Clinical Effectiveness of Intravenous Racemic Ketamine Infusions in a Large Community Sample of Patients With Treatment-Resistant Depression, Suicidal Ideation, and Generalized Anxiety Symptoms: A Retrospective Chart Review.
Introduction: Few studies have been published to date exploring the effectiveness of ketamine for treatment-resistant depression (TRD) in large clinical samples. We report on the clinical outcomes of a large cohort treated with ketamine as part of clinical practice. Methods: Deidentified electronic chart data were obtained from a multisite private ketamine infusion clinic for 424 patients with TRD seen from November 9, 2017, to May 4, 2021. Ketamine infusions were administered at a starting dose of 0.5 mg/kg/40 minutes for 6 infusions within 21 days. Maintenance infusions were offered based on clinical response. Changes in outcome measures (scores on the Patient Health Questionnaire-9 [PHQ-9] and Generalized Anxiety Disorder-7 [GAD-7]) within subjects were analyzed using longitudinal multilevel modeling with Kaplan-Meier estimates. Logistic regression was used to analyze for a priori theorized potential moderators of response. Results: Significant improvements from baseline were observed over time on the main outcomes (all P < .001). Based on PHQ-9 self-report data, within 6 weeks of infusion initiation, a 50% response rate and 20% remission rate for depressive symptoms were observed. Response and remission rates were 72% and 38%, respectively, after 10 infusions, and there was a 50% reduction in self-harm/suicidal ideation (SI) symptom scores within 6 weeks. Half of patients with SI at baseline no longer had it after 6 infusions. A 30% reduction in anxiety symptoms (per the GAD-7) was observed. Conclusions: Ketamine was effective at reducing symptoms of SI, depression, and anxiety. The high rates of response and remission were similar to those for interventional treatments in community samples of TRD. Comparative efficacy trials with other interventions and randomized controlled trials of racemic ketamine infusion as the primary treatment for SI are needed.


Potential of GRID2 receptor gene for preventing TNF-induced neurodegeneration in autism.
Autism is one of the most common subtypes of autism spectrum disorder (ASD). Recent studies suggested a relationship between immune-dependent coding genes and ASD, indicating that long term neuroimmunological anomalies affect brain development and synaptic transmission among neural networks. Furthermore, various studies focused on biomarker potential of TNF-α in autism. Ionotropic receptors are also studied as potential marker for autism since altered gene expression levels are observed in autistic patients. GRID2 is a candidate ionotropic receptor which is involved glutamate transfer. In this study, to propose TNF-α dependent cellular processes involved in autism aetiology in relation to GRID2 we performed a bioinformatic network analysis and identified potential pathways and genes that are involved in TNF-α induced changes at GRID2 receptor levels. As a result, we ascertained the GRID2 receptor gene as a candidate gene and further studied the association between GRID2 expression levels and TNF-induced neurodegeneration. Our bioinformatic analyses and experimental results revealed that TNF-α regulates GRID2 gene expression by activating Cdc42 and GOPC genes. Moreover, increased TNF-α levels leads to increase of caspase-3 protein levels triggering neuronal apoptosis leading to neuronal deficiency, which is one of the major symptoms of autism. The study is the first to show the role of TNF-α in regulation of GRID2 gene expression and its signalling pathway. As a result, GRID2 gene can be a suppressor in TNF-induced neurodegeneration which may help to understand the main factors leading to autism.


Association of stress with symptoms of atopic dermatitis.
Psychological stress and atopic dermatitis (AD) symptoms appear to form a vicious cycle. This study compared the degree of stress and impairment of dermatology life quality between patients with AD and healthy controls, and examined for neuropeptides and neurotrophins associated with stress in AD. Questionnaires, comprising five tests evaluating depression, anxiety, interaction anxiousness, private body consciousness, and dermatology life quality, were examined in age- and sex-matched patients with AD (n = 28) and healthy controls (n = 28). Immunohistochemical staining of nerve growth factor, substance P, corticotrophin-releasing factor receptor and neuropeptide Y was performed in the AD-involved and normal skin. Patients with AD showed high scores on all of the questionnaires, including Beck Depression Inventory, state anxiety, trait anxiety, Interaction Anxiousness Scale, Private Body Consciousness subscale, and Dermatology Life Quality Index. All of the parameters, except for Beck Depression Inventory, showed higher values in AD than healthy controls (p < 0.001). Statistically significant correlations were observed between each psychological parameter and Dermatology Life Quality Index. Among the clinical parameters, only pruritus was positively correlated with state anxiety (R = 0.573, p < 0.05) and trait anxiety (R = 0.525, p < 0.05). The Eczema Area and Severity Index score did not show any significant correlations with psychological parameters. Nerve growth factor-reactive cells were observed more abundantly and intensely in both epidermis and dermis of AD involved skin (n = 4) than in healthy controls (n = 3) (p = 0.022 and 0.029, respectively). Also, the number and intensity of neuropeptide Y-positive cells was significantly greater in the entire epidermis of patients with AD than in healthy controls (n = 3) (p = 0.029 and 0.026, respectively). We conclude that anxiety may be associated with the induction of pruritus through neuro-peptide Y and nerve growth factor.


Clinical Improvements in Very Dry Skin from a Natural Ingredient-Based Moisturizing Cream Compared With a Leading Colloidal Oatmeal Control.
The objective of this 6-week clinical study was to demonstrate the effectiveness of a natural ingredient-based moisturizing cream versus a colloidal oatmeal moisturizing cream in improving the hydration, barrier function, appearance, and feel of dry leg skin. Thirty-two subjects completed the study. After a 5-day washout, subjects used the natural ingredient-based moisturizing cream and oatmeal-containing cream on randomly-assigned legs twice a day for a period of three weeks. For the following two weeks subjects did not use any moisturizer on their legs. Skin moisture measurements showed a statistically significant increase in hydration for both products at all time points during the treatment phase of the study. Both products reduced transepidermal water loss measurements during the treatment phase of the study, showing their abilities to improve stratum corneum barrier function. Clinical evaluations showed that both products significantly decreased visual dryness and tactile roughness during the treatment phase. Improvements in the assessed clinical parameters persisted even after treatment cessation. In conclusion, the natural ingredient-based moisturizing cream was highly effective in providing moisturization and improving the skin barrier of subjects with very dry leg skin. It also produced significant improvements in visual dryness and tactile roughness that persisted during regression. Overall, these results show that the natural ingredient-based moisturizing cream delivers comparable benefits to that of a colloidal oatmeal-containing benchmark product and is an option for health care providers and consumers who seek relief from dry skin and prefer a product with all-natural ingredients. J Drugs Dermatol. 2018;17(7):758-764.


Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics.
The ability of leukemia cells to accumulate methotrexate polyglutamate (MTXPG) is an important determinant of the antileukemic effects of methotrexate (MTX). We measured in vivo MTXPG accumulation in leukemia cells from 101 children with acute lymphoblastic leukemia (ALL) and established that B-lineage ALL with either TEL-AML1 or E2A-PBX1 gene fusion, or T-lineage ALL, accumulates significantly lower MTXPG compared with B-lineage ALL without these genetic abnormalities or compared with hyperdiploid (fewer than 50 chromosomes) ALL. To elucidate mechanisms underlying these differences in MTXPG accumulation, we used oligonucleotide microarrays to analyze expression of 32 folate pathway genes in diagnostic leukemia cells from 197 children. This revealed ALL subtype-specific patterns of folate pathway gene expression that were significantly related to MTXPG accumulation. We found significantly lower expression of the reduced folate carrier (SLC19A1, an MTX uptake transporter) in E2A-PBX1 ALL, significantly higher expression of breast cancer resistance protein (ABCG2, an MTX efflux transporter) in TEL-AML1 ALL, and lower expression of FPGS (which catalyzes formation of MTXPG) in T-lineage ALL, consistent with lower MTXPG accumulation in these ALL subtypes. These findings reveal distinct mechanisms of subtype-specific differences in MTXPG accumulation and point to new strategies to overcome these potential causes of treatment failure in childhood ALL.


Outcomes, feasibility and acceptability of a group support psychotherapeutic intervention for depressed HIV-affected Ugandan adults: a pilot study.
Psychotherapy is the recommended first line treatment for mild to moderate depression. However, its availability in low resource settings is limited. We developed a manualized culturally sensitive group support psychotherapeutic intervention for depressed HIV affected Ugandan adults. In this study, we aimed to assess its feasibility, acceptability and impact on depression, functioning, social support and self-esteem. A total of 77 depressed individuals were assigned to the group intervention (n=48) and a wait-list control group (n=29), and assessed before, during and at the end of the intervention. The self-reporting questionnaire, a locally relevant function assessment instrument, the Rosenberg self-esteem scale, and the multiple dimensions perceived social support scale were administered to assess depression symptoms, functioning, self-esteem and social support at three assessment periods. Multivariate longitudinal regression models were used to determine change in outcomes over time between the two groups. Participants were asked to evaluate the intervention. Post -intervention assessments indicate that, in comparison to the wait-list control group, the intervention group had a faster reduction in depression symptom scores [OR=0.00,95% CI, 0.00-0.003] and faster increase in functioning scores [OR=4.82, 95% CI, 2.39 to 9.75], social support scores [OR=2.68, 95% CI, 1.50-4.78] and self-esteem [OR=1.90, 95% CI 1.48-2.44]. Sixty-three percent of participants strongly agreed that the intervention had reduced their depression and would recommend it to other depressed individuals. Inadequate study power due to small sample sizes may result in imprecise confidence intervals even when there are significant differences. The use of non-random samples could have resulted in selection bias. This intervention appears feasible, acceptable and promising in treating depression and restoring function, enhancing social support and self-esteem. Larger and randomized evaluations are warranted.


Exploring the meaning of health security for disaster resilience through people's perspectives in Bangladesh.
There has been significant interest in the rhetoric of health security in recent years from both global and local perspectives. Understanding health in the context of disaster vulnerability presents an opportunity to examine how improved health might reduce the effects of environmental disasters and other crises. To this end, a project was implemented in Bangladesh to establish the potential of a health security approach for disaster resilience amongst people living in high risk environments. This paper explores what we might mean by health security through engaging community level perspectives in the southeast coastal belt of Bangladesh, an area prone to cyclone and flood. This has been examined with respect to variation in gender and wealth of households. Household surveys, interviews and focus group discussions were some of the methods used to collect data. The findings show that health related coping strategies and agentive capabilities in the context of impending crises vary from one micro-context to the next. This suggests a dynamic and integrative resilience that could be built on further, but one which remains remote from wider discourses on health security.


