Curcumin: a novel treatment for skin-related disorders.
Curcumin, or diferuloylmethane, is a crystalline compound which gives the East Asian spice turmeric its bright yellow color. The medicinal properties of this spice have been referenced in numerous countries and cultures throughout the world. Today, there is growing scientific evidence suggesting curcumin's utility in the treatment of chronic pain, inflammatory dermatoses, acceleration of wound closure, skin infections, as well as cosmetic ailments such as dyspigmentation. In addition, curcumin may have a protective role against various pollutants and cytotoxic agents, indicating that it may be beneficial in a mitigational or prophylaxis role. Although turmeric has been used for thousands of years in alternative medicine, curcumin has yet to emerge as a component of our mainstream dermatologic therapeutic armamentarium. Interestingly, curcumin provides an ideal alternative to current therapies because of its relative safety profile even at high doses. Although the advantageous properties of curcumin in medicine are well established, its therapeutic potential thus far has been limited because of its poor oral bioavailablity. Topical administration of curcumin can directly deliver it to the affected tissue making it useful in treating skin-related disorders. However, limitations still exist such as the cosmetically unpleasing bright yellow-orange color, its poor solubility, and its poor stability at a high pH. Here the current literature detailing the potential and current use of curcumin in dermatology is reviewed.


Effectiveness of professional oral health care intervention on the oral health of residents with dementia in residential aged care facilities: a systematic review protocol.
The objective of this review is to critically appraise and synthesize evidence on the effectiveness of professional oral health care intervention on the oral health of aged care residents with dementia.More specifically the objectives are to identify the efficacy of professional oral health care interventions on general oral health, the presence of plaque and the number of decayed or missing teeth. Dementia poses a significant challenge for health and social policy in Australia. The quality of life of individuals, their families and friends is impacted by dementia. Older people with dementia often have other health comorbidities resulting in the need for a higher level of care. From 2009 to 2010, 53% of permanent residents in Residential Aged Care Facilities (RACFs) had dementia on admission. Older Australians are retaining more of their natural teeth, therefore residents entering RACFs will have more of their natural teeth and require complex dental work than they did in previous generations. Data from the Australian Institute of Health and Welfare showed that more than half the residents in RACFs are now partially dentate with an average of 12 teeth each. Furthermore, coronal and root caries are significant problems, especially in older Australians who are cognitively impaired.Residents in aged care facilities frequently have poor oral health and hygiene with moderate to high levels of oral disease and overall dental neglect. This is reinforced by aged care staff who acknowledge that the demands of feeding, toileting and behavioral issues amongst residents often take precedence over oral health care regimens. Current literature shows that there is a general reluctance on the part of aged care staff to prioritize oral care due to limited knowledge as well as existing psychological barriers to working on another person's mouth. Although staff routinely deal with residents' urinary and faecal incontinence, deep psychological barriers exist when working on someone's mouth due to their own personal values of oral health or their views that residents should be looking after their own teeth or dentures. Furthermore, residents with behavioral issues associated with dementia frequently have their oral hygiene neglected as they may be resistant and violent towards receiving oral care from aged care staff. Studies have shown that residents with dementia will often refuse to open their mouth or partake in oral hygiene care by aged care staff. The aged care staff in return often do not pursue an oral care regimen for these "difficult" residents, perpetuating the cycle of oral neglect and resultant disease.Dental hygienists are qualified oral health professionals who are specifically trained to develop individualized oral health care plans and preventative programs to reduce oral health disease in the community. Residents with dementia in aged care facilities have the right to live their lives comfortably and free of oral discomfort or pain. A Victorian study conducted by Hopcraft et al. investigated the ability of a dental hygienist to undertake a dental examination/screening for residents in aged care facilities, to develop a preventative and periodontal treatment plan and to refer patients appropriately to a dentist. Results from this study demonstrated that there was an excellent agreement between the dentist and dental hygienist regarding the decision to refer residents to a dentist for treatment, demonstrating high sensitivity (99.6%) and high specificity (82.9%). Residents from 31 Victorian RACFs (n=510) were examined by a single experienced dental epidemiologist and one of four dental hygienists using a simple mouth mirror and probe. Hopcraft et al. concluded that hygienists should be utilized more widely in providing holistic oral health care to residents in aged care facilities.Recently, Lewis et al. discussed the need to develop models of care to improve access to dental care for frail and functionally dependent elderly people in aged care facilities, with the model of care involving dental hygienists/oral health therapists having merit.The concept of professional oral care involves an oral health professional such as a dental hygienist or oral health therapist supervising or assisting residents with their oral care. Oral care involves the mechanical removal of plaque and food debris using a toothbrush, interproximal brush and floss.In 2014, Morino et al. explored the efficacy of short term professional oral care from dental hygienists once a week after breakfast for one month. In this study, the dental hygienists did not perform dental scaling but brushed subjects' teeth using a toothbrush and interdental brush. Dental plaque scores decreased significantly (Fisher's two-tailed tests, p<0.05) in the professional oral health intervention group. Interestingly, the positive effects of this short term intervention were sustained for the following three months (Wilcoxon test, p<0.05).A pilot study in Arkansas was conducted by Amerine et al. and utilized the dental hygienist as the "oral health champion" in the residential aged care facility using the Oral Health Assessment Tool (OHAT) and Geriatric Oral Health Assessment Index (GOHAI) scores to measure oral health. The results from this study showed improvements in three measured areas (tongue health, denture status and oral cleanliness) in the dental hygiene champion group. These findings suggest that the presence of a dental hygiene champion in long term care facilities may positively impact the oral health of residents requiring assistance with their oral care. However, the authors noted further research in this concept is required.Van Der Putten GJ et al. explored the effectiveness of a supervised implementation of an oral health care guideline in care homes. In each ward of the care homes, a nurse who acted as the ward oral health care organiser (WOO) was appointed. The dental hygienist and an investigator would attend the RACFs every six weeks to support them. The dental hygienist would train the WOO, and the WOO would train the ward nurses and nurse assistants. Participants were allocated into an intervention or a control group. The intervention group received supervised oral care. Statistically significant differences in mean dental and denture plaque scores at six months in both groups occurred (student t-test, p < 0.0001). This research study implemented an intervention using the train-the-trainer approach and although improvements in dental and denture plaque scores were seen in the six-month period, the long-term effects of this intervention are unknown. Further studies exploring the long-term effects of staff training on oral health education are needed as well as ongoing staff training in aged care facilities.A systematic review on oral health and aspiration pneumonia conducted by Vander Maarel-Wierink et al. has suggested that, in the frail elderly, the best intervention to reduce the incidence of aspiration pneumonia is brushing of teeth after each meal, cleaning dentures once a day, and receiving professional oral health care once a week.The need to advocate for a new model of geriatric dentistry is critical. A holistic multi-disciplinary approach to health care for residents entering aged care homes is imperative to achieve better oral health and comfort for residents, especially with Australia's ageing dentate population. A dental examination and assessment on admission to a RACF should be conducted by a Registered Nurse (RN), followed by an oral health professional such as a dentist, dental hygienist or oral health therapist. Current practice in the majority of Australian government funded nursing homes is that the RN or the Assistant in Nursing (AIN) conduct the oral health assessment as part of the aged care funding instrument (ACFI). Ongoing oral health care supported by an oral health professional is important throughout the individual's residency and eventual palliation whilst in an aged care facility.No systematic reviews conducted on the impact of professional oral care on the oral health of elderly people living in residential aged care facilities could be located, despite extensive searching of Medline, CINAHL, EMBASE, Web of Science, Cochrane Central Register of Trials and Dentistry & Oral Sciences Source (DOSS) databases. A JBI systematic review was conducted in 2004, titled, "Oral hygiene care for adults with dementia in residential aged care facilities"; however, this review examined the prevalence, incidence and increments of oral diseases; the use of assessment tools to evaluate oral health; preventative oral hygiene care strategies; and the provision of dental treatment and so had a different clinical focus. Twenty studies were included for analysis in the review conducted by Weening-Verbree et al, The studies in this review addressed oral health knowledge of aged care staff and mostly were conducted as an educational session delivered by dental hygienists or dentists.Overall, the current evidence available on interventions to improve oral health for residents living in aged care facilities is inadequate and should be explored further.


Arsenic, mode of action at biologically plausible low doses: what are the implications for low dose cancer risk?
Arsenic is an established human carcinogen. However, there has been much controversy about the shape of the arsenic response curve, particularly at low doses. This controversy has been exacerbated by the fact that the mechanism(s) of arsenic carcinogenesis are still unclear and because there are few satisfactory animal models for arsenic-induced carcinogenesis. Recent epidemiological studies have shown that the relative risk for cancer among populations exposed to <or=60 ppb As in their drinking water is often lower than the risk for the unexposed control population. We have found that treatment of human keratinocyte and fibroblast cells with 0.1 to 1 microM arsenite (As(III)) also produces a low dose protective effect against oxidative stress and DNA damage. This response includes increased transcription, protein levels and enzyme activity of several base excision repair genes, including DNA polymerase beta and DNA ligase I. At higher concentrations (> 10 microM), As induces down-regulation of DNA repair, oxidative DNA damage and apoptosis. This low dose adaptive (protective) response by a toxic agent is known as hormesis and is characteristic of many agents that induce oxidative stress. A mechanistic model for arsenic carcinogenesis based on these data would predict that the low dose risk for carcinogenesis should be sub-linear. The threshold dose where toxicity outweighs protection is hard to predict based on in vitro dose response data, but might be estimated if one could determine the form (metabolite) and concentration of arsenic responsible for changes in gene regulation in the target tissues.


