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Skin Picking Disorder affects 4% of the general population, with serious quality of life impacts, and potentially life threatening complications. Standard psychoactive medications do not help most patients. Similarly, Mouse Ulcerative Dermatitis (skin lesions caused by excessive abnormal grooming behavior) is very common in widely used inbred strains of mice, and represents a serious animal welfare issue and cause of mortality. Treatment options for Ulcerative Dermatitis are largely palliative and ineffective. We have proposed mouse Ulcerative Dermatitis as a model for human Skin Picking Disorder based on similar epidemiology, behavior, and its comorbidity and mechanistic overlap with hair pulling (trichotillomania). We predicted that mouse Ulcerative Dermatitis would be treated by N-Acetylcysteine, as this compound is highly effective in treating both Skin Picking Disorder and Trichotillomania. Furthermore, we hypothesized that N-Acetylcysteine's mode of action is as a precursor to the production of the endogenous antioxidant glutathione in the brain, and therefore intranasal glutathione would also treat Ulcerative Dermatitis. Accordingly, we show in a heterogenous prospective trial, the significant reduction in Ulcerative Dermatitis lesion severity in mice receiving either N-acetylcysteine (oral administration) or glutathione (intranasal). The majority of mice treated with N-acetylcysteine improved slowly throughout the course of the study. Roughly half of the mice treated with glutathione showed complete resolution of lesion within 2-4 weeks, while the remainder did not respond. These findings are the first to show that the use of N-acetylcysteine and Glutathione can be curative for mouse Ulcerative Dermatitis. These findings lend additional support for mouse Ulcerative Dermatitis as a model of Skin Picking Disorder and also support oxidative stress and glutathione synthesis as the mechanism of action for these compounds. As N-Acetylcysteine is poorly tolerated by many patients, intranasal glutathione warrants further study as potential therapy in Skin Picking, trichotillomania and other body-focused repetitive behavior disorders.

Germ-free (GF) mice, which are depleted of their resident microbiota, are the gold standard for exploring the role of the microbiome in health and disease; however, they are of limited value in the study of human-specific pathogens because they do not support their replication. Here, we develop GF mice systemically reconstituted with human immune cells and use them to evaluate the role of the resident microbiome in the acquisition, replication and pathogenesis of two human-specific pathogens, Epstein–Barr virus (EBV) and human immunodeficiency virus (HIV). Comparison with conventional (CV) humanized mice showed that resident microbiota enhance the establishment of EBV infection and EBV-induced tumorigenesis and increase mucosal HIV acquisition and replication. HIV RNA levels were higher in plasma and tissues of CV humanized mice compared with GF humanized mice. The frequency of CCR5 + CD4 + T cells throughout the intestine was also higher in CV humanized mice, indicating that resident microbiota govern levels of HIV target cells. Thus, resident microbiota promote the acquisition and pathogenesis of two clinically relevant human-specific pathogens. Resident microbiota contribute to HIV and EBV infection in a germ-free humanized mouse model.

Human Immunodeficiency Virus (HIV) appears to have the ability to create an \"infectious or virological synapse\" in which CD4, chemokine receptors, and cell adhesion molecules, in particular, Leukocyte Function Associated-antigen-1 (LFA-1), all gather within a localized patch on the cell membrane. Furthermore, viral receptors and adhesion molecules are recruited into the target cell-side of the synapse in a cholesterol-dependent manner. Integrins affect raft domains in a spatial fashion. Loss of integrin-mediated adhesion causes rapid internalization of several raft markers, including GM1 and GPI-anchored proteins. LFA-1 may play an important role in supplying costimulatory signals upon virus docking, fusion, and infection. Previous findings from our laboratory showed monoclonal antibodies (MAb) specific for LFA-1 inhibited Human Immunodeficiency Virus (HIV) transmission in cultured primarily cells. To extend these findings, three lines of investigation were undertaken. First, the ability of the cholesterol-lowering agent lovastatin to modulate virus infection and integrin function in virus-cell interactions was examined. Lovastatin inhibited HIV-1 and SIV transmission at clinically relevant levels in primary cells and T-cell lines. Virally infected cells cultured in the presence of lovastatin did not bind the LFA-1 ligand, Intercellular Cell Adhesion Molecule (ICAM)-1, and virus produced from these cells was less infectious. This suggested that LFA-1 on virus particles is inactive due to lovastatin treatment of virus-producing cells. Secondly, studies were carried out to determine if LFA-1-ICAM-1 interactions play a role in limiting apoptosis, a process linked to both HIV and integrin biology. In HIV-infected cells treated with anti-LFA-1 MAb, treated with lovastatin, or a small molecule antagonist to LFA-1, increased cell death was observed. These results suggest that LFA-1-mediated signaling may be necessary to prevent HIV-1---induced apoptosis, which would allow the spread of infection in the culture. The data indicate that statins may have effects on virus attachment, infectivity, and tropism. Finally, we proposed to inhibit the function of LFA-1 in vivo by administration of a function blocking monoclonal antibody in a non-human primate model. It is hypothesized that inhibition of LFA-1 will greatly limit the establishment of infection in macaques exposed to SIV vaginally. Efforts were focused on producing and characterizing a suitable monoclonal antibody against pig-tailed macaque (Macaca nemestrina) LFA-1 and establishing conditions for administering the monoclonal antibody.