Sleep disordered breathing, insomnia symptoms, and sleep quality in a clinical cohort of U.S. Hispanics in south Florida.
There is a paucity of information on the epidemiology of sleep disorders among US Hispanics. This study describes the frequency of sleep disordered breathing (SDB) risk, insomnia complaints, poor sleep quality, and daytime somnolence in a clinical cohort of ethnically diverse US Hispanics living in South Florida. We explored the presence of sleep disorders in a cohort of Hispanics seen at primary care, pulmonary, and sleep clinics at the University of Miami and Miami Veterans Affair Medical Center. Participants completed validated questionnaires, evaluating risk of SDB, presence of insomnia symptoms, sleep quality, and daytime sleepiness. Polysomnography was completed on the majority of the sleep clinic participants. Participants (N = 282; 62% male; mean age 54 ± 15 years; mean BMI 31 ± 6 kg/m(2)) included Hispanics of Cuban, Puerto Rican, Central/South American, and Caribbean heritage. Excessive daytime sleepiness was noted by 45% of participants. Poor sleep quality was reported by 49%; 76% screened high risk for SDB, and 68% had insomnia symptoms. Sleep disorders were more commonly reported in sleep clinic participants; however, 54% of non-sleep clinic participants were high risk for SDB, 35% had insomnia complaints, 28% had poor sleep quality, and 18% reported daytime sleepiness. Sleep disorders (including SDB) are common in clinical samples of Hispanics in South Florida. These findings highlight the urgent need for linguistically relevant and culturally responsive screening, awareness and education programs in clinical sleep medicine among US Hispanics. Shafazand S; Wallace DM; Vargas SS; Del Toro Y; Dib S; Abreu AR; Ramos A; Nolan B; Baldwin CM; Fleming L. Sleep disordered breathing, insomnia symptoms, and sleep quality in a clinical cohort of US Hispanics in South Florida. J Clin Sleep Med 2012;8(5):507-514.


Evaluation of response strategies against epidemics due to Neisseria meningitidis C in Niger.
To inform public health recommendations, we evaluated the effectiveness and efficiency of current and hypothetical surveillance and vaccine response strategies against Neisseria meningitidis C meningitis epidemics in 2015 in Niger. We analysed reports of suspected and confirmed cases of meningitis from the region of Dosso during 2014 and 2015. Based on a definition of epidemic signals, the effectiveness and efficiency of surveillance and vaccine response strategies were evaluated by calculating the number of potentially vaccine-preventable cases and number of vaccine doses needed per epidemic signal. A total of 4763 weekly health area reports, collected in 90 health areas with 1282 suspected meningitis cases, were included. At a threshold of 10 per 100 000, the total number of estimated vaccine-preventable cases was 29 with district-level surveillance and vaccine response, 141 with health area-level surveillance and vaccination and 339 with health area-level surveillance and district-level vaccination. While being most effective, the latter strategy required the largest number of vaccine doses (1.8 million), similar to the strategy of surveillance and vaccination at district level (1.3 million), whereas the strategy of surveillance and vaccination at health area level would have required only 0.8 million doses. Thus, efficiency was lowest for district-level surveillance and highest for health area-level surveillance with district-level vaccination. In this analysis, we found that effectiveness and efficiency were higher at health area-level surveillance and district-level vaccination than for other strategies. Use of N. meningitidis C vaccines in a preventive strategy thus should be considered, in particular as most reactive vaccine response strategies in our analysis had little impact on disease burden.


An anticipatory governance approach to carbon nanotubes.
Carbon nanotubes (CNTs) are novel materials with remarkable properties; possible beneficial applications include aircraft frames, hydrogen storage, environmental sensors, electrical transmission, and many more. At the same time, precise characterization of their potential toxicity remains elusive, in part because engineered nanostructures pose challenges to existing assays, predictive models, and dosimetry. While these obstacles are surmountable, their presence suggests that scientific uncertainty regarding the hazards of CNTs is likely to persist. Traditional U.S. policy approaches implicitly pose the question: "What level of evidence is necessary and sufficient to justify regulatory action?" In the case of CNTs, such a strategy of risk analysis is of limited immediate utility to both regulators essaying to carry out their mandates, and users of CNTs seeking to provide an appropriate level of protection to employees, customers, and other stakeholders. In contrast, the concept of anticipatory governance suggests an alternative research focus, that is: "Given the conflicted character of the data, how should relevant actors respond?" Adopting the latter theoretical framework, this article argues that currently available data support treating CNTs "as if" they are hazardous, while simultaneously highlighting some systemic uncertainties in many of the experiments carried out to date. Such a conclusion implies limiting exposure throughout product lifecycles, and also points to the possible applicability of various conceptual tools, such as life-cycle and multicriteria decision analysis approaches, in choosing appropriate courses of action in the face of prolonged uncertainty.


Contact transmission of vesicular stomatitis virus New Jersey in pigs.
To determine how viral shedding and development or lack of clinical disease relate to contact transmission of vesicular stomatitis virus New Jersey (VSV-NJ) in pigs and determine whether pigs infected by contact could infect other pigs by contact. 63 pigs. Serologically naive pigs were housed in direct contact with pigs that were experimentally inoculated with VSV-NJ via ID inoculation of the apex of the snout, application to a scarified area of the oral mucosa, application to intact oral mucosa, or ID inoculation of the ear. In a second experiment, pigs infected with VSV-NJ by contact were moved and housed with additional naive pigs. Pigs were monitored and sampled daily for clinical disease and virus isolation and were serologically tested before and after infection or contact. Contact transmission developed only when vesicular lesions were evident. Transmission developed rapidly; contact pigs shed virus as early as 1 day after contact. In pens in which contact transmission was detected, 2 of 3 or 3 of 3 contact pigs were infected. Transmission was lesion-dependent; however, vesicular lesions often were subtle with few or no clinical signs of infection. Contact transmission was efficient, with resulting infections ranging from subclinical (detected only by seroconversion) to clinical (development of vesicular lesions). Long-term maintenance of VSV-NJ via contact transmission alone appears unlikely. Pigs represent an efficient large-animal system for further study of VSV-NJ pathogenesis and transmission.


Insights into insulin-mediated regulation of CYP2E1: miR-132/-212 targeting of CYP2E1 and role of phosphatidylinositol 3-kinase, Akt (protein kinase B), mammalian target of rapamycin signaling in regulating miR-132/-212 and miR-122/-181a expression in primary cultured rat hepatocytes.
Several microRNAs (miRNAs) were selected for characterization of their response to insulin signaling based on in silico predictions of targeting CYP2E1 mRNA and previous reports implicating their role in hepatic metabolism and disease. CYP2E1 expression decreases with increasing insulin concentration and has been shown to be regulated by the phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. In primary cultured rat hepatocytes, insulin at 0.1, 1.0, and 10 nM elevated miRNA-132 and -212 expression ∼2- and 1.8-fold, respectively, whereas expression of miRNA-181a and -122 increased ∼1.6- and 1.4-fold, respectively. In contrast, insulin failed to alter significantly the expression of miRNA let-7a. Mechanistic studies using inhibitors of PI3-K, Akt, and mTOR were used to examine the role of the insulin signaling pathway on miR expression and resulted in significant suppression of the insulin-mediated elevation of miR-132, miR-212, and miR-122 levels, with a lesser effect observed for miR-181a. Targeting of the rat CYP2E1 3'-untranslated region (UTR) by miR-132 and -212 was demonstrated with an in vitro luciferase reporter assay. These data show that insulin, which regulates CYP2E1 through the PI3-K, Akt, mTOR signaling pathway, also regulates the expression of miRs that target the 3'-UTR of CYP 2E1 mRNA and are involved in the regulation of hepatic metabolism and disease.


Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial.
Ovarian cancer continues to have a poor prognosis with the majority of women diagnosed with advanced disease. Therefore, we undertook the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) to determine if population screening can reduce deaths due to the disease. We report on ovarian cancer mortality after long-term follow-up in UKCTOCS. In this randomised controlled trial, postmenopausal women aged 50-74 years were recruited from 13 centres in National Health Service trusts in England, Wales, and Northern Ireland. Exclusion criteria were bilateral oophorectomy, previous ovarian or active non-ovarian malignancy, or increased familial ovarian cancer risk. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer generated random numbers to annual multimodal screening (MMS), annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. Follow-up was through national registries. The primary outcome was death due to ovarian or tubal cancer (WHO 2014 criteria) by June 30, 2020. Analyses were by intention to screen, comparing MMS and USS separately with no screening using the versatile test. Investigators and participants were aware of screening type, whereas the outcomes review committee were masked to randomisation group. This study is registered with ISRCTN, 22488978, and ClinicalTrials.gov, NCT00058032. Between April 17, 2001, and Sept 29, 2005, of 1 243 282 women invited, 202 638 were recruited and randomly assigned, and 202 562 were included in the analysis: 50 625 (25·0%) in the MMS group, 50 623 (25·0%) in the USS group, and 101 314 (50·0%) in the no screening group. At a median follow-up of 16·3 years (IQR 15·1-17·3), 2055 women were diagnosed with tubal or ovarian cancer: 522 (1·0%) of 50 625 in the MMS group, 517 (1·0%) of 50 623 in the USS group, and 1016 (1·0%) of 101 314 in the no screening group. Compared with no screening, there was a 47·2% (95% CI 19·7 to 81·1) increase in stage I and 24·5% (-41·8 to -2·0) decrease in stage IV disease incidence in the MMS group. Overall the incidence of stage I or II disease was 39·2% (95% CI 16·1 to 66·9) higher in the MMS group than in the no screening group, whereas the incidence of stage III or IV disease was 10·2% (-21·3 to 2·4) lower. 1206 women died of the disease: 296 (0·6%) of 50 625 in the MMS group, 291 (0·6%) of 50 623 in the USS group, and 619 (0·6%) of 101 314 in the no screening group. No significant reduction in ovarian and tubal cancer deaths was observed in the MMS (p=0·58) or USS (p=0·36) groups compared with the no screening group. The reduction in stage III or IV disease incidence in the MMS group was not sufficient to translate into lives saved, illustrating the importance of specifying cancer mortality as the primary outcome in screening trials. Given that screening did not significantly reduce ovarian and tubal cancer deaths, general population screening cannot be recommended. National Institute for Health Research, Cancer Research UK, and The Eve Appeal.