Postmortem observations on rumen wall histology and gene expression and ruminal and caecal content of beef cattle fattened on barley-based rations.
Sub-acute ruminal acidosis (SARA) can reduce the production efficiency and impair the welfare of cattle, potentially in all production systems. The aim of this study was to characterise measurable postmortem observations from divergently managed intensive beef finishing farms with high rates of concentrate feeding. At the time of slaughter, we obtained samples from 19 to 20 animals on each of 6 beef finishing units (119 animals in total) with diverse feeding practices, which had been subjectively classified as being high risk (three farms) or low risk (three farms) for SARA on the basis of the proportions of barley, silage and straw in the ration. We measured the concentrations of histamine, lipopolysaccharide (LPS), lactate and other short-chain fatty acids (SCFAs) in ruminal fluid, LPS and SCFA in caecal fluid. We also took samples of the ventral blind sac of the rumen for histopathology, immunohistopathology and gene expression. Subjective assessments were made of the presence of lesions on the ruminal wall, the colour of the lining of the ruminal wall and the shape of the ruminal papillae. Almost all variables differed significantly and substantially among farms. Very few pathological changes were detected in any of the rumens examined. The animals on the high-risk diets had lower concentrations of SCFA and higher concentrations of lactate and LPS in the ruminal fluid. Higher LPS concentrations were found in the caecum than the rumen but were not related to the risk status of the farm. The diameters of the stratum granulosum, stratum corneum and of the vasculature of the papillae, and the expression of the gene TLR4 in the ruminal epithelium were all increased on the high-risk farms. The expression of IFN-γ and IL-1β and the counts of cluster of differentiation 3 positive and major histocompatibility complex class two positive cells were lower on the high-risk farms. High among-farm variation and the unbalanced design inherent in this type of study in the field prevented confident assignment of variation in the dependent variables to individual dietary components; however, the CP percentage of the total mixed ration DM was the factor that was most consistently associated with the variables of interest. Despite the strong effect of farm on the measured variables, there was wide inter-animal variation.


Acrolein exposure is associated with increased cardiovascular disease risk.
Acrolein is a reactive aldehyde present in high amounts in coal, wood, paper, and tobacco smoke. It is also generated endogenously by lipid peroxidation and the oxidation of amino acids by myeloperoxidase. In animals, acrolein exposure is associated with the suppression of circulating progenitor cells and increases in thrombosis and atherogenesis. The purpose of this study was to determine whether acrolein exposure in humans is also associated with increased cardiovascular disease (CVD) risk. Acrolein exposure was assessed in 211 participants of the Louisville Healthy Heart Study with moderate to high (CVD) risk by measuring the urinary levels of the major acrolein metabolite-3-hydroxypropylmercapturic acid (3-HPMA). Generalized linear models were used to assess the association between acrolein exposure and parameters of CVD risk, and adjusted for potential demographic confounders. Urinary 3-HPMA levels were higher in smokers than nonsmokers and were positively correlated with urinary cotinine levels. Urinary 3-HPMA levels were inversely related to levels of both early (AC133(+)) and late (AC133(-)) circulating angiogenic cells. In smokers as well as nonsmokers, 3-HPMA levels were positively associated with both increased levels of platelet-leukocyte aggregates and the Framingham Risk Score. No association was observed between 3-HPMA and plasma fibrinogen. Levels of C-reactive protein were associated with 3-HPMA levels in nonsmokers only. Regardless of its source, acrolein exposure is associated with platelet activation and suppression of circulating angiogenic cell levels, as well as increased CVD risk.


Self-assembled trityl radical capsules--implications for dynamic nuclear polarization.
A new class of guest-induced, bi-radical self-assembled organic capsules is reported. They are formed by the inclusion of a tetramethylammonium (TMA) cation between two monomers of the stable trityl radical OX63. OX63 is extensively used in dissolution dynamic nuclear polarization (DNP) where it leads to NMR sensitivity enhancements of several orders of magnitude. The supramolecular properties of OX63 have a strong impact on its DNP properties. An especially relevant case is the polarization of choline-containing metabolites, where complex formation between choline and OX63 results in faster relaxation.


Imidazolium-based catenane host for bromide recognition in aqueous media.
The synthesis of a novel catenated system which is dense in cationic hydrogen bonding imidazolium units is described. The interlocked host system displays a preference for binding of bromide over other halides, overcoming basicity and Hofmeister trends, under aqueous conditions. This is the first example of an imidazolium-based catenane acting as an anion host through C-H hydrogen bonding.


Does the "office nurse" level of training matter in the family medicine office?
The "office nurse" or clinical associate (registered nurse [RN], licensed practical nurse[LPN], or medical assistant [MA]) is a key member of the family medicine care team, but little is known about the influence of their level of training on team performance. The performance of the clinical dyad (clinician and associate) was studied in relation to the level of training of the nurse. The dyad's performance was measured by the performance indicators of diabetes scores, patient satisfaction, and productivity. Dyads with a RN scored higher in meeting all 5 of the diabetes quality indicators (27.8%) than those with a LPN (19.3%) or an MA (14.7%). For patient satisfaction, the RN dyads also scored higher than the other dyad groups (positive responses: RN, 96.8%; LPN, 95.5%; MA, 94.6%). Productivity was the same in all groups. Better diabetes performance was seen in those practices with fewer competing demands: nonrural versus rural (22.2% vs 15.1%, respectively), and those not doing obstetrics versus those doing obstetrics (20.3% vs 15.1%, respectively), and for physicians versus associate providers (18.8% vs 15.1%, respectively). Higher patient satisfaction was observed in those dyads who were nonrural verus rural (96.6 vs 94.1%), among those doing obstetrics (96.0% vs 94.9%), and in physicians verus associate providers (95.7% vs 93.2%). The number of years working with the same clinician was twice as high for RNs (6.63) and LPNs (6.57) than for MAs (3.29). A higher level of education of the clinical associate seems to confer skills that enhance the care team's management of chronic illness such as diabetes. This could potentially decrease the practice burden on other team members while facilitating the team's objectives in meeting quality indicators.


A selective trade-off for territoriality and non-territoriality in the polymorphic damselfly Mnais costalis.
Males of the damselfly Mnais costalis occur as territorial orange-winged 'fighter' males or non-territorial clear-winged 'sneaker' males. Their morph life histories differ considerably but the estimated lifetime reproductive success is the same for the two morphs. In this study we compared the developmental and reproductive costs associated with the two morphs. Orange-winged male and female reproductive costs resulted in a decline in adult fat reserves with increasing age. In contrast, the fat reserves of clear-winged males remained constant with adult age. Body size was positively correlated with mating success in orange-winged males, but had no influence on the mating success of clear-winged males. The orange-winged male flight muscle ratios (FMRs) were significantly higher than the clear-winged male and female FMRs. However, there was no difference in the size-corrected fat reserves of the two morphs; both had higher fat reserves than females. The gain in mass between eclosion and reproduction in orange-winged males and females was almost double the mass gained by clear-winged males, suggesting that clear-winged male development is less costly. An experiment in which pre-reproductive levels of nutrition were manipulated confirmed this.


Hb H hydrops fetalis syndrome associated with the interaction of two common determinants of alpha thalassaemia (--MED/(alpha)TSaudi(alpha)).
To date, more than 35 single or oligonucleotide mutations of the alpha genes that cause alpha thalassaemia have been described. Their interactions give rise to widely variable clinical manifestations, from a mild hypochromic, microcytic anaemia to a lethal intrauterine anaemia associated with hydrops fetalis. Understanding the molecular genetics enables accurate genotyping, genetic counselling and prenatal testing for the most severe forms of alpha thalassaemia. Here we show for the first time that the interaction between two relatively common forms of alpha thalassaemia (--MED/(alpha)TSaudi(alpha)) may be associated with a clinically severe form of alpha thalassaemia, Hb H hydrops fetalis.


Chronic back pain in patients with rheumatoid arthritis and in a control population: prevalence and disability--a 5-year follow-up.
To determine the prevalence of chronic back pain and its changes over 5 years in patients with RA compared with community controls and to evaluate the influence of chronic back pain in functional capacity, general pain and global health. The prevalence of chronic back pain in 1076 patients with RA and in 1491 community controls was evaluated using a mailed questionnaire, which also queried the functional capacity on the HAQ, and general pain and global health on visual analogue scales. Chronic back pain was more frequent in the general population than in patients with RA: 19% of patients with RA and 25% of controls reported chronic back pain (P < 0.001). After 5 years, 57% of these patients initally reporting pain and 58% of controls still reported chronic back pain. In community controls with and without chronic back pain, the median HAQ, general pain and global health were 0.13 vs 0.00, 28 vs 6 and 28 vs 11, respectively (P < 0.001). The figures were 0.88 vs 0.63 (P = 0.05), 42 vs 26 and 42 vs 30 (P < 0.001), respectively, in patients with RA. All analyses were adjusted for age and sex. Chronic back pain does not occur more frequently in patients with RA than in the general population. Almost 60% of patients and controls who reported chronic back pain still reported it 5 years later. In patients with RA and in the control population, subjects with chronic back pain had worse functional capacity, general pain and global health.


International comparative evaluation of knee replacement with fixed or mobile non-posterior-stabilized implants.
Mobile-bearing total knee prostheses were designed to reduce wear and improve implant survivorship following total knee arthroplasty. However, the benefit of mobile-bearing total knee arthroplasty remains unproven. Both mobile-bearing and fixed-bearing total knee arthroplasty implants are available in posterior-stabilized and non-posterior-stabilized designs. With the latter, the implant does not recreate the function of the posterior cruciate ligament (PCL) with a posterior-stabilizing cam mechanism. The purpose of the present study was to compare mobile-bearing, non-posterior-stabilized devices with fixed-bearing, non-posterior-stabilized devices used in total knee arthroplasty through a novel multinational study design. Through the use of a distributed health data network, primary total knee arthroplasties performed for osteoarthritis from 2001 to 2010 were identified from six national and regional total joint arthroplasty registries. Multivariate meta-analysis was performed with use of linear mixed models, with the primary outcome of interest being revision for any reason. Survival probabilities and their standard errors were extracted from each registry for each unique combination of the covariates. A total of 319,616 patients (60% female) underwent non-posterior-stabilized total knee arthroplasty. A fixed-bearing, non-posterior-stabilized design was used in 258,190 (81%) of the knees and a mobile-bearing, non-posterior-stabilized design in 61,426 (19%) of the knees. Sixty-nine percent of the patients who received a fixed-bearing implant were over sixty-five years of age, compared with 63% of those who received a mobile-bearing implant. Mobile-bearing designs had a higher risk of revision, with a hazard ratio of 1.43 (95% confidence interval, 1.36 to 1.51; p < 0.001). Previous comparisons of mobile-bearing and fixed-bearing total knee arthroplasty outcomes have been inconclusive. The current study utilized an advanced, harmonized distributed analysis of six national and regional joint-replacement registries. To our knowledge, it is the largest analysis of mobile-bearing total knee arthroplasty to date. Mobile-bearing, non-posterior-stabilized designs presented a greater risk of failure than was found for fixed-bearing, non-posterior-stabilized designs. Caution should be used in the selection of the mobile-bearing non-posterior-stabilized design for total knee replacement.


