Association of Dietary Niacin Intake With Incident Hip Fracture, BMD, and Body Composition: The Cardiovascular Health Study.
Interest in niacin has increased in the setting of reports suggesting that niacin plays a role in diseases of aging. No study to date has examined the association of dietary niacin intake with multiple skeletal health parameters including bone mineral density (BMD), hip fractures, and body composition, and none have included both African American and white men and women. Participants included 5187 men and women ≥65 years from the Cardiovascular Health Study (CHS). Mean daily dietary niacin intake was 32.6 mg, with quartiles 1 through 4 defined as 3.6 to 21.8 mg/day, 21.9 to 30.2 mg/day, 30.3 to 40.9 mg/day, and 41.0 to 102.4 mg/day, respectively. Risk of incident hip fracture per 10 mg increment of daily dietary niacin intake was estimated using proportional hazards models. During a median follow-up of 13 years, 725 participants had an incident hip fracture. In models adjusted for demographic and clinical characteristics and diet, dietary niacin intake was significantly associated with an increased risk of hip fractures (hazard ratio [HR] 1.12; 95% CI, 1.01 to 1.24) with spline models suggesting a U-shaped association. In post hoc analyses, both the lowest (HR 1.31; 95% CI, 1.04 to 1.66) and highest (HR 1.53; 95% CI, 1.20 to 1.95) quartiles of niacin intake were associated with an increased risk of incident hip fracture versus quartiles 2 and 3. There was a trend for a significant inverse association of dietary niacin intake with hip BMD (p = 0.06), but no significant association with total body BMD or any body composition measures. In this cohort of elderly, community-dwelling African American and white men and women, both high and low dietary niacin intakes were associated with a significantly increased risk of subsequent hip fracture, suggesting a possible U-shaped association. By comparison, dietary niacin may have an inverse linear association with hip BMD. © 2018 American Society for Bone and Mineral Research.


Clinical significance of chromatin-spliceosome acute myeloid leukemia: a report from the Northern Italy Leukemia Group (NILG) randomized trial 02/06.
Secondary acute myeloid leukemia (sAML) after myelodysplastic or myeloproliferative disorders is a high-risk category currently identified by clinical history or specific morphological and cytogenetic abnormalities. However, in the absence of these features, uncertainties remain to identify the secondary nature of some cases otherwise defined as de novo AML. To test whether a chromatin-spliceosome (CS) mutational signature might better inform the definition of the de novo AML group, we analyzed a prospective cohort of 413 newly diagnosed AML patients enrolled into a randomized clinical trial (NILG AML 02/06) and provided with accurate cytogenetic and molecular characterization. Among clinically defined de novo AML, 17.6% carried CS mutations (CS-AML) and showed clinical characteristics closer to sAML (older age, lower white blood cell counts and higher rate of multilineage dysplasia). Outcomes in this group were adverse, more similar to those of sAML as compared to de novo AML (overall survival, 30% in CS-AML and 17% in sAML vs 61% in de novo AML, P<0.0001; disease free survival, 26% in CS-AML and 22% in sAML vs 54% of de novo AML, P<0.001) and independently confirmed by multivariable analysis. Allogeneic transplant in first complete remission improved survival in both sAML and CS-AML patients. In conclusion, these findings highlight the clinical significance of identifying CS-AML for improved prognostic prediction and potential therapeutic implications. (NILG AML 02/06: ClinicalTrials.gov Identifier: NCT00495287).


Defense and protection mechanisms in lung exposed to asbestiform fiber: the role of macrophage migration inhibitory factor and heme oxygenase-1.
Fluoro-edenite (FE), an asbestiform fiber, is responsible for many respiratory pathologies: chronic obstructive diseases, pleural plaques, fibrosis, and malignant mesothelioma. Macrophage migration inhibitory factor (MIF) is one of the first cytokines produced in response to lung tissue damage. Heme oxygenase-1 (HO-1) is a protein with protective effects against oxidative stress. It is up regulated by several stimuli including pro-inflammatory cytokines and factors that promote oxidative stress. In this research, the in vivo model of sheep lungs naturally exposed to FE was studied in order to shed light on the pathophysiological events sustaining exposure to fibers, by determining immunohistochemical lung expression of MIF and HO-1. Protein levels expression of HO-1 and MIF were also evaluated in human primary lung fibroblasts after exposure to FE fibers in vitro. In exposed sheep lungs, MIF and HO-1 immunoexpression were spread involving the intraparenchymal stroma around bronchioles, interstitium between alveoli, alveolar epithelium and macrophages. High MIF immunoexpression prevails in macrophages. Similar results were obtained in vitro, but significantly higher values were only detected for HO-1 at concentrations of 50 and 100 μg/mL of FE fibers. MIF and HO-1 expressions seem to play a role in lung self-protection against uncontrolled chronic inflammation, thus counteracting the strong link with cancer development, induced by exposure to FE. Further studies will be conducted in order to add more information about the role of MIF and HO-1 in the toxicity FE-induced.


Receipt of preventive dental care among special-needs children enrolled in Medicaid: a crisis in need of attention.
Although not widely recognized, tooth decay is the most common childhood chronic disease among children ages five to seventeen. Despite higher rates of dental caries and greater needs, low-income minority children enrolled in Medicaid are more likely to go untreated relative to their higher income counterparts. No research has examined this issue for children with special needs. We analyzed Medicaid enrollment and claims data for special-needs children enrolled in the District of Columbia Medicaid program to evaluate receipt of recommended preventive dental care. Use of preventive dental care is abysmally low and has declined over time. Enrollment in managed care rather than fee for service improves the likelihood that special-needs children receive recommended preventive dental services, whereas residing farther from the Metro is an impediment to receipt of dental care.


Ca2+-dependent regulation of synaptic SNARE complex assembly via a calmodulin- and phospholipid-binding domain of synaptobrevin.
Synaptic core complex formation is an essential step in exocytosis, and assembly into a superhelical structure may drive synaptic vesicle fusion. To ascertain how Ca(2+) could regulate this process, we examined calmodulin binding to recombinant core complex components. Surface plasmon resonance and pull-down assays revealed Ca(2+)-dependent calmodulin binding (K(d) = 500 nM) to glutathione S-transferase fusion proteins containing synaptobrevin (VAMP 2) domains but not to syntaxin 1 or synaptosomal-associated protein of 25 kDa (SNAP-25). Deletion mutations, tetanus toxin cleavage, and peptide synthesis localized the calmodulin-binding domain to VAMP(77-94), immediately C-terminal to the tetanus toxin cleavage site (Q(76)-F(77)). In isolated synaptic vesicles, Ca(2+)/calmodulin protected native membrane-inserted VAMP from proteolysis by tetanus toxin. Assembly of a (35)S-SNAP-25, syntaxin 1 GST-VAMP(1-96) complex was inhibited by Ca(2+)/calmodulin, but assembly did not mask subsequent accessibility of the calmodulin-binding domain. The same domain contains a predicted phospholipid interaction site. SPR revealed calcium-independent interactions between VAMP(77-94) and liposomes containing phosphatidylserine, which blocked calmodulin binding. Circular dichroism spectroscopy demonstrated that the calmodulin/phospholipid-binding peptide displayed a significant increase in alphahelical content in a hydrophobic environment. These data provide insight into the mechanisms by which Ca(2+) may regulate synaptic core complex assembly and protein interactions with membrane bilayers during exocytosis.


Effect of high doses of oral risedronate (20 mg/day) on serum parathyroid hormone levels and urinary collagen cross-link excretion in postmenopausal women with spinal osteoporosis.
The present study describes the biological effects of risedronate, a pyridinyl bisphosphonate, on bone and assesses the safety and tolerability of risedronate when given at high doses, with or without calcium, to postmenopausal women with spinal osteoporosis. This single-center descriptive, double-blind, placebo-controlled, randomized, parallel group study included 32 postmenopausal white women with at least one radiographically confirmed vertebral compression fracture. Patients were randomized to one of four different dose regimen groups: (i) R-P, risedronate 20 mg/day for 14 days, followed by placebo for 42 days; (ii) R-CP-P, risedronate 20 mg/day for 14 days, followed by elemental calcium 1000 mg/day and placebo for 14 days, then by placebo for 28 days; (iii) R-CP-R-CP, risedronate 20 mg/day for 7 days, followed by elemental calcium 1000 mg/day and placebo for 21 days, then risedronate 20 mg/day for 7 days, and finally elemental calcium 1000 mg/day and placebo for 21 days; and (iv) P, placebo for 56 days. The biological response was investigated by measuring serum calcium, parathyroid hormone (PTH), and 2 h urinary pyridinoline/creatinine (Pyr/Cr) and deoxypyridinoline/creatinine (DPyr/Cr) ratios at baseline and at days 3, 7, 14, 21, 28, 35, 42, 49, 56, and 84. Overall, there were no consistent trends observed between the active group and placebo for serum calcium. In groups R-P, R-CP-P, and R-CP-R-CP, mean serum PTH levels were elevated above baseline values for the entire 56 day treatment period and remained elevated, although to a lesser extent, at the day 84 follow-up visit. The effect of calcium supplementation on PTH was variable. Urinary Pyr/Cr and DPyr/Cr ratios were decreased from baseline over the entire study period in all groups receiving risedronate. The maximum observed percent decreases from baseline for Pyr/Cr and DPyr/Cr were -46.9% and -58.8%, respectively, at day 49 in the R-CP-R-CP group. In conclusion, risedronate given orally at a dose of 20 mg/day, continuously for 7 or 14 days, resulted in the expected biological response in osteoporotic women. The time course of changes in PTH levels following cessation of dosing was unaffected by calcium supplementation. There was no evidence of a PTH-mediated rebound in bone resorption following cessation of therapy. Furthermore, based on collagen cross-link data, patients did not show an excessive reduction in bone turnover.