Patient Satisfaction and Quality of Life Before and After Treatment of Pancreatic and Periampullary Cancer: A Prospective Multicenter Study.
This study sought to assess patient satisfaction and quality of life (QoL) before and after treatment of pancreatic and periampullary cancer. We conducted a prospective multicenter study of patients treated for pancreatic and periampullary cancer. General patient satisfaction was measured using the EORTC satisfaction with care questionnaire (IN-PATSAT32) at baseline and 3 months after treatment initiation, with a 10-point change on the Likert scale considered clinically meaningful. QoL was measured using the EORTC Core Quality of Life Questionnaire (QLQ-C30). The influence of treatment (curative and palliative) on patient satisfaction and QoL was determined. Of 100 patients, 71 completed follow-up questionnaires. General satisfaction with care decreased from 74.3 before treatment to 61.9 after treatment (P<.001), whereas global QoL increased from 68.4 to 71.4 (P=.39). Clinically meaningful reductions were also observed for the reported interpersonal skills of doctors (from 73.4 to 63.3) and exchange of information within the care team (from 63.5 to 52.5). Satisfaction scores were lower for patients treated with curative intent than for those treated with palliative intent regarding interpersonal skills of doctors (P=.01), information provision by doctors (P=.004), information provision by nurses (P=.02), availability of nurses (P=.004), exchange of information within the care team (P=.01), and hospital access (P=.02). In multivariable analysis, clinicopathologic or QoL factors were not independently associated with general patient satisfaction. Satisfaction with care, but not QoL, decreased after pancreatic cancer treatment. Improvements in communication and interpersonal skills are needed to maintain patient satisfaction after treatment.


Intracellular targeting and structural conservation of a prohormone-processing endoprotease.
The prohormone-processing endoprotease (KEX2 gene product) of the yeast Saccharomyces cerevisiae is a membrane-bound, 135,000-dalton glycoprotein, which contains both asparagine-linked and serine- and threonine-linked oligosaccharide and resides in a secretory compartment. Analysis of mutant kex2 genes truncated at their 3' end indicates that carboxyl terminal domains of the enzyme are required for its proper localization within the cell. A human gene product, "furin," shares 50% identity with the catalytic domain of Kex2 protease and is, therefore, a candidate for a human prohormone-processing enzyme.


Generation of electric potentials by bone in response to mechanical stress.
The amplitude of electrical potentials generated in stressed bone is dependent upon the rate and magnitude of bony deformation, while polarity is determined by the direction of bending. Areas under compression develop negative potentials with respect to other areas. Similar results were obtained both in living and dead bone. Removal of the inorganic fraction from bone abolishes its ability to generate stress potentials. It is probable that these potentials influence the activity of osseous cells directly. Furthermore, it is conceivable that they may direct, in some manner, the aggregation pattern of the macromolecules of the extracellular matrix.


Trienamine catalyzed asymmetric synthesis and biological investigation of a cytochalasin B-inspired compound collection.
Due to their enhanced metabolic needs many cancers need a sufficient supply of glucose, and novel inhibitors of glucose import are in high demand. Cytochalasin B (CB) is a potent natural glucose import inhibitor which also impairs the actin cytoskeleton leading to undesired toxicity. With a view to identifying selective glucose import inhibitors we have developed an enantioselective trienamine catalyzed synthesis of a CB-inspired compound collection. Biological analysis revealed that indeed actin impairment can be distinguished from glucose import inhibition and led to the identification of the first selective glucose import inhibitor based on the basic structural architecture of cytochalasin B.


Studies on mediator production by highly purified human T and B lymphocytes.
Highly purified populations of T and B lymphocytes obtained by affinity column separation were stimulated by antigen and their ability to produce two mediators, migration inhibitory factor (MIF) and lymphocyte mitogenic factor (LMF) was assessed. Both T- and B-cell populations made MIF; the production of MIF was antigen-specific using purified protein derivative of tuberculin, streptokinase-streptodornase, and Candida antigens. The MIF activity from both populations could not be attributed to antigen-antibody complexes as the inhibitory activity eluted from Sephadex G-100 columns in the same region corresponding to mol wt 23,000 daltons. Further studies indicate that the T cells producing MIF are proliferating cells whereas the B cells producing this mediator are not. In contrast, LMF was made only by T cells and not B cells when these populations were stimulated by antigen. The LMF induced the [(3)H]thymidine incorporation into both T and B cells obtained from donors lacking sensitivity to the antigens used to elicit the factor. Chromatographic studies indicate that LMF eluted from Sephadex G-100 in a fraction of mol wt 23,000 daltons where MIF is also found; however, since B cells produce MIF but not LMF, these two factors appear to be distinct from one another. Some of the implications of these findings are discussed. The explanation for the production or lack of production of MIF by lymphocytes obtained from patients with immunodeficiency disorders requires reinterpretation.


A study of weight transmission through the cervical and upper thoracic regions of the vertebral column in man.
The role of the neural arch in weight transmission in the cervical and upper thoracic regions of the vertebral column has been investigated. Measurements at the levels of C2, C4, C6, C7, T1 and T5 vertebrae were made in 44 adult male vertebral columns. At each level, the area of the inferior surface of the body was compared with the area of the inferior articular facets, the pedicle index and the arch index; inclination of the pedicle in relation to the body was also measured. On the basis of these studies it was found that at C2 level the compressive force acting on the superior articular surfaces was transmitted to the inferior surface of the body and to the two inferior articular facets. From C2 to C7, compressive force is transmitted through three parallel columns - one anterior, formed by the bodies and intervertebral discs, and two posterior, formed by the articulations of the articular processes on either side. Due to the posterior curvature in the cervical region, the posterior columns here sustain more of the compressive force. From C7 level downwards, the compressive force is transmitted through two columns, i.e. one anterior formed by the bodies and intervertebral discs and one posterior formed by successive articulations of the laminae. Below C7 level, compressive force from the posterior column is partly transferred to the anterior column through the pedicles at T1 and T2. In the upper thoracic region, due to the anterior curvature, the main part of the compressive force is transmitted through the anterior column, which sustains even greater compressive force than is suggested by body area, with resulting increased stress.


A model for the coregulation of smooth muscle actomyosin by caldesmon, calponin, tropomyosin, and the myosin regulatory light chain.
The purpose of these studies was to evaluate the effects of the actin-binding proteins tropomyosin, caldesmon, and calponin on the activation of smooth muscle actomyosin by phosphorylation of the regulatory light chain of myosin (LC20), and to interpret these findings in the context of a two-state kinetic model for the cross-bridge cycle. An in vitro motility assay was used to broadly classify each regulatory protein according to whether it modulates the apparent on-rate for cross bridges (fapp) or the apparent off-rate (gapp). In addition to measuring actin-filament velocity, a method was developed to measure relative changes in the force exerted on actin filaments under isometric conditions. Based primarily on the results of these motility studies, a qualitative model is proposed in which LC20 phosphorylation, tropomyosin, and caldesmon all regulate fapp and calponin regulates gapp. The model predicts that the sensitivity of activation by LC20 phosphorylation is determined by tropomyosin, caldesmon, and calponin, whereas unloaded shortening velocity is regulated primarily by calponin.


Pain and bloody ear discharge in a returning traveler.
Cochliomyia hominivorax, the New World screwworm, was a serious livestock pest in the southern United States until the 1960s, when it was successfully eradicated by the release of sterile male flies. It remains endemic in parts of the Caribbean and South America, and there is concern that climate change may extend its geographic distribution. Cochliomyia hominivorax is voracious and can cause extensive damage to soft tissue and bone. We describe the case of a 26-year-old traveler who presented with otalgia and bloody otorrhea after returning from a vacation in the Dominican Republic, where exposure to screwworm flies most likely occurred during a nap on the beach. The causative agent was recognized by its characteristic larval anatomy, which includes pigmented dorsal tracheal trunks and posterior spiracles with an open peritreme.


COVID-19 in a Cohort of Patients with Congenital Myasthenic Syndrome.
Congenital Myasthenic Syndromes (CMS) are a rare group of genetic disorders of neuromuscular transmission. Some subtypes of CMS can be associated with respiratory and bulbar weakness and these patients may therefore be at high risk of developing a severe disease from COVID-19. We screened 73 patients with genetically confirmed CMS who were attending the UK national referral centre for evidence of previous Severe Acute Respiratory Syndrome Corona Virus 2 infection and their clinical outcome. Of 73 patients, seven had history of confirmed COVID-19. None of the infected patients developed a severe disease, and there were no signals that CMS alone carries a high risk of severe disease from COVID-19.


New perspectives on vitamin D food fortification based on a modeling of 25(OH)D concentrations.
In Germany, vitamin D intake from food and synthesis in the skin is low, which leads to low 25(OH)D serum concentrations. In contrast to many other countries, general vitamin D food fortification is still prohibited in Germany, although the European Commission published a regulatory framework to harmonize addition of vitamins to foods. Thus the purpose of our study was to develop a vitamin D fortification model, taking into account all vitamin D sources with the goal to fulfill requirements of intake recommendations or preferable 25(OH)D serum concentrations. Finally, the aim was to assess the suitability of different carriers and associated risks. We developed a mathematical bottom-up model of 25(OH)D serum concentrations based on data about vitamin D sources of the German population such as sunlight, food and supplements for all federal states taking seasonal and geographical variations into account. We used this model to calculate the optimal fortification levels of different vitamin D carriers in two approaches. First we calculated required fortification levels based on fixed intake recommendations from e.g. the IOM or the DGE and second based on achieving certain 25(OH)D serum concentrations. To lift 25(OH)D serum concentration in Germany to 75 nmol/L, e.g. 100 g bread has to be fortified with 11.3 μg during winter, resulting in a daily vitamin D intake of 23.7 μg. Bread seems to be a suitable carrier for base supply. However, overdose risk with a single fortified product is higher than the risk with several fortified carriers. With the model in hand, it is possible to conceive vitamin D fortification strategies for different foodstuffs and model its impact on 25(OH)D serum concentrations.


