 years of surgery, prevention is a key focus for cardiac transplant teams today. CAV is caused by both immunologic mechanisms (e.g., acute rejection and anti-HLA antibodies) and non-immunologic mechanisms relating to the transplant itself or the recipient (e.g., donor age, hypertension, hyperlipidemia and pre-existing diabetes) or to the side effects often associated with immunosuppression with calcineurin inhibitors or corticosteroids (e.g., cytomegalovirus infection, nephrotoxicity and new-onset diabetes after transplantation). The calcineurin inhibitors, cyclosporine and tacrolimus, effectively prevent acute rejection, but do not prevent the development of CAV. CAV prevention will require a combined approach of new adjunct immunosuppressant agents (e.g., the proliferation signal inhibitors) and reduction in cardiovascular risk. Hypertension, hyperlipidemia and diabetes are also associated with the immunosuppression required to prevent organ rejection. Some studies have shown that hypertension is present more frequently in cyclosporine-treated patients than in tacrolimus-treated patients and that tacrolimus may be associated with a more favorable lipid profile. On the other hand, tacrolimus may be more diabetogenic than cyclosporine with current data suggesting a trend but no statistically significant supporting evidence. New-onset diabetes after transplantation is at times difficult to manage and may be an important determinant along with hypertension and hyperlipidemia of ischemic heart disease, cerebrovascular disease and peripheral vascular disease. The choice of calcineurin inhibitor for an immunosuppressive regimen in heart transplantation should consider the associated relative cardiovascular risks.


Evaluation and treatment of constipation in children and adolescents.
Childhood constipation is common and almost always functional without an organic etiology. Stool retention can lead to fecal incontinence in some patients. Often, a medical history and physical examination are sufficient to diagnose functional constipation. Further evaluation for Hirschsprung disease, a spinal cord abnormality, or a metabolic disorder may be warranted in a child with red flags, such as onset before one month of age, delayed passage of meconium after birth, failure to thrive, explosive stools, and severe abdominal distension. Successful therapy requires prevention and treatment of fecal impaction, with oral laxatives or rectal therapies. Polyethylene glycol-based solutions have become the mainstay of therapy, although other options, such as other osmotic or stimulant laxatives, are available. An increase in dietary fiber may improve the likelihood that laxatives can be discontinued in the future. Education is equally important as medical therapy and should include counseling families to recognize withholding behaviors; to use behavior interventions, such as regular toileting and reward systems; and to expect a chronic course with prolonged therapy, frequent relapses, and a need for close follow-up. Referral to a subspecialist is recommended only when there is concern for organic disease or when the constipation persists despite adequate therapy.


Quantitative evaluation and modeling of two-dimensional neovascular network complexity: the surface fractal dimension.
Modeling the complex development and growth of tumor angiogenesis using mathematics and biological data is a burgeoning area of cancer research. Architectural complexity is the main feature of every anatomical system, including organs, tissues, cells and sub-cellular entities. The vascular system is a complex network whose geometrical characteristics cannot be properly defined using the principles of Euclidean geometry, which is only capable of interpreting regular and smooth objects that are almost impossible to find in Nature. However, fractal geometry is a more powerful means of quantifying the spatial complexity of real objects. This paper introduces the surface fractal dimension (Ds) as a numerical index of the two-dimensional (2-D) geometrical complexity of tumor vascular networks, and their behavior during computer-simulated changes in vessel density and distribution. We show that Ds significantly depends on the number of vessels and their pattern of distribution. This demonstrates that the quantitative evaluation of the 2-D geometrical complexity of tumor vascular systems can be useful not only to measure its complex architecture, but also to model its development and growth. Studying the fractal properties of neovascularity induces reflections upon the real significance of the complex form of branched anatomical structures, in an attempt to define more appropriate methods of describing them quantitatively. This knowledge can be used to predict the aggressiveness of malignant tumors and design compounds that can halt the process of angiogenesis and influence tumor growth.


A callosal disconnection syndrome of vascular origin.
To study the after-effects of a selective lesion of the corpus callosum on the capacity in transferring spatial information on arm posture derived from kinesthesia and vision. Neuropsychological and psychophysical evaluations of a patient with callosal damage. Institute of Neurology, University of "Tor Vergata", Rome, Italy and Research Centre, IRCCS "S. Lucia", Rome, Italy. P.V., a 59 years old man suffering from a vascular lesion of the left half of corpus callosum and left callosal radiations. Sensori-motor and cognitive tasks. Exo- and egocentric pointing abilities tasks. Impairments due to a disconnection between the two cerebral hemispheres were pointed out. About pointing abilities, errors were greater when each hand pointed to the remembered location of the other hand. Errors decreased dramatically with eyes open for right hand pointing to remembered location of left and right hand, and left hand pointing to remembered location of left hand. Open eyes left hand pointing to remembered location of right hand remained as poor as with eyes closed. The results appear compatible with the following network: visual information from striate and extrastriate cortex is passed forward to parietal cortex bilaterally (even in PV due to the splenium sparing). Kinesthetic information from parietal cortex of left and right hemisphere converge on a single visuokinesthetic center, lateralized to the left hemisphere. Information about limb position in three-dimensional space is then encoded in body-centered coordinates and passed forward to motor and premotor cortex in the frontal lobe. These frontal regions are those disconnected in PV.


Cross-sectional analysis of the correlation between serum uric acid and trabecular bone score: NHANES 2005-2008.
Serum uric acid (SUA) has been discovered to be associated with bone mineral density (BMD), but its relationship with trabecular bone score (TBS) remains unclear. Thus, the aim of our study was to investigate the association between SUA levels and TBS. Our study included 5895 individuals over 20 years old (3061 men and 2834 women) from NHANES 2005-2008. To analyze the association between SUA and TBS, multivariate linear regression models with covariate adjustments were applied. Furthermore, population description, stratified analysis, single factor analysis, smooth curve fitting, interaction analysis, and threshold effect and saturation effect analysis were also conducted. After adjusting for covariates, SUA showed a strong negative relationship with total TBS (β = 0.319; 95% CI 0.145-0.494; P < 0.001). The relationship between SUA levels and total TBS was found to be nonlinear, with inflection points at 4.8 mg/dL for the overall population, 4.2 mg/dL for women, and 5.7 mg/dL for non-Hispanic whites, indicating a saturation effect. Additionally, no interactions were found in any of the subgroups. Our study found a negative association between SUA and total TBS in adults. Maintaining SUA at a saturated level can benefit in preventing osteoporosis and fractures.


Exposure-Response Assessment of Enzalutamide and Its Major Metabolites in a Real-World Cohort of Patients with Metastatic Castration-Resistant Prostate Cancer.
Enzalutamide is an oral agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC); N-desmethyl enzalutamide is its active metabolite, which has clinically relevant anti-androgen capacities similar to enzalutamide, and carboxylic acid enzalutamide is an inactive metabolite. The aim of our study was to investigate the relationship between enzalutamide and N-desmethyl enzalutamide exposure and treatment response in a real-world cohort of patients with mCRPC. Retrospective, observational, pharmacokinetic study. Outpatient clinic at a tertiary cancer center in Amsterdam, the Netherlands. Sixty-five patients with mCRPC who were treated with enzalutamide 160 mg daily and had at least one steady-state enzalutamide plasma concentration between May 2015 and June 2018; of these patients, 38 were prostate-specific antigen (PSA) responders and 27 were nonresponders. Plasma concentrations, determined by using liquid chromatography with tandem mass spectrometry (LC-MS/MS), were compared between PSA responders and nonresponders. Three clinical end points were evaluated separately in this study: PSA-independent progression-free survival (PFS), time to PSA progression (TTPP), and rate of PSA response (defined as ≥ 50% decrease in PSA level from baseline). Enzalutamide toxicity was defined as discontinuation due to adverse events, dose reductions due to adverse events, or temporary treatment interruption. For these analyses, plasma concentrations of enzalutamide and N-desmethyl enzalutamide were divided into quartiles. Mean ± SD plasma concentrations in the 65 patients were as follows: enzalutamide 11.2 ± 2.8 μg/ml, N-desmethyl enzalutamide 9.9 ± 2.9 μg/ml, and carboxylic acid enzalutamide 6.1 ± 4.3 μg/ml. Plasma concentrations were not significantly different in the PSA responder versus nonresponder groups for enzalutamide (11.5 vs 10.6 μg/ml, p=0.20), N-desmethyl enzalutamide (10.1 vs 9.6 μg/ml, p=0.48), and carboxylic acid enzalutamide (6.5 vs 5.5 μg/ml, p=0.34). Univariate and multivariate analyses did not show a relationship between plasma concentrations and PSA-independent PFS, TTPP, or toxicity. This study confirmed that enzalutamide plasma concentrations were not related to PSA-independent PFS, TTPP, or toxicity in patients with mCRPC, and demonstrated that plasma concentrations of its major metabolites were also not associated with treatment response. Based on these findings, there is no role for therapeutic drug monitoring of enzalutamide in patients with mCRPC in daily practice.