Oral bisphosphonate use and total knee/hip implant survival: validation of results in an external population-based cohort.
Aseptic loosening is the most common cause of revision arthroplasty. Bisphosphonates could minimize this through their antiresorptive effects. This study was undertaken to investigate the association between bisphosphonate use and implant survival. A retrospective cohort study was conducted within the Danish nationwide registries (5.5 million residents). Using procedure codes of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, we identified patients age ≥40 years undergoing total joint replacement in 1998-2007. We excluded users of disease-modifying antirheumatic drugs as well as patients with rheumatoid arthritis, Paget's disease, or hip fracture. Participants were classified as bisphosphonate users if they had been receiving treatment for ≥6 months. A time-varying exposure was used to avoid immortal time bias. Up to 6 bisphosphonate nonusers undergoing arthroplasty were matched to each bisphosphonate user, using propensity scores. Stratified Cox regression was performed to model implant survival according to bisphosphonate use. Further, we studied the associations of implant survival with duration of use, adherence (medication possession ratio), and timing of therapy initiation (preoperative/postoperative). Of 95,392 patients with a primary total joint replacement, 80,342 (84.2%) were eligible. We identified 1,590 bisphosphonate users (2.0%), and 1,558 of them (98.0%) were matched to 8,966 bisphosphonate nonusers. Twenty-seven of the 1,558 bisphosphonate users (1.73%) and 399 of the 8,966 matched nonusers (4.45%) underwent revision surgery during the study followup period (at a median 2.61 years after the first surgery [interquartile range 1.04-5.41 years]). Cox regression showed a reduced risk of revision surgery in bisphosphonate users (hazard ratio 0.41 [95% confidence interval 0.27-0.61]). This association was strongest in patients with the longest duration of treatment and/or the best adherence. Oral bisphosphonate users have a 59% reduced risk of revision surgery. This association is only present when bisphosphonates are started after arthroplasty surgery. Confirmation in randomized controlled trials is urgently needed.


Nigella sativa as an anti-inflammatory agent in asthma.
Nigella sativa (N. sativa) has several pharmacological actions which include antioxidant, antidiabetic, anticancer, antitussive, immunomodulator, analgesic, antimicrobial, anti-inflammatory, spasmolytic, and bronchodilator. The purpose of this study is to measure the effectivity of N. sativa ethanol extract as anti-inflammation on peritoneal Wistar rat mast cells. The laboratory experiment was used to investigate the effectivity of N. sativa as an anti-inflammatory on mast cells. Six groups of mast cells were stimulated by C 48/80 to release histamine. Group 1 were without N. sativa, while group 2, 3, 4, 5, and 6 were given N. sativa with concentrations of 0.1 mg/ml, 0.2 mg/ml, 0.3 mg/ml, 0.4 mg/ml and 0.5 mg/ml, respectively. Histamine concentration was measured by high-performance liquid chromatography-fluorometry. The study showed that N. sativa ethanol extract effectively inhibit histamine release from peritoneal Wistar rat mast cells proportionally to its concentration. N. sativa is effective as an anti-inflammation on mast cells by inhibition of histamine release and has no toxic effect on mast cell. N. sativa could be considered as a potential therapy for asthma therapy and prevention.


Possible stimulation of anti-tumor immunity using repeated cold stress: a hypothesis.
The phenomenon of hormesis, whereby small amounts of seemingly harmful or stressful agents can be beneficial for the health and lifespan of laboratory animals has been reported in literature. In particular, there is accumulating evidence that daily brief cold stress can increase both numbers and activity of peripheral cytotoxic T lymphocytes and natural killer cells, the major effectors of adaptive and innate tumor immunity, respectively. This type of regimen (for 8 days) has been shown to improve survival of mice infected with intracellular parasite Toxoplasma gondii, which would also be consistent with enhanced cell-mediated immunity. This paper hypothesizes that brief cold-water stress repeated daily over many months could enhance anti-tumor immunity and improve survival rate of a non-lymphoid cancer. The possible mechanism of the non-specific stimulation of cellular immunity by repeated cold stress appears to involve transient activation of the sympathetic nervous system, hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes, as described in more detail in the text. Daily moderate cold hydrotherapy is known to reduce pain and does not appear to have noticeable adverse effects on normal test subjects, although some studies have shown that it can cause transient arrhythmias in patients with heart problems and can also inhibit humoral immunity. Sudden immersion in ice-cold water can cause transient pulmonary edema and increase permeability of the blood-brain barrier, thereby increasing mortality of neurovirulent infections. The proposed procedure is an adapted cold swim (5-7 minutes at 20 degrees Celsius, includes gradual adaptation) to be tested on a mouse tumor model. Mortality, tumor size, and measurements of cellular immunity (numbers and activity of peripheral CD8+ T lymphocytes and natural killer cells) of the cold-exposed group would be compared to those of control groups (warm swim and no treatment). Cold-water stress would be administered twice a day for the duration of several months. If the hypothesis is supported by empirical studies and the method is shown to be safe, this could lead to the development of an adjunctive immunotherapy for some (non-lymphoid) cancers, including those caused by viral infections.


Soil microorganisms of the McMurdo Sound area, Antarctica.
A study of soil microorganisms of Ross Island and the adjacent mainland was carried out during the brief austral summer of 1961-1962. In some cases, seasonal changes in microbial numbers were observed, although microorganisms could not be detected in some soils. Bacterial species common to temperate regions were isolated from a number of different samples. Thermophilic bacteria were present in some of the soils, and a significant portion of the bacterial population was capable of growth at 2 C. The soil microflora were capable of carrying out certain reactions of the nitrogen cycle at a very slow rate. In addition to temperature, other environmental factors which might influence growth and metabolic activity were discussed.


Multiplex detection of bacteria associated with normal microbiota and with bacterial vaginosis in vaginal swabs by use of oligonucleotide-coupled fluorescent microspheres.
Bacterial vaginosis (BV) is a recurrent condition that is associated with a range of negative outcomes, including the acquisition of human immunodeficiency virus and other sexually transmitted diseases, preterm births, and pelvic inflammatory disease. In contrast to the Lactobacillus-dominated normal vaginal microbiota, BV is characterized by a lack of lactobacilli and an abundance of anaerobic and gram-negative organisms, including Gardnerella vaginalis and Atopobium vaginae. To date, the laboratory diagnosis of BV has relied upon the fulfillment of criteria determined by microscopic observation of Gram-stained vaginal swabs. We describe a molecular-based method for the easy determination of the species profile within the vaginal microbiota based on the amplification of the chaperonin-60 genes of all bacteria present in the swab and hybridization of the amplicon to species-specific oligonucleotide-coupled fluorescent beads that are identified by flow cytometry with a Luminex instrument. We designed a nineplex Luminex array for characterization of the vaginal microbiota and applied it to the analysis of vaginal swabs from individuals from Africa and North America. Using the presence of A. vaginae or G. vaginalis, or both, as the defining criterion for BV, we found that the method was highly specific and sensitive for the diagnosis of BV using microscopy as a gold standard.


MUS81 nuclease activity is essential for replication stress tolerance and chromosome segregation in BRCA2-deficient cells.
Failure to restart replication forks stalled at genomic regions that are difficult to replicate or contain endogenous DNA lesions is a hallmark of BRCA2 deficiency. The nucleolytic activity of MUS81 endonuclease is required for replication fork restart under replication stress elicited by exogenous treatments. Here we investigate whether MUS81 could similarly facilitate DNA replication in the context of BRCA2 abrogation. Our results demonstrate that replication fork progression in BRCA2-deficient cells requires MUS81. Failure to complete genome replication and defective checkpoint surveillance enables BRCA2-deficient cells to progress through mitosis with under-replicated DNA, which elicits severe chromosome interlinking in anaphase. MUS81 nucleolytic activity is required to activate compensatory DNA synthesis during mitosis and to resolve mitotic interlinks, thus facilitating chromosome segregation. We propose that MUS81 provides a mechanism of replication stress tolerance, which sustains survival of BRCA2-deficient cells and can be exploited therapeutically through development of specific inhibitors of MUS81 nuclease activity.


Concussion BASICS II: Baseline serum biomarkers, head impact exposure, and clinical measures.
To examine the effect of concussion history and cumulative exposure to collision sports on baseline serum biomarker concentrations, as well as associations between biomarker concentrations and clinical assessments. In this observational cohort study, β-amyloid peptide 42 (Aβ42), total tau, S100 calcium binding protein B (S100B), ubiquitin carboxy-terminal hydrolyzing enzyme L1 (UCH-L1), glial fibrillary acidic protein, microtubule associated protein 2, and 2',3'-cyclic-nucleotide 3'-phosphodiesterase serum concentrations were measured in 415 (61% male, 40% white, aged 19.0 ± 1.2 years) nonconcussed collegiate athletes without recent exposure to head impacts. Regression analyses were used to evaluate the relationship between self-reported history of concussion(s), cumulative years playing collision sports, clinical assessments, and baseline biomarker concentrations. Football-specific analyses were performed using a modified Cumulative Head Impact Index. Clinical assessments included symptom, cognitive, balance, and oculomotor tests. Athletes with a greater number of concussions had a higher baseline Aβ42 concentration only (ρ = 0.140, p = 0.005, small effect size). No biomarker concentrations correlated with cumulative exposure to collision sports. Race status fully mediated the correlations of S100B, UCH-L1, and Aβ42 with cognitive scores. Football exposure, specifically, was not associated with serum biomarker concentrations or clinical assessment scores based on the modified Cumulative Head Impact Index. Concussion-related serum biomarkers showed no consistent association with concussion history, cumulative exposure to collision sports, or clinical assessments in a sample of healthy collegiate athletes. Serum Aβ42 concentrations could increase following multiple previous concussions. Considering race status is essential when investigating links between biomarkers and cognition. The biomarkers studied may not detect residual effects of concussion or repetitive head impact exposure in otherwise asymptomatic collegiate athletes without recent exposure to head impacts. Much more research is needed for identifying reliable and valid blood biomarkers of brain trauma history.


Relationship Among Panoramic Radiography Findings, Biochemical Markers of Bone Turnover and Hip BMD in the Diagnosis of Postmenopausal Osteoporosis.
Recent investigations have shown that panoramic radiography might be a useful tool in the early diagnosis of osteoporosis. In addition, bone turnover biochemical markers might be valuable in predicting osteoporosis and fracture risks in the elderly, especially in post-menopausal women. The aim of the present study was to evaluate the relationship among the radiomorphometric indices of the mandible, biochemical markers of the bone turnover and hip BMD in a group of post-menopausal women. Evaluations of mandibular cortical width (MCW), mandibular cortical index (CI), panoramic index (PMI) and alveolar crest resorption ratio (M/M ratio) were carried out on panoramic radiographs of 140 post-menopausal women with an age range of 44-82 years. Hip BMD was measured by DEXA method. BMD values were divided into three groups of normal (T score>-1.0), osteopenic (T score, -2.5 to -1.0) and osteoporotic (T score<-2.5). Serum alkaline phosphatase and 25(OH) D(3) were measured. A decrease in MCW by 1 mm increases the likelihood of osteopenia or osteoporosis up to 40%, having taken into consideration the effect of menopause duration. A 1 mm decrease in MCW increased the likelihood of moderate or severe erosion of the lower cortex of the mandible up to 28% by taking age into consideration. The results did not demonstrate a statistically significant relationship between bone turnover markers and mandibular radiomorphometric indices. Panoramic radiography gives sufficient information to make an early diagnosis regarding osteoporosis in post-menopausal women. Panoramic radiographs may be valuable in the prevention of osteoporotic fractures in elderly women.