Regulation of inorganic phosphate transport systems in Saccharomyces cerevisiae.
A kinetic study of Pi transport with 32Pi revealed that Saccharomyces cerevisiae has two systems of Pi transport, one with a low Km value (8.2 microM) for external Pi and the other with a high Km value (770 microM). The low-Km system was derepressed by Pi starvation, and the activity was expressed under the control of a genetic system which regulates the repressible acid and alkaline phosphatases. The function of the PHO2 gene, which is essential for the derepression of repressible acid phosphatase but not for the derepression of repressible alkaline phosphatase, was also indispensable for the derepression of the low-Km system.


The implications of trade liberalization for diet and health: a case study from Central America.
Central America has undergone extensive trade liberalization over the past two decades, and has recently signed a Free Trade Agreement with the United States. The region is also experiencing a dual burden of malnutrition with the growth of dietary patterns associated with the global 'nutrition transition'. This study describes the relationship between trade liberalization policies and food imports and availability, and draws implications for diet and health, using Central America as a case study region. Changes in tariff and non-tariff barriers for each country were documented, and compared with time-series graphs of import, production and availability data to show the outcome of changes in trade policy in relation to food imports and food availability. Changes in trade policy in Central America have directly affected food imports and availability via three avenues. First, the lowering of trade barriers has promoted availability by facilitating higher imports of a wide range of foods. Second, trade liberalization has affected food availability through promoting domestic meat production. Third, reductions in barriers to investment appear to be critical in expansion of processed food markets. This suggests that changes in trade policies have facilitated rising availability and consumption of meat, dairy products, processed foods and temperate (imported fruits) in Central America. This study indicates that the policies of trade liberalization in Central American countries over the past two decades, particularly in relation to the United States, have implications for health in the region. Specifically, they have been a factor in facilitating the "nutrition transition", which is associated with rising rates of obesity and chronic diseases such as cardiovascular disease and cancer. Given the significant cost of chronic disease for the health care system, individuals and the wider community, it is critical that preventive health measures address such upstream determinants of poor nutrition.


Rationale for the coadministration of albendazole and ivermectin to humans for malaria parasite transmission control.
Recently there have been calls for the eradication of malaria and the elimination of soil-transmitted helminths (STHs). Malaria and STHs overlap in distribution, and STH infections are associated with increased risk for malaria. Indeed, there is evidence that suggests that STH infection may facilitate malaria transmission. Malaria and STH coinfection may exacerbate anemia, especially in pregnant women, leading to worsened child development and more adverse pregnancy outcomes than these diseases would cause on their own. Ivermectin mass drug administration (MDA) to humans for malaria parasite transmission suppression is being investigated as a potential malaria elimination tool. Adding albendazole to ivermectin MDAs would maximize effects against STHs. A proactive, integrated control platform that targets malaria and STHs would be extremely cost-effective and simultaneously reduce human suffering caused by multiple diseases. This paper outlines the benefits of adding albendazole to ivermectin MDAs for malaria parasite transmission suppression.


NTP Toxicology and Carcinogenesis Studies of Ethylene Oxide (CAS No. 75-21-8) in B6C3F1 Mice (Inhalation Studies).
Ethylene oxide is a major industrial chemical used primarily as an intermediate in the manufacture of other chemicals; e.g., ethylene glycol, a major component of automotive and other antifreeze products. Exposure to ethylene oxide is greatest in the health care industry, where an estimated 75,000 workers are potentially exposed. Ethylene oxide was nominated for toxicology and carcinogenesis studies in B6C3F1 mice because of its extensive production; the potential for human exposure in the workplace, from medical devices, or from food; the positive results of genetic toxicology assays; and the previous use of only F344/N rats in inhalation carcinogenicity studies. Two inhalation studies reported in 1984 by Snellings et al. and by Lynch et al. demonstrated carcinogenic responses in F344/N rats. Results were similar in both studies and consisted of increased incidences of mononuclear cell leukemia, peritoneal mesotheliomas, and primary brain tumors. Experimental Design: Toxicology and carcinogenesis studies of ethylene oxide (greater than 99% pure) were conducted by exposing groups of 50 B6C3F1 mice of each sex to air containing 0, 50, or 100 ppm ethylene oxide, 6 hours per day, 5 days per week for 102 weeks. These doses were selected because, in 14-week studies, all mice exposed at 600 ppm died within 1 week, and all mice exposed at 400 ppm died by week 4. Rhinitis was observed in both sexes exposed at 200, 400, and 600 ppm as was renal tubular degeneration in both sexes at 100, 200, and 400 ppm. The latter effects observed at 100 ppm were slight and deemed not to be life threatening in 2-year studies. Two-Year Studies: Survival of exposed and control mice was comparable in the 2-year studies (male: control, 28/50; low dose, 31/50; high dose, 34/50; female: 25/50; 24/50;31/50). Final mean body weights in exposed mice were 95%-102% of those of the controls. No compound-related clinical signs were observed. Those neoplastic lesions that occurred at elevated incidences in mice exposed to ethylene oxide are reported in the following table (see page 6 of the Technical Report). In male mice, alveolar/bronchiolar carcinomas, alveolar/bronchiolar adenomas, and papillary cystadenomas of the harderian gland occurred with positive trends. In female mice, alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, papillary cystadenomas of the harderian gland, malignant lymphomas, and uterine adenocarcinomas occurred with positive trends. Mammary gland tumors also were increased in exposed female mice. Data Audit: An audit of the experimental data was conducted for the 2-year studies of ethylene oxide. No data discrepancies were found that influenced the final interpretations. Conclusions: Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activity for B6C3F1 mice as indicated by dose-related increased incidences of benign or malignant neoplasms of the lung and benign neoplasms of the harderian gland in both male and female B6C3F1 mice following exposure to ethylene oxide vapors at 50 and 100 ppm. In female mice, ethylene oxide caused additional malignant neoplasms of the uterus, mammary gland, and hematopoietic system (lymphoma). Synonyms: oxirane; EO; ETO; dihydrooxirene; dimethylene oxide; 1,2-epoxyethane; oxane; a,beta-oxidoethane


Thrombotic thrombocytopenic purpura and autoimmunity: a tale of shadows and suspects.
The key pathogenic feature of TTP is the formation of platelet aggregates within the microcirculation; however, the etiology of such aggregates has been elusive for years. A large amount of evidence points to an abnormal interaction between damaged vascular endothelium and platelets, although the cause of the primary microvascular endothelial cell injury is seldom clear. The autoimmune hypothesis often recurs, and this is based on a number of observations: the claimed superiority of plasma-exchange over plasma infusion, the anecdotal report of the presence of immunocomplexes and autoantibodies in TTP patients, the efficacy of the administration of corticosteroids and other immunosuppressant agents, and the concomitant occurrence of TTP in association with autoimmune diseases, especially systemic lupus erythematosus (SLE). This review will focus on the complex relationships between TTP and humoral autoimmunity; in particular, similarities and differences between TTP, SLE and antiphospholipid (aPL) antibodies syndrome, as well as the putative role of several other antibodies directed towards endothelial cells and/or platelets, including the recently discovered anti-CD36 antibodies and antivWF-cleaving metalloprotease, will be discussed. The authors have been involved in the study and treatment of TTP and autoimmune diseases for years; furthermore, the PubMed data base of the National Library of Congress has been extensively searched using the Internet. Although over the years evidence has increased in favor of the autoimmune hypothesis for TTP etiopathogenesis, TTP should not yet be considered an autoimmune disease. Autoantibodies should be regarded as only one of the many different insults which can trigger microvascular thrombosis even though the autoimmune theory of the pathogenesis of TTP is gaining more and more strength. As far as concerns the relationship between TTP, SLE and aPL antibodies-related disorders, these diseases should be distinguished on the basis of both different clinical presentations and accurate antibody screening, although this approach should definitely not delay the prompt start of treatment.


Distamycin A inhibits HMGA1-binding to the P-selectin promoter and attenuates lung and liver inflammation during murine endotoxemia.
The architectural transcription factor High Mobility Group-A1 (HMGA1) binds to the minor groove of AT-rich DNA and forms transcription factor complexes ("enhanceosomes") that upregulate expression of select genes within the inflammatory cascade during critical illness syndromes such as acute lung injury (ALI). AT-rich regions of DNA surround transcription factor binding sites in genes critical for the inflammatory response. Minor groove binding drugs (MGBs), such as Distamycin A (Dist A), interfere with AT-rich region DNA binding in a sequence and conformation-specific manner, and HMGA1 is one of the few transcription factors whose binding is inhibited by MGBs. To determine whether MGBs exert beneficial effects during endotoxemia through attenuating tissue inflammation via interfering with HMGA1-DNA binding and modulating expression of adhesion molecules. Administration of Dist A significantly decreased lung and liver inflammation during murine endotoxemia. In intravital microscopy studies, Dist A attenuated neutrophil-endothelial interactions in vivo following an inflammatory stimulus. Endotoxin induction of P-selectin expression in lung and liver tissue and promoter activity in endothelial cells was significantly reduced by Dist A, while E-selectin induction was not significantly affected. Moreover, Dist A disrupted formation of an inducible complex containing NF-kappaB that binds an AT-rich region of the P-selectin promoter. Transfection studies demonstrated a critical role for HMGA1 in facilitating cytokine and NF-kappaB induction of P-selectin promoter activity, and Dist A inhibited binding of HMGA1 to this AT-rich region of the P-selectin promoter in vivo. We describe a novel targeted approach in modulating lung and liver inflammation in vivo during murine endotoxemia through decreasing binding of HMGA1 to a distinct AT-rich region of the P-selectin promoter. These studies highlight the ability of MGBs to function as molecular tools for dissecting transcriptional mechanisms in vivo and suggest alternative treatment approaches for critical illness.