A sex difference in hepatic glutathione S-transferase B and the effect of hypophysectomy.
The glutathione S-transferases are a group of proteins with overlapping substrate specificities and ligand-binding capacities. This report examines certain approaches to the measurement of transferase B (ligandin) in the rat liver. The ratio of catalytic activities toward 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene gives some indication of the relative proportions of the various transferases present in 100 000 g supernatants. The fraction of catalytic activity towards 1-chloro-2,4-dinitrobenzene, due to transferase B, was best measured by immunoprecipitation with anti-(transferase B). Male rat liver exhibited three times more activity towards 1,2-dichloro-4-nitrobenzene than female tissue; however, the activities towards 1-chloro-2,4-dinitrobenzene were almost identical. By assuming a specific activity of 11 mumol/min per mg, immunoprecipitable transferase B comprised 4.5 +/- 0.2% of total protein in the 100 000 g supernatant of female rat liver, and 70% of the transferase activity towards 1-chloro-2,4-dinitrobenzene. The amount of transferase B in the 100 000 g supernatant from male rat liver is significantly lower with respect to both fraction of total protein (3.3 +/- 0.2%) and overall transferase activity towards 1-chloro-2,4-dinitrobenzene (48%). Hypophysectomy eliminated this sex difference in the hepatic concentration of glutathione S-transferase B.


Pathomechanisms in celiac disease.
Celiac disease is a complex autoimmune disease which is characterized by a strong genetic association (HLA-DQ2 or -DQ8), gluten as nutritional etiological factor, and the enzyme tissue transglutaminase as endomysial autoantigen. Patients develop highly predictive IgA autoantibodies to tTG. Certain gluten peptides are presented by the disease-associated HLA-DQ2/DQ8 molecules leading to stimulation of gluten-specific T cells. This immune response which is driven in the lamina propria causes the mucosal transformation characteristic for celiac disease. Increased intestinal expression of tTG in patients with CD appears to play an important role in the pathogenesis of CD. Thus, modification of gluten peptides by tTG, especially deamidation of certain glutamine residues, can enhance their binding to HLA-DQ2 or -DQ8 and potentiate T cell stimulation. Furthermore, tTG-catalyzed cross-linking and consequent haptenization of gluten with extracellular matrix proteins allows for storage and extended availability of gluten in the mucosa. New therapeutic approaches aim at proteolytic destruction of immunodominant gliadin peptides that are resistant to intestinal enzymes by bacterial prolyl endopeptidases, the inhibition of tTG activity with highly specific enzyme inhibitors or at HLA-DQ2/DQ8 blocking peptide analogues.


[Dynamics of secretory and serum immunoglobulins in children in the course of vaccinations with live poliomyelitis monovaccines].
The influence of vaccination with live poliomyelitis monovaccines on the formation of immunoglobulins in the blood serum and the buccal secrets was studied in infants under 1 year. There was a correlation between rises in the levels of serum immunoglobulins (Ig) of the A, G, and M classes and titers of neutralizing antibody to the three poliomyelitis virus types. The highest level of secretory IgA was observed after immunization with type I monovaccine. The level of secretory IgA correlated with the virus-neutralizing activity of the buccal cavity secretes for poliomyelitis virus types I, II, and III. After immunization with type II and III monovaccines there was an insignificant increase of the IgA content in the buccal cavity secretes. In contrast to poliovirus type I which was isolated from throat samples in 40% of the vaccinees, the other two types of poliomyelitis virus were not found in throat swabs. It is suggested that in the course of immunization with live poliovirus vaccine there are differences in the immunogenesis to poliovirus of different types.


Cardiac output in adult and neonatal rats utilizing impedance cardiography.
Impedance cardiography (IC) has the potential to be applied to very small animals for the measurement of cardiac output (Q). To evaluate this, Q measured by impedance (ZQ) and thermal dilution (TDQ) were compared in adult Sprague-Dawley rats. Absolute values for TDQ were comparable with ZQ (e.g., 29.7 vs. 26.0 ml.min-1.100 g-1), and both equally followed the change in Q caused by hemorrhage and reinfusion of blood. IC was also evaluated in neonatal rats (1 and 7 day old). Control ZQ values were 113 ml.min-1.100 g-1 for the 1-day-old rats, and 104 ml.min-1.100 g-1 for 7-day-old rats. Both stroke volume and Q decreased with head-up tilt and increased with head-down tilt for both ages. Therefore, in the neonate, ZQ decreased appropriately with age and with preload reduction. From these results, it is concluded that IC can be utilized to evaluate cardiac function in neonatal and adult rats.


A detailed analysis of duplications appearing during early, high multiplicity infections with polyoma virus.
Serial undiluted passage of polyoma virus derived from transfection of mouse fibroblasts with well defined wild-type genomes results in the appearance of a very heterogeneous population of defective virus particles. Many of these variants show duplications which not only contain the cis-acting region minimally required for efficient replication, but also other regions. A detailed analysis of the duplication patterns appearing in high multiplicity infections is presented. We performed heteroduplex analyses of duplicated fragments using mung bean nuclease and demonstrated that the pattern of duplication junctions is conserved qualitatively and quantitatively. However, the distribution of fragment sizes varied in a number of independently derived virus stocks. Amplification of viral nucleotide sequences is an early event in virus replication, occurring at least as early as 3 days post-transfection. The pattern of duplication did not change significantly in successive early passages at high multiplicity. Although duplication was accompanied by deletion of various parts of the viral genome, a sequence bordering the duplications at the late side of the origin of replication was retained as a single copy in all defective viruses. The relevance of these findings to the mechanism that creates the duplications and the biological activity of defective virus is discussed.


Basal telencephalic regions connected with the olfactory bulb in a Madagascan hedgehog tenrec.
In an attempt to gain insight into the organization and evolution of the basal forebrain, the region was analysed cytoarchitecturally, chemoarchitecturally, and hodologically in a lower placental mammal, the lesser hedgehog tenrec. Particular emphasis was laid on the subdivision of the olfactory tubercle, the nuclear complex of the diagonal band, and the cortical amygdala. The proper tubercule and the rostrolateral tubercular seam differed from each other with regard to their immunoreactivity to calbindin and calretinin, as well as their afferents from the piriform cortex. Interestingly, the tubercular seam showed similar properties to the dwarf cell compartment, located immediately adjacent to the islands of Calleja. The most prominent input to the olfactory bulb (OfB) originated from the diagonal nuclear complex. This projection was ipsilateral, whereas the bulbar afferents from the hypothalamus and the mesopontine tegmentum were bilateral. The amygdala projected only sparsely to the OfB, but received a prominent bulbar projection. An exception was the nucleus of the lateral olfactory tract, which was poorly connected with the OfB. Unlike other species with an accessory OfB, the projections from the tenrec's main OfB did not show a topographic organization upon the lateral and medial olfactory amygdala. However, there was an accessory amygdala, which could be differentiated from the lateral nuclei by its intense reaction to NADPh-diaphorase. This reaction was poor in the diagonal nuclear complex as in monkey but unlike in rat. The variability of cell populations and olfactory bulb connections shown here may help to clarify both phylogenetic relationships and the significance of individual basal telencephalic subdivisions.