Antibacterial proteins in rainbow trout, Oncorhynchus mykiss.
Antibacterial proteins are an important part of the innate immune system for all animals. They have been extensively studied in mammals, amphibians and invertebrates, but have received only scant attention in fish. Their expression and processing, however, provide a way of monitoring defence vigour during development or with seasonal changes in physiology. The aim of the present work was to identify and characterise antibacterial proteins in rainbow trout. In vitro analyses of extracts of the peripheral blood leucocytes, head kidney leucocytes and mucus from adult unstimulated (non-immune) fish showed marked antibacterial activity against Gram positive bacteria. Fractionation by ion exchange chromatography and RP-HPLC of head kidney extracts showed the presence of two forms of lysozyme but no constitutively expressed antimicrobial proteins of < 10 kDa. By contrast, chromatographic analyses of mucus revealed at least four antibacterial proteins. Two are conventional lysozymes, a third is an unusual lysozyme-like protein with a low isoelectric point, and the fourth is a highly hydrophobic, cationic peptide of c. 3 kDa.


Artificial Intelligence Decision Support for Medical Triage.
Applying state-of-the-art machine learning and natural language processing on approximately one million of teleconsultation records, we developed a triage system, now certified and in use at the largest European telemedicine provider. The system evaluates care alternatives through interactions with patients via a mobile application. Reasoning on an initial set of provided symptoms, the triage application generates AI-powered, personalized questions to better characterize the problem and recommends the most appropriate point of care and time frame for a consultation. The underlying technology was developed to meet the needs for performance, transparency, user acceptance and ease of use, central aspects to the adoption of AI-based decision support systems. Providing such remote guidance at the beginning of the chain of care has significant potential for improving cost efficiency, patient experience and outcomes. Being remote, always available and highly scalable, this service is fundamental in high demand situations, such as the current COVID-19 outbreak.


Recombinant human DNase I in cystic fibrosis patients with severe pulmonary disease: a short-term, double-blind study followed by six months open-label treatment.
Chronic pulmonary infection is the major cause of morbidity and mortality in cystic fibrosis (CF). Recombinant human deoxyribonuclease (rhDNase) in vitro has been shown to dramatically reduce the viscoelasticity of the sputum from CF patients. Phase II and III clinical trials have shown the drug to be safe, and that patients with a forced vital capacity (FVC) of > 40% predicted show an improvement in pulmonary function when receiving rhDNase. The current study evaluates the safety and efficacy of rhDNase in the most severly ill CF patients (FVC < 40% predicted). A double-blind, randomized, placebo-controlled trial in which patients received either 2.5 mg rhDNase twice daily or placebo for a period of 14 days followed by a 6 month open extension period (OEP) is reported. Seventy patients were recruited for the double-blind study, and 64 entered the OEP of whom 38 completed. During the OEP, all patients received 2.5 mg rhDNase twice daily. In both the double-blind period and the OEP the drug appeared to be safe. During the double-blind study, forced expiratory volume in one second (FEV1) and FVC improved in both groups but there was no statistically significant difference between the groups. In the OEP, there was mean improvement in percentage predicted FEV1 and FVC, 9 and 18%, respectively, for all patients participating. In conclusion, DNase is safe when administered in conjunction with a rigorous regimen of chest physiotherapy to severely ill patients (FVC < 40% predicted) with CF. The double-blind, 14 day study showed no significant improvement in pulmonary function but some patients may have improved after longer administration of rhDNase.


Biphasic finite element simulation of the TMJ disc from in vivo kinematic and geometric measurements.
Understanding the biomechanical nature of the degeneration of the temporomandibular joint requires a coupling between experimental measurements and numerical simulation. In this study, geometry measured from MRI, and motion obtained from a specially designed optoelectronic system are fed into a three-dimensional biphasic finite element analysis to generate the spatial and temporal mechanical response of the disc. This study demonstrates how this coupling can effectively predict the biomechanical response of the temporomandibular joint disc to physiological loading. For small jaw opening movements, asymmetries in the load of the disc are found, with especially higher shear stresses in the lateral portion.


Comparing action gestures and classifier verbs of motion: evidence from Australian Sign Language, Taiwan Sign Language, and nonsigners' gestures without speech.
Recent research into signed languages indicates that signs may share some properties with gesture, especially in the use of space in classifier constructions. A prediction of this proposal is that there will be similarities in the representation of motion events by sign-naive gesturers and by native signers of unrelated signed languages. This prediction is tested for deaf native signers of Australian Sign Language (Auslan), deaf signers of Taiwan Sign Language (TSL), and hearing nonsigners using the Verbs of Motion Production task from the Test Battery for American Sign Language (ASL) Morphology and Syntax. Results indicate that differences between the responses of nonsigners, Auslan signers, and TSL signers and the expected ASL responses are greatest with handshape units; movement and location units appear to be very similar. Although not definitive, these data are consistent with the claim that classifier constructions are blends of linguistic and gestural elements.


High risk of malnutrition associated with depressive symptoms in older South Africans living in KwaZulu-Natal, South Africa: a cross-sectional survey.
Malnutrition contributes to functional and cognitive decline in older adults, which results in decreased quality of life and loss of independence. This study aimed to identify determinants of nutritional risk among community-dwelling adults in KwaZulu-Natal, South Africa. A cross-sectional survey was undertaken in 1008 subjects aged 60 years and over who were randomly selected by systematic sampling. Demographics, socioeconomic data and self-reported history of medical conditions were recorded. The Mini Nutritional Assessment-Short Form (MNA-SF) was used to screen for nutritional risk, and the Centre for Epidemiologic Studies Depression scale was administered to all subjects. Descriptive statistics and the Pearson chi-square and Kruskal-Wallis tests were used for statistical analysis. Logistic regression modelling determined predictors of nutritional risk. Of the 984 participants (mean age = 68.8 ± 7.4 years; range 60-103 years) who completed the MNA-SF, 51% were classified as having a normal nutritional status, 43.4% at risk for malnutrition and 5.5% classified as malnourished. Men were more likely to be either at risk for malnutrition or be malnourished than women (p = 0.008), as were subjects with a monthly household income of ≤R1600 per month (~133 USD) (p = 0.003). In logistic regression models, depressed people were 2.803 (p < 0.001) times more likely to be at risk or be malnourished than those not depressed. A high prevalence of risk of malnutrition was identified in older South Africans living in an urban area with poor infrastructure. Further investigations are warranted to determine whether the higher prevalence of depressive symptomatology in nutritionally at risk individuals is a determinant or a consequence of malnutrition, in order to develop targeted nutritional interventions in this age group.


Virtual reality perspective-taking increases cognitive empathy for specific others.
Previous research shows that virtual reality perspective-taking experiences (VRPT) can increase prosocial behavior toward others. We extend this research by exploring whether this effect of VRPT is driven by increased empathy and whether the effect extends to ostensibly real-stakes behavioral games. In a pre-registered laboratory experiment (N = 180), participants interacted with an ostensible partner (a student from the same university as them) on a series of real-stakes economic games after (a) taking the perspective of the partner in a virtual reality, "day-in-the-life" simulation, (b) taking the perspective of a different person in a "day-in-the-life" simulation, or (c) doing a neutral activity in a virtual environment. The VRPT experience successfully increased participants' subsequent propensity to take the perspective of their partner (a facet of empathy), but only if the partner was the same person whose perspective participants assumed in the virtual reality simulation. Further, this effect of VRPT on perspective-taking was moderated by participants' reported feeling of immersion in the virtual environment. However, we found no effects of VRPT experience on behavior in the economic games.


The mismeasure of ape social cognition.
In his classic analysis, Gould (The mismeasure of man, WW Norton, New York, 1981) demolished the idea that intelligence was an inherent, genetic trait of different human groups by emphasizing, among other things, (a) its sensitivity to environmental input, (b) the incommensurate pre-test preparation of different human groups, and (c) the inadequacy of the testing contexts, in many cases. According to Gould, the root cause of these oversights was confirmation bias by psychometricians, an unwarranted commitment to the idea that intelligence was a fixed, immutable quality of people. By virtue of a similar, systemic interpretive bias, in the last two decades, numerous contemporary researchers in comparative psychology have claimed human superiority over apes in social intelligence, based on two-group comparisons between postindustrial, Western Europeans and captive apes, where the apes have been isolated from European styles of social interaction, and tested with radically different procedures. Moreover, direct comparisons of humans with apes suffer from pervasive lapses in argumentation: Research designs in wide contemporary use are inherently mute about the underlying psychological causes of overt behavior. Here we analyze these problems and offer a more fruitful approach to the comparative study of social intelligence, which focuses on specific individual learning histories in specific ecological circumstances.


Selective expression rather than specific function of Txk and Itk regulate Th1 and Th2 responses.
Itk and Txk/Rlk are Tec family kinases expressed in T cells. Itk is expressed in both Th1 and Th2 cells. By contrast, Txk is preferentially expressed in Th1 cells. Although Itk is required for Th2 responses in vivo and Txk is suggested to regulate IFN-gamma expression and Th1 responses, it remains unclear whether these kinases have distinct roles in Th cell differentiation/function. We demonstrate here that Txk-null CD4(+) T cells are capable of producing both Th1 and Th2 cytokines similar to those produced by wild-type CD4(+) T cells. To further examine whether Itk and Txk play distinct roles in Th cell differentiation and function, we examined Itk-null mice carrying a transgene that expresses Txk at levels similar to the expression of Itk in Th2 cells. Using two Th2 model systems, allergic asthma and schistosome egg-induced lung granulomas, we found that the Txk transgene rescued Th2 cytokine production and all Th2 symptoms without notable enhancement of IFN-gamma expression. These results suggest that Txk is not a specific regulator of Th1 responses. Importantly, they suggest that Itk and Txk exert their effects on Th cell differentiation/function at the level of expression.