Sunitinib promotes myogenic regeneration and mitigates disease progression in the mdx mouse model of Duchenne muscular dystrophy.
Duchenne muscular dystrophy (DMD) is a lethal, muscle degenerative disease causing premature death of affected children. DMD is characterized by mutations in the dystrophin gene that result in a loss of the dystrophin protein. Loss of dystrophin causes an associated reduction in proteins of the dystrophin glycoprotein complex, leading to contraction-induced sarcolemmal weakening, muscle tearing, fibrotic infiltration and rounds of degeneration and failed regeneration affecting satellite cell populations. The α7β1 integrin has been implicated in increasing myogenic capacity of satellite cells, therefore restoring muscle viability, increasing muscle force and preserving muscle function in dystrophic mouse models. In this study, we show that a Food and Drug Administration (FDA)-approved small molecule, Sunitinib, is a potent α7 integrin enhancer capable of promoting myogenic regeneration by stimulating satellite cell activation and increasing myofiber fusion. Sunitinib exerts its regenerative effects via transient inhibition of SHP-2 and subsequent activation of the STAT3 pathway. Treatment of mdx mice with Sunitinib demonstrated decreased membrane leakiness and damage owing to myofiber regeneration and enhanced support at the extracellular matrix. The decreased myofiber damage translated into a significant increase in muscle force production. This study identifies an already FDA-approved compound, Sunitinib, as a possible DMD therapeutic with the potential to treat other muscular dystrophies in which there is defective muscle repair.


Successful management of aggressive fibromatosis of the neck using wide surgical excision: a case report.
Aggressive fibromatosis is a benign tumor, thought to arise from deep musculoaponeurotic structures, rarely found in the head or neck. However, when it does occur in the head and neck region, it tends to be more aggressive and associated with significant morbidity, which may be attributed to the vital vascular, neurological or anatomical structures in close proximity. We report the case of a 39-year-old Pakistani man who presented with a two-month history of a lump on the right side of his neck. The mass was excised and histopathological analysis revealed a case of aggressive fibromatosis. Due to the rarity of the condition no guidelines are available on the indications and extent of each modality. Due to its aggressive behavior and tendency to invade local structures and recur, a multi-modality management strategy is usually employed. On the basis of this case, we suggest that aggressive surgery is a viable management option and may be successfully used as a single modality treatment.


A disorder of sympathomimetic amines leading to increased vascular permeability may be the etiologic factor in various treatment refractory health problems in women.
There is an evidence that increased capillary permeability in the standing position is related to a deficit in the sympathetic nervous system. The leakage of this fluid leads to various clinical conditions which frequently puzzle the consulting physician because despite the frequency of this condition intelligent physicians and patients are unaware of the cause of their condition. One of the most common manifestations is the inability to lose weight despite proper dieting. A randomized study comparing the efficacy of a diuretic, a converting enzyme inhibitor, spironolactone and a sympathomimetic amine on weight loss in diet refractory women found that only the latter in the form of dextroamphetamine sulfate demonstrated significant weight reduction over a six month time span. In fact, the dextroamphetamine sulfate proved effective when given in the next 6 months to the three groups failing to respond for the first 6 months. The diagnosis of a deficit in sympathomimetic amines is established by demonstrating an abnormal clearance of a water load in the erect position and exclusion of other conditions that are associated with an abnormal free water clearance, e.g., hypothyroidism, renal or liver disease or congestive heart failure. The original definition of an abnormal water load test was excretion of <55% of a 1500 ml water load in 6h but we found that <75% defines a greater population who suffer from this problem. There are several conditions that have proven refractory to conventional theory that respond quickly and effectively to sympathomimetic amines. There have been many anecdotal reports of relieving interactable pain syndromes quickly and efficiently with sympathomimetic amine theory, despite failure with a multitude of other therapies. These include interstitial cystitis and pelvic pain that was attributed to endometriosis, gastrointestinal pain including esophagitis and gastroparesis, headaches, joint pain, fibromyalgia, and carpal tunnel syndrome. It is not clear if the improvement in pain is related to a decrease in fluid retention or a direct effect of the sympathomimetic amines on the sympathetic nervous system. Sympathomimetic amine theory has helped other conditions besides pain, e.g., chronic fatigue, vasomotor symptoms in young women not associated with decreased ovarian egg reserve, and chronic urticaria resistant to all other therapies. Thus, these studies strongly suggest that physicians be aware of this condition involving a deficit in the sympathetic nervous system when faced with various enigmatic complaints especially if standard therapy has not proven effective.


Dissecting the influence of regional dura mater on cranial suture biology.
Craniosynostosis is a relatively common developmental disorder that leads to a number of serious consequences. Previous studies have shown the influence of dura mater on the overlying cranial suture. This study was conducted to determine the role of regional dura mater versus the intrinsic nature of the suture in directing the overlying suture's fate. The authors examined the effect of regional dura mater on the fate and morphology of the posterofrontal and coronal sutures. In 8-day-old Sprague-Dawley rats, calvarial disks, consisting of the posterofrontal and coronal sutures, were excised and placed in one of three positions: (1) native position (control group), (2) rotated 45 degrees, or (3) rotated 90 degrees (n = 5 animals per group). The animals were euthanized 1 month postoperatively, and the sutures were analyzed histologically. The control group revealed normal suture morphology (n = 5). In the 45-degree rotation group, which placed the posterofrontal and coronal sutures over non-suture-associated dura mater, the posterofrontal sutures fused with thin morphology, and the coronal sutures remained patent (n = 5). In the 90-degree rotation group, the posterofrontal sutures, which were positioned over coronal suture-associated dura mater, were found to be fused with thinner morphology. The coronal sutures of the 90-degree rotation group, which were placed over posterofrontal suture-associated dura mater, remained patent but had acquired a posterofrontal-like morphology (n = 5). This study further elucidates variations in the biology of dura mater, depending on its location. Furthermore, these results illustrate the interplay between regional dura mater and the inherent characteristics of the suture complex in determining suture biology.


Ity influences the production of IFN-gamma by murine splenocytes stimulated in vitro with Salmonella typhimurium.
The Ity-Lsh-Bcg genetic locus in the mouse has been documented to confer innate resistance to at least three intracellular pathogens: Salmonella typhimurium, Leishmania donovani, and Mycobacterium. Expression of the resistance gene(s) results in a slower net growth of these pathogens in the reticuloendothelial system early postinfection. Although it is clear that the resident macrophages in resistant mice are functionally superior with regard to antimicrobial activity, the exact mechanism(s) underlying the control exerted by this gene is not understood. Using S. typhimurium infection as a model, we have examined the influence of this resistance gene(s) on the production of IFN-gamma, a cytokine known to play an important role in host-defense against several intracellular pathogens. We compared IFN-gamma production by splenocytes from resistant (Ity(r)) and sensitive (Ity(s)) inbred mouse strains after stimulation in vitro with S. typhimurium. Spleen cells from Ity(r) mouse strains produced significantly higher levels of IFN-gamma when compared to spleen cells obtained from Ity(s) mouse strains. Enhanced IFN-gamma production was not a generalized response to bacteria. Listeria monocytogenes induced comparable levels of IFN-gamma production from both Ity(r) (CBA/J) and Ity(s) (C57BL/6) mice. Splenocytes from Ity congenic mouse strains displayed similar differences in the level of IFN-gamma produced after S. typhimurium stimulation, with spleen cells from the Ity(r) strain producing significantly higher levels of IFN-gamma when compared to spleen cells from the Ity(s) strain. A requirement for adherent cells and/or adherent cell-derived factors has been documented for IFN-gamma production by S. typhimurium-stimulated splenocytes. Interestingly, supernatant from adherent cells obtained from Ity(r) mouse strains was found to induce the production of significantly higher levels of IFN-gamma when compared to adherent cell supernatant from Ity(s) strains. Nylon wool nonadherent cells from Ity(s) mouse strains produced high levels of IFN-gamma when exposed to supernatants obtained from adherent cells of Ity(r) mouse strains. In contrast, nylon wool nonadherent cells from Ity(r) mouse strains produced reduced levels of IFN-gamma when exposed to supernatant obtained from adherent cells of Ity(s) mouse strains. Thus, modulation of IFN-gamma production appears to be a function of the Ity(r) gene(s). This study documents for the first time that the Ity locus may play a role in controlling resistance to Salmonella infection by regulating IFN-gamma production by NK cells.


The structure-specific endonuclease Mus81-Eme1 promotes conversion of interstrand DNA crosslinks into double-strands breaks.
Repair of interstrand crosslinks (ICLs) requires multiple-strand incisions to separate the two covalently attached strands of DNA. It is unclear how these incisions are generated. DNA double-strand breaks (DSBs) have been identified as intermediates in ICL repair, but enzymes responsible for producing these intermediates are unknown. Here we show that Mus81, a component of the Mus81-Eme1 structure-specific endonuclease, is involved in generating the ICL-induced DSBs in mouse embryonic stem (ES) cells in S phase. Given the DNA junction cleavage specificity of Mus81-Eme1 in vitro, DNA damage-stalled replication forks are suitable in vivo substrates. Interestingly, generation of DSBs from replication forks stalled due to DNA damage that affects only one of the two DNA strands did not require Mus81. Furthermore, in addition to a physical interaction between Mus81 and the homologous recombination protein Rad54, we show that Mus81(-/-) Rad54(-/-) ES cells were as hypersensitive to ICL agents as Mus81(-/-) cells. We propose that Mus81-Eme1- and Rad54-mediated homologous recombination are involved in the same DNA replication-dependent ICL repair pathway.


Application of Response Surface Methodology to Study the Effects of Brisket Fat, Soy Protein Isolate, and Cornstarch on Nutritional and Textural Properties of Rabbit Sausages.
The effects of brisket fat, soy protein isolate, and cornstarch on chemical and textural properties of rabbit sausages were studied using surface response methodology. Sausage samples were prepared using a five-level three-variable Central Composite Rotatable Design with 16 combinations, including two replicates of the center point, carried out in random order. The level of brisket fat (BF), soy protein isolate (SPI), and cornstarch (CS) in the sausage formulation ranged within 8.3-16.7%, 0.7-2.3%, and 1.3-4.7%, respectively. Increasing BF decreased moisture and ash contents but increased protein and fat contents of the sausages (p < 0.05). Increasing SPI increased moisture content but decreased ash and carbohydrate contents of the sausages (p < 0.05). Increasing CS increased carbohydrate content (p < 0.05). Increasing BF increased hardness, adhesiveness, cohesiveness, and chewiness but decreased springiness (p < 0.05). SPI addition increased springiness but decreased adhesiveness, cohesiveness, and chewiness (p < 0.05). In conclusion, varying the levels of BF and SPI had a more significant effect on chemical and textural properties of rabbit sausages than CS.