454 pyrosequencing-based analysis of gene expression profiles in the amphipod Melita plumulosa: transcriptome assembly and toxicant induced changes.
Next generation sequencing using Roche's 454 pyrosequencing platform can be used to generate genomic information for non-model organisms, although there are bioinformatic challenges associated with these studies. These challenges are compounded by a lack of a standardized protocol to either assemble data or to evaluate the quality of a de novo transcriptome. This study presents an assembly of the control and toxicant responsive transcriptome of Melita plumulosa, an Australian amphipod commonly used in ecotoxicological studies. RNA was harvested from control amphipods, juvenile amphipods, and from amphipods exposed to either metal or diesel contaminated sediments. This RNA was used as the basis for a 454 based transcriptome sequencing effort. Sequencing generated 1.3 million reads from control, juvenile, metal-exposed and diesel-exposed amphipods. Different read filtering and assembly protocols were evaluated to generate an assembly that (i) had an optimal number of contigs; (ii) had long contigs; (iii) contained a suitable representation of conserved genes; and (iv) had long ortholog alignment lengths relative to the length of each contig. A final assembly, generated using fixed-length trimming based on the sequence quality scores, followed by assembly using the MIRA algorithm, produced the best results. The 26,625 contigs generated via this approach were annotated using Blast2GO, and the differential expression between treatments and control was determined by mapping with BWA followed by DESeq. Although the mapping generated low coverage, many differentially expressed contigs, including some with known developmental or toxicological function, were identified. This study demonstrated that 454 pyrosequencing is an effective means of generating reference transcriptome information for organisms, such as the amphipod M. plumulosa, that have no genomic information available in databases or in closely related sequenced species. It also demonstrated how optimization of read filtering protocols and assembly approaches changes the utility of results obtained from next generation sequencing studies, and establishes criteria to determine the quality of a de novo assembly in species lacking a reference genome. This new transcriptomic knowledge provides the genomic foundation for the creation of microarray and qPCR assays, serving as a reference transcriptome in future RNAseq studies, and allowing both the biology and ecotoxicology of this organism to be better understood. This approach will allow genomics-based methodology to be applied to a wider range of environmentally relevant species.


Aeolian Prokaryotic Communities of the Global Dust Belt Over the Red Sea.
Aeolian prokaryotic communities (APC) are important components of bioaerosols that are transported freely or attached to dust particles suspended in the atmosphere. Terrestrial and marine ecosystems are known to release and receive significant prokaryote loads into and from the surrounded atmospheric air. However, compared to terrestrial systems, there is a lack of microbial characterization of atmospheric dust over marine systems, such as the Red Sea, which receives significant terrestrial dust loads and is centrally located within the Global Dust Belt. Prokaryotic communities are likely to be particularly important in the Global Dust Belt, the area between the west coast of North Africa and Central Asia that supports the highest dust fluxes on the planet. Here we characterize the diversity and richness of the APC over the Red Sea ecosystem, the only sea fully contained within the Global Dust Belt. MiSeq sequencing was used to target 16S ribosomal DNA of two hundred and forty aeolian dust samples. These samples were collected at ∼7.5 m high above the sea level at coastal and offshore sampling sites over a 2-year period (2015-2017). The sequencing outcomes revealed that the APC in the atmospheric dust is dominated by Proteobacteria (42.69%), Firmicutes (41.11%), Actinobacteria, (7.69%), and Bacteroidetes (3.49%). The dust-associated prokaryotes were transported from different geographical sources and found to be more diverse than prokaryotic communities of the Red Sea surface water. Marine and soil originated prokaryotes were detected in APC. Hence, depending on the season, these groups may have traveled from other distant sources during storm events in the Red Sea region, where the APC structure is influenced by the origin and the concentration of aeolian dust particles. Accordingly, further studies of the impact of atmospheric organic aerosols on the recipient environments are required.


High intra-uterine exposure to infliximab following maternal anti-TNF treatment during pregnancy.
Typically, inflammatory bowel disease (IBD) patients are in their reproductive years, raising questions about safely using antitumour necrosis factor antibodies like infliximab (IFX) during pregnancy. IgG antibodies naturally cross the placenta, especially during the last trimester. To prevent foetal intra-uterine exposure, stopping IFX treatment at gestational week 30 is recommended. However, whether this limits intra-uterine and early postnatal IFX exposure is unestablished. To determine the intra-uterine exposure to IFX following maternal treatment with IFX. Four pregnant IBD patients intentionally continued IFX during pregnancy. IFX levels were assessed in newborns' cord blood and the mothers' peripheral blood at delivery. The children's development during the first 3-6 months, infections, vaccine reactions and antibody responses to vaccinations against Haemophilus influenzae type b and Pneumococcus were assessed. The patients stopped IFX therapy at gestational week 21, 26, 26 and 30, respectively. In three infants, therapeutic IFX levels were present in cord blood at levels of 5.5-13.7 μg/mL and were two- to three-fold higher than in the peripheral blood of their mothers. During the 3- to 6-month follow-up, the children developed normally without signs of infections or allergic reactions, and had normal antibody titres after routine childhood vaccinations. The use of IFX until gestational week 30 leads to foetal intra-uterine exposure to IFX at levels that exceed those in the mothers' peripheral blood. Although no short-term complications were detected, the high IFX levels observed in newborns raise concerns about unknown effects of IFX on the developing immune system.


Clustering and activity tuning of Kv1 channels in myelinated hippocampal axons.
Precise localization of axonal ion channels is crucial for proper electrical and chemical functions of axons. In myelinated axons, Kv1 (Shaker) voltage-gated potassium (Kv) channels are clustered in the juxtaparanodal regions flanking the node of Ranvier. The clustering can be disrupted by deletion of various proteins in mice, including contactin-associated protein-like 2 (Caspr2) and transient axonal glycoprotein-1 (TAG-1), a glycosylphosphatidylinositol-anchored cell adhesion molecule. However, the mechanism and function of Kv1 juxtaparanodal clustering remain unclear. Here, using a new myelin coculture of hippocampal neurons and oligodendrocytes, we report that tyrosine phosphorylation plays a critical role in TAG-1-mediated clustering of axonal Kv1.2 channels. In the coculture, myelin specifically ensheathed axons but not dendrites of hippocampal neurons and clustered endogenous axonal Kv1.2 into internodes. The trans-homophilic interaction of TAG-1 was sufficient to position Kv1.2 clusters on axonal membranes in a neuron/HEK293 coculture. Mutating a tyrosine residue (Tyr⁴⁵⁸) in the Kv1.2 C terminus or blocking tyrosine phosphorylation disrupted myelin- and TAG-1-mediated clustering of axonal Kv1.2. Furthermore, Kv1.2 voltage dependence and activation threshold were reduced by TAG-1 coexpression. This effect was eliminated by the Tyr⁴⁵⁸ mutation or by cholesterol depletion. Taken together, our studies suggest that myelin regulates both trafficking and activity of Kv1 channels along hippocampal axons through TAG-1.


Irrigation of soil with reclaimed wastewater acts as a buffer of microbial taxonomic and functional biodiversity.
The usage of reclaimed wastewater (RWW) for irrigation of agricultural soils is increasingly being acknowledged for reducing water consumption by promoting reuse of treated wastewater, and for the delivery of extant nutrients in the soil. The downside is that RWW may be a vector for contamination of soils with contaminants of emerging concern (CECs), if left uncontrolled. Its usage is anticipated to alter the soil properties, consequently also the soil microbial community. In the present study, soil microcosms were set to monitor how short periods (up to fourteen days) of RWW irrigation influence the soil ecosystem, namely its physicochemical properties, functioning, and colonising microbiota (differentiating fungi from bacteria). Two scenarios were studied: clean soil and soil contaminated (spiked) with 9 CECs, at conditions that limit any abiotic decay processes, monitoring along time fluctuations in the taxonomic and functional microbiota diversity. As shortly as fourteen days, the irrigation of either soil with RWW did not significantly (p > 0.05) alter its physicochemical properties and scarcely impacted the bioremediation processes of the CECs that showed decay levels ranging from 24% to 100%. Bacillus spp. dominance was enhanced along time in all the soil microcosms (reaching over 70% of the total abundance on the 7th day) but the RWW help to preserve, to some extent, high bacterial diversity. Besides, irrigation with RWW acted as a buffer of the soil mycobiota, limiting alterations in its composition caused either along time (to a minor degree) or due to contamination with CECs (to a great degree). This includes limiting the rise of Rhizopus sp. relative abundance. Collectively, our data support the utility of short-term periods of RWW irrigation for preserving the soil microbial diversity and functioning, especially when fungi are considered.