Respiratory rate: measurement of variability over time and accuracy at different counting periods.
The respiratory rates/minute of 97 children were monitored every 10-15 minutes over one hour, by an observer and by pneumogram, at which times two 30 second and one 60 second counts were obtained. The children were under 5 years of age with lower respiratory tract infections (n = 20), upper respiratory tract infections (n = 34), or controls without acute respiratory infection (n = 43). The difference between respiratory rate count determined simultaneously by observation and pneumogram in relation to their mean count was analysed for the 60 second counting period, 30 plus 30 second period, and the 30 second period doubled. The mean difference for the 60 second period was 1.79, for the 30 plus 30 second period 1.42, and for the 30 second period doubled 1.72. The variability between respiratory rate counts determined by observation and pneumogram was significantly lower in counts obtained when the subject was sleeping and higher when agitated compared with obtaining a count when the subject was awake and calm or feeding. The variability was also significantly lower in subjects with lower respiratory tract infections compared with those with upper respiratory tract infections and control subjects without respiratory symptoms. In the same patient, over the one hour, 50% of the 60 second counts varied by up to 14 breaths/minute and 75% by up to 21 breaths/minute. The least variability was seen in children with a lower respiratory tract infection, who tended to maintain their rapid breathing in contrast to those with an upper respiratory tract infection and controls without respiratory symptoms. About 10% of initial 30 second counts, 12% of 60 second, and 16% of initial and repeat 30 second attempts to obtain accurate counts failed. Failures occurred more frequently in children <2 months of age and those agitated. The data from this study suggest that one minute's counting either at a stretch or in two blocks of 30 second intervals is better than counting the respiratory rate for 30 seconds, when the child is either awake and calm or when asleep.


The influence of the economic and social environment on deliberate self-harm and suicide: an ecological and person-based study.
Geographic variations in the incidence of deliberate self-harm (DSH) and suicide have been shown to be associated with area-based measures of socio-economic deprivation and social fragmentation. Previous studies have been subject to methodological limitations. None has investigated whether ecological associations are reflected in characteristics of individuals involved in suicidal behaviour. DSH patients presenting to a general hospital between 1985 and 1995 and suicides (including open verdicts) from the same catchment area were studied. Mean annual rates of DSH and suicide by gender were calculated for electoral wards. The wards were amalgamated into 20 groups according to their ranking for socio-economic deprivation (Townsend) and social fragmentation scores. Associations of these variables with DSH and suicide rates were investigated. Characteristics of DSH patients living in ward groups with the highest and lowest socio-economic deprivation and social fragmentation scores were compared. Socio-economic deprivation was associated with DSH rates among males (r = 0.89) and females (r = 0.87). After controlling for social fragmentation the associations remained relatively strong, particularly in young males. Associations with social fragmentation in both genders (males, r = 0.83; females, r = 0.86) were attenuated after controlling for socio-economic deprivation. For suicide, the only significant association was with socio-economic deprivation in males (r = 0.79), but this was attenuated after controlling for social fragmentation. The characteristics of individual DSH patients reflected those of the areas where they lived. Reducing socio-economic deprivation and its associated problems may be an important strategy in the prevention of suicidal behaviour, especially in young men.


Functional vascular smooth muscle-like cells derived from adult mouse uterine mesothelial cells.
In mammalian visceral organs, vascular smooth muscle cells (VSMCs) originate from an epithelial-to-mesenchymal transition (EMT) of embryonic mesothelial cells (MCs). The ability of adult MCs to recapitulate EMT and to acquire smooth muscle (SM) markers upon provasculogenic culture suggested they might retain embryonic vasculogenic differentiation potential. However, it remains unknown whether adult MCs-derived SM-like cells may acquire specific vascular SM lineage markers and the functionality of differentiated contractile VSMCs. Here, we describe how a gentle trypsinization of adult mouse uterine cords could selectively detach their outermost uterine mesothelial layer cells. As other MCs; uterine MCs (UtMCs) uniformly expressed the epithelial markers β-catenin, ZO-1, E-cadherin, CD54, CD29, and CK18. When cultured in a modified SM differentiation media (SMDM) UtMCs initiated a loss of epithelial characteristics and gained markers expression of EMT (Twist, Snail, and Slug), stem and progenitor (Nanog, Sox2, C-kit, Gata-4, Isl-1, and nestin), SM (α-SMA, calponin, caldesmon, SM22α, desmin, SM-MHC, and smoothelin-B) and cardiac (BMP2, BMP4, ACTC1, sACTN, cTnI, cTnT, ANF, Cx43, and MLC2a). UtMCs repeatedly subcultured in SMDM acquired differentiated VSM-like characteristics and expressed smoothelin-B in the typical stress-fiber pattern expression of contractile VSMCs. Relevantly, UtMCs-derived VSM-like cells could generate "mechanical force" to compact collagen lattices and displayed in diverse degree voltage (K(+)) and receptor (endothelin-1, oxytocin, norepinephrine, carbachol and vasopressin)-induced [Ca(2+)](i) rises and contraction. Thus, we show for the first time that UtMCs could recapitulate in vitro differentiative events of early cardiovascular differentiation and transdifferentiate in cells exhibiting molecular and functional characteristics of VSMCs.


Retinal hemorrhage, a common sign of prognostic significance in cerebral malaria.
Retinal hemorrhages were seen in 21 patients among a group of 144 with strictly-defined cerebral malaria. Hemorrhages were multiple in 17 cases and bilateral in 14. There was subhyaloid extension in two. Soft exudates were seen in two, the retinae were considered edematous in four and in one there was bilateral papilledema. Retinal hemorrhages were significantly associated with several indices of severity of Plasmodium falciparum infection: high parasitemia with schizontemia, anemia, elevated serum creatinine and reduced plasma antithrombin III. Only two patients with hemorrhages were both severely anemic and thrombocytopenic. It is suggested that retinal hemorrhages, a frequent finding in cerebral malaria, may be visible evidence of vascular lesions involved in the pathogenesis of this condition.


Walterinnesia aegyptia venom combined with silica nanoparticles enhances the functioning of normal lymphocytes through PI3K/AKT, NFκB and ERK signaling.
The toxicity of snake venom varies over time in some species. The venom of newborn and small juvenile snakes appears to be more potent than adults of the same species, and a bite from a snake that has not fed recently, such as one that has just emerged from hibernation, is more dangerous than one that has recently fed due to the larger volume of venom injected. Therefore, the potency of a snake's venom is typically determined using the LD50 or IC50 tests. In the present study, we evaluated the anti-tumor potential of snake venom from Walterinnesia aegyptia (WEV) on the human breast carcinoma cell line MDA-MB-231, as well as its effect on the normal mice peripheral blood mononuclear cells (PBMCs). This venom was used alone (WEV) or in combination with silica nanoparticles (WEV+NP). The IC50 values of WEV alone and WEV+NP in the MDA-MB-231 cells were determined to be 50 ng/ml and 20 ng/ml, respectively. Interestingly, at these concentrations, the venom did not affect the viability of normal human PBMCs. To investigate the in vivo effects of this venom further, three groups of mice were used (15 mice in each group): Group I was the control, Group II was subcutaneously injected with WEV, and Group III was injected with WEV+NP. Using flow cytometry and western blot analysis, we found that the blood lymphocytes of WEV-injected mice exhibited a significant increase in actin polymerization and cytoskeletal rearrangement in response to CXCL12 through the activation of AKT, NF-κB and ERK. These lymphocytes also showed a significant increase in their proliferative capacity in response to mitogen stimulation compared with those isolated from the control mice (P < 0.05). More importantly, in the WEV+NP-treated mice, the biological functions of normal lymphocytes were significantly (P < 0.05) enhanced in comparison with those of WEV-treated mice. Our data reveal the unique biological effects of WEV, and we demonstrated that its combination with nanoparticles strongly enhanced these biological effects.


Side-chain effects on peptidyl-prolyl cis/trans isomerisation.
Peptidyl-prolyl cis/trans isomerisation has been frequently found as a rate limiting step in the folding of proteins. In order to determine whether the nature of the amino acid preceding proline controls the probability of cis prolyl bonds in native proteins, systematic studies on the thermodynamics and kinetics of the prolyl isomerisation in the pentapeptide series Ac-Ala-Xaa-Pro-Ala-Lys-NH2 were performed. All proteinogenic amino acids were substituted in the position preceding proline. When measured by 1H-NMR and CD spectroscopy both isomers proved to be devoid of ordered structure in the whole series of the oligopeptides in aqueous solution. Thus, isomerization rates and cis/trans ratios calculated from solvent jump and 1H-NMR magnetisation transfer experiments exclusively reflect the side-chain effects of the Xaa position in the peptide series. There is a rough correlation between the cis content in the oligopeptides and the propensity of Xaa-Pro cis prolyl bonds in proteins. This correlation suggests that the prolyl bond conformation is mainly determined by local effects in proteins. The rate constants kc-->t of pentapeptides containing unionised amino acids preceding proline range from 3.2 x 10(-3) s-1 (Xaa = Ala) to 0.5 x 10(-3) s-1 (Xaa = Trp) at 4 degrees C. Proline clustering led to an isomerisation cycle indicating considerable influence on the isomerisation rates of the peptide bond conformations flanking the rotating bond. Both tyrosine and histidine specifically reduce isomerisation rates severalfold by deprotonation of their respective side-chains.


Patient reported outcomes 6 to 12 months after interpersonal violence: A multicenter cohort study.
Violence continues to be a significant public health burden, but little is known about the long-term outcomes of these patients. Our goal was to determine the impact of violence-related trauma on long-term functional and psychosocial outcomes. We identified trauma patients with moderate to severe injuries (Injury Severity Score, ≥9) treated at one of three level 1 trauma centers. These patients were asked to complete a survey over the phone between 6 and 12 months after injury evaluating both functional and psychosocial outcomes (12-item Short Form Survey, Trauma Quality of Life, posttraumatic stress disorder [PTSD] screen, chronic pain, return to work). Patients were classified as having suffered a violent injury if the mechanism of injury was a stab, gunshot, or assault. Self-inflicted wounds were excluded. Adjusted logistic regression models were built to determine the association between a violent mechanism of injury and long-term outcomes. A total of 1,050 moderate to severely injured patients were successfully followed, of whom 176 (16.8%) were victims of violence. For the victims of violence, mean age was 34.4 years (SD, 12.5 years), 85% were male, and 57.5% were Black; 30.7% reported newly needing help with at least one activity of daily living after the violence-related event. Fifty-nine (49.2%) of 120 patients who were working before their injury had not yet returned to work; 47.1% screened positive for PTSD, and 52.3% reported chronic pain. On multivariate analysis, a violent mechanism was significantly associated with PTSD (odds ratio, 2.57; 95% confidence interval, 1.59-4.17; p < 0.001) but not associated with chronic pain, return to work, or functional outcomes. The physical and mental health burden after violence-related trauma is not insignificant. Further work is needed to identify intervention strategies and social support systems that may be beneficial to reduce this burden. Prognostic and epidemiological, level III.