Rural-Urban Disparities in Time to Diagnosis and Treatment for Colorectal and Breast Cancer.
Background: Longer cancer pathways may contribute to rural-urban survival disparities, but research in this area is lacking. We investigated time to diagnosis and treatment for rural and urban patients with colorectal or breast cancer in Victoria, Australia.Methods: Population-based surveys (2013-2014) of patients (aged ≥40, approached within 6 months of diagnosis), primary care physicians (PCPs), and specialists were collected as part of the International Cancer Benchmarking Partnership, Module 4. Six intervals were examined: patient (symptom to presentation), primary care (presentation to referral), diagnostic (presentation/screening to diagnosis), treatment (diagnosis to treatment), health system (presentation to treatment), and total interval (symptom/screening to treatment). Rural and urban intervals were compared using quantile regression including age, sex, insurance, and socioeconomic status.Results: 433 colorectal (48% rural) and 489 breast (42% rural) patients, 621 PCPs, and 370 specialists participated. Compared with urban patients, patients with symptomatic colorectal cancer from rural areas had significantly longer total intervals at the 50th [18 days longer, 95% confidence interval (CI): 9-27], 75th (53, 95% CI: 47-59), and 90th percentiles (44, 95% CI: 40-48). These patients also had longer diagnostic and health system intervals (6-85 days longer). Breast cancer intervals were similar by area of residence, except the patient interval, which was shorter for rural patients with either cancer in the higher percentiles.Conclusions: Rural residence was associated with longer total intervals for colorectal but not breast cancer; with most disparities postpresentation.Impact: Interventions targeting time from presentation to diagnosis may help reduce colorectal cancer rural-urban disparities. Cancer Epidemiol Biomarkers Prev; 27(9); 1036-46. ©2018 AACR.


Connect 4: A Novel Paradigm to Elicit Positive and Negative Insight and Search Problem Solving.
Researchers have typically defined insight as a sudden new idea or understanding accompanied by an emotional feeling of Aha. Recently, examples of negative insight in everyday creative problem solving have been identified. These are seen as sudden and sickening moments of realization experienced as an Uh-oh rather than Aha. However, such experiences have yet to be explored from an experimental perspective. One barrier to doing so is that methods to elicit insight in the laboratory are constrained to positive insight. This study therefore aimed to develop a novel methodology that elicits both positive and negative insight solving, and additionally provides the contrasting experiences of analytic search solving in the same controlled conditions. The game of Connect 4 was identified as having the potential to produce these experiences, with each move representing a solving episode (where best to place the counter). Eighty participants played six games of Connect 4 against a computer and reported each move as being a product of positive search, positive insight, negative search or negative insight. Phenomenological ratings were then collected to provide validation of the experiences elicited. The results demonstrated that playing Connect 4 saw reporting of insight and search experiences that were both positive and negative, with the majority of participants using all four solving types. Phenomenological ratings suggest that these reported experiences were comparable to those elicited by existing laboratory methods focused on positive insight. This establishes the potential for Connect 4 to be used in future problem solving research as a reliable elicitation tool of insight and search experiences for both positive and negative solving. Furthermore, Connect 4 may be seen to offer more true to life solving experiences than other paradigms where a series of problems are solved working toward an overall superordinate goal rather than the presentation of stand-alone and un-related problems. Future work will need to look to develop versions of Connect 4 with greater control in order to fully utilize this methodology for creative problem solving research in experimental psychology and neuroscience contexts.


Resolving the Burden of Low Back Pain in Military Service Members and Veterans (RESOLVE): Protocol for a Multisite Pragmatic Clinical Trial.
Physical therapy (PT) is frequently used for the management of low back pain (LBP) within the US Departments of Defense (DOD) and Veterans Affairs (VA). However, variations in PT practice patterns and use of ineffective interventions lower the quality and increase the cost of care. Although adherence to the clinical practice guidelines (CPGs) can improve the outcomes and cost-effectiveness of LBP care, PT CPG adherence remains below 50%. The Resolving the Burden of Low Back Pain in Military Service Members and Veterans (RESOLVE) trial will evaluate the effectiveness of an active PT CPG implementation strategy using an education, audit, and feedback model for reducing pain, disability, medication use, and cost of LBP care within the DOD and VA health care systems. The RESOLVE trial will include 3,300 to 7,260 patients with LBP across three DOD and two VA medical facilities using a stepped-wedge study design. An education, audit, and feedback model will be used to encourage physical therapists to better adhere to the PT CPG recommendations. The Oswestry Disability Index and the Defense and Veterans Pain Rating Scale will be used as primary outcomes. Secondary outcomes will include the LBP-related medication use, medical resource utilization, and biopsychosocial predictors of outcomes. Statistical analyses will be based on the intention-to-treat principle and will use linear mixed models to compare treatment conditions and examine the interactions between treatment and subgrouping status (e.g., limb loss). The RESOLVE trial will provide a pragmatic approach to evaluate whether better adherence to PT CPGs can reduce pain, disability, medication use, and LBP care cost within the DOD and VA health care systems.


A Comparative Study of Receptor-Targeted Magnetosome and HSA-Coated Iron Oxide Nanoparticles as MRI Contrast-Enhancing Agent in Animal Cancer Model.
Magnetosomes are specialized organelles arranged in intracellular chains in magnetotactic bacteria. The superparamagnetic property of these magnetite crystals provides potential applications as contrast-enhancing agents for magnetic resonance imaging. In this study, we compared two different nanoparticles that are bacterial magnetosome and HSA-coated iron oxide nanoparticles for targeting breast cancer. Both magnetosomes and HSA-coated iron oxide nanoparticles were chemically conjugated to fluorescent-labeled anti-EGFR antibodies. Antibody-conjugated nanoparticles were able to bind the MDA-MB-231 cell line, as assessed by flow cytometry. To compare the cytotoxic effect of nanoparticles, MTT assay was used, and according to the results, HSA-coated iron oxide nanoparticles were less cytotoxic to breast cancer cells than magnetosomes. Magnetosomes were bound with higher rate to breast cancer cells than HSA-coated iron oxide nanoparticles. While 250 μg/ml of magnetosomes was bound 92 ± 0.2%, 250 μg/ml of HSA-coated iron oxide nanoparticles was bound with a rate of 65 ± 5%. In vivo efficiencies of these nanoparticles on breast cancer generated in nude mice were assessed by MRI imaging. Anti-EGFR-modified nanoparticles provide higher resolution images than unmodified nanoparticles. Also, magnetosome with anti-EGFR produced darker image of the tumor tissue in T2-weighted MRI than HSA-coated iron oxide nanoparticles with anti-EGFR. In vivo MR imaging in a mouse breast cancer model shows effective intratumoral distribution of both nanoparticles in the tumor tissue. However, magnetosome demonstrated higher distribution than HSA-coated iron oxide nanoparticles according to fluorescence microscopy evaluation. According to the results of in vitro and in vivo study results, magnetosomes are promising for targeting and therapy applications of the breast cancer cells.


Clinical practice of acute pancreatitis in Japan: An analysis of nationwide epidemiological survey in 2016.
To provide updates on clinical practice of acute pancreatitis (AP) in Japan, we conducted a nationwide epidemiological survey. This study consisted of a two-staged survey; the number of AP patients was estimated by the first-stage survey and their clinical features were examined by the second-stage survey. We surveyed AP patients who had visited hospitals in 2016. The estimated number of AP patients in 2016 was 78,450, with an overall incidence of 61.8 per 100,000 persons. We obtained detailed clinical information of 2994 AP patients, including 706 (23.6%) severe cases classified according to the Japanese severity criteria. The male-to-female sex ratio was 2.0, and the mean age at onset was 59.9 years in males and 66.5 years in females. Alcohol was the most common etiology (42.8%) in males and gallstones in females (37.7%). The AP-associated mortality was 6.1% in severe AP cases, which was decreased by 40% compared to the 2011 survey. Antibiotics were administered to most cases, with carbapenem being frequently used. Enteral nutrition was given in 31.8% of severe cases, but majority cases received after 48 h. Among the 107 patients who received intervention for walled-off necrosis, five patients received surgery-first approach, 66 received endoscopic ultrasound-guided transluminal drainage, and 19 underwent step-up approach. We clarified the current status of AP in Japan including the significant reduction of mortality in severe cases, shift to endoscopic approaches for walled-off necrosis, and poor compliance of the recommendations in the guidelines including management of enteral nutrition and antibiotic administration.


Cdc53p acts in concert with Cdc4p and Cdc34p to control the G1-to-S-phase transition and identifies a conserved family of proteins.
Regulation of cell cycle progression occurs in part through the targeted degradation of both activating and inhibitory subunits of the cyclin-dependent kinases. During G1, CDC4, encoding a WD-40 repeat protein, and CDC34, encoding a ubiquitin-conjugating enzyme, are involved in the destruction of these regulators. Here we describe evidence indicating that CDC53 also is involved in this process. Mutations in CDC53 cause a phenotype indistinguishable from those of cdc4 and cdc34 mutations, numerous genetic interactions are seen between these genes, and the encoded proteins are found physically associated in vivo. Cdc53p defines a large family of proteins found in yeasts, nematodes, and humans whose molecular functions are uncharacterized. These results suggest a role for this family of proteins in regulating cell cycle proliferation through protein degradation.


Physical activity, sedentary behavior, and endometrial cancer risk in the NIH-AARP Diet and Health Study.
Consistent with a strong hormonal etiology, endometrial cancer is thought to be influenced by both obesity and physical activity. Although obesity has been consistently related to risk, associations with physical activity have been inconclusive. We examined relationships of activity patterns with endometrial cancer incidence in the NIH-AARP Diet and Health Study cohort, which included 109,621 women, ages 50-71, without cancer history, who in 1995-1996 completed a mailed baseline questionnaire capturing daily routine and vigorous (defined as any period of >or=20 min of activity at work or home causing increases in breathing, heart rate, or sweating) physical activity. A second questionnaire, completed by 70,351 women, in 1996-1997 collected additional physical activity information. State cancer registry linkage identified 1,052 primary incident endometrial cancers from baseline through December 31, 2003. In multivariate proportional hazards models, vigorous activity was inversely associated with endometrial cancer in a dose-response manner (p for trend = 0.02) (relative risk (RR) for >or=5 times/week vs. never/rarely = 0.77, 95% confidence interval (CI): 0.63-0.95); this association was more pronounced among overweight and obese women (body mass index >or=25; RR = 0.61, 95% CI: 0.47-0.79) than among lean women (body mass index <25; RR = 0.76, 95% CI: 0.52-1.10; p for interaction = 0.12). Although we observed no associations with light/moderate, daily routine or occupational physical activities, risk did increase with number of hours of daily sitting (p for trend = 0.02). Associations with vigorous activities, which may interact with body mass index, suggest directions for future research to clarify underlying biologic mechanisms, including those relating to hormonal alterations.