High-fat feeding reduces endothelium-dependent vasodilation in rats: differential mechanisms for saturated and unsaturated fatty acids?
1. Chronic feeding with a high-fat diet can cause metabolic syndrome in rodents similar to humans, but the role of saturated versus unsaturated fats in vascular tension remains unclear. 2. The present study shows that rats on a diet rich in either saturated or unsaturated fat had higher blood pressure compared with chow-fed rats (approximately 130 vs 100 mmHg, respectively), along with hyperlipidaemia and insulin resistance. Compared with responses of phenylephrine-preconstricted artery segments from chow-fed rats, vasorelaxation of isolated renal arteries from high-fat fed rats was reduced substantially (> 50%) in response to acetylcholine (0.01-10 micromol/L) and moderately to nitroprusside (>or=1 micromol/L) at low concentrations. Acetylcholine-induced vasorelaxation of arteries from high-fat fed rats was also more sensitive to inhibition by the nitric oxide (NO) synthase inhibitors NG-nitro-L-arginine and methylene blue. 3. In human umbilical vein endothelial cells, the production of NO and endothelin-1 was significantly inhibited by unsaturated fatty acids. In comparison, saturated fatty acids stimulated endothelin-1 production without altering NO production. 4. The data indicate that both saturated and unsaturated high-fat feeding may result in an increase in blood pressure owing to reduced endothelium-dependent vasorelaxation in the arterial system. The impaired endothelium-dependent vasorelaxation induced by saturated and unsaturated fatty acids may involve different mechanisms.


Serologic responses to pneumocystis proteins in HIV patients with and without Pneumocystis jirovecii pneumonia.
Immune responses to Pneumocystis jirovecii are not well understood in HIV infection, but antibody responses to proteins may be useful as a marker of Pneumocystis risk or presence of Pneumocystis pneumonia (PcP). Retrospective analysis of a prospective cohort. Enzyme-linked immunosorbent assays of antibodies to recombinant Pneumocystis proteins of major surface glycoprotein fragments (MsgC1, C3, C8, and C9) and of antibody titers to recombinant kexin protein (KEX1) were performed on 3 sequential serum samples up to 18 months before and 3 samples after first AIDS-defining illness from Multicenter AIDS Cohort Study participants and compared between those who had PcP or a non-PcP AIDS-defining illness. Fifty-four participants had PcP and 47 had a non-PcP AIDS-defining illness. IgG levels to MsgC fragments were similar between groups before first AIDS-defining illness, but the PcP group had higher levels of IgG to MsgC9 (median units/mL 50.2 vs. 22.2, P = 0.047) post-illness. Participants with PcP were more likely to have an increase in MsgC3 [odds ratio (OR): 3.9, P = 0.02], MsgC8 (OR: 5.5, P = 0.001), and MsgC9 (OR: 4.0, P = 0.007). The PcP group was more likely to have low KEX1 IgG before development of PcP (OR: 3.6, P = 0.048) independent of CD4 cell count and to have an increase in high IgG titers to KEX1 after PcP. HIV-infected individuals develop immune responses to both Msg and kexin proteins after PcP. Low KEX1 IgG titers may be a novel marker of future PcP risk before CD4 cell count has declined below 200 cells per microliter.


Genetic analysis of beet curly top virus: evidence for three virion sense genes involved in movement and regulation of single- and double-stranded DNA levels.
The monopartite DNA genome of beet curly top geminivirus (BCTV, strain Logan) contains four leftward, complementary sense open reading frames (ORFs) designated L1, L2, L3, and L4 and three rightward, virion sense ORFs designated R1, R2, and R3 (R1 encodes the coat protein). The R3 ORF has not been reported previously in the BCTV genome, and evidence for three functional virion sense genes on one genome component has not been presented before for any geminivirus. We investigated the functions of the virion sense ORFs by introducing mutations into each of them. We found that in Nicotiana benthamiana plants, BCTV genomes containing mutations in ORF R1 were not infectious, whereas an R3- mutant was very weakly infectious. The small proportion of plants infected by the R3- mutant remained asymptomatic and contained greatly reduced amounts of viral DNA. An R2- mutant was highly infectious but asymptomatic, and in infected plants it accumulated mostly the double-stranded DNA (dsDNA) replicative form in nearly wild-type amounts. All of the mutants replicated in tobacco protoplasts, although R1- and R2- mutants accumulated reduced amounts of genomic single-stranded DNA (ssDNA) relative to wild-type virus. In the case of R2- mutants, the reduction was large (approx. ninefold) and was accompanied by a similar increase in dsDNA levels. The results suggest that the R1 and R3 gene products are required for efficient movement of the virus in the infected plant, whereas the R2 gene product may be involved in the regulation of ssDNA vs dsDNA levels.


Gold nanoparticle based microbial detection and identification.
Microorganisms belong to one of the biggest threats to humanity. Rapid detection and identification of microbes in environmental, food and clinical samples is required for safety purposes as well as diagnosis of infectious diseases. Conventional techniques for microbial detection, though reliable and gold standard, are time consuming, expensive and unsuitable for field situations. Advent of novel techniques involving Nanotechnology has been promising for the development of rapid and low cost strategies for rapid detection and identification of microbes with higher sensitivity. Gold nanoparticles find a significant place in medicine, material sciences as well as diagnostics for their unique optical and physiochemical properties. This review focuses at recent advancements in the development of gold nanoparticle based assays for microbial detection and identification.


Occurrence of sibling species of Lutzomyia longipalpis (Diptera: Psychodidae) in Venezuela: first evidence from reproductively isolated sympatric populations.
The delimitation of cryptic species within the main vector of the American visceral leishmaniasis, Lutzomyia longipalpis, remains a topic of controversy. An analysis of genetic variability based on 8 enzymatic loci revealed fixed differences in 2 diagnostic loci, adenylate kinase (Ak) and hexokinase (Hk), between sympatric and allopatric populations at 4 localities in Venezuela. The absence of heterozygotes for these 2 loci within 1 locality indicates, for the first time, the presence of 2 sympatric reproductively isolated populations or cryptic species within L. longipalpis. Significant differences were also detected between these cryptic species in the allele frequencies of glucose-6-phosphate isomerase (Gpi) and malate dehydrogenase, decarboxylating (Me). One species showed mean heterozygosities that ranged between 6.6% and 6.7%, with 1.6-1.9 alleles detected per locus, while the other had mean heterozygosities that ranged from 4.3% to 6.3%, with 1.3-1.6 alleles per locus. Comparisons of isozyme profiles with published data suggests that 1 species is similar to the L. longipalpis described in Colombian and Brazilian populations, whereas the other has not been previously reported.


Admixture mapping identifies introgressed genomic regions in North American canids.
Hybrid zones typically contain novel gene combinations that can be tested by natural selection in a unique genetic context. Parental haplotypes that increase fitness can introgress beyond the hybrid zone, into the range of parental species. We used the Affymetrix canine SNP genotyping array to identify genomic regions tagged by multiple ancestry informative markers that are more frequent in an admixed population than expected. We surveyed a hybrid zone formed in the last 100 years as coyotes expanded their range into eastern North America. Concomitant with expansion, coyotes hybridized with wolves and some populations became more wolflike, such that coyotes in the northeast have the largest body size of any coyote population. Using a set of 3102 ancestry informative markers, we identified 60 differentially introgressed regions in 44 canines across this admixture zone. These regions are characterized by an excess of exogenous ancestry and, in northeastern coyotes, are enriched for genes affecting body size and skeletal proportions. Further, introgressed wolf-derived alleles have penetrated into Southern US coyote populations. Because no wolves currently exist in this area, these alleles are unlikely to have originated from recent hybridization. Instead, they probably originated from intraspecific gene flow or ancient admixture. We show that grey wolf and coyote admixture has far-reaching effects and, in addition to phenotypically transforming admixed populations, allows for the differential movement of alleles from different parental species to be tested in new genomic backgrounds.


Oxidant stress in healthy normal-weight, overweight, and obese individuals.
This study was undertaken to investigate the association among BMI and lipid hydroperoxide (LH), total antioxidant status (TAS), superoxide dismutase (SOD), and reduced glutathione (GSH). Ninety (n = 90) healthy males and females (n = 23/67) (29 normal weight (BMI: 22.74 +/- 0.25 kg/m(2)), 36 overweight (BMI: 27.18 +/- 0.23 kg/m(2)), and 25 obese (33.78 +/- 0.48 kg/m(2))) participated in the study. Data collected included anthropometric measures, fasting blood glucose, lipid profile, LH, TAS, and enzymatic antioxidants (SOD, and reduced GSH). The results of the study showed that obese individuals had significantly increased LH levels compared to normal-weight individuals (obese vs. normal weight (0.88 +/- 0.05 vs. 0.67 +/- 0.03 micromol/l, P < 0.01)) but the increased levels were not significantly different when compared to the overweight group (obese vs. overweight (0.88 +/- 0.05 vs. 0.79 +/- 0.05 micromol/l)). No other consistent significant differences in TAS, SOD, and GSH were identified between groups. This study concluded that only obesity and not moderate overweight elevates LH levels. Furthermore, the levels of TAS, SOD, and GSH in obesity do not explain the increased LH levels observed in obesity.


Real-time imaging of the HIV-1 transcription cycle in single living cells.
The dynamic nature of cellular processes is emerging as an important modulator of physiological and pathological events. The key event in the life cycle of the human immunodeficiency virus type 1 (HIV-1) is transcription: it controls both viral gene expression and the latent phenotype. The basal transcription machinery and cellular and viral regulatory elements are dynamically recruited to the proviral DNA embedded into chromatin and to newly synthesized viral RNA. Their interactions determine fundamental steps, such as RNA polymerase recruitment, initiation, elongation, splicing, termination, and processing of pre-mRNA. The study of these events requires a novel armamentarium of techniques for live-cell imaging and fluorescence tagging of proteins and nucleic acids. The final outcome should not be only a descriptive view of the process but, most importantly, a quantitative analysis of the kinetics involved. Here, we provide an overview of the methodologies available for fluorescent labeling proteins and nucleic acids in live-cell imaging. We also describe the concept of fluorescent recovery after photobleaching (FRAP) and how it can be used to obtain information about HIV RNA transcription dynamics in living cells.


Gas chromatographic technologies for the analysis of essential oils.
Essential oil analysis has basically had one technical goal: to achieve the best possible separation performance by using the most effective, available technology of the day. The result achieved from this may then be used to answer the research or industrial analysis questions which necessitated the analysis. This may be for comparative purposes, where one oil is contrasted with other(s) for quality control or investigation of adulteration, to discover new components, or to characterise the chemical classes of compounds present. Clearly, today the analyst turns to chromatography as the provider of separation and then may supplement that with mass spectrometry to aid identification. The power of GC-MS means that advances in both the separation technique, and improvements in mass spectrometry detection - along with improved data handling tools - will immediately be relevant to the essential oil area. This present review outlines the developmental nature of instrumental approaches to essential oil analysis using gas chromatography. Mass spectrometry will be included to the extent that it represents the hyphenation of choice for most analysts when analysing essential oils. Thus single-column and multi-dimensional analysis will be covered, as will sample handling or introduction techniques prior to the analysis step, where these techniques provide some measure of separation. The recent demonstration of comprehensive gas chromatography will be discussed as the potentially most powerful separation method for essential oils. This brief review is not intended to be a comprehensive dissertation on the field of essential oil analysis since that would require sufficient space to occupy a book in its own right. Rather, it will outline selected considerations and developments, to help explain where new technology has been applied to advantage in this field.