Kinetics of enzymatic depolymerization of guar galactomannan.
A new mathematical model based on Michaelis Menten (MM) kinetics is developed to predict the changes in molecular weight distribution (MWD) during the enzymatic depolymerization of guar galactomannan. The model accounts for the effect of branching by considering the guar molecule as a substrate having three types of bonds with different MM kinetic parameters. The overall kinetics of the enzymatic reactions then can be represented in terms of composite kinetic parameters that are functions of the MM parameters for the individual bonds. The depolymerization is assumed to follow a random scission mechanism, in which an enzyme randomly attacks the substrate molecule at any one of the three types of bonds, and leaves the substrate on cleavage of the bond. Expressions for the variation in molecular weights during depolymerization are developed by applying moment generating techniques to the kinetic model. The model is evaluated against the complete MWD obtained using gel permeation chromatography. During the initial stages of depolymerization, the enzymatic reaction is in the zero-order regime of MM kinetics and the polydispersity index (PDI) increases with time. Subsequently, the PDI decreases as the depolymerization tends to follow first order kinetics. We also show that for a zero-order, random or nonrandom scission, the variation of PDI with time can exhibit a maximum. These analyses confirm that an increase in PDI during the depolymerization is not necessarily due to nonrandom scission, as previously concluded.


Optimizing tissue-specific antisense oligonucleotide-peptide conjugates.
Cell-targeting peptides which improve tissue-specific delivery of antisense oligonucleotides (AONs) are a new exciting "next-generation" potential AON therapy. New peptides are regularly developed which increase targeting and cell penetration for the AON treatment of mRNA misregulated diseases. Optimization of these peptide conjugate AONs requires systematic treatment and methods of analysis. This chapter describes methods for analyzing cell-targeting peptide conjugated AONs in primary cultured cell lines and for local and systemic delivery to the mouse for the treatment of Duchenne muscular dystrophy (DMD). Chimeric and novel cell-penetrating peptides have already been described to induce high levels of exon skipping and dystrophin protein expression in tissues body-wide at very low doses of AON. Screening of future novel peptides may be achieved by preliminary in vitro screening followed by in vivo administration of the most promising peptide-conjugated AONs. Physiological and functional correction of dystrophin protein may be confirmed by a number of techniques as described and allows for the fast-tracking of candidate peptides to drug trial for DMD.


Osteoinductive superparamagnetic Fe nanocrystal/calcium phosphate heterostructured microspheres.
Functional magnetic and biocompatible particles are of great interest because of their potential use in various bioapplications such as hyperthermia for cancer treatment, magnetic resonance imaging (MRI) contrast agents and drug delivery. Herein, we introduce a facile method for synthesizing magnetic Fe nanocrystal/Fe-substituted calcium phosphate (Fe/FeCaP) heterostructured microspheres using a two-step procedure: (1) one-pot hydrothermal synthesis to prepare uniform-sized FeCaP microspheres and (2) post-reduction annealing at 600 °C for Fe extraction from FeCaP. This approach results in the fabrication of Fe/FeCaP heterostructured microspheres that exhibit superparamagnetism with a saturation magnetization of 10.77 emu g-1. The Fe/FeCaP particles annealed at 600 °C show a much higher magnetic moment compared with the non-annealed FeCaP particles. Moreover, T2-weighted MRI phantom images reveal that the Fe/FeCaP heterostructured microspheres possess higher relaxivity than paramagnetic FeCaP, demonstrating their potential as superior and biocompatible MRI contrast agents. Moreover, the enhancement in osteoconductivity for Fe/FeCaP microspheres without any evidence of cytotoxicity was verified. Our results demonstrate the great potential of multi-functional Fe/FeCaP microspheres for use as biocompatible bone regeneration agents as well as MRI contrast agents.


Implications from assessing environmental effects on spatio-temporal pattern of schistosomiasis in the Yangtze Basin, China.
Schistosomiasis remains a major public health problem in the South China, particularly in lake and marshland regions. Modelling the spatio-temporal pattern of schistosomiasis guides disease prevention and control programs and is a research area of growing interest. However, few attempts have been made to evaluate the changing (nonlinear) effects of environmental determinants on schistosomiasis. In this context, a hierarchical spatiotemporal model was applied to evaluate how environmental determinants affect the changing trend of schistosomiasis in Anhui Province, China, based on annual parasitological and environmental data for the period 1997-2010. Results showed that - compared to changing effect - environmental factors had a constant (linear) effect on schistosomiasis. The disease was also found to fluctuate over time, which was due to the two latest national schistosomiasis control programs. In addition to statistical benefits of this approach, our analysis implied that climate change might not contribute to variation of schistosomiasis; rather, prevention activities affect schistosomiasis when the disease prevalence remains at a low level. Finally, the analytical method proposed in our study provides a template for modelling the spatio-temporal pattern of a disease whose transmission is largely determined by environmental determinants.


Pulmonary toxicity following exposure to a tile coating product containing alkylsiloxanes. A clinical and toxicological evaluation.
Coating products are widely used for making surfaces water and dirt repellent. However, on several occasions the use of these products has been associated with lung toxicity. In the present study, we evaluated the toxic effects of an aerosolized tile-coating product. Thirty-nine persons, who reported respiratory and systemic symptoms following exposure to the tile-coating product, were clinically examined. The product was analysed chemically and furthermore, the exposure scenario was reconstructed using a climate chamber and the toxicological properties of the product were studied using in vivo and by in vitro surfactometry. The symptoms developed within few hours and included coughing, tachypnoea, chest pain, general malaise and fever. The physical examination revealed perihilar lung infiltrates on chest radiograph and reduced blood oxygen saturation. The acute symptoms resolved gradually within 1-3 days and no delayed symptoms were observed. By means of mass spectrometry and X-ray spectroscopy, it was shown that the product contained non-fluorinated alkylsiloxanes. The exposure conditions in the supermarket were reconstructed under controlled conditions in a climate chamber and particle and gas exposure levels were monitored over time allowing estimation of human exposure levels. Mice exposed to the product developed symptoms of acute pulmonary toxicity in a concentration-and time-dependent manner. The symptoms of acute pulmonary toxicity likely resulted from inhibition of the pulmonary surfactant function as demonstrated by in vitro surfactometry. Among these patients only a partial association between the level of exposure and the degree of respiratory symptoms was observed, which could be because of a high inter-individual difference in sensitivity and time-dependent changes in the chemical composition of the aerosol. Workers need to cautiously apply surface coating products because the contents can be highly toxic through inhalation, and the aerosols can disperse to locations remote from the worksite and affect bystanders.


Beyond structures of highly symmetric purified viral capsids by cryo-EM.
Cryogenic transmission electron microscopy (cryo-EM) is widely used to determine high-resolution structures of symmetric virus capsids. The method holds promise for extending studies beyond purified capsids and their symmetric protein shells. The non-symmetric genome component has been addressed in dsRNA cypoviruses and ssRNA bacteriophages Qβ and MS2. The structure of human herpes simplex virus type 1 capsids has been determined within intact virions to resolve capsid-tegument interactions. Electron tomography under cryogenic conditions (cryo-ET), has allowed resolving an early membrane fusion intermediate of Rift Valley fever virus. Antibody-affinity based sample grids allow capturing of virions directly from cell cultures or even clinical samples. These and other emerging methods will support studies to address viral entry, assembly and neutralization processes at increasingly high resolutions and native conditions.


Trichomonosis and subsequent risk of prostate cancer in the Prostate Cancer Prevention Trial.
We previously observed a positive association between a history of trichomonosis, a sexually transmitted infection caused by the protozoan, Trichomonas vaginalis, and prostate cancer risk in the Health Professionals Follow-up Study. To determine the reproducibility of this finding, we conducted a second, prospective investigation of trichomonosis and prostate cancer in the Prostate Cancer Prevention Trial. Participants were men (>or=55 years of age) with no evidence of prostate cancer at enrollment (n = 18,882). Men were screened annually for prostate cancer, and if not diagnosed during the trial, were offered an end-of-study prostate biopsy. Cases were a sample of men diagnosed with prostate cancer on any biopsy after visit 2 or on their end-of-study biopsy (n = 616). Controls were men not diagnosed with prostate cancer during the trial or on their end-of-study biopsy (n = 616). Controls were frequency-matched to cases by age, treatment arm, and family history of prostate cancer. Serum from visit 2 was tested for anti-T. vaginalis IgG antibodies. No association was observed between T. vaginalis serostatus and prostate cancer. 21.5% of cases and 24.8% of controls had low seropositivity, and 15.2% and 15.0% had high seropositivity. Compared to seronegative men, the odds ratio of prostate cancer for men with low seropositivity was 0.83 [95% confidence interval (CI): 0.63-1.09), and that for men with high seropositivity was 0.97 (95% CI: 0.70-1.34). Given the original strong biologic rationale and potential for prevention, additional studies are warranted to help resolve discrepancies between study findings and to further investigate this hypothesis from a variety of different approaches.