Part-list cuing effects in younger and older adults' episodic recall.
Providing a subset of previously studied items as retrieval cues can both impair and improve memory for the remaining items. Here, we investigated such part-list cuing effects in younger and older adults' episodic recall, using listwise directed forgetting to manipulate study context access at test. When context access was maintained, part-list cuing impaired recall regardless of age. In contrast, when context access was impaired, part-list cuing improved recall in younger but not in older adults. The results are consistent with the proposal that older adults show intact inhibition and blocking of competing information, but reduced capability for episodic context reactivation. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Circulating regulatory T cells in endometrial cancer: a role for age and menopausal status.
Regulatory T cells (Treg) are a sub-population of T cells that suppress self-reactivity and are implicated in immune tolerance towards malignant cells. Circulating Treg cells are increased in several cancers. In endometrial cancer Treg cells have been investigated only in tumour tissues and, in contrast to some other tumours, fewer Treg cells were reported in endometrial cancer compared with benign controls. Flow cytometry was used to determine the frequency of circulating Treg cells in women undergoing hysterectomy for either endometrial cancer (n = 24) or non- cancer-related conditions (n = 21). Circulating Treg cells were more abundant in women with cancer compared to those without (4.68% vs. 3.66%, p = 0.05, Mann-Whitney test). This relationship disappeared, however, when only data from post-menopausal women were included in the analysis. Mean Treg cell frequency was 4.65% in postmenopausal women with cancer (n = 23) and 4.73% in postmenopausal controls (n = 5) (p = 0.9). In women without cancer we found that mean Treg cell frequency was higher in postmenopausal women (4.73%, n = 5) in comparison to premenopausal controls (3.33%, n = 16) (p = 0.02). These results suggest that the increased proportion of Treg cells seen in endometrial cancer patients might be, at least in part, attributed to their postmenopausal status or age.


Adenomatous polyposis coli is present near the minimal level required for accurate graded responses to the Wingless morphogen.
The mechanisms by which the Wingless (Wg) morphogen modulates the activity of the transcriptional activator Armadillo (Arm) to elicit precise, concentration-dependent cellular responses remain uncertain. Arm is targeted for proteolysis by the Axin/Adenomatous polyposis coli (Apc1 and Apc2)/Zeste-white 3 destruction complex, and Wg-dependent inactivation of destruction complex activity is crucial to trigger Arm signaling. In the prevailing model for Wg transduction, only Axin levels limit destruction complex activity, whereas Apc is present in vast excess. To test this model, we reduced Apc activity to different degrees, and analyzed the effects on three concentration-dependent responses to Arm signaling that specify distinct retinal photoreceptor fates. We find that both Apc1 and Apc2 negatively regulate Arm activity in photoreceptors, but that the relative contribution of Apc1 is much greater than that of Apc2. Unexpectedly, a less than twofold reduction in total Apc activity, achieved by loss of Apc2, decreases the effective threshold at which Wg elicits a cellular response, thereby resulting in ectopic responses that are spatially restricted to regions with low Wg concentration. We conclude that Apc activity is not present in vast excess, but instead is near the minimal level required for accurate graded responses to the Wg morphogen.


Tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone initiates and enhances pancreatitis responses.
Clinical studies indicate that cigarette smoking increases the risk for developing acute pancreatitis. The nicotine metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a major cigarette smoke toxin. We hypothesized that NNK could sensitize to pancreatitis and examined its effects in isolated rat pancreatic acini and in vivo. In acini, 100 nM NNK caused three- and fivefold activation of trypsinogen and chymotrypsinogen, respectively, above control. Furthermore, NNK pretreatment in acini enhanced zymogen activation in a cerulein pancreatitis model. The long-term effects of NNK were examined in vivo after intraperitoneal injection of NNK (100 mg/kg body wt) three times weekly for 2 wk. NNK alone caused zymogen activation (6-fold for trypsinogen and 2-fold for chymotrypsinogen vs. control), vacuolization, pyknotic nuclei, and edema. This NNK pretreatment followed by treatment with cerulein (40 μg/kg) for 1 h to induce early pancreatitis responses enhanced trypsinogen and chymotrypsinogen activation, as well as other parameters of pancreatitis, compared with cerulein alone. Potential targets of NNK include nicotinic acetylcholine receptors and β-adrenergic receptors; mRNA for both receptor types was detected in acinar cell preparations. Studies with pharmacological inhibitors of these receptors indicate that NNK can mediate acinar cell responses through an nonneuronal α(7)-nicotinic acetylcholine receptor (α(7)-nAChR). These studies suggest that prolonged exposure to this tobacco toxin can cause pancreatitis and sensitize to disease. Therapies targeting NNK-mediated pathways may prove useful in treatment of smoking-related pancreatitis.


Modulation of human lymphocyte responses by neutrophil-derived factors: effects of neutrophils and neutrophil-derived factos.
Lymphocytes and polymorphonuclear neutrophils (PMNs) occur together in inflammatory sites. We have examined the possibility that PMNs, or PMN-derived factors, might influence human peripheral blood lymphocyte (PBL) functions. PBL were cultured with or without antigen or phytomitogen, and with or without purified PMNs, PMN lysates or supernatants (SPTs) from PMNs that had phagocytized zymosan-complement complexes. PMN-derived enhancing and inhibitory activities were identified. Studies indicated: (1) PMNs exhibited concentration-dependent enhancement or inhibition of PVL methyl-3H-thymidine uptake; (2) lysates of PMNs similarly inhibited PBLs at high concentrations, enhanced with dilution, and inhibited with further dilution; (3) SPTs from PMN that had phagocytized zymosan-complement also exhibited concentration-dependent enhancement and inhibition; (4) inhibition did not result from (a) mitogen binding or inactivation, (b) exhaustion of in vitro nutrients, (c) change of expected kinetics of responses, (d) alterations of cell numbers or viability; (5) enhancement and inhibition of PBL persisted after exposure to PMN SPT and washing before stimulation; and (6) PMN SPTs increased PBL ability to rosette with sheep erythrocytes. These observations identified two or more PMN-derived factors that may be important in modulating lymphocyte responses in acute and chronic inflammation.


Heterogeneous networks do not promote cooperation when humans play a Prisoner's Dilemma.
It is not fully understood why we cooperate with strangers on a daily basis. In an increasingly global world, where interaction networks and relationships between individuals are becoming more complex, different hypotheses have been put forward to explain the foundations of human cooperation on a large scale and to account for the true motivations that are behind this phenomenon. In this context, population structure has been suggested to foster cooperation in social dilemmas, but theoretical studies of this mechanism have yielded contradictory results so far; additionally, the issue lacks a proper experimental test in large systems. We have performed the largest experiments to date with humans playing a spatial Prisoner's Dilemma on a lattice and a scale-free network (1,229 subjects). We observed that the level of cooperation reached in both networks is the same, comparable with the level of cooperation of smaller networks or unstructured populations. We have also found that subjects respond to the cooperation that they observe in a reciprocal manner, being more likely to cooperate if, in the previous round, many of their neighbors and themselves did so, which implies that humans do not consider neighbors' payoffs when making their decisions in this dilemma but only their actions. Our results, which are in agreement with recent theoretical predictions based on this behavioral rule, suggest that population structure has little relevance as a cooperation promoter or inhibitor among humans.