Interleukin-2 as an adjunct to antiretroviral therapy for HIV-positive adults.
Human immunodeficiency virus (HIV) continues to be a leading cause of morbidity and mortality, particularly in sub-Saharan Africa. Although antiretroviral drugs have helped to improve the quality of life and life expectancy of HIV-positive individuals, there is still a need to explore other interventions that will help to further reduce the disease burden. One potential strategy is the use of interleukin-2 (IL-2) in combination with antiretroviral therapy (ART). IL-2 is a cytokine that regulates the proliferation and differentiation of lymphocytes and may help to boost the immune system. To assess the effects of interleukin-2 (IL-2) as an adjunct to antiretroviral therapy for HIV-positive adults. We searched the following sources up to 26 May 2016: the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; Embase; the Web of Science; LILACS; the World Health Organization (WHO) International Clinical Trial Registry Platform (ICTRP); and ClinicalTrials.gov. We also checked conference abstracts, contacted experts and relevant organizations in the field, and checked the reference list of all studies identified by the above methods for any other potentially eligible studies. Randomized controlled trials (RCTs) that evaluated the effects of IL-2 as an adjunct to ART in reducing the morbidity and mortality in HIV-positive adults. Two review authors independently screened records and selected trials that met the inclusion criteria, extracted data, and assessed the risk of bias in the included trials. Where possible, we compared the effects of interventions using risk ratios (RR), and presented them with 95% confidence intervals (CI). We assessed the overall certainty of the evidence using the GRADE approach. Following a comprehensive literature search up to 26 May 2016, we identified 25 eligible trials. The interventions involved the use of IL-2 in combination with ART compared with ART alone. There was no difference in mortality apparent between the IL-2 group and the ART alone group (RR 0.97, 95% CI 0.80 to 1.17; 6 trials, 6565 participants, high certainty evidence). Seventeen of 21 trials reported an increase in the CD4 cell count with the use of IL-2 compared to control using different measures (21 trials, 7600 participants). Overall, there was little or no difference in the proportion of participants with a viral load of less than 50 cells/mL or less than 500 cells/mL by the end of the trials (RR 0.97, 95% CI 0.81 to 1.15; 5 trials, 805 participants, high certainty evidence) and (RR 0.96, 95% CI 0.82 to 1.12; 4 trials, 5929 participants, high certainty evidence) respectively. Overall there may be little or no difference in the occurrence of opportunistic infections (RR 0.79, 95% CI 0.55 to 1.13; 7 trials, 6141 participants, low certainty evidence). There was probably an increase in grade 3 or 4 adverse events (RR 1.47, 95% CI 1.10 to 1.96; 6 trials, 6291 participants, moderate certainty evidence). None of the included trials reported adherence. There is high certainty evidence that IL-2 in combination with ART increases the CD4 cell count in HIV-positive adults. However, IL-2 does not confer any significant benefit in mortality, there is probably no difference in the incidence of opportunistic infections, and there is probably an increase in grade 3 or 4 adverse effects. Our findings do not support the use of IL-2 as an adjunct to ART in HIV-positive adults. Based on our findings, further trials are not justified.


Trajectory-Based Classification of Recovery in Sensorimotor Complete Traumatic Cervical Spinal Cord Injury.
To test the hypothesis that sensorimotor complete traumatic cervical spinal cord injury is a heterogenous clinical entity comprising several subpopulations that follow fundamentally different trajectories of neurologic recovery. We analyzed demographic and injury data from 655 patients who were pooled from 4 prospective longitudinal multicenter studies. Group based trajectory modeling was applied to model neurologic recovery trajectories over the initial 12-months postinjury and to identify predictors of recovery trajectories. Neurologic outcomes included: Upper Extremity Motor Score, Total Motor Scores and AIS grade improvement. The analysis identified 3 distinct trajectories of neurologic recovery. These clinical courses included: (1) Marginal recovery trajectory: characterized by minimal or no improvement in motor strength or change in AIS grade status (remained grade A); (2) Moderate recovery trajectory: characterized by low baseline motor scores that improved approximately 13 points; or AIS conversion of one grade point; (3) Good recovery trajectory: characterized by baseline motor scores in the upper quartile that improved to near maximum values within 3 months of injury. Patients following the moderate or good recovery trajectories were of younger age, had more caudally located injuries, a higher degree of preserved motor and sensory function at baseline examination and exhibited a greater extent of motor and sensory function in the zone of partial preservation. Cervical complete SCI can be classified into one of 3 distinct subpopulations with fundamentally different trajectories of neurologic recovery. This study defines unique clinical phenotypes based on potential for recovery, rather than baseline severity of injury alone. This approach may prove beneficial in clinical prognostication and in the design and interpretation of clinical trials in SCI.


Human factors and the safety of surgical and anaesthetic care.
Safety of patients in the operating theatre relies on a cordial and efficient working relationship between all members of the theatre team. A team that communicates well, defines the roles of its members and is aware of their limitations will provide safe patient care. In this review, we will examine how human factors engineering - the science of how to design processes, equipment and environments to optimise the human contributions to performance - can be used to improve safety and efficiency of surgery. Although these are often dismissed as 'common sense', we will explain how these solutions emerge not from healthcare but from diverse disciplines such as psychology, design and engineering.


Mode of inhibition of short-patch base excision repair by thymine glycol within clustered DNA lesions.
Clustered DNA damage, where two or more lesions are located proximally to each other, is frequently induced by ionizing radiation. Individual base lesions within a cluster are repaired by base excision repair. In this study we addressed the question of how thymine glycol (Tg) within a cluster would affect the repair of opposing lesions by human cell extracts. We have found that Tg located opposite to an abasic site does not affect cleavage of this site by apurinic/apyrimidinic (AP) endonuclease. However, Tg significantly compromised the next step of the repair. Although purified DNA polymerase beta was able to incorporate the correct nucleotide (dAMP) opposite to Tg, the rate of incorporation was reduced by 3-fold. Tg does not affect 5'-sugar phosphate removal by the 2-deoxyribose-5-phosphate (dRP) lyase activity of DNA polymerase beta, but further processing of the strand break by purified DNA ligase III was slightly diminished. In agreement with these findings, although an AP site located opposite to Tg was efficiently incised in human cell extract, only a limited amount of fully repaired product was observed, suggesting that such clustered DNA lesions may have a significantly increased lifetime in human cells compared with similar single-standing lesions.


Co-ordination of base excision repair and genome stability.
Base excision repair (BER) is a major DNA repair pathway employed in mammalian cells that is required to maintain genome stability, thus preventing several human diseases, such as ageing, neurodegenerative diseases and cancer. This is achieved through the repair of damaged DNA bases, sites of base loss and single strand breaks of varying complexity that are continuously induced endogenously or via exogenous mutagens. Whilst the enzymes involved in BER are now well known and characterised, the role of the co-ordination of BER enzymatic activities in the cellular response to DNA damage and the mechanisms regulating this process are only now being revealed. Post-translational modifications of BER proteins, including ubiquitylation and phosphorylation, are increasingly being identified as key processes that regulate BER. In this review we will summarise recent evidence discovering novel mechanisms that are involved in maintaining genome stability by regulation of the key BER proteins in response to DNA damage.


Neighborhood-level associations with HIV infection among young men who have sex with men in Chicago.
The rising incidence of HIV infection among young men who have sex with men (YMSM) is a substantial public health concern. Traditional research on HIV among YMSM has focused largely on individual-level predictors and infrequently accounts for contextual or neighborhood-level factors such as ethnic composition and socioeconomic status. This study used neighborhood-level data from the US Census and other public sources, and individual-level data from a longitudinal cohort of YMSM in Chicago (Crew 450). Of the original 450 YMSM in the cohort, 376 reported living in Chicago (83.6 %) and were included in the analytic sample. A clustering approach was used to group the 77 community areas together by common characteristics, resulting in the identification of 11 distinct clusters. An unconditional model of individual HIV status indicated a significant amount of variance existed between neighborhood clusters (χ (2) = 21.66; p = 0.006). When individual-level variables were added to the model, only having an HIV-positive sex partner (OR = 6.41; CI 2.40, 17.1) and engaging in exchange sex in the past 6 months (OR = 3.25; 95 % CI 1.33, 7.93) were significant predictors of HIV status. Clusters with higher Walk Scores were less likely to contain HIV-positive individuals (OR = 0.94; 95 % CI 0.90, 0.98). Conversely, clusters with a larger proportion of vacant buildings were more likely to contain HIV-positive individuals (OR = 1.19; 95 % CI 1.07, 1.33). Future research among YMSM needs to investigate the mechanisms by which neighborhood of residence might influence engagement in risk behaviors or acquisition of HIV.


Synthetic octacalcium phosphate-enhanced reparative dentine formation via induction of odontoblast differentiation.
Synthetic octacalcium phosphate (OCP) has been suggested to be a useful biomaterial for the regeneration of hard tissues, including bone. However, it remains unknown whether OCP induces dentine formation by dental pulp. We investigated biomineralization of dental pulp exposed to synthetic OCP in vitro and in vivo. When dental pulp was exposed directly to OCP, rapid formation of reparative dentine (RD) was induced and expression of dentine sialoprotein synthesis was observed in dental pulp adjacent to newly synthesized RD. OCP inhibited the proliferation of rat pulp cells and also promoted their odontoblastic differentiation in vitro, as alkaline phosphatase activity, mineralization of pulp cells and the expression level of dentine sialophosphoprotein were enhanced. Direct contact between OCP and pulp cells is required for OCP to exhibit its effects in vitro. The expression level of Runx2, a transcription factor whose downregulation is closely related to odontoblast differentiation, was downregulated in pulp cells cultured with OCP. Structural changes of OCP during culture were determined by Fourier transform infrared spectroscopy. OCP tended to be converted to carbonate hydroxyapatite after incubation with or without pulp cells, which may be analogous to biological apatite crystals. Taken together, our data suggest that synthetic OCP supports RD formation by dental pulp and downregulation of Runx2 may be involved in that stimulatory activity. Furthermore, OCP-apatite conversion is involved in this stimulatory capacity of OCP.


Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n.
The sequence of a Pst I restriction fragment was determined that demonstrate instability in fragile X syndrome pedigrees. The region of instability was localized to a trinucleotide repeat p(CCG)n. The sequence flanking this repeat were identical in normal and affected individuals. The breakpoints in two somatic cell hybrids constructed to break at the fragile site also mapped to this repeat sequence. The repeat exhibits instability both when cloned in a nonhomologous host and after amplification by the polymerase chain reaction. These results suggest variation in the trinucleotide repeat copy number as the molecular basis for the instability and possibly the fragile site. This would account for the observed properties of this region in vivo and in vitro.


The normal width of the linea alba in nulliparous women.
The function of the linea alba is to maintain the abdominal muscles at a certain proximity to each other. In the case of long-lasting increased intra-abdominal pressure, the linea alba widens. Yet, as the existence of the linea a priori implicates a physiological distance between the two rectus muscles, the question arises as to what the normal width of the linea alba is. To evaluate the normal width of the linea alba, we examined 150 nulliparous women between 20 and 45 years of age with a body mass index < 30 kg m(-2) by ultrasound at three reference points: the origin at the xiphoid and 3 cm above and 2 cm below the umbilicus. The examination revealed a broad range of widths at the three reference points. The linea was widest at 3 cm above the umbilicus (-35 mm), followed by the reference point 2 cm below the umbilicus (-31 mm) and the origin at the xiphoid (-31 mm). The mean width was 7 +/- 5 mm at the xiphoid and 13 +/- 7 mm above and 8 +/- 6 mm below the umbilicus. For the definition of the normal width of the linea, the 10th and 90th percentiles were taken. The linea alba can be considered "normal" up to a width of 15 mm at the xiphoid, up to 22 mm at the reference point 3 cm above the umbilicus and up to 16 mm at the reference point 2 cm below the umbilicus in nulliparous women.


Gender Comparison of Receipt of Government-Funded Health Services and Medication Prescriptions for the Management of Patients With Cardiovascular Disease in Primary Care.
Cardiovascular disease (CVD) and risk factors remains a major burden in terms of disease, disability, and death in the Australian population and mental health is considered as an important risk factor affecting cardiovascular disease. A multidisciplinary collaborative approach in primary care is required to ensure an optimal outcome for managing cardiovascular patients with mental health issues. Medicare introduced numerous primary care health services and medications that are subsidised by the Australian government in order to provide a more structured approach to reduce and manage CVD. However, the utilisation of these services nor gender comparison for CVD management in primary care has been explored. Therefore, the aim is to compare the provision of subsidised chronic disease management plans (CDMPs), mental health care and prescription of guideline-indicated medications to men and women with CVD in primary care practices for secondary prevention. De-identified data for all active patients with CVD were extracted from 50 Australian primary care practices. Outcomes included the frequency of receipt of CDMPs, mental health care and prescription of evidence-based medications. Analyses adjusted for demography and clinical characteristics, stratified by gender, were performed using logistic regression and accounted for clustering effects by practices. Data for 14,601 patients with CVD (39.4% women) were collected. The odds of receiving the CDMPs was significantly greater amongst women than men (preparation of general practice management plan [GPMP]: (46% vs 43%; adjusted OR [95% CI]: 1.22 [1.12, 1.34]). Women were more likely to have diagnosed with mental health issues (32% vs 20%, p<0.0001), however, the adjusted odds of men and women receiving any government-subsidised mental health care were similar. Women were less often prescribed blood pressure, lipid-lowering and antiplatelet medications. After adjustment, only an antiplatelet medication or agent was less likely to be prescribed to women than men (44% vs 51%; adjusted OR [95% CI]: 0.84 [0.76, 0.94]). Women were more likely to receive CDMPs but less likely to receive antiplatelet medications than men, no gender difference was observed in the receipt of mental health care. However, the receipt of the CDMPs and the mental health treatment consultations were suboptimal and better use of these existing services could improve ongoing CVD management.


Linking Brain Age Gap to Mental and Physical Health in the Berlin Aging Study II.
From a biological perspective, humans differ in the speed they age, and this may manifest in both mental and physical health disparities. The discrepancy between an individual's biological and chronological age of the brain ("brain age gap") can be assessed by applying machine learning techniques to Magnetic Resonance Imaging (MRI) data. Here, we examined the links between brain age gap and a broad range of cognitive, affective, socioeconomic, lifestyle, and physical health variables in up to 335 adults of the Berlin Aging Study II. Brain age gap was assessed using a validated prediction model that we previously trained on MRI scans of 32,634 UK Biobank individuals. Our statistical analyses revealed overall stronger evidence for a link between higher brain age gap and less favorable health characteristics than expected under the null hypothesis of no effect, with 80% of the tested associations showing hypothesis-consistent effect directions and 23% reaching nominal significance. The most compelling support was observed for a cluster covering both cognitive performance variables (episodic memory, working memory, fluid intelligence, digit symbol substitution test) and socioeconomic variables (years of education and household income). Furthermore, we observed higher brain age gap to be associated with heavy episodic drinking, higher blood pressure, and higher blood glucose. In sum, our results point toward multifaceted links between brain age gap and human health. Understanding differences in biological brain aging may therefore have broad implications for future informed interventions to preserve mental and physical health in old age.


Marijuana use and inpatient outcomes among hospitalized patients: analysis of the nationwide inpatient sample database.
The purpose of this paper is to examine the relationship between marijuana use and health outcomes among hospitalized patients, including those hospitalized with a diagnosis of cancer. A total of 387,608 current marijuana users were identified based on ICD-9 codes for marijuana use among hospitalized patients in the Nationwide Inpatient Sample database between 2007 and 2011. Logistic regression analysis was performed to determine the association between marijuana use and heart failure, cardiac disease, stroke, and in-hospital mortality. All models were adjusted for age, gender, race, residential income, insurance, residential region, pain, and number of comorbidities. Among hospitalized patients, marijuana use was associated with a 60% increased odds of stroke (OR: 1.60, 95% CI: 1.44-1.77) compared with non-users, but significantly reduced odds of heart failure (OR: 0.78, 95% CI: 0.75-0.82), cardiac disease (OR: 0.86, 95% CI: 0.82-0.91), or in-hospital mortality (OR: 0.41, 95% CI: 0.38-0.44). Among cancer patients, odds of in-hospital mortality was significantly reduced among marijuana users compared with non-users (OR: 0.44, 95% CI: 0.35-0.55). Hospitalized marijuana users were more likely to experience a stroke compared with non-users, but less likely to experience in-hospital mortality. Prospective studies will be needed to better characterize the health effects of marijuana use, especially among older, sicker, and/or hospitalized patients. In the meantime, conversations regarding marijuana use/misuse may be warranted in the clinical setting in order for patients and healthcare providers to adequately weigh the anticipated benefits of marijuana use with potentially significant health risks.


Desmosomes--dual junctional principles of intra- and supracellular order in epithelial differentiation and tissue formation.
The cells of most normal and malignantly growing tissues are connected by "adhering junctions", i.e. distinct sites of "homotypic" contact between the plasma membranes of two cells of the same or a similar kind, associated on the cytoplasmic side by a dense plaque at which often bundles of cytoskeletal filaments anchor. Of the various types of adhering junctions desmosomes are characteristic of epithelia and carcinomas but also occur in some other cell types. Their molecular components have recently been identified and characterized by cDNA-cloning and sequencing. Unexpectedly, the molecular complement of desmosomes has been found to show certain differences in different epithelia, with particularly complex patterns in stratified squamous epithelia as well as in tumors and cultured cell lines derived therefrom. In addition, molecular principles important in the assembly of desmosomes and in the specific anchorage of intermediate-sized filaments (IFs) at desmosomal plaques have been elucidated. The possible value of cell type-specific isoforms of desmosomal components as markers for the subtyping of carcinomas and the role of desmosomal cadherins during invasion and metastasis of carcinomas are discussed.


Role of bile acids in inflammatory bowel disease.
Bile acids (BAs) are the end product of cholesterol catabolism. Their synthesis is regulated by the nuclear receptor farnesoid X receptor, also involved in the control of their enterohepatic circulation. Inflammatory bowel diseases (IBD), which include Crohn's disease (CD) and ulcerative colitis (UC), are multifactorial diseases characterized by diarrhea. The pathogenesis of diarrhea in IBD is still debated. The most important factor is the inflammatory process of the intestinal wall, causing alterations of solute and water absorption/secretion, deterioration of epithelial cell integrity, disruption of the intestinal microflora homeostasis, and impairment of specific transport mechanisms within the gut (including that of BAs). In this review, we summarize the current state of the art in this area and we critically evaluate the alterations of BA metabolism in patients with CD and UC.


Characterisation of major peptides in 'jack jumper' ant venom by mass spectrometry.
The jack jumper ant, Myrmecia pilosula, is endemic to South-Eastern Australia, where around 2.7% of the population has a history of systemic allergic reactions (anaphylaxis) to its venom. Previous work had indicated that there were several allergenic peptides derived from the cDNA Myr p 1, the major expressed allergenic product being a 56-residue peptide (Myr p 1 57-->112, 'pilosulin 1', approximately 6052 Da). Another major allergen had been described as a 27 residue peptide derived from the cDNA Myr p 2 (Myr p 2 49-->75, 'pilosulin 2', approximately 3212 Da), possibly existing as part of a disulfide complex. As a preliminary step in detailed stability studies of a pharmaceutical product used for venom immunotherapy, LC-MS and Edman sequencing analysis of venom collected from various locations by both electrical stimulation and venom sac dissection was undertaken. More than 50 peptides in the 4-9 kDa range were detected in LC-MS analyses. A subsequence of Myr p 2 was found as part of the major peptide present in all samples; this was a bis-disulphide linked, antiparallel aligned heterodimer consisting of Myr p 2 49-->74, (des-Gly(27)-pilosulin 2, approximately 3155 Da) and a previously unreported peptide of approximately 2457 Da. Pilosulin 1 was found by a combination of tandem mass spectrometry and Edman sequencing to exist mainly, and sometimes exclusively, as a previously unreported approximately 6067 Da variant, in which the valine at residue 5 is replaced by isoleucine. A range of hydrolysis products of [Ile(5)]pilosulin 1 and pilosulin 1 were also detected in partially degraded venom. Further IgE-binding studies using these peptides are warranted and a revision of the nomenclature of allergenic components of M. pilosula venom may be required to conform with established IUIS guidelines.