New Insights on Moojase, a Thrombin-Like Serine Protease from Bothrops moojeni Snake Venom.
Snake venom serine proteases (SVSPs) are enzymes that are capable of interfering in various parts of the blood coagulation cascade, which makes them interesting candidates for the development of new therapeutic drugs. Herein, we isolated and characterized Moojase, a potent coagulant enzyme from Bothrops moojeni snake venom. The toxin was isolated from the crude venom using a two-step chromatographic procedure. Moojase is a glycoprotein with N-linked glycans, molecular mass of 30.3 kDa and acidic character (pI 5.80⁻6.88). Sequencing of Moojase indicated that it is an isoform of Batroxobin. Moojase was able to clot platelet-poor plasma and fibrinogen solutions in a dose-dependent manner, indicating thrombin-like properties. Moojase also rapidly induced the proteolysis of the Aα chains of human fibrinogen, followed by the degradation of the Bβ chains after extended periods of incubation, and these effects were inhibited by PMSF, SDS and DTT, but not by benzamidine or EDTA. RP-HPLC analysis of its fibrinogenolysis confirmed the main generation of fibrinopeptide A. Moojase also induced the fibrinolysis of fibrin clots formed in vitro, and the aggregation of washed platelets, as well as significant amidolytic activity on substrates for thrombin, plasma kallikrein, factor Xia, and factor XIIa. Furthermore, thermofluor analyses and the esterase activity of Moojase demonstrated its very high stability at different pH buffers and temperatures. Thus, studies such as this for Moojase should increase knowledge on SVSPs, allowing their bioprospection as valuable prototypes in the development of new drugs, or as biotechnological tools.


Determination of the Main Phase Transition Temperature of Phospholipids by Nanoplasmonic Sensing.
Our study demonstrates that nanoplasmonic sensing (NPS) can be utilized for the determination of the phase transition temperature (Tm) of phospholipids. During the phase transition, the lipid bilayer undergoes a conformational change. Therefore, it is presumed that the Tm of phospholipids can be determined by detecting conformational changes in liposomes. The studied lipids included 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). Liposomes in gel phase are immobilized onto silicon dioxide sensors and the sensor cell temperature is increased until passing the Tm of the lipid. The results show that, when the system temperature approaches the Tm, a drop of the NPS signal is observed. The breakpoints in the temperatures are 22.5 °C, 41.0 °C, and 55.5 °C for DMPC, DPPC, and DSPC, respectively. These values are very close to the theoretical Tm values, i.e., 24 °C, 41.4 °C, and 55 °C for DMPC, DPPC, and DSPC, respectively. Our studies prove that the NPS methodology is a simple and valuable tool for the determination of the Tm of phospholipids.


Maternal Overnutrition Induces Long-Term Cognitive Deficits across Several Generations.
Ample evidence from epidemiological studies has linked maternal obesity with metabolic disorders such as obesity, cardiovascular disease, and diabetes in the next generation. Recently, it was also shown that maternal obesity has long-term effects on the progeny's central nervous system. However, very little is known regarding how maternal overnutrition may affect, in particular, the cognitive abilities of the offspring. We reported that first-generation offspring exposed to a maternal high-fat diet (MHFD) displayed age-dependent cognitive deficits. These deficits were associated with attenuations of amino acid levels in the medial prefrontal cortex and the hippocampus regions of MHFD offspring. Here, we tested the hypothesis that MHFD in mice may induce long-term cognitive impairments and neurochemical dysfunctions in the second and third generations. We found that MHFD led to cognitive disabilities and an altered response to a noncompetitive receptor antagonist of the N-Methyl-D-aspartic acid (NMDA) receptor in adult MHFD offspring in both second and third generations in a sex-specific manner. Our results suggest that maternal overnutrition leads to an increased risk of developing obesity in subsequent generations as well as to cognitive impairments, affecting learning and memory processes in adulthood. Furthermore, MHFD exposure may facilitate pathological brain aging which is not a consequence of obesity. Our findings shed light on the long-term effects of maternal overnutrition on the development of the central nervous system and the underlying mechanisms which these traits relate to disease predisposition.


Events and Causal Mappings Modeled in Conceptual Spaces.
The aim of the article is to present a model of causal relations that is based on what is known about human causal reasoning and that forms guidelines for implementations in robots. I argue for two theses concerning human cognition. The first is that human causal cognition, in contrast to that of other animals, is based on the understanding of the forces that are involved. The second thesis is that humans think about causality in terms of events. I present a two-vector model of events, developed by Gärdenfors and Warglien, which states that an event is represented in terms of two main components - the force of an action that drives the event, and the result of its application. Apart from the causal mapping, the event model contains representations of a patient, an agent, and possibly some other roles. Agents and patients are objects (animate or inanimate) that have different properties. Following my theory of conceptual spaces, they can be described as vectors of property values. At least two spaces are needed to describe an event, an action space and a result space. The result of an event is modeled as a vector representing the change of properties of the patient before and after the event. In robotics the focus has been on describing results. The proposed model also includes the causal part of events, typically described as an action. A central part of an event category is the mapping from actions to results. This mapping contains the central information about causal relations. In applications of the two-vector model, the central problem is how the event mapping can be learned in a way that is amenable to implementations in robots. Three processes are central for event cognition: causal thinking, control of action and learning by generalization. Although it is not yet clear which is the best way to model how the mappings can be learned, they should be constrained by three corresponding mathematical properties: monotonicity (related to qualitative causal thinking); continuity (plays a key role in activities of action control); and convexity (facilitates generalization and the categorization of events). I argue that Bayesian models are not suitable for these purposes, but some more geometrically oriented approach to event mappings should be used.


Properties of Triheteromeric N-Methyl-d-Aspartate Receptors Containing Two Distinct GluN1 Isoforms.
N-Methyl-d-aspartate (NMDA)-type glutamate receptors mediate excitatory synaptic transmission in the central nervous system and play critical roles in many neuronal processes. The physiologic roles of NMDA receptors are shaped by their functional properties, which are highly dependent on subunit composition. Most NMDA receptors are assembled from two GluN1 and two GluN2 subunits, but diversity in subunit composition is made possible by eight GluN1 splice variants (i.e., isoforms) and four distinct GluN2 subunits (GluN2A-D). We demonstrate using Förster resonance energy transfer and fluorescence lifetime imaging that GluN1-1a and GluN1-1b isoforms, which include or lack residues encoded by exon 5, form triheteromeric GluN1-1a/GluN1-1b/GluN2A (1a/1b/2A) and GluN1-1a/GluN1-1b/GluN2B (1a/1b/2B) receptors. We describe the selective expression of NMDA receptors containing two different GluN1 isoforms, and show that triheteromeric 1a/1b/2A and 1a/1b/2B receptors exhibit intermediate deactivation kinetics and pharmacological properties compared with the respective diheteromeric GluN1-1a/GluN1-1a/GluN2 and GluN1-1b/GluN1-1b/GluN2 receptors. These results highlight the intriguing possibility that neurons can finely tune NMDA receptor signaling by shifting the ratio of expressed GluN1-1a and GluN1-1b isoforms. Furthermore, we evaluate the contribution of channel pore residues to magnesium block and calcium permeability. These data point to the asymmetric contribution of pore residues in GluN1 and GluN2 to magnesium block, and reveal that a single copy of pore residues from GluN3 subunits strongly attenuates magnesium block and calcium permeability of NMDA receptors. Thus, the selective expression of NMDA receptors containing two distinct GluN1 isoforms provides new opportunities to study functional properties relevant to neuronal receptors.


Neuroprotective effects of phytosterol esters against high cholesterol-induced cognitive deficits in aged rat.
Accumulating epidemiological and experimental studies have confirmed that a high-cholesterol diet is detrimental to cognitive performance in animal models. Phytosterols, a class of naturally occurring structural components in plant foods, have been demonstrated to possess cholesterol-lowering and antioxidant effects. Phytosterol esters (PSE) are esters of phytosterol. The aim of this study was to evaluate the neuroprotective effects of PSE on cognitive deficit induced by a cholesterol-enriched diet in aged rats, and to explore their underlying mechanisms for these effects. Based on their Morris water maze performance, the latencies differed by <1.5 standard deviations (SDs) on days 3-5 of testing, 60 rats were chosen from 12-month-old female Sprague Dawley aged rats and were randomized into three groups, which were fed either a control diet, a high cholesterol diet (HCD) or a high-cholesterol diet supplemented with 2% PSE (HCD + PSE) for 6 months. In our study, we found that PSE treatment maintained the body weight balance, reduced the serum lipid levels, and improved the cognitive performance of aged rats in the Morris water maze test, as evaluated by shortened escape latencies. Importantly, histological and immunohistochemical results in the brain showed that PSE supplementation may have a neuroprotective effect that alleviates neuroinflammation in aged rats. This neuroprotective effect significantly inhibited degeneration, resulting in a significant increase in the number of pyramidal cells and an apparent decrease in the number of astrocytes compared to rats that were fed only a HCD. Furthermore, PSE improved cholinergic activities by restoring the acetylcholine (ACh) content and decreasing acetylcholinesterase (AChE) activity in the cerebral cortex, as well as by elevating choline acetyl transferase (ChAT) activity in the hippocampus and the cerebral cortex. These results suggest that PSE can play a useful role in alleviating cognitive deficit induced by a cholesterol-enriched diet and ageing.


Macroscopic Domains within an Oriented TQ1 Film Visualized Using 2D Polarization Imaging.
Large-area self-assembly of functional conjugated polymers holds a great potential for practical applications of organic electronic devices. We obtained well-aligned films of poly[2,3-bis(3-octyloxyphenyl)quinoxaline-5,8-diyl-alt-thiophene-2,5-diyl] (TQ1) using the floating film transfer method. Thereby, a droplet of the TQ1 solution was injected on top of the surface of an immiscible liquid substrate, at the meniscus formed at the edge of a Petri dish, from where the polymer solution and the film spread in one direction. Characterization of the TQ1 film using the recently developed two-dimensional polarization imaging (2D POLIM) revealed large, millimeter-sized domains of oriented polymer chains. The irregular shape of the contact line at the droplet source induced the appearance of disordered stripes perpendicular to the spreading direction. A correlation of polarization parameters measured using 2D POLIM revealed the microstructure of such stripes, providing valuable information for further improvement and possible upscaling of this promising method.