National and sub-national environmental burden of disease in Iran from 1990 to 2013-study profile.
Development of national evidence-based public health strategies requires a deep understanding of the role of major risk factors (RFs) and the burden of disease (BOD). In this article, we explain the framework for studying the national and sub-national Environmental Burden of Disease (EBD) in Iran as a part of the National and Sub-national Burden of Disease (NASBOD) study. The distribution of exposures to environmental RFs and their attributable effect size over 1990-2013 will be estimated through comprehensive reviews of either published or unpublished sources. Statistical modeling will be used to impute missing data in the distribution of RFs exposures for each district-year. National and sub-national BOD attributable to these RFs will be estimated in the following metrics: Prevalence, death, years of life lost due to premature death (YLL), years of life lost due to disability (YLD), and disability-adjusted life years lost (DALYs). The BOD attributable to the current distribution of exposures will be compared with a counterfactual exposure distribution scenario-here, the theoretical-minimum-risk exposure distribution. Inequalities in the distribution of exposure to RFs will be analyzed and manifested nationwide using geographic information systems. The EBD study aims to provide an official report to Iranian Ministry of Health and Medical Education, to publish a series of articles on the exposure trends of the selected environmental RFs, to estimate the BOD attributable to these RFs, and to assess inequalities and its determinants in the distribution of exposure to RFs. Iran's territory is large with diverse population, socioeconomic, and geographic areas. Results of this comparative risk assessment study may pave the way for health policy makers to plan more comprehensive and cost-effective evidence-based strategies.


Neoral use in the cardiac transplant recipient.
CyA is the core immunosuppressant of choice for the majority of transplant patients. The introduction of Neoral, a new microemulsion formulation of CyA. and more recently a range of adjunctive immunosuppressants have further enhanced the efficacy and tolerability of CyA-based immunosuppression. In the first year following transplantation the major causes of morbidity and death are graft failure, acute rejection, and systemic infection. Patients with deteriorated pulmonary circulation before transplantation are at increased risk of early postoperative death. Risk factors for early acute rejection include female donor sex, young donor age, and multiple HLA-DR mismatches. The principal cause of death in the long term is graft vasculopathy which accounted for 40% of all deaths. Risk factors that have been hypothesized to play a role in the pathogenesis of graft vasculopathy include hyperlipidemia, recipient age and gender, donor age, the number of HLA AB and DR mismatches, and CMV infection. Strategies proposed to reduce the risk of graft vasculopathy include aggressive use of lipid-lowering agents, avoidance of low CyA doses, and the use of adjunctive rapamycin or RAD therapy. Rejection surveillance therefore relies on routine serial endomyocardial biopsy. Recent research suggests that a more accurate assessment of the state of the graft can be obtained by considering the results across a number of biopsy samples obtained from different parts of the heart, rather than basing clinical judgment on the worst single result obtained. New molecular markers such as granzyme A mRNA are likely to improve the power of histology to diagnose and predict rejection. Neoral pharmacokinetics give greater bioavailability and less intrapatient variability than Sandimmune. In the keynote OLN 351 study comparing Neoral with Sandimmune in de novo heart transplant recipients, fewer Neoral patients needed antilymphocyte therapy to treat rejection, fewer female patients had rejection episodes in the Neoral group, the tolerability of the two formulations was equivalent, and there was a lower incidence of infections in the Neoral group. The clinical impact of Neoral in comparison with Sandimmune in de novo heart transplant patients has been investigated in a number of additional trials, including long-term studies, which have confirmed that Neoral is associated with: Lower CyA doses than Sandimmune. Equal or greater antirejection efficacy than Sandimmune. Comparable tolerability to Sandimmune. During the administration of intravenous CyA as an induction therapy in the days immediately following transplantation, there is evidence to suggest that a 6-hour infusion given twice daily, which mimics the pharmacokinetic profile of oral dosing, may be clinically more effective than a continuous 24-hour infusion. Milligram-for-milligram dose conversion from Sandimmune to Neoral is feasible. Following conversion, a reduction in the CyA dose may be required in the majority of patients to maintain target levels. In pediatric patients, the rate of elimination of CyA is greater and bioavailability increases with increasing age. Younger patients (less than 8 years of age) may be managed more effectively with a 3-times-daily, rather than a twice-daily dosing schedule. A number of studies have compared the clinical effects of Sandimmune and Neoral in maintenance therapy for cardiac transplant patients. As with de novo patients, these studies have found the new formulation of CyA to be associated with lower rates of acute rejection, lower therapeutic doses, and comparable tolerability. Milligram-to-milligram conversion from the old to the new CyA formulation is generally well tolerated, although in a minority of patients there is a significant increase in CyA levels. These may be associated with a transient increase in side effects which resolve on dose reduction. There is a dose-sparing effect with Neoral. Routine monitoring of both CyA and serum creatinine levels are adv


Successful localization of the Broca area with short-train pulses instead of 'Penfield' stimulation.
Direct electrical stimulation of functional cortical areas is a standard procedure in epilepsy and glioma surgery. Many previous studies support that stimulation of the motor cortex with short-train pulses is a less epileptogenic alternative to the 50-60Hz 'Penfield' technique. However, whether the short-train stimulation is useful also in mapping of speech areas is unclear. In this case report we present a patient with oligodendroglioma near the Broca area. Extraoperative electrical stimulation via a subdural grid electrode was primarily performed to locate the speech area. The cortex was stimulated with short-train pulses (5 pulses, 0.5 pulse duration and 3ms interpulse interval) in addition to 1-3s 50Hz stimulation. The patient had speech arrest from both types of stimulation techniques during a naming task. It was however critical that the short (14.5ms) train stimulation was synchronized with the presentation of the naming objects. If not, there was no speech arrest. Despite this possible pitfall, this case has encouraged us to further try short-train stimulation in attempts to reduce stimulus-triggered seizures during mapping of eloquent areas.


In-shoe pressure distribution in "unstable" (MBT) shoes and flat-bottomed training shoes: a comparative study.
Footwear comfort in many clinical situations is dependent on the ability of the 'shoe' to redistribute plantar pressure. Offloading the metatarsal heads may be achieved by fitting an insole, but recently a new design of shoe with a curved under sole (Masai Barefoot Technology or "MBT shoe") has been advocated. The aim of this study was to directly assess the effect of such shoes on gait pattern. Normal subjects were recruited and asked to walk sequentially in (a) flat-soled training shoes and (b) midfoot bearing shoes (MBT shoe). Mean and peak pressures in four anatomically defined areas of the foot, and the total area of sole contact were measured electronically by an in-shoe system (Pedar Ltd., UK). Standing in the Masai shoes resulted in a 21% lesser peak pressure under the midfoot and an 11% lesser peak pressure under the heel in comparison to the figures found when patients wore their training shoes. There was a 76% compensatory increase in pressure under the toes. In essence there was a significant shift in pressure towards the front of the foot.


Effects of mesalamine (5-aminosalicylic acid) on bacterial gene expression.
5-Aminosalicylic acid (5-ASA) is a well-established treatment for inflammatory bowel disease (IBD) and may reduce the risk of colon cancer in patients with chronic colitis, but the mechanisms underlying these effects have not been fully elucidated. Although 5-ASA delivery is targeted to the distal gut, little is known about its effects on the luminal bacteria that reside there. Intestinal bacteria are believed play a role in causing or perpetuating IBD, and bioremediation has been studied as a therapeutic strategy. In an effort to better understand the bacteriological effects of 5-ASA, we examined the role of this compound at the level of bacterial gene expression. 5-ASA was screened for its effects on a random promoter library representing the genome of Salmonella enterica serovar Typhimurium as a model enteric bacterium. Forty-five constructs representing 38 unique promoters were found to be responsive to 5-ASA, and included genes involved in bacterial invasion, cellular metabolism, and stress resistance. Several genes of unknown function were also identified. These effects occurred at 5-ASA concentrations that are relevant to those achieved in the distal intestinal tract in patients with IBD but did not inhibit bacterial growth. Bacterial invasiveness was decreased by 5-ASA. Some of the identified genes had homologs among commensal Gram-negative enteric bacteria. This study demonstrates that 5-ASA has potent effects on bacterial gene expression. These novel findings implicate intestinal bacteria as pharmacological targets of 5-ASA, perhaps contributing to the therapeutic action of this important class of IBD drugs.