Psychometric validation of the obsessive belief questionnaire and interpretation of intrusions inventory--Part 2: Factor analyses and testing of a brief version.
The Obsessive Belief Questionnaire (OBQ) and the Interpretation of Intrusions Inventory (III) were designed to assess beliefs and appraisals considered critical to the pathogenesis of obsessions. In previous reports we have described the construction and psychometric properties of these measures. In this study a battery of questionnaires assessing anxiety, depression, and obsessive compulsive symptoms was completed by 410 outpatients diagnosed with obsessive compulsive disorder, 105 non-obsessional anxious patients, 87 non-clinical adults from the community, and 291 undergraduate students. Items from 6 theoretically derived subscales of the OBQ were submitted to factor analysis. Three factors emerged reflecting (1) Responsibility and threat estimation, (2) Perfectionism and intolerance for uncertainty, and (3) Importance and control of thoughts. A 44-item version (OBQ-44) composed of high-loading items from the 3 factors showed good internal consistency and criterion-related validity in clinical and non-clinical samples. Subscales showed less overlap than original scales. Factor analysis of the III yielded a single factor, suggesting the total score be used in lieu of the 3 rationally derived subscales. The scales performed well on tests of convergent validity. Discriminant validity was promising; hierarchical regression analyses indicated that the OBQ subscales and III generally predicted OC symptoms after controlling for general distress. A revision of the OBQ, the OBQ-44, is included in the appendix


Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity.
Adipose tissue secretes proteins referred to as adipokines, many of which promote inflammation and disrupt glucose homeostasis. Here we show that secreted frizzled-related protein 5 (Sfrp5), a protein previously linked to the Wnt signaling pathway, is an anti-inflammatory adipokine whose expression is perturbed in models of obesity and type 2 diabetes. Sfrp5-deficient mice fed a high-calorie diet developed severe glucose intolerance and hepatic steatosis, and their adipose tissue showed an accumulation of activated macrophages that was associated with activation of the c-Jun N-terminal kinase signaling pathway. Adenovirus-mediated delivery of Sfrp5 to mouse models of obesity ameliorated glucose intolerance and hepatic steatosis. Thus, in the setting of obesity, Sfrp5 secretion by adipocytes exerts salutary effects on metabolic dysfunction by controlling inflammatory cells within adipose tissue.


Mesothelial inclusion cysts (so-called benign cystic mesothelioma)--a clinicopathological analysis of six cases.
The report presents six cases of mesothelial inclusion cysts (MIC), detected in five females (22-53 years of age) and one male (47 years old). The lesions were unifocal (four cases) and multifocal (two cases), and were located on the surface of the peritoneum in the cul de sac, on the intestines, urinary bladder, uterine adnexa, also involved round ligament within the pelvis and in the inguinal canal (one patient). Additionally, in one female, small cysts, free-floating in the peritoneal cavity were present. In three patients, clinical signs resulted directly from the presence of MIC. One female had been 7 years previously operated on due to endometrioid ovarian cysts. Apart from MIC, three patients presented with concomitant diseases: appendicitis (two cases), peritoneal pseudomyxoma or primary ovarian carcinoma. Gross appearance: the lesions were polycystic, the surgical materials ranging from three fragments measuring 0.5 cm each to seven fragments, with the maximum size of 14x6 cm. The cysts were from microscopic size to 2 cm in diameter, the majority were thin-walled, semitranslucent, filled with clear or yellowish fluid or gelatinous contents. In one case, the cyst walls were thicker and showed intense inflammatory lesions and fibrinous exudate. Microscopically, the majority of cysts were lined with a single layer of flattened or cuboid mesothelial cells (CK+, calretinin+). In two patients, the mesothelium demonstrated diffuse squamous cell metaplasia; in one individual, the cells focally formed small papillae and were vacuolated. No mucus was observed either in the cytoplasm or outside the cells. Immunohistochemical reactions to CEA, ER, PR and MIB-1 were negative. Intramural proliferations and intracystic detached clumps of cells showed both mesothelial cells (without any mitotic activity and signs of atypia) and macrophages (CD68+). To date, the follow-up has been 7 years and 3 years in two individuals, and from 1 to 7 months in the remaining three patients--all of them are free from recurrent disease. One female failed to report for follow-up examinations. The report also presents the review of literature.


A Hospital-wide Outbreak of Serratia marcescens, and Ishikawa's "Fishbone" Analysis to Support Outbreak Control.
A nosocomial outbreak of Serratia marcescens in respiratory samples predominantly from patients in a surgical intensive care unit is reported. Most of these patients were cardiac surgical patients. Initially, a vigorous but inconclusive investigation was implemented on the basis of standardized (according the US Centers for Disease Control and Prevention) steps of outbreak investigation. Then, a systemic quality management approach with "fishbone" analysis was added. As a consequence, plausible causes for the outbreak were identified: (i) S marcescens was found on the transesophageal echocardiography probe used during cardiac surgery; and (ii) the quality of the surface disinfection was insufficient due to multiple reasons and was completely reengineered. In conclusion, in addition to the standardized steps of outbreak investigation, the complementary use of quality management tools such as the Ishikawa "fishbone" analysis is helpful for outbreak control. The complete reengineering of the disinfectant procurement and logistics is assumed to have been the most effective measure to control the described outbreak.


Gene expression profiling of microsatellite unstable and microsatellite stable endometrial cancers indicates distinct pathways of aberrant signaling.
Microsatellite instability (MSI) is a molecular phenotype present in approximately 25% of endometrial cancers. We examined the global gene expression profiles of early-stage endometrioid endometrial cancers with and without the MSI phenotype to test the hypothesis that MSI phenotype may determine a unique molecular signature among otherwise similar cancers. Unsupervised principal component analysis of the expression data from these cases indicated two distinct groupings of cancers based on MSI phenotype. A relatively small number of array features (392) at high statistical value (P < 0.001) were identified that drive the instability signature in these cancers; 109 of these transcripts differed by at least 2-fold. These data identify distinct gene expression profiles for MSI and microsatellite stable (MSS) cancers, which suggest that cancers with MSI develop in part by different mechanisms from their similar stable counterparts. In particular, we found evidence that two members of the secreted frizzled related protein family (SFRP1 and SFRP4) were more frequently down-regulated in MSI cancers as compared with MSS cancers. Down-regulation was accompanied by promoter hypermethylation for SFRP1. SFRP1 was hypermethylated in 8 of 12 MSI cancers whereas only 3 of 16 MSS cancers were methylated. The WNT target fibroblast growth factor 18 was found to be up-regulated in MSI cancers. These data classify histologically similar endometrioid endometrial cancers into two distinct groupings with implications affecting therapy and prevention.


An invasive Mimosa in India does not adopt the symbionts of its native relatives.
The large monophyletic genus Mimosa comprises approx. 500 species, most of which are native to the New World, with Central Brazil being the main centre of radiation. All Brazilian Mimosa spp. so far examined are nodulated by rhizobia in the betaproteobacterial genus Burkholderia. Approximately 10 Mya, transoceanic dispersal resulted in the Indian subcontinent hosting up to six endemic Mimosa spp. The nodulation ability and rhizobial symbionts of two of these, M. hamata and M. himalayana, both from north-west India, are here examined, and compared with those of M. pudica, an invasive species. Nodules were collected from several locations, and examined by light and electron microscopy. Rhizobia isolated from them were characterized in terms of their abilities to nodulate the three Mimosa hosts. The molecular phylogenetic relationships of the rhizobia were determined by analysis of 16S rRNA, nifH and nodA gene sequences. Both native Indian Mimosa spp. nodulated effectively in their respective rhizosphere soils. Based on 16S rRNA, nifH and nodA sequences, their symbionts were identified as belonging to the alphaproteobacterial genus Ensifer, and were closest to the 'Old World' Ensifer saheli, E. kostiensis and E. arboris. In contrast, the invasive M. pudica was predominantly nodulated by Betaproteobacteria in the genera Cupriavidus and Burkholderia. All rhizobial strains tested effectively nodulated their original hosts, but the symbionts of the native species could not nodulate M. pudica. The native Mimosa spp. in India are not nodulated by the Burkholderia symbionts of their South American relatives, but by a unique group of alpha-rhizobial microsymbionts that are closely related to the 'local' Old World Ensifer symbionts of other mimosoid legumes in north-west India. They appear not to share symbionts with the invasive M. pudica, symbionts of which are mostly beta-rhizobial.


Effect of Codend Circumference on the Size Selection of Square-Mesh Codends in Trawl Fisheries.
It is well established that increasing mesh number in the circumference of a diamond-mesh trawl codend can reduce size selection for round fish, whereas selection for flat fish species is unaffected. This effect has also been documented in Mediterranean trawl fisheries. In contrast, no information is available with regard to the effect of increasing mesh number in the circumference of square-mesh codends on the size selection of round fish and flat fish species. A field study was devised to bridge this gap and formulate proposals aimed at improving trawl fishery management. Size selection data were collected for a round fish species, red mullet (Mullus barbatus), and two flat fish species, Mediterranean scaldfish (Arnoglossus laterna) and solenette (Buglossidium luteum). Fishing trials were conducted in the Adriatic Sea (Central Mediterranean) using three square-mesh codends that differed only in mesh number around the circumference. Results demonstrated that increasing the number of meshes from 107 to 213 reduced the 50% retention length (L50) for red mullet by 2.5 cm but did not affect size selection for the two flat fish species. In some fisheries, regulatory provisions regarding the number of meshes in the circumference should therefore be carefully considered both for diamond- and square-mesh codends.


Non-small cell lung cancer.
Most patients with non-small cell lung cancer (NSCLC) are diagnosed with advanced cancer. These guidelines only include information about stage IV NSCLC. Patients with widespread metastatic disease (stage IV) are candidates for systemic therapy, clinical trials, and/or palliative treatment. The goal is to identify patients with metastatic disease before initiating aggressive treatment, thus sparing these patients from unnecessary futile treatment. If metastatic disease is discovered during surgery, then extensive surgery is often aborted. Decisions about treatment should be based on multidisciplinary discussion.