The management of patients with arteriovenous malformations and associated intracranial aneurysms.
Few published studies have focused specifically on the unique management issues encountered in treating patients with arteriovenous malformations (AVMs) and associated intracranial aneurysms. The primary objective of this study was to retrospectively review the clinical and radiographic features of these patients. Medical records of all patients seen at Stanford University Hospital between 1988 and 1996 with a diagnosis of AVMs were retrospectively reviewed. Aneurysms were identified by conventional angiography and characterized by size, number, and location relative to the AVMs. AVMs were graded according to the Spetzler-Martin scale. Odds ratios were calculated for the risk of intracranial hemorrhage. Variables included age, sex, number of aneurysms, and AVM grade. Forty-five of 600 patients (7.5%) were identified as having coexisting intracranial aneurysms. All 45 patients had high-flow malformations, and 58% had AVMs of Spetzler-Martin Grade IV or higher. A majority of patients had multiple aneurysms. There was a statistically significant increase in AVM hemorrhage in female patients (odds ratio, 8.53 [1.87-38.98]; P < 0.005). There was no statistically significant correlation between the development of hemorrhage and either age, AVM grade, or the number of aneurysms. Twenty-three patients (51%) presented with intracranial hemorrhage: bleeding occurred from the AVMs in 15 and from ruptured aneurysms in 5, and the source of the bleeding could not be determined in 3. Overall, nine patients (20%) bled from ruptured aneurysms: five at presentation, two during or within 3 weeks of AVM treatment, and two from new aneurysms. Two of these nine patients died as a direct result of aneurysmal subarachnoid hemorrhage. Five patients (11%) developed new aneurysms. Aneurysms associated with AVMs are at risk for rupture before, during, and immediately after treatment of the AVMs. New aneurysms may arise in patients with high-flow AVMs. The risk of intracranial hemorrhage from either source is higher in female patients. To reduce the complications of intracranial hemorrhage in these patients, we recommend a management protocol designed to treat the aneurysms by surgical or endovascular means before administering definitive therapy for the AVMs. Meticulous intraoperative blood pressure control and fluid management during aneurysm surgery is critical to avoid hemorrhage from the AVMs.


Performance characteristics and applications of a proton transfer reaction-mass spectrometer for measuring volatile organic compounds in ambient air.
Data illustrating the performance characteristics of a proton transfer reaction-mass spectrometer (PTR-MS) under both laboratory and field conditions are presented. Under laboratory conditions, we demonstrate that PTR-MS measures (within 10%) a 2.6 ppbv concentration of gaseous dimethyl sulfide. Using a stepwise dilution of a gaseous isoprene standard, we demonstrate the linearity of the response of PTR-MS across 3 orders of magnitude of mixing ratios, from 100 ppbv to less than 100 pptv. By combining this data set with that of its monosubstituted 13C isotopic analogue, we demonstrate the ability of the instrumentto reliably measure concentrations as low as approximately 50 pptv and to detect concentrations at significantly lower levels. We conclude our laboratory characterization by investigating the components of the instrument noise signal (drift, mean, and range) and develop an expression (noise statistic) that reliably predicts the instrumental noise associated with any signal across a wide range of masses. In the field, we deployed a PTR-MS at a clean-air coastal site and an urban kerbside monitoring station to demonstrate the measurement of atmospheric dimethyl sulfide and benzene concentrations, respectively. At both sites, we were able to monitor diurnal variations in concentrations at unprecedented temporal resolutions (<5 min between successive measurements). We then demonstrate how the noise statistic can be applied to enable real fluctuations in atmospheric VOC concentrations to be reliably distinguished from instrument noise. We conclude by demonstrating how PTR-MS can be used to measure real-time VOC emission rate changes from vegetation in response to external forcing by examining the effect varying photon-flux density has upon emissions of isoprene from a Sitka spruce tree.


Exogenous estrogen therapy, testicular cancer, and the male to female transgender population: a case report.
Over the last 40 years, there has been a significant increase in the incidence of testicular cancer. The epidemiologic evidence to understand this phenomenon is unclear, however exogenous estrogen exposure is thought to be a driver in the development of testicular cancer. This is of particular importance in the transgender population because utilization of exogenous estrogen therapy is an essential aspect of the transition process. We present the case of a 38-year-old Caucasian male to female transgender patient who presented with metastatic testicular cancer 15 months after initiating estrogen therapy. She presented to our emergency department with worsening back pain and fatigue. A clinical examination revealed a right-sided testicular mass. A computed tomography scan of her abdomen/pelvis identified a right groin lesion measuring 6.4 cm, a retroperitoneal mass causing right-sided hydronephrosis, an extensive deep vein thrombosis, and pathologic abdominal lymphadenopathy. Germ cell tumor markers revealed an alpha-fetoprotein of < 2.5 μg/L and a beta-human chorionic gonadotrophin of 2526 IU/L. Her lactate dehydrogenase was 5294 U/L. Medical oncology advised the discontinuation of hormonal therapy at this time. On the basis of elevation in germ cell tumor markers and the burden of disease, she was treated with four cycles of bleomycin, etoposide, and cisplatin chemotherapy. A decision to defer upfront radical inguinal orchiectomy was made due to not wanting to have an early interruption in anticoagulation. Following the completion of the chemotherapy, a 6 cm retroperitoneal mass persisted. Due to the location of the mass and surgical morbidity associated with excision, she was followed with positron emission tomography-computed tomography by Uro-oncology, with no evidence of recurrent disease 2 years since the time of diagnosis. While there are recognized risks associated with estrogen therapy less is known about the extent to which exogenous estrogen can serve as a driver of malignancy. With recent experimental evidence revealing a pro-growth impact of estrogen on human testicular cells, continued reporting of similar cases in the literature is imperative to see if a link between exogenous estrogen exposure and testicular cancer exists.


Changes in gut microbiota during development of compulsive checking and locomotor sensitization induced by chronic treatment with the dopamine agonist quinpirole.
Long-term treatment of rats with the D2/D3 dopamine agonist quinpirole induces compulsive checking (proposed as animal model of obsessive-compulsive disorder) and locomotor sensitization. The mechanisms by which long-term use of quinpirole produces those behavioral transformations are not known. Here we examined whether changes in gut microbiota play a role in these behavioral phenomena, by monitoring the development of compulsive checking and locomotor sensitization at the same time as measuring the response of gut microbiota to chronic quinpirole injections. Two groups of rats received nine injections of saline (n=16) or quinpirole (n=15; 0.25 mg/kg), at weekly intervals for the first 5 weeks and then two injections per week until the end of treatment. After each injection, rats were placed on a large open field for 55 min, and their behavior was video recorded for subsequent analysis. Fecal matter was collected after each trial and frozen for bacterial community profiling of the 16S rRNA gene, using paired-end reads of the V3 region. The results indicated that the induction of locomotor sensitization and compulsive checking was accompanied by changes in several communities of bacteria belonging to the order Clostridiales (class Clostridia, phylum Firmicutes), and predominantly in Lachnospiraceae and Ruminococcaceae families of bacteria. It is suggested that changes in these microbes may serve to support the energy use requirements of compulsive checking and obsessive-compulsive disorder.


Tailored lay health worker intervention improves breast cancer screening outcomes in non-adherent Korean-American women.
Despite rapidly increasing incidence rates of breast cancer, recent immigrants such as Korean-American (KA) women report disproportionately lower utilization of screening tests compared with other ethnic groups. Early screening of breast cancer for this population may be greatly facilitated by indigenous lay health workers (LHWs). We conducted an intervention trial with a 6-month follow-up. Trained LHWs recruited 100 KA women 40 years of age or older who had not had a mammogram during the past 2 years. Ninety-three completed follow-up questionnaires. A 120-min, in-class education combined with LHW follow-up counseling and navigation assistance through the health care system was provided. Rates of breast cancer screening behaviors significantly increased at 6 months (P < 0.001); changes between pre- and post-intervention were 31.9% for mammography, 23% for clinical breast examination and 36.2% for breast self-examination. Modesty toward screening significantly decreased over time, but we did not find any significant differences in breast cancer knowledge and beliefs before and after the intervention. Results support the efficacy of this neighborhood-based, culturally sensitive intervention. Further research should seek to replicate these findings and to incorporate more self-care skills such as health literacy when designing an intervention program for linguistically and culturally isolated immigrant women.


The proinflammatory activity of recombinant serum amyloid A is not shared by the endogenous protein in the circulation.
Elevated serum levels of the acute-phase protein serum amyloid A (SAA) are a marker for active rheumatoid arthritis (RA), and SAA can also be found in the tissues of patients with active RA. Based on a number of studies with recombinant SAA (rSAA), the protein has been suggested to be a potent proinflammatory mediator that activates human neutrophils, but whether endogenous SAA shares these proinflammatory activities has not been directly addressed. The present study was undertaken to investigate whether SAA in the plasma of patients with RA possesses proinflammatory properties and activates neutrophils in a manner similar to that of the recombinant protein. Neutrophil activation was monitored by flow cytometry, based on L-selectin shedding from cell surfaces. Whole blood samples from healthy subjects and from RA patients with highly elevated SAA levels were studied before and after stimulation with rSAA as well as purified endogenous SAA. Recombinant SAA potently induced cleavage of L-selectin from neutrophils and in whole blood samples. Despite highly elevated SAA levels, L-selectin was not down-regulated on RA patient neutrophils as compared with neutrophils from healthy controls. Spiking SAA-rich whole blood samples from RA patients with rSAA, however, resulted in L-selectin shedding. In addition, SAA purified from human plasma was completely devoid of neutrophil- or macrophage-activating capacity. The present findings show that rSAA is proinflammatory but that this activity is not shared by endogenous SAA, either when present in the circulation of RA patients or when purified from plasma during an acute-phase response.


Partner's presence during initiation of epidural labor analgesia does not decrease maternal stress: a prospective randomized controlled trial.
Epidural analgesia reduces pain and anxiety during childbirth. In this randomized controlled trial, we sought to determine whether partner presence during the initiation of epidural analgesia reduces stress of both the mother and her partner and their perception of maternal pain. Healthy, nulliparous women who were accompanied by their partners and requested neuraxial analgesia were enrolled into the study. The study took place in the Labor and Delivery Unit of a large tertiary hospital in Israel. Upon request for epidural analgesia, both partners were assessed for baseline anxiety (numerical rating scale, 0 to 10), systolic blood pressure, heart rate, estimated contraction pain of parturient (verbal rating scale for pain, 0 to 10), and salivary amylase. After measurements, couples were randomized into 1 of 2 groups: "partner in" and "partner out." Immediately after epidural catheter insertion, anxiety, arterial blood pressure, heart rate, and salivary amylase were measured again in both partners. Both partners were asked to complete the State Anxiety Inventory questionnaire measuring current anxiety. The parturient was asked to rate the pain of epidural catheter insertion. The primary outcome measurement was parturient and partner anxiety as assessed by the numerical rating scale. Eighty-four couples were randomized (partner in 41, partner out 42, protocol violation 1). At baseline there was no difference in self-reported anxiety of parturients between the partner-in and partner-out groups (median interquartile range 7.5 [6.0 to 9.0] versus 7.0 [3.5 to 8.5]; P = 0.26, difference in medians = -1.0; 95% confidence interval [CI] of difference -2.0 to 1.0). After epidural catheter insertion, parturients in the partner-in group had a higher level of anxiety than those in the partner-out group (8.0 [7.0 to 10.0] versus 7.0 [5.0 to 9.0]; P = 0.03, difference in medians -1.0; 95% CI of difference -2.0 to 0.0). Pain scores during epidural catheter placement were higher in partner-in than in partner-out groups (7.0 [4.0 to 8.0] versus 4.0 [3.0 to 6.0]; P = 0.004, difference in medians = -2.0; 95% CI of difference -3.0 to -1.0). Partner presence during epidural catheter insertion for labor analgesia did not decrease anxiety levels. To the contrary, anxiety and pain of epidural catheter placement were greater if the partner remained in the room.