FAST: a framework for simulation and analysis of large-scale protein-silicon biosensor circuits.
This paper presents a computer aided design (CAD) framework for verification and reliability analysis of protein-silicon hybrid circuits used in biosensors. It is envisioned that similar to integrated circuit (IC) CAD design tools, the proposed framework will be useful for system level optimization of biosensors and for discovery of new sensing modalities without resorting to laborious fabrication and experimental procedures. The framework referred to as FAST analyzes protein-based circuits by solving inverse problems involving stochastic functional elements that admit non-linear relationships between different circuit variables. In this regard, FAST uses a factor-graph netlist as a user interface and solving the inverse problem entails passing messages/signals between the internal nodes of the netlist. Stochastic analysis techniques like density evolution are used to understand the dynamics of the circuit and estimate the reliability of the solution. As an example, we present a complete design flow using FAST for synthesis, analysis and verification of our previously reported conductometric immunoassay that uses antibody-based circuits to implement forward error-correction (FEC).


SELECTIVE ELIMINATION OF CHLOROPLASTIDIAL DNA FOR METAGENOMICS OF BACTERIA ASSOCIATED WITH THE GREEN ALGA CAULERPA TAXIFOLIA (BRYOPSIDOPHYCEAE)(1).
Molecular analyses of bacteria associated with photosynthetic organisms are often confounded by coamplification of the chloroplastidial 16S rDNA with the targeted bacterial 16S rDNA. This major problem has hampered progress in the characterization of bacterial communities associated to photosynthetic organisms and has limited the full realization of the potential offered by the last generation of metagenomics approaches. A simple and inexpensive method is presented, based on ethanol and bleach treatments prior to extraction, to efficiently discard a great part of chloroplastidial DNA without affecting the characterization of bacterial communities through pyrosequencing. Its effectiveness for the description of bacterial lineages associated to the green alga Caulerpa taxifolia (M. Vahl) C. Agardh was much higher than that of the preexisting enrichment protocols proposed for plants. Furthermore, this new technique requires a very small amount of biological material compared to the other current protocols, making it more realistic for systematic use in ecological and phylogenetic studies and opening promising prospects for metagenomics of green algae, as shown by our data.


Differential effect of N-carboxymethylisatoylation on the DNA polymerase activity, the 5' leads to 3'-exonuclease activity and the 3' leads to 5'-exonuclease activity of DNA polymerase I of Escherichia coli.
Treatment with native DNA polymerase I of Escherichia coli with the acylating agent N-carboxymethylisatoic acid anhydride (NCMIA) results under specific conditions in a rapid loss of polymerase activity, an increase in 5' leads to 3'-exonuclease activity and in unchanged 3' leads to 5'-exonuclease activity. When a nucleoside triphosphate and Mg2+ was present the polymerase activity was completely protected against the effect of NCMIA. Treatment with higher concentration of the acylating agent under these conditions led to a loss of 3' leads to 5'-exonuclease activity without any appreciable loss of polymerase activity. Treatment with NCMIA of the two catalytically active fragments of the enzyme led to very similar results. In this case both the polymerase activity and the 3' leads to 5'-exonuclease activity deteriorated more rapidly on treatment with the acylating reagent. The increase in 5' leads to 3'-exonuclease activity as a result of modification of the native enzyme appeared to be due to a change in the optimum conditions with regard to concentration of the assay buffer used. These changes are very similar to those seen when the polymerase is cleaved by limited proteolysis. From the results obtained it is concluded that NCMIA reacts primarily with a site at or near the triphosphate-Mg2+ complex binding site, leading to an almost complete loss of polymerase activity. The acylating reagent reacts also with another group on the native enzyme resulting in a modification of the 5' leads to 3'-exonuclease activity, and at high concentrations with a group leading to a slow loss of 3' leads to 5'-exonuclease activity.


Soil Candidate Phyla Radiation Bacteria Encode Components of Aerobic Metabolism and Co-occur with Nanoarchaea in the Rare Biosphere of Rhizosphere Grassland Communities.
Candidate Phyla Radiation (CPR) bacteria and nanoarchaea populate most ecosystems but are rarely detected in soil. We concentrated particles of less than 0.2 μm in size from grassland soil, enabling targeted metagenomic analysis of these organisms, which are almost totally unexplored in largely oxic environments such as soil. We recovered a diversity of CPR bacterial and some archaeal sequences but no sequences from other cellular organisms. The sampled sequences include Doudnabacteria (SM2F11) and Pacearchaeota, organisms rarely reported in soil, as well as Saccharibacteria, Parcubacteria, and Microgenomates. CPR and archaea of the phyla Diapherotrites, Parvarchaeota, Aenigmarchaeota, Nanoarchaeota, and Nanohaloarchaeota (DPANN) were enriched 100- to 1,000-fold compared to that in bulk soil, in which we estimate each of these organisms comprises approximately 1 to 100 cells per gram of soil. Like most CPR and DPANN sequenced to date, we predict these microorganisms live symbiotic anaerobic lifestyles. However, Saccharibacteria, Parcubacteria, and Doudnabacteria genomes sampled here also harbor ubiquinol oxidase operons that may have been acquired from other bacteria, likely during adaptation to aerobic soil environments. We conclude that CPR bacteria and DPANN archaea are part of the rare soil biosphere and harbor unique metabolic platforms that potentially evolved to live symbiotically under relatively oxic conditions. IMPORTANCE Here, we investigated overlooked microbes in soil, Candidate Phyla Radiation (CPR) bacteria and Diapherotrites, Parvarchaeota, Aenigmarchaeota, Nanoarchaeota, and Nanohaloarchaeota (DPANN) archaea, by size fractionating small particles from soil, an approach typically used for the recovery of viral metagenomes. Concentration of these small cells (<0.2 μm) allowed us to identify these organisms as part of the rare soil biosphere and to sample genomes that were absent from non-size-fractionated metagenomes. We found that some of these predicted symbionts, which have been largely studied in anaerobic systems, have acquired aerobic capacity via lateral transfer that may enable adaptation to oxic soil environments. We estimate that there are approximately 1 to 100 cells of each of these lineages per gram of soil, highlighting that the approach provides a window into the rare soil biosphere and its associated genetic potential.


ORAC and DPPH assay comparison to assess antioxidant capacity of tea infusions: relationship between total polyphenol and individual catechin content.
Commercially available tea infusions are the major source of catechins for preparing bottled tea beverages and tea supplements available in the market today. In the present study, we analyzed five tea infusions to measure the total antioxidant capacity (TAC) by oxygen radical absorbance capacity (ORAC) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging capacity (DRSC) assays, total polyphenol content by the colorimetric method and individual catechin content by high-performance liquid chromatography. Four major tea catechins were also analyzed for their TAC to reveal differential antioxidant behavior of the tea infusions, resulting in the ORAC and DRSC methods. The correlation coefficients between DRSC and the total polyphenol or total catechin content of the tea infusions were 1.0 and 0.99. However, the values fall to 0.73 and 0.69, respectively, while the ORAC activity was correlated with total polyphenol and total catechin content. Determining the TAC of individual tea catechins showed that ORAC of epicatechin was seven-fold higher than that of epigallocatechin gallate; on the contrary, epigallocatechin gallate showed significantly (P < 0.05) stronger DRSC activity than epicatechin. By evaluating the structure-activity relationship, this study further revealed that OH substitution at the 3' position in pyrogallol moieties contributes to the lower ORAC value of epigallocatechin and epigallocatechin gallate comparing with their non-3'-OH counterparts, such as epicatechin and epicatechin gallate, respectively. Also, numbers of OH substitutions were poorly correlated with the observed ORAC value unlike the DRSC. Overall, results of this study enabled us to hypothesize that substances having a lower TAC value in the ORAC assay compared with that in DPPH assays may pertain to a pro-oxidant effect by generating reactive oxygen species in an aqueous buffer, at a physiological pH. We also propose that substances exhibiting lower TAC value in the ORAC assay compared with that in the DPPH assay are powerful pro-oxidants compared with the substances showing a higher TAC value in the ORAC assay than that in the DPPH assay.