Effects of stratospheric ozone depletion, solar UV radiation, and climate change on biogeochemical cycling: interactions and feedbacks.
Climate change modulates the effects of solar UV radiation on biogeochemical cycles in terrestrial and aquatic ecosystems, particularly for carbon cycling, resulting in UV-mediated positive or negative feedbacks on climate. Possible positive feedbacks discussed in this assessment include: (i) enhanced UV-induced mineralisation of above ground litter due to aridification; (ii) enhanced UV-induced mineralisation of photoreactive dissolved organic matter (DOM) in aquatic ecosystems due to changes in continental runoff and ice melting; (iii) reduced efficiency of the biological pump due to UV-induced bleaching of coloured dissolved organic matter (CDOM) in stratified aquatic ecosystems, where CDOM protects phytoplankton from the damaging solar UV-B radiation. Mineralisation of organic matter results in the production and release of CO2, whereas the biological pump is the main biological process for CO2 removal by aquatic ecosystems. This paper also assesses the interactive effects of solar UV radiation and climate change on the biogeochemical cycling of aerosols and trace gases other than CO2, as well as of chemical and biological contaminants. Interacting effects of solar UV radiation and climate change on biogeochemical cycles are particularly pronounced at terrestrial-aquatic interfaces.


The value of needle renal allograft biopsy. III. A prospective study.
Previous studies of the value of percutaneous renal transplant biopsy have been retrospective. We prospectively studied whether biopsy affected patient management. Thirty-five patients with elevated serum creatinine level underwent 44 biopsies in situations in which the diagnosis was in doubt. At the time of biopsy, all clinical and laboratory data were reviewed, and a proposed treatment plan was outlined. Biopsy results were available within 24 hours. We evaluated whether biopsy influenced treatment. Other than hematuria (less than 24 hours), there were no complications. Nine biopsy specimens (20.5%) were inadequate for evaluation. Forty-six percent of adequate biopsy specimens (36% of total biopsy specimens) influenced patient management. Adequate biopsy specimens resulted in a change in treatment in 10 of 19 patients receiving prednisone and azathioprine and 6 of 16 receiving prednisone and cyclosporine. The remaining biopsy specimens, although not changing management confirmed the treatment plan in ambiguous clinical situations. We conclude that percutaneous biopsy is an important aid in patient management.


Effects of Varying Load Intensity on Skeletal Muscle Damage Between Two Isovolumic Resistance Exercise Bouts.
There are limited data comparing the efficacy of resistance loads within the hypertrophy range for promoting muscular growth, particularly when similar training volumes are utilized. The purpose of this study was to determine if two similar volume-loads, utilizing different intensities, would produce dissimilar muscular damage and inflammation. Eleven resistance-trained, college-aged males participated in this study. After testing 1RM barbell squats, participants completed two similar volume-load barbell squat sessions at two different resistance loads (67% and 85% of 1RM) on two separate visits. Venous blood samples were collected at baseline and one hour after completion of each exercise session. Plasma was isolated and analyzed for myoglobin and C-reactive protein (CRP) expression via ELISA. Plasma myoglobin expression was significantly elevated above baseline (BASE) values only after the 85% of 1RM (HHL) session (p =0.031), though the 67% (LHL) trial (p = 0.054; η2 = 0.647) was approaching significance (BASE: 1.42±.12 ng/mL; LHL: 4.65±1.13 ng/mL; HHL: 5.00±1.01 ng/mL). No changes in plasma CRP were observed. Despite attempts to equate volumes between resistances, mean total volume-load was significantly higher during the 67% of 1RM trial than during the 85% trial. Resistance loads at 85% of 1RM inflict significantly increased muscle damage over baseline values, even when significantly less total volume was lifted during the 85% trial. Individuals looking to maximize strength and hypertrophy during general training or during rehabilitation may benefit from these findings when determining the appropriate training load.


Polymorphism of DNA sequence in the human pro alpha 2(I) collagen gene.
The human pro alpha 2(I) collagen gene was analysed for the presence of restriction fragment length polymorphisms. DNA from randomly selected unrelated persons of three Southern African populations was cleaved with one of eight different restriction enzymes, electrophoresed, blotted, and hybridised with cDNA and genomic probes specific for the pro alpha 2(I) gene. An MspI polymorphism was detected which results from the loss of a cleavage site within the 3' half of the gene. In two of the populations studied, the polymorphism occurred at significant frequencies, and should therefore prove useful as a genetic marker for the study of inherited disorders of connective tissue involving collagen structure or biosynthesis.


Persistence of Severe Pulmonary Hypertension After Transcatheter Aortic Valve Replacement: Incidence and Prognostic Impact.
Severe pulmonary hypertension (PH) is considered to negatively affect the outcome after transcatheter aortic valve replacement. However, a clear understanding of the pattern, evolution, and clinical impact of different grades of PH in this setting is lacking. A total of 990 consecutive patients were enrolled in 6 high-volume centers and analyzed as follows: group 1, systolic pulmonary artery pressure (sPAP) <40 mm Hg (346 patients; 35%); group 2, sPAP 40 to 60 mm Hg (426 patients; 43%); and group 3, sPAP >60 mm Hg (218 patients; 22%). At 1 month, mortality rate did not differ across the groups. When compared with groups 1 and 2, patients in group 3 had a higher-rate of New York Heart Association 3 to 4 (26% versus 12% and 10%), and a higher-rate of hospitalization for heart failure (7% versus 3% and 3%). At 1 year, when compared with patients in group 1, patients in group 2 and 3 had both a higher overall mortality (hazard ratio [HR], 1.5 [1.3-3.2]; P=0.01 and HR, 2.3 [1.8-2.8]; P=0.001) and a higher cardiac mortality (HR, 1.3 [1.1-2.1]; P=0.01 and HR, 1.7 [1.3-2.5]; P=0.002). After 1 month, the sPAP decreased ≥15 mm Hg in 32% and 35% of the patients in groups 2 and 3. Baseline sPAP >60 mm Hg (HR, 1.6 [1.1-2.3]; P=0.03) and, in a larger extent, a persistent severe PH after 1 month (HR, 2.4 [1.5-2.8]; P=0.004), independently predicted 1-year mortality, whereas the 1-month reduction of the sPAP did not. The persistence of severe PH after transcatheter aortic valve replacement is a stronger predictor of 1-year mortality than baseline severe PH. The early reduction of sPAP is not associated with a reduced mortality. The benefit of transcatheter aortic valve replacement in terms of quality of life is substantial in patients with and without a reduction of sPAP at early follow-up.


African signatures of recent positive selection in human FOXI1.
The human FOXI1 gene codes for a transcription factor involved in the physiology of the inner ear, testis, and kidney. Using three interspecies comparisons, it has been suggested that this may be a gene under human-specific selection. We sought to confirm this finding by using an extended set of orthologous sequences. Additionally, we explored for signals of natural selection within humans by sequencing the gene in 20 Europeans, 20 East Asians and 20 Yorubas and by analysing SNP variation in a 2 Mb region centered on FOXI1 in 39 worldwide human populations from the HGDP-CEPH diversity panel. The genome sequences recently available from other primate and non-primate species showed that FOXI1 divergence patterns are compatible with neutral evolution. Sequence-based neutrality tests were not significant in Europeans, East Asians or Yorubas. However, the Long Range Haplotype (LRH) test, as well as the iHS and XP-Rsb statistics revealed significantly extended tracks of homozygosity around FOXI1 in Africa, suggesting a recent episode of positive selection acting on this gene. A functionally relevant SNP, as well as several SNPs either on the putatively selected core haplotypes or with significant iHS or XP-Rsb values, displayed allele frequencies strongly correlated with the absolute geographical latitude of the populations sampled. We present evidence for recent positive selection in the FOXI1 gene region in Africa. Climate might be related to this recent adaptive event in humans. Of the multiple functions of FOXI1, its role in kidney-mediated water-electrolyte homeostasis is the most obvious candidate for explaining a climate-related adaptation.


In Vitro and In Vivo Studies on HPMA-Based Polymeric Micelles Loaded with Curcumin.
Curcumin-loaded polymeric micelles composed of poly(ethylene glycol)-b-poly(N-2-benzoyloxypropyl methacrylamide) (mPEG-b-p(HPMA-Bz)) were prepared to solubilize and improve the pharmacokinetics of curcumin. Curcumin-loaded micelles were prepared by a nanoprecipitation method using mPEG5kDa-b-p(HPMA-Bz) copolymers with varying molecular weight of the hydrophobic block (5.2, 10.0, and 17.1 kDa). At equal curcumin loading, micelles composed of mPEG5kDa-b-p(HPMA-Bz)17.1kDa showed better curcumin retention in both phosphate-buffered saline (PBS) and plasma at 37 °C than micelles based on block copolymers with smaller hydrophobic blocks. No change in micelle size was observed during 24 h incubation in plasma using asymmetrical flow field-flow fractionation (AF4), attesting to particle stability. However, 22-49% of the curcumin loading was released from the micelles during 24 h from formulations with the highest to the lowest molecular weight p(HPMA-Bz), respectively, in plasma. AF4 analysis further showed that the released curcumin was subsequently solubilized by albumin. In vitro analyses revealed that the curcumin-loaded mPEG5kDa-b-p(HPMA-Bz)17.1kDa micelles were internalized by different types of cancer cells, resulting in curcumin-induced cell death. Intravenously administered curcumin-loaded, Cy7-labeled mPEG5kDa-b-p(HPMA-Bz)17.1kDa micelles in mice at 50 mg curcumin/kg showed a long circulation half-life for the micelles (t1/2 = 42 h), in line with the AF4 results. In contrast, the circulation time of curcumin was considerably shorter than that of the micelles (t1/2α = 0.11, t1/2β = 2.5 h) but ∼5 times longer than has been reported for free curcumin (t1/2α = 0.02 h). The faster clearance of curcumin in vivo compared to in vitro studies can be attributed to the interaction of curcumin with blood cells. Despite the excellent solubilizing effect of these micelles, no cytostatic effect was achieved in neuroblastoma-bearing mice, possibly because of the low sensitivity of the Neuro2A cells to curcumin.