Phorbol ester-mediated association of protein kinase C to the nuclear fraction in NIH 3T3 cells.
Treatment of intact NIH 3T3 cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) causes a rapid redistribution (stabilization) of protein kinase C to the particulate fraction. Part of the enzyme activity stabilized to the membrane fraction in response to TPA can be recovered associated with nuclear-cytoskeletal components. An apparently pure nuclear fraction prepared from NIH 3T3 cells was found to contain 25-30% of the total membrane-associated protein kinase C activity when isolated in the presence of Ca2+. In untreated control cells, most of this activity found with the nuclear fraction can be extracted by chelators. Phorbol ester (TPA) treatment of NIH 3T3 cells induces the tight association of protein kinase C to the nucleus; this tightly bound activity is not dissociable by chelators and can be recovered only by solubilization with detergent. Nuclei purified from untreated human promyelocytic leukemic HL-60 cells contain higher amounts of chelator-stable, detergent-extractable protein kinase C activity compared with control NIH 3T3 cells. However, TPA treatment of HL-60 cells does not enhance the amount of protein kinase C found tightly associated with the nuclear fraction. Immunohistochemical studies with polyclonal antibodies directed against protein kinase C further indicate that TPA treatment of NIH 3T3 cells does significantly enhance the amount of protein kinase C found tightly associated with the nucleus and cytoskeleton, whereas exposure of HL-60 cells to TPA does not appreciably alter the amount of protein kinase C observed to be associated with the nuclear fraction. The TPA-mediated association (activation) of protein kinase C to the nuclear and cytoskeletal fractions with NIH 3T3 cells is further supported by the enhanced phosphorylation of specific endogenous proteins noted when purified nuclei and cytoskeletal preparations are incubated with [gamma-32P]ATP. These results suggest that tumor promoters may induce association (activation) of protein kinase C with different subcellular components to alter the availability of endogenous substrates. This may result in differential responses by different cell types during exposure to tumor promoters.


Exorcism: a psychiatric viewpoint.
Doctors, for several reasons, should be concerned with exorcism is the view of Professor Trethowan, who in this paper, looks at the main features of exorcism as practised in the middle ages and now appearing in the modern world, as was seen in the recent Ossett case in Britain. He examines in some detail the nature of supposed demoniacal possession and describes its symptoms and signs. He also touches on the social, as opposed to the religious, background in which demoniacal possession flourished (not lacking in the world today), so leading to an examination of the psychodynamic aspects of demoniacal possession and the question of absolute evil. Finally he compares the techniques of exorcism and of modern psychiatric practice.


Biofilm formation by saprophytic and pathogenic leptospires.
Leptospires exist as saprophytic organisms that are aquatic or as pathogens that are able to survive in water. Leptospirosis is transmitted to humans through environmental surface waters contaminated by the urine of mammals, usually rodents, which are chronically infected by pathogenic strains. The ecology of Leptospira spp. prompted us to evaluate if these spirochaetes were able to form biofilms. This study investigated the characteristics of biofilm development by both saprophytic and pathogenic Leptospira species using microscopic examinations and a polystyrene plate model. Biofilms were formed preferentially on glass and polystyrene surfaces. Electron microscopic images showed cells embedded in an extracellular matrix. The formation of such a biofilm is consistent with the life of saprophytic strains in water and may help pathogenic strains to survive in environmental habitats and to colonize the host.


Effects of rhG-CSF on neutrophil functions and bone marrow parameters in diabetic rats.
Neutrophils have an important role in the host defense. The elevated serum glucose levels of diabetics affect traditional host defenses such as neutrophil counts and functions. The causes of these impairments are not clear. We aimed to investigate changes of peripheral neutrophil counts and functions and their relation with bone marrow cells in diabetic rats. Thirty-two rats were divided into four equal groups. Group 1 were controls and Groups 2 and 4 were made diabetic by a single intraperitoneal injection of streptozotocin. Granulocyte colony stimulating factor (G-CSF) was injected subcutaneously into Groups 3 and 4. White blood cell count, neutrophil counts and function and bone marrow cell count were determined. Peripheral blood cell counts, neutrophil phagocytosis index were decreased but neutrophil adhesivity index was not different in the diabetes-induced group. There was a difference in circulating white blood cell counts and neutrophil counts between the rhG-CSF treated and non-treated groups. The phagocytosis index of neutrophil in diabetic rats was significantly diminished by rhG-CSF treatment. A hyperplasia of early cells of the myeloid series in G-CSF treated groups was observed when compared with those of nontreated groups (p<0.001). A significant decrease was noted in the number of mature marrow segmented cells diabetic groups (p<0.001). Finally, G-CSF has been shown to cause neutrophilia by acting as a releasing factor for mature marrow neutrophils in diabetic rats. These results suggest that G-CSF may be used to improve nonspecific immunity in diabetic patients.


Inner dynein arms but not outer dynein arms require the activity of kinesin homologue protein KHP1(FLA10) to reach the distal part of flagella in Chlamydomonas.
Inner dynein arms, but not outer dynein arms, require the activity of KHP1(FLA10) to reach the distal part of axonemes before binding to outer doublet microtubules. We have analyzed the rescue of inner or outer dynein arms in quadriflagellate dikaryons by immunofluorescence microscopy of p28(IDA4), an inner dynein arm light chain, or IC69(ODA6), an outer dynein arm intermediate chain. In dikaryons two strains with different genetic backgrounds share the cytoplasm. As a consequence, wild-type axonemal precursors are transported to and assembled in mutant axonemes to complement the defects. The rescue of inner dynein arms containing p28 in ida4-wild-type dikaryons progressively occurred from the distal part of the axonemes and with time was extended towards the proximal part. In contrast, the rescue of outer dynein arms in oda2-wild-type dikaryons progressively occurred along the entire length of the axoneme. Rescue of inner dynein arms containing p28 in ida4fla10-fla10 dikaryons was similar to the rescue observed in ida4-wild-type dikaryons at 21 degrees C, whereas it was inhibited at 32 degrees C, a nonpermissive temperature for KHP1(FLA10). In contrast, rescue of outer dynein arms in oda2fla10-fla10 dikaryons was similar to the rescue observed in oda2-wild-type dikaryons at both 21 degrees and 32 degrees C and was not inhibited at 32 degrees C. Positioning of substructures in the internal part of the axonemal shaft requires the activity of kinesin homologue protein 1.


Incidence of the beet leafhopper-transmitted virescence agent phytoplasma in local populations of the beet leafhopper, Circulifer tenellus, in Washington State.
Phytoplasma diseases are increasingly becoming important in vegetable crops in the Pacific Northwest. Recently, growers in the Columbia Basin and Yakima Valley experienced serious outbreaks of potato purple top disease that caused significant yield loss and a reduction in tuber processing quality. It was determined that the beet leafhopper-transmitted virescence agent (BLTVA) phytoplasma was the causal agent of the disease in the area and that this pathogen was transmitted by the beet leafhopper, Circulifer tenellus Baker (Hemiptera: Cicadellidae). To provide the most effective management of phytoplasmas, timing of insecticide applications targeted against insects vectoring these pathogens should be correlated with both insect abundance and infectivity. Beet leafhoppers were collected from a potato field and nearby weeds in Washington throughout the 2005, 2006, and 2007 growing seasons and tested for BLTVA by PCR to determine the incidence of this phytoplasma in the insects. In addition, overwintering beet leafhoppers were collected throughout Columbia Basin and Yakima Valley and tested for BLTVA to investigate if these insects might constitute a source of inoculum for this phytoplasma from one season to the next. Results showed that 29.6% of overwintering leafhoppers collected near potato fields carried the phytoplasma. BLTVA-infected leafhoppers were also found in both potatoes and nearby weedy habitats throughout the growing season. PCR testing indicated that a large proportion of beet leafhoppers invading potatoes were infected with the phytoplasma, with an average of 20.8, 34.8, and 9.2% in 2005, 2006, and 2007, respectively. Similarly, BLTVA infection rate in leafhoppers collected from weeds in the vicinity of potatoes averaged 28.3, 24.5, and 5.6% in 2005, 2006, and 2007, respectively. Information from this study will help develop action thresholds for beet leafhopper control to reduce incidence of purple top disease in potatoes.


Immunohistochemical detection and localization of a 72-kilodalton heat shock protein in autoimmune thyroid disease.
Recently described immunological functions for heat shock proteins (HSPs) and our previous demonstration of site-selective HSP-72 expression in cultured fibroblasts derived from extrathyroidal manifestations of Graves' disease (GD) prompted us to determine whether expression of the inducible 72-kilodalton HSP can be detected in human thyroid tissues. Immunohistochemistry was performed on formalin-fixed paraffin-embedded thyroid tissue specimens from patients with GD, Hashimoto's thyroiditis (HD), and multinodular goiter (MNG) as well as on normal thyroid tissue. A mouse monoclonal anti-HSP-72 antibody and an ultrasensitive avidin-biotin-peroxidase complex detection system were used for these studies. Striking differences in HSP-72 immunoreactivity were detected both between tissues from GD and HD compared with MNG and normal thyroid and between GD thyroid glands treated preoperatively with antithyroid medication and untreated GD glands. Strong HSP-72 reactivity in GD and HD tissues was detected in thyroid follicles as well lymphocytic infiltrates. No HSP-72 reactivity was detected in MNG or normal thyroid tissue. HSP-72 immunoreactivity was markedly reduced in GD glands that received preoperative antithyroid drug treatment. In conclusion, high levels of HSP-72 expression in autoimmune thyroid disease may reflect a state of chronic cellular stress, but could also represent an immunomodulatory factor of relevance in the autoimmune process in GD.