Glyoxalase I overexpression ameliorates renal ischemia-reperfusion injury in rats.
Methylglyoxal (MG), a highly reactive carbonyl compound generated by carbohydrate oxidation and glycolysis, is the major precursor of protein glycation and induces cytotoxicity leading to apoptosis. Although recent studies have emphasized that MG accumulates in not only chronic oxidative stress-related diseases but also acute hypoxic conditions, the pathogenic contribution of MG in acute diseases is unclear. MG is efficiently metabolized by the glyoxalase system, namely, glyoxalase I. We investigated the pathophysiological role of glyoxalase I as an MG detoxifier in rat renal ischemia-reperfusion (I/R) injury. I/R-induced tubulointerstitial injury was associated with a deterioration in renal glyoxalase I activity independent of its cofactor, GSH, as well as an increase in renal MG level. In in vitro studies, knockdown of glyoxalase I by small interference RNA transfection in rat tubular cells exacerbated cell death by hypoxia-reoxygenation compared with control cells. We also examined whether glyoxalase I overexpression prevented renal I/R damage in rats overexpressing human glyoxalase I with enzyme activity in the kidney 17-fold higher than in wild-type. The histological and functional manifestations of I/R in these rats were significantly ameliorated in association with a decrease in intracellular MG adduct accumulation, oxidative stress, and tubular cell apoptosis. In conclusion, glyoxalase I exerts renoprotective effects in renal I/R injury via a reduction in MG accumulation in tubular cells.


Socioeconomic disparities in prehospital stroke care.
Recent studies have revealed socioeconomic disparities in stroke outcomes. Here, we investigated whether prehospital stroke care differs with respect to socioeconomic status (SES). Consecutive stroke and TIA patients (n = 3006) admitted to stroke units at Sahlgrenska University Hospital, Gothenburg, Sweden, from 1 November 2014 to 31 July 2016, were included. Data on prehospital care were obtained from a local stroke register. Socioeconomic status was classified according to the average level of income and education within each patient's neighbourhood (postcode area). The median system delay from calling the emergency medical communication centre (EMCC) to start of brain computed tomography on hospital arrival was 3 h 47 min (95% confidence interval (CI) 3 h 30 min to 4 h 05 min) for patients within the lowest SES tertile and 3 h 17 min (95% CI 3 h 00 min to 3 h 37 min) for the highest tertile (p < 0.05). Patients with a lower SES were less likely to receive the highest priority in the ambulance (p < 0.05) and had lower rates of prehospital recognition of stroke/TIA (p < 0.05) than those with a high SES. No inequities were found concerning EMCC prioritisation or the probability of ambulance transport. We found socioeconomic inequities in prehospital stroke care which could affect the efficacy of acute stroke treatment. The ambulance nurses' ability to recognise stroke/TIA may partly explain the observed inequities.


Outpatient Management of Diabetic Hand Infections.
Purpose For many providers, hand infections among diabetic patients is a condition that necessitates focused inpatient care. These patients are believed to have decreased innate immunity to fight infection, a more virulent course, and difficulty with recovery. Diabetes is considered by some to represent an additional risk factor that can result in an unfavorable outcome if not managed in an aggressive manner. Our own experience suggests that many of these patients can be safely managed in the outpatient setting. The purpose of this project was to better define the clinical outcomes for this population. Methods Evidence-based criteria were utilized to direct inpatient versus outpatient treatment pathways. A database was developed to track hand infections treated by the specialty service. The primary outcome was the resolution of hand infection. Secondary outcomes included specific treatment responses as well as patient characteristic comparisons of the different treatment groups. Independent variables included (parenteral and enteral) antibiotic use and bedside interventions performed. Patients were followed to complete the resolution of infection. Results For all patients managed as outpatients, diabetic patients had statistically significantly decreased improvement rates at two weeks as compared to non-diabetic patients (62% vs 75%, p =0.024). This difference disappeared at two months. Among diabetic patients, those with the highest rate of recovery at two weeks (90%) received intravenous antibiotics, bedside procedures, and oral antibiotics. Patients who did not receive antibiotics or undergo bedside procedures had the lowest percent of improvement (37%). Across all treatment subgroups, bedside procedure was the most impactful intervention. Less than 10% of patients were converted from outpatient to inpatient care, both diabetic and non-diabetic. Conclusions We reviewed our experience managing diabetes mellitus hand infections treated in the outpatient setting. Appropriate and effective treatment is possible, and the results are equivalent to those of patients without diabetes mellitus.


Similarity in recombination rate estimates highly correlates with genetic differentiation in humans.
Recombination varies greatly among species, as illustrated by the poor conservation of the recombination landscape between humans and chimpanzees. Thus, shorter evolutionary time frames are needed to understand the evolution of recombination. Here, we analyze its recent evolution in humans. We calculated the recombination rates between adjacent pairs of 636,933 common single-nucleotide polymorphism loci in 28 worldwide human populations and analyzed them in relation to genetic distances between populations. We found a strong and highly significant correlation between similarity in the recombination rates corrected for effective population size and genetic differentiation between populations. This correlation is observed at the genome-wide level, but also for each chromosome and when genetic distances and recombination similarities are calculated independently from different parts of the genome. Moreover, and more relevant, this relationship is robustly maintained when considering presence/absence of recombination hotspots. Simulations show that this correlation cannot be explained by biases in the inference of recombination rates caused by haplotype sharing among similar populations. This result indicates a rapid pace of evolution of recombination, within the time span of differentiation of modern humans.


Multiple cAMP Phosphodiesterases Act Together to Prevent Premature Oocyte Meiosis and Ovulation.
Luteinizing hormone (LH) acts on the granulosa cells that surround the oocyte in mammalian preovulatory follicles to cause meiotic resumption and ovulation. Both of these responses are mediated primarily by an increase in cyclic adenosine monophosphate (cAMP) in the granulosa cells, and the activity of cAMP phosphodiesterases (PDEs), including PDE4, contributes to preventing premature responses. However, two other cAMP-specific PDEs, PDE7 and PDE8, are also expressed at high levels in the granulosa cells, raising the question of whether these PDEs also contribute to preventing uncontrolled activation of meiotic resumption and ovulation. With the use of selective inhibitors, we show that inhibition of PDE7 or PDE8 alone has no effect on the cAMP content of follicles, and inhibition of PDE4 alone has only a small and variable effect. In contrast, a mixture of the three inhibitors elevates cAMP to a level comparable with that seen with LH. Correspondingly, inhibition of PDE7 or PDE8 alone has no effect on meiotic resumption or ovulation, and inhibition of PDE4 alone has only a partial and slow effect. However, the fraction of oocytes resuming meiosis and undergoing ovulation is increased when PDE4, PDE7, and PDE8 are simultaneously inhibited. PDE4, PDE7, and PDE8 also function together to suppress the premature synthesis of progesterone and progesterone receptors, which are required for ovulation. Our results indicate that three cAMP PDEs act in concert to suppress premature responses in preovulatory follicles.


Improving the safety of street-vended food.
An integrated plan of action for improving street food involving health and other regulatory authorities, vendors and consumers should address not only food safety, but also environmental health management, including consideration of inadequate sanitation and waste management, possible environmental pollution, congestion and disturbances to traffic. However, WHO cautions that, in view of their importance in the diets of urban populations, particularly the socially disadvantaged, every effort should be made to preserve the benefits provided by varied, inexpensive and often nutritious street food. Therefore, authorities concerned with street food management must balance efforts aimed at reducing the negative aspects on the environment with the benefits of street food and its important role in the community. Health authorities charged with responsibility for food safety control should match risk management action to the level of assessed risk. The rigorous application of codes and enforcement of regulations more suited to larger and permanent food service establishments is unlikely to be justifiable. Such rigorous application of codes and regulations may result in disappearance of the trade with consequent aggravation of hunger and malnutrition. Moreover, most codes and regulations have not been based on any systematic identification and assessment of health hazards associated with different types of foods and operations as embodied in the HACCP approach which has been recognized by Codex as the most cost-effective means for promoting food safety. WHO encourages the development of regulations that empower vendors to take greater responsibility for the preparation of safe food, and of codes of practice based on the HACCP system.