Epidemiology of osteoporosis.
Osteoporosis is a major public health problem through its association with age-related fractures. Although fracture risk at any skeletal site depends upon a complex interaction between bone strength and trauma, recent epidemiologic studies confirm that bone density is currently the best single predictor of future fracture. The increasing burden of osteoporotic fractures urgently requires effective preventive strategies aimed at maximizing peak bone density, preventing excessive bone loss, and reducing the risk of falls.


Methods for Single-Molecule Sensing and Detection Using Bacteriophage Phi29 DNA Packaging Motor.
Bacteriophage phi29 DNA packaging motor consists of a dodecameric portal channel protein complex termed connector that allows transportation of genomic dsDNA and a hexameric packaging RNA (pRNA) ring to gear the motor. The elegant design of the portal protein has facilitated its applications for real-time single-molecule detection of biopolymers and chemicals with high sensitivity and selectivity. The robust self-assembly property of the pRNA has enabled biophysical studies of the motor complex to determine the stoichiometry and structure/folding of the pRNA at single-molecule level. This chapter focuses on biophysical and analytical methods for studying the phi29 motor components at the single-molecule level, such as single channel conductance assays of membrane-embedded connectors; single molecule photobleaching (SMPB) assay for determining the stoichiometry of phi29 motor components; fluorescence resonance energy transfer (FRET) assay for determining the structure and folding of pRNA; atomic force microscopy (AFM) for imaging pRNA nanoparticles of various size, shape, and stoichiometry; and bright-field microscopy with magnetomechanical system for direct visualization of viral DNA packaging process. The phi29 system with explicit engineering capability has incredible potentials for diverse applications in nanotechnology and nanomedicine including, but not limited to, DNA sequencing, drug delivery to diseased cells, environmental surveillance, and early disease diagnosis.


Peripartum infections and associated maternal mortality in rural Malawi.
To assess associations between maternal mortality and severe morbidity and human immunodeficiency virus (HIV) infection, uptake of antiretroviral therapy, obstetric infections, and nonobstetric infections in a rural Malawian district, where the estimated HIV prevalence is 21%. We studied the incidence and outcomes of maternal peripartum infections between September 2007 and September 2009 at the district hospital. We used a facility-based prospective cohort study design, including all cases of severe maternal peripartum infection up to 42 days postpartum, and recorded maternal and pregnancy-related characteristics. We assessed the association between mortality and covariates (including nonobstetric infection, HIV prevalence, and uptake of antiretroviral therapy) using univariable and multivariable logistic regression models. In total, 140 infections occurred: 79 (56%) obstetric and 53 (38%) nonobstetric (eight unknown). Half of the women were HIV-positive. Multivariable analysis showed that nonobstetric infection was the most important explanatory variable for mortality (adjusted odds ratio [OR] 4.23, 95% confidence interval [CI] 1.53-11.73). HIV-positive women not on antiretroviral therapy were at higher risk of mortality (adjusted OR 3.02, 95% CI 1.06-8.60) but there was no significant mortality increase among those on treatment (adjusted OR 0.51, 95% CI 0.10-2.71). The most common infections were puerperal sepsis (obstetric, case fatality rate 7%) and pneumonia (nonobstetric, case fatality rate 41%). Untreated HIV infection and nonobstetric infections are independently associated with maternal mortality. Prompt treatment of HIV and nonobstetric infections in pregnant women must be prioritized to reduce maternal mortality. II.


Different repartition of the cryptic species of black aspergilli according to the anatomical sites in human infections, in a French University hospital.
Black aspergilli of the section Nigri are rarely differentiated at the species level when originating from human specimens. We wondered whether some cryptic species could be more frequently observed in some clinical entities. We analyzed the 198 black isolates consecutively collected from the external ear canal (EEC; n = 66), respiratory specimens (n = 99), and environment (n = 33). DNA was extracted and species identification was performed upon the partial calmodulin gene. We identified by decreasing frequency: Aspergillus welwitschiae (35.3%), Aspergillus tubingensis (34.3%), Aspergillus niger (17.2%), Aspergillus luchuensis (4%), Aspergillus aff. welwitschiae (3%), Aspergillus neoniger (2%), Aspergillus piperis (1.5%), Aspergillus japonicus (1.0%), Aspergillus vadensis (0.5%), and two Aspergillus tubingensis clade (1%). The distribution of the three main cryptic species was different between EEC and respiratory samples (P < 0.001) but not different between respiratory and environment samples (P = 0.264). Aspergillus welwitschiae was more often associated with EEC (54.5%), whereas A. tubingensis and A. niger were predominant in respiratory samples (39.4 and 26.3%, respectively). Among the 99 respiratory isolates, only 10 were deemed responsible for probable invasive aspergillosis, of which six were mixed with other pathogenic moulds. This study shows the interest to pursue the identification of clinical isolates in the Aspergillus section Nigri to unravel some specific associations with clinical entities. The association of A. welwitschiae with otomycosis suggests a better fitness to infect/colonize the ear canal. Also, members of the Aspergillus section Nigri alone are rarely responsible for invasive aspergillosis. We analyzed 198 black aspergilli isolates collected from different samples type to determine their species identification. We observe a different distribution of species between ear canal and respiratory samples (P < 0.001), suggesting a better fitness of A. welwitschiae to infect the ear canal.


Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China.
Previous studies have showed clinical characteristics of patients with the 2019 novel coronavirus disease (COVID-19) and the evidence of person-to-person transmission. Limited data are available for asymptomatic infections. This study aims to present the clinical characteristics of 24 cases with asymptomatic infection screened from close contacts and to show the transmission potential of asymptomatic COVID-19 virus carriers. Epidemiological investigations were conducted among all close contacts of COVID-19 patients (or suspected patients) in Nanjing, Jiangsu Province, China, from Jan 28 to Feb 9, 2020, both in clinic and in community. Asymptomatic carriers were laboratory-confirmed positive for the COVID-19 virus by testing the nucleic acid of the pharyngeal swab samples. Their clinical records, laboratory assessments, and chest CT scans were reviewed. As a result, none of the 24 asymptomatic cases presented any obvious symptoms while nucleic acid screening. Five cases (20.8%) developed symptoms (fever, cough, fatigue, etc.) during hospitalization. Twelve (50.0%) cases showed typical CT images of ground-glass chest and 5 (20.8%) presented stripe shadowing in the lungs. The remaining 7 (29.2%) cases showed normal CT image and had no symptoms during hospitalization. These 7 cases were younger (median age: 14.0 years; P=0.012) than the rest. None of the 24 cases developed severe COVID-19 pneumonia or died. The median communicable period, defined as the interval from the first day of positive nucleic acid tests to the first day of continuous negative tests, was 9.5 days (up to 21 days among the 24 asymptomatic cases). Through epidemiological investigation, we observed a typical asymptomatic transmission to the cohabiting family members, which even caused severe COVID-19 pneumonia. Overall, the asymptomatic carriers identified from close contacts were prone to be mildly ill during hospitalization. However, the communicable period could be up to three weeks and the communicated patients could develop severe illness. These results highlighted the importance of close contact tracing and longitudinally surveillance via virus nucleic acid tests. Further isolation recommendation and continuous nucleic acid tests may also be recommended to the patients discharged.


Polymorphisms in the vitamin D receptor gene are associated with reduced rate of sputum culture conversion in multidrug-resistant tuberculosis patients in South Africa.
Vitamin D modulates the inflammatory and immune response to tuberculosis (TB) and also mediates the induction of the antimicrobial peptide cathelicidin. Deficiency of 25-hydroxyvitamin D and single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene may increase the risk of TB disease and decrease culture conversion rates in drug susceptible TB. Whether these VDR SNPs are found in African populations or impact multidrug-resistant (MDR) TB treatment has not been established. We aimed to determine if SNPs in the VDR gene were associated with sputum culture conversion among a cohort of MDR TB patients in South Africa. We conducted a prospective cohort study of adult MDR TB patients receiving second-line TB treatment in KwaZulu-Natal province. Subjects had monthly sputum cultures performed. In a subset of participants, whole blood samples were obtained for genomic analyses. Genomic DNA was extracted and genotyped with Affymetrix Axiom Pan-African Array. Cox proportional models were used to determine the association between VDR SNPs and rate of culture conversion. Genomic analyses were performed on 91 MDR TB subjects enrolled in the sub-study; 60% were female and median age was 35 years (interquartile range [IQR] 29-42). Smoking was reported by 21% of subjects and most subjects had HIV (80%), were smear negative (57%), and had cavitary disease (55%). Overall, 87 (96%) subjects initially converted cultures to negative, with median time to culture conversion of 57 days (IQR 17-114). Of 121 VDR SNPs examined, 10 were significantly associated (p<0.01) with rate of sputum conversion in multivariable analyses. Each additional risk allele on SNP rs74085240 delayed culture conversion significantly (adjusted hazard ratio 0.30, 95% confidence interval 0.14-0.67). Polymorphisms in the VDR gene were associated with rate of sputum culture conversion in MDR TB patients in this high HIV prevalence setting in South Africa.


Cyclophilin D-dependent oligodendrocyte mitochondrial ion leak contributes to neonatal white matter injury.
Postnatal failure of oligodendrocyte maturation has been proposed as a cellular mechanism of diffuse white matter injury (WMI) in premature infants. However, the molecular mechanisms for oligodendrocyte maturational failure remain unclear. In neonatal mice and cultured differentiating oligodendrocytes, sublethal intermittent hypoxic (IH) stress activated cyclophilin D-dependent mitochondrial proton leak and uncoupled mitochondrial respiration, leading to transient bioenergetic stress. This was associated with development of diffuse WMI: poor oligodendrocyte maturation, diffuse axonal hypomyelination, and permanent sensorimotor deficit. In normoxic mice and oligodendrocytes, exposure to a mitochondrial uncoupler recapitulated the phenotype of WMI, supporting the detrimental role of mitochondrial uncoupling in the pathogenesis of WMI. Compared with WT mice, cyclophilin D-knockout littermates did not develop bioenergetic stress in response to IH challenge and fully preserved oligodendrocyte maturation, axonal myelination, and neurofunction. Our study identified the cyclophilin D-dependent mitochondrial proton leak and uncoupling as a potentially novel subcellular mechanism for the maturational failure of oligodendrocytes and offers a potential therapeutic target for prevention of diffuse WMI in premature infants experiencing chronic IH stress.