Determinants of breastfeeding practices among mothers in Malawi: a population-based survey.
High rates of early initiation and exclusive breastfeeding have been reported in Malawi, yet the underlying factors are unknown. Our objective is to examine the determinants of breastfeeding practices for mothers of infants less than 24 months old in Malawi. A cross-sectional study was conducted using nationally representative data from the 2010 Malawi Demographic and Health Survey. Multivariate logistic regression analysis was used. Of 7282 women, 95.4% initiated breastfeeding within 1 hour after birth; thereafter 71.3% of women practiced exclusive breastfeeding, 6.1% predominantly breastfed, and 1.9% chose bottle feeding exclusively. The odds of early initiation were higher among women with frequent antenatal care visits and multiparous mothers. Similarly, frequent antenatal care visits and hospital delivery were positive determinants for exclusive breastfeeding. Infants at 6 months of age were more likely to predominantly breastfeed than they were at 1 month. The odds of bottle feeding were higher among women who were educated, who delivered at a hospital. Optimal breastfeeding practices are highly prevalent in Malawi. Health care practice emphasizing frequent antenatal care visits that provide breastfeeding education and breastfeeding support in hospital care after childbirth are important for sustaining breastfeeding.


The ban on phenacetin is associated with changes in the incidence trends of upper-urinary tract cancers in Australia.
Phenacetin is an analgesic that causes renal diseases and cancers of the upper-urinary tract (UUT). It was banned in most countries from the late 1960s. This study aimed to evaluate, for the first time, the long-term population impact of the phenacetin ban on UUT cancer rates. We used cancer registry data from Australia, where phenacetin was widely used, to study age- and sex-specific incidence trends of cancers of the renal pelvis and the ureter after the phenacetin ban (1979). Incidence rate ratios and average annual percentage change (AAPC) were calculated to quantify changes in rates over time. Incidence rates of renal pelvis cancer decreased by 52% in women and 39% in men between 1983-1987 and 2003-2007. The decline in women was stronger in states where the use of phenacetin was the most widespread, e.g. New South Wales (AAPC: -4.1%; 95% CI -5.3, -2.9) and Queensland (AAPC: -3.3%; 95% CI -4.9, -1.8), and after the mid-1990s. Incidence rates of ureteral cancer remained stable for both sexes throughout the study period. Our findings strongly suggest a beneficial impact of the ban on phenacetin on the incidence of renal pelvis cancer in Australia, particularly among women.


CLIMATE VARIABILITY, LAND OWNERSHIP AND MIGRATION: EVIDENCE FROM THAILAND ABOUT GENDER IMPACTS.
Scholars point to climate change, often in the form of more frequent and severe drought, as a potential driver of migration in the developing world, particularly for places where populations rely on agriculture for their livelihoods. To date, however, there have been few large-scale, longitudinal studies that explore the relationship between climate change and migration. This study significantly extends current scholarship by evaluating distinctive effects of climatic variation and models these effects on men's and women's responsiveness to drought and rainfall. Our study also investigates how land ownership moderates these effects. We find small, but significant, increases in migration above existing migratory levels during periods of prolonged climatic stress, and that these patterns differ both by gender and land tenure.


Glutathione is required by Rhizobium etli for glutamine utilization and symbiotic effectiveness.
Here, we provide genetic and biochemical evidence indicating that the ability of Rhizobium etli bacteria to efficiently catabolize glutamine depends on its ability to produce reduced glutathione (l-γ-glutamyl-l-cysteinylglycine [GSH]). We find that GSH-deficient strains, namely a gshB (GSH synthetase) and a gor (GSH reductase) mutant, can use different amino acids, including histidine, alanine, and asparagine but not glutamine, as sole source of carbon, energy, and nitrogen. Moreover, l-buthionine(S,R)-sulfoximine, a GSH synthesis inhibitor, or diamide that oxidizes GSH, induced the same phenotype in the wild-type strain. Among the steps required for its utilization, glutamine uptake, occurring through the two well-characterized carriers (Aap and Bra systems) but not glutamine degradation or respiration, was largely reduced in GSH-deficient strains. Furthermore, GSH-deficient mutants of R. etli showed a reduced symbiotic efficiency. Exogenous GSH was sufficient to rescue glutamine uptake or degradation ability, as well as the symbiotic effectiveness of GSH mutants. Our results suggest a previously unknown GSH-glutamine metabolic relationship in bacteria.


Effects of a replication of a multicomponent model for preventing adolescent pregnancy in three Kansas communities.
A significant amount of attention has been devoted to the complex issue of teenage pregnancy and to programs for reducing pregnancy among adolescents. Careful evaluations of such programs are needed to ascertain what strategies will be most effective at reducing teenage pregnancy. A pretest-posttest comparison group design was used to analyze the effects of a comprehensive multicomponent school and community intervention on estimated pregnancy rates and birthrates among young people in three Kansas communities: Geary County, Franklin County and selected neighborhoods of Wichita. There were high levels of program activity in all three communities during the intervention period, including teacher training and sexuality education for students. Survey respondents rated highly such project interventions as the extension of school-linked clinic hours to accommodate student schedules and support groups established in middle schools. Between 1994 and 1997, the proportions of adolescents reporting that they had ever had sex decreased significantly among all ninth and 10th graders in Geary County, from 51% to 38% among females and from 63% to 43% among males. In Franklin County, more males in grades 11 and 12 reported using condoms in 1996 (55%) than had done so in 1994 (39%). Age at first intercourse remained relatively stable in Franklin and Geary counties during the intervention period. The estimated pregnancy rate among adolescents aged 14-17 decreased between 1994 and 1997 in Geary Country, while it increased in comparison areas. The estimated pregnancy rates among 14-17-year-olds decreased in both Franklin County and its comparison communities. The birthrate declined both in one target area of Wichita and in its comparison area from 1991-1993 to 1994-1996. Over the same time period, the birthrate increased in a second target area of Wichita, while it decreased in the comparison community. This evaluation of a comprehensive multicomponent program for adolescent pregnancy prevention contributes to our understanding of this model and its replicability in diverse communities. Ongoing program evaluation is important for developing initiatives and for refining strategies so they respond to local conditions.


Breath markers of oxidative stress and airway inflammation in Seasonal Allergic Rhinitis.
Oxidative stress (OS) is well documented in asthma, but so far, little data has been reported in nonasthmatic patients with Seasonal Allergic Rhinitis (SAR). The aim of this study is to investigate the degree of OS and airway inflammation in patients with SAR, with and without concomitant asthma (SAR+A), using breath markers in exhaled air and in Exhaled Breath Condensate (EBC). In addition, the effects of natural allergen exposure and intranasal steroid treatment on these markers were evaluated. Exhaled NO (eNO) and CO, combined with measurements of 8-Isoprostane (Iso-8), Leukotriene B4 (LTB4) and nitrate/nitrite in EBC, were performed in 23 patients, 11 with SAR and 12 with SAR+A, and 16 healthy subjects. Iso-8 and LTB4 were significantly increased in both groups of patients (median values 43.6 pg/ ml and 138.4 pg/ml in SAR group; 38.9 pg/ml, and 164.6 pg/ml in SAR+A group respectively; p>0.05) compared to healthy subjects (18.6 pg/ml and 7.8 pg/ml; p<0.05). Nitrate/nitrite and eNO levels were elevated in both groups compared to controls, but were significantly higher in the SAR+A compared to SAR group (nitrate/nitrite 9 microM and 3.9 microM; p=0.025; and eNO 18.5 ppb and 12.5 ppb, respectively; p>0.05). Nasal steroids caused significant reduction in LTB4 and 8-isoprostane levels in both groups of patients (p<0.05), while nitrate levels and eNO concentration were little affected by nasal treatment. OS markers were decreased at normal levels out of pollen season. Natural allergen exposure induces OS and airway inflammation, as assessed by measurements of markers in EBC and exhaled air, in patients with SAR who have no clinical signs of lower airway involvement. Besides, intranasal steroid treatment may have a regulatory role in the OS.


Efficacy of phototherapy devices and outcomes among extremely low birth weight infants: multi-center observational study.
Evaluate the efficacy of phototherapy (PT) devices and the outcomes of extremely premature infants treated with those devices. This substudy of the National Institute of Child Health and Human Development Neonatal Research Network PT trial included 1404 infants treated with a single type of PT device during the first 24±12 h of treatment. The absolute (primary outcome) and relative decrease in total serum bilirubin (TSB) and other measures were evaluated. For infants treated with one PT type during the 2-week intervention period (n=1223), adjusted outcomes at discharge and 18 to 22 months corrected age were determined. In the first 24 h, the adjusted absolute (mean (±s.d.)) and relative (%) decrease in TSB (mg dl(-1)) were: light-emitting diodes (LEDs) -2.2 (±3), -22%; Spotlights -1.7 (±2), -19%; Banks -1.3 (±3), -8%; Blankets -0.8 (±3), -1%; (P<0.0002). Some findings at 18 to 22 months differed between groups. LEDs achieved the greatest initial absolute reduction in TSB but were similar to Spots in the other performance measures. Long-term effects of PT devices in extremely premature infants deserve rigorous evaluation.


Optimism, response to treatment of depression, and rehospitalization after coronary artery bypass graft surgery.
Optimism has been associated with a lower risk of rehospitalization after coronary artery bypass graft (CABG) surgery, but little is known about how optimism affects treatment of depression in post-CABG patients. Using data from a collaborative care intervention trial for post-CABG depression, we conducted exploratory post hoc analyses of 284 depressed post-CABG patients (2-week posthospitalization score in the 9-item Patient Health Questionnaire ≥ 10) and 146 controls without depression who completed the Life Orientation Test - Revised (full scale and subscale) to assess dispositional optimism. We classified patients as optimists and pessimists based on the sample-specific Life Orientation Test - Revised distributions in each cohort (full sample, depressed, nondepressed). For 8 months, we assessed health-related quality of life (using the 36-item Short-Form Health Survey) and mood symptoms (using the Hamilton Rating Scale for Depression [HRS-D]) and adjudicated all-cause rehospitalization. We defined treatment response as a 50% or higher decline in HRS-D score from baseline. Compared with pessimists, optimists had lower baseline mean HRS-D scores (8 versus 15, p = .001). Among depressed patients, optimists were more likely to respond to treatment at 8 months (58% versus 27%, odds ratio = 3.02, 95% confidence interval = 1.28-7.13, p = .01), a finding that was not sustained in the intervention group. The optimism subscale, but not the pessimism subscale, predicted treatment response. By 8 months, optimists were less likely to be rehospitalized (odds ratio = 0.54, 95% confidence interval = 0.32-0.93, p = .03). Among depressed post-CABG patients, optimists responded to depression treatment at higher rates. Independent of depression, optimists were less likely to be rehospitalized by 8 months after CABG. Further research should explore the impact of optimism on these and other important long-term post-CABG outcomes.