[Parameters of oxidative stress in patients with gastric cancer].
We studied effect of the neoplastic process and surgical treatment on parameters of the oxidative system in patients with stomach cancer including serum and gastric tissue levels of malonic dialdehyde, lactic and pyruvic acids in stage I-IV malignancy before and after radical surgery. The development and generalization of the neoplastic process are associated with the activation of oxidative reactions leading to endotoxicosis. Specific anticarcinogenic treatments (including surgery) aggravate changes in the oxidative systems and further deteriorate quality of life and tolerance of the treatment.


Educational technologies for accident prevention due to falls in childhood: a scoping review.
to map evidence on educational technology use for accident prevention due to falls in childhood. a scoping review, carried out in October and November 2022, in the MEDLINE, Web of Science, BDENF and CINAHL databases and LILACS bibliographic index. There was no delimitation of language or time. Data were extracted and analyzed descriptively by two independent researchers. The research protocol was registered in the Open Science Framework. twenty-six studies were selected. Booklets, pamphlets and leaflets were the most used technologies, presenting health services as the most frequent environment to develop research on fall prevention. The technologies developed were important outcomes: increased knowledge of children, family members, caregivers, health and education professionals. educational technology use makes it possible to increase knowledge, adopt safe practices and reduce falls.


Obligatory roles of dopamine D1 receptors in the dentate gyrus in antidepressant actions of a selective serotonin reuptake inhibitor, fluoxetine.
Depression is a leading cause of disability. Current pharmacological treatment of depression is insufficient, and development of improved treatments especially for treatment-resistant depression is desired. Understanding the neurobiology of antidepressant actions may lead to development of improved therapeutic approaches. Here, we demonstrate that dopamine D1 receptors in the dentate gyrus act as a pivotal mediator of antidepressant actions in mice. Chronic administration of a selective serotonin reuptake inhibitor (SSRI), fluoxetine, increases D1 receptor expression in mature granule cells in the dentate gyrus. The increased D1 receptor signaling, in turn, contributes to the actions of chronic fluoxetine treatment, such as suppression of acute stress-evoked serotonin release, stimulation of adult neurogenesis and behavioral improvement. Importantly, under severely stressed conditions, chronic administration of a D1 receptor agonist in conjunction with fluoxetine restores the efficacy of fluoxetine actions on D1 receptor expression and behavioral responses. Thus, our results suggest that stimulation of D1 receptors in the dentate gyrus is a potential adjunctive approach to improve therapeutic efficacy of SSRI antidepressants.


Texture improvement of fresh and frozen mangoes with pectin methylesterase and calcium infusion.
A major problem of mango products is texture loss. The effect of commercial pectin methylesterase (PME) and calcium infusion on improvement of the texture of both fresh and frozen-thawed mango cubes was investigated in the present study. The weight gain and moisture content of mango samples were greater at relatively high vacuum level (10 kPa). The PME activity of samples infused with PME and calcium at 10 kPa increased fourfold in comparison with that of control and water-infused samples. The combined effect of PME and calcium was found to improve the texture and microstructure of both fresh and frozen-thawed mangoes. Fresh mangoes infused with PME and calcium at 10 kPa showed significantly higher firmness than control fresh samples. Frozen-thawed mangoes infused with PME and calcium at 50 kPa and atmospheric pressure had superior texture and microstructure in comparison with control frozen-thawed samples. The results of the present analysis allow for a better appreciation of the role of PME, calcium and appropriate infusion conditions in improving the texture of both fresh and frozen-thawed mangoes.


Reactivity of larger intracranial arteries using 7 T MRI in young adults.
The larger intracranial conduit vessels contribute to the total cerebral vascular resistance, and understanding their vasoreactivity to physiological stimuli is required when attempting to understand regional brain perfusion. Reactivity of the larger cerebral conduit arteries remains understudied due to a need for improved imaging methods to simultaneously assess these vessels in a single stimulus. We characterized reactivity of basal intracranial conduit arteries (basilar, right and left posterior, middle and anterior cerebral arteries) and the right and left internal carotid arteries, to manipulations in end-tidal CO2 (PetCO2). Cross-sectional area changes (%CSA) were evaluated from high-resolution (0.5 mm isotropic) images collected at 7 T using a T1-weighted 3D SPACE pulse sequence, providing high contrast between vessel lumen and surrounding tissue. Cerebrovascular reactivity was calculated as %CSA/ΔPetCO2 in eight healthy individuals (18-23 years) during normocapnia (41 ± 4 mmHg), hypercapnia (48 ± 4 mmHg; breathing 5% CO2, balance oxygen), and hypocapnia (31 ± 8 mmHg; via hyperventilation). Reactivity to hypercapnia ranged from 0.8%/mmHg in the right internal carotid artery to 2.7%/mmHg in the left anterior cerebral artery. During hypocapnia, vasoconstriction ranged from 0.9%/mmHg in the basilar artery to 2.6%/mmHg in the right posterior cerebral artery. Heterogeneous cerebrovascular reactivity to hypercapnia and hypocapnia was characterized across basal intracranial conduit and internal carotid arteries.


Genetics of migraine in the age of genome-wide association studies.
Genetic factors importantly contribute to migraine. However, unlike for rare monogenic forms of migraine, approaches to identify genes for common forms of migraine have been of limited success. Candidate gene association studies were often negative and positive results were often not replicated or replication failed. Further, the significance of positive results from linkage studies remains unclear owing to the inability to pinpoint the genes under the peaks that may be involved in migraine. Problems hampering these studies include limited sample sizes, methods of migraine ascertainment, and the heterogeneous clinical phenotype. Three genome-wide association studies are available now and have successfully identified four new genetic variants associated with migraine. One new variant (rs1835740) modulates glutamate homeostasis, thus integrates well with current concepts of neurotransmitter disturbances. This variant may be more specific for severe forms of migraine such as migraine with aura than migraine without aura. Another variant (rs11172113) implicates the lipoprotein receptor LRP1, which may interact with neuronal glutamate receptors, thus also providing a link to the glutamate pathway. In contrast, rs10166942 is in close proximity to TRPM8, which codes for a cold and pain sensor. For the first time this links a gene explicitly implicated in pain related pathways to migraine. The potential function of the fourth variant rs2651899 (PRDM16) in migraine is unclear. All these variants only confer a small to moderate change in risk for migraine, which concurs with migraine being a heterogeneous disorder. Ongoing large international collaborations will likely identify additional gene variants for migraine.


Antihistaminic and antiviral activities of steroids of Turbinaria conoides.
The steroids 3,6,17-trihydroxy-stigmasta-4,7,24(28)-triene (A) and 14,15,18,20-diepoxyturbinarin (B) were isolated from the cyclohexane extract of brown alga, Turbinaria conoides (J. Agardh) Kutzing, and have been reported for their antimicrobial activity by us. In this study, the isolated compounds were evaluated for comprehensive antihistaminic, antiviral and cytotoxicity screening. The antihistaminic study was performed using in vitro standard animal models. Evaluation of the potency (EC(50)), affinity (pA(2)) and the maximal response (E(max)) of the histamine alone and in the presence of the compounds were determined. Antiviral activity and cytotoxicity were performed in Crandell-Rees feline kidney (CRFK) cells by a colorimetric formazan-based MTS assay. No significant antiviral activity or cytotoxicity were observed for the compounds in the CRFK cells. Compound A inhibited the histamine-induced concentration at 20 µg mL(-1)(p < 0.05). The most significant inhibition (97%) was observed for compound B (p < 0.01) at the same concentration, which was comparable to that of the positive control chlorpheniramine maleate (10 µg mL(-1)). This potentiality suggests that 14,15,18,20-diepoxyturbinarin (B) can be developed as a new lead antihistaminic agent.