Bystander exposure to ultra-low-volume insecticide applications used for adult mosquito management.
A popular and effective management option for adult mosquitoes is the use of insecticides applied by ultra-low-volume (ULV) equipment. However, there is a paucity of data on human dermal exposure to insecticides applied by this method. The objective of the current study was to estimate dermal exposures to the insecticide active ingredient permethrin using water- (Aqua-Reslin®) and oil-based (Permanone® 30-30) formulations with passive dosimetry. No significant differences in deposition of permethrin were observed between years, distance from the spray source, front or back of the body, or the placement of the patches on the body. However, exposure to Aqua-Reslin was significantly greater than Permanone 30-30 and average concentrations deposited on the body were 4.2 and 2.1 ng/cm2, respectively. The greater deposition of Aqua-Reslin is most likely due to the higher density of the water-based formulation which causes it to settle out faster than the lighter oil-based formulation of Permanone 30-30. The estimated average absorbed dermal exposure for permethrin from Aqua-Reslin and Permanone 30-30 was 0.00009 and 0.00005 mg/kg body weight, respectively. We also found that ground deposition of ULV insecticides can be used as a surrogate for estimating dermal exposure. The estimated exposures support the findings of previous risk assessments that exposure to ULV applications used for mosquito management are below regulatory levels of concern.


Benefits of ion mobility for analysing monochloropropane-diol esters.
This paper reports the first application and benefits of ion mobility in combination with liquid chromatography and a transportable time-of-flight mass spectrometer to the analysis of monochloropropane-diol esters (MCPDE) in vegetable oils. The additional selectivity obtained with the ion mobility allowed the quantitative analysis of MCPDEs as such in their intact form (direct analysis) without any chemical derivatisation and, furthermore, without any enrichment or purification step. This gain in selectivity manifests primarily in the resolution of interferences originating, for example, from the diacylglycerol components of palm oil. In silico calculations confirm that resolution of such interferences would require mass resolutions higher than 200,000 at m/z 600, e.g., in the case of signals of the 41K isotope of the PO DAG and the signals of the sodiated PO MCPD. While such resolution can be obtained on certain state-of-the-art costly and laboratory-exhaustive research instruments, this study demonstrates that even transportable time-of-flight MS can achieve the required selectivity when combined with ion mobility. Further advantage of the described approach is that the applied sample preparation is only dilution with minimum consumable requirements and can be performed quickly even outside laboratories directly in the field. The described results suggest that the application of ion mobility in addition to LC-MS is likely to push the boundaries of contaminant analysis especially for high-throughput screening investigations.


Risk of anal cancer in HIV-infected and HIV-uninfected individuals in North America.
Anal cancer is one of the most common cancers affecting individuals infected with human immunodeficiency virus (HIV), although few have evaluated rates separately for men who have sex with men (MSM), other men, and women. There are also conflicting data regarding calendar trends. In a study involving 13 cohorts from North America with follow-up between 1996 and 2007, we compared anal cancer incidence rates among 34 189 HIV-infected (55% MSM, 19% other men, 26% women) and 114 260 HIV-uninfected individuals (90% men). Among men, the unadjusted anal cancer incidence rates per 100 000 person-years were 131 for HIV-infected MSM, 46 for other HIV-infected men, and 2 for HIV-uninfected men, corresponding to demographically adjusted rate ratios (RRs) of 80.3 (95% confidence interval [CI], 42.7-151.1) for HIV-infected MSM and 26.7 (95% CI, 11.5-61.7) for other HIV-infected men compared with HIV-uninfected men. HIV-infected women had an anal cancer rate of 30/100 000 person-years, and no cases were observed for HIV-uninfected women. In a multivariable Poisson regression model, among HIV-infected individuals, the risk was higher for MSM compared with other men (RR, 3.3; 95% CI, 1.8-6.0), but no difference was observed comparing women with other men (RR, 1.0; 95% CI, 0.5-2.2). In comparison with the period 2000-2003, HIV-infected individuals had an adjusted RR of 0.5 (95% CI, .3-.9) in 1996-1999 and 0.9 (95% CI, .6-1.2) in 2004-2007. Anal cancer rates were substantially higher for HIV-infected MSM, other men, and women compared with HIV-uninfected individuals, suggesting a need for universal prevention efforts. Rates increased after the early antiretroviral therapy era and then plateaued.


Lesbian, Gay, Bisexual, and Transgender Patient Care: Medical Students' Preparedness and Comfort.
Phenomenon: Lesbian, gay, bisexual, and transgender (LGBT) individuals face significant barriers in accessing appropriate and comprehensive medical care. Medical students' level of preparedness and comfort caring for LGBT patients is unknown. An online questionnaire (2009-2010) was distributed to students (n = 9,522) at 176 allopathic and osteopathic medical schools in Canada and the United States, followed by focus groups (2010) with students (n = 35) at five medical schools. The objective of this study was to characterize LGBT-related medical curricula, to determine medical students' assessments of their institutions' LGBT-related curricular content, and to evaluate their comfort and preparedness in caring for LGBT patients. Of 9,522 survey respondents, 4,262 from 170 schools were included in the final analysis. Most medical students (2,866/4,262; 67.3%) evaluated their LGBT-related curriculum as "fair" or worse. Students most often felt prepared addressing human immunodeficiency virus (HIV; 3,254/4,147; 78.5%) and non-HIV sexually transmitted infections (2,851/4,136; 68.9%). They felt least prepared discussing sex reassignment surgery (1,061/4,070; 26.1%) and gender transitioning (1,141/4,068; 28.0%). Medical education helped 62.6% (2,669/4,262) of students feel "more prepared" and 46.3% (1,972/4,262) of students feel "more comfortable" to care for LGBT patients. Four focus group sessions with 29 students were transcribed and analyzed. Qualitative analysis suggested students have significant concerns in addressing certain aspects of LGBT health, specifically with transgender patients. Insights: Medical students thought LGBT-specific curricula could be improved, consistent with the findings from a survey of deans of medical education. They felt comfortable, but not fully prepared, to care for LGBT patients. Increasing curricular coverage of LGBT-related topics is indicated with emphasis on exposing students to LGBT patients in clinical settings.


Targeting serum glucocorticoid-regulated kinase-1 in squamous cell carcinoma of the head and neck: a novel modality of local control.
The inhibition of serum glucocorticoid-regulated kinase-1 (SGK-1) has been found to decrease growth of colon and prostate cancer cells. The purpose of this study is to evaluate the therapeutic effect of SGK-1 inhibition in head and neck squamous cell carcinoma (SCC). Human head and neck tumors (HTB41/43) were established in athymic mice. Growth rates between mice treated with vehicle (PBS) injection (group 1, n = 5), SGK-1 Inhibitor GSK 650394 (group 2, n = 6), systemic cisplatin (group 3, n = 6), and a combination of SGK-1 Inhibitor and cisplatin (group 4, n = 6) were compared using repeated measures one-way ANOVA with Newman-Keuls Multiple Comparison Test. Tumor cells were subsequently submitted to further analyses. At the end of the experiment mean tumor sizes were 122.33+/-105.86, 76.73+/-36.09, 94.52+/-75.92, and 25.76+/-14.89 mm2 (mean +/- SD) for groups 1 to 4. Groups 2 and 3 showed decreased tumor growth compared to controls (p<0.001). Group 4 displayed even greater growth suppression (p<0.0001). Importantly, group 4 fared better than group 3 (p<0.001). CD44 expression was reduced in group 2 (p<0.05), and to an even greater extent in groups 3 and 4 (p<0.0025). A trend towards reduction of HER 2 expression was noted in group 4. SGK-1 inhibition suppresses tumor growth, and in combination with systemic cisplatin exceeds the effect of cisplatin alone. Decreased expression of CD44 and HER 2 implies depletion of tumor stem cells, and less tumorigenicity. SGK-1 inhibition represents a potential modality of local control for palliation in advanced cases.


The xeroderma pigmentosum group E gene product DDB2 activates nucleotide excision repair by regulating the level of p21Waf1/Cip1.
The xeroderma pigmentosum group E gene product DDB2, a protein involved in nucleotide excision repair (NER), associates with the E3 ubiquitin ligase complex Cul4A-DDB1. But the precise role of these interactions in the NER activity of DDB2 is unclear. Several models, including DDB2-mediated ubiquitination of histones in UV-irradiated cells, have been proposed. But those models lack clear genetic evidence. Here we show that DDB2 participates in NER by regulating the cellular levels of p21(Waf1/Cip1). We show that DDB2 enhances nuclear accumulation of DDB1, which binds to a modified form of p53 containing phosphorylation at Ser18 (p53(S18P)) and targets it for degradation in low-dose-UV-irradiated cells. DDB2(-/-) mouse embryonic fibroblasts (MEFs), unlike wild-type MEFs, are deficient in the proteolysis of p53(S18P). Accumulation of p53(S18P) in DDB2(-/-) MEFs causes higher expression p21(Waf1/Cip1). We show that the increased expression of p21(Waf1/Cip1) is the cause NER deficiency in DDB2(-/-) cells because deletion or knockdown of p21(Waf1/Cip1) reverses their NER-deficient phenotype. p21(Waf1/Cip1) was shown to bind PCNA, which is required for both DNA replication and NER. Moreover, an increased level of p21(Waf1/Cip1) was shown to inhibit NER both in vitro and in vivo. Our results provide genetic evidence linking the regulation of p21(Waf1/Cip1) to the NER activity of DDB2.


Genital tuberculosis as the cause of tuboovarian abscess in an immunosuppressed patient.
Although tuberculosis (TB) is a major health problem worldwide, primary extrapulmonary tuberculosis (EPTB), and in particular female genital tract infection, remains a rare event. A 35-year-old human immunodeficiency virus (HIV) seropositive woman of African descent with lower abdominal pain and fever of two days duration underwent surgery due to left adnexal mass suggesting pelvic inflammatory disease. The surgical situs showed a four quadrant peritonitis, consistent with the clinical symptoms of the patient, provoked by a tuboovarian abscess (TOA) on the left side. All routine diagnostic procedures failed to determine the causative organism/pathogen of the infection. Histopathological evaluation identified a necrotic granulomatous salpingitis and specific PCR analysis corroborated Mycobacterium tuberculosis (M. Tb). Consequently, antituberculotic therapy was provided. In the differential diagnosis of pelvic inflammatory disease, internal genital tuberculosis should be considered. Moreover, physicians should consider tuberculous infections early in the work-up of patients when immunosuppressive conditions are present.