Asked by reporters whether he could relent and sign on to Ms. [Angela Merkel]'s goals, Mr. [Bush] said: \"No. I talked about what I'm for. Remember? I said I'm for sitting together with the nations to sit down and discuss a way forward.\" \"This will fold into the U.N. framework,\" Mr. Bush said. \"And that enables us to get China and India at the table to discuss how we can all move forward together.\" Under the Kyoto agreement, China and India are not covered by mandatory cuts in greenhouse gas emissions. PHOTO 2; Michael Kappeler/Agence France-Presse/Getty Images: German Chancellor Angela Merkel and President Bush talk before lunch yesterday on the first day of the Group of Eight summit. Joe Klamar/Agence France-Presse/Getty Images: THE G-8 SUMMIT: PLENTY OF ROOM FOR DISSENT/ Riot police try to arrest anti- globalization activists dressed as clowns near Bollhagen, northeastern Germany, on the first official day of the Group of Eight summit yesterday. President Bush presented himself as caught in the middle of the international climate debate, fending off allies' calls for specific steps to reverse global warming while encouraging major developing nations to join eventual climate negotiations.(Photo, Page A-1)

\"This will fold into the U.N. framework,\" [Bush] said. \"And that enables us to get China and India at the table to discuss how we can all move forward together.\" Under the Kyoto agreement, China and India are exempt from mandatory cuts in greenhouse gas emissions. \"Russia's not a threat, nor is the missile defense we're proposing a threat to Russia,\" Bush said, repeating his assertion that the system is intended to protect against attack from \"rogue\" countries, including Iran. Despite those assurances, [Vladimir Putin] has said he might respond by re-aiming some of his missile arsenal at targets in Europe. Bush said there was no need to respond militarily to Putin's threat. \"I don't think Vladimir Putin intends to attack [Europe], and so I'll talk to him about it,\" he said.

Understanding the behaviour of flexible metal–organic frameworks (MOFs)—porous crystalline materials that undergo a structural change upon exposure to an external stimulus—underpins their design as responsive materials for specific applications, such as gas separation, molecular sensing, catalysis and drug delivery. Reversible transformations of a MOF between open- and closed-pore forms—a behaviour known as ‘breathing’—typically occur through well-defined crystallographic transitions. By contrast, continuous breathing is rare, and detailed characterization has remained very limited. Here we report a continuous-breathing mechanism that was studied by single-crystal diffraction in a MOF with a diamondoid network, (Me 2 NH 2 )[In(ABDC) 2 ] (ABDC, 2-aminobenzene-1,4-dicarboxylate). Desolvation of the MOF in two different solvents leads to two polymorphic activated forms with very different pore openings, markedly different gas-adsorption capacities and different CO 2 versus CH 4 selectivities. Partial desolvation introduces a gating pressure associated with CO 2 adsorption, which shows that the framework can also undergo a combination of stepped and continuous breathing. Breathing metal–organic frameworks (MOFs) are functional materials whose molecular-scale pores can reversibly open and close. In contrast to typical defined structural transitions, continuous breathing has now been observed for a diamondoid MOF. Removal of two different solvents leads to two desolvated MOF polymorphs with dramatically different porosities and gas uptake properties, including CO 2 /CH 4 selectivities. Partial desolvation introduces pressure-gated CO 2 adsorption.

Pathogens that persist in an environmental reservoir can drive host populations to extinction because host abundance does not limit pathogen survival or reproduction. Fungal pathogens are of particular conservation concern because many fungi are generalists that persist in the environment. One example is Pseudogymnoascus destructans , the causative agent of white-nose syndrome (WNS), which has caused severe declines in hibernating bat populations across North America. Treatment of environmental reservoirs could help reduce transmission of P. destructans , and thus, reduce bat population declines from WNS. We tested the efficacy of two environmental cleaning agents, ultraviolet-C radiation and polyethylene glycol, in three mines where P. destructans established an environmental reservoir and caused declines in winter colony size of hibernating bats in Ontario, Alabama, and Arkansas. We observed considerable variation between sites but, based on our experimental design, treatments did not reduce environmental P. destructans prevalence or load and there was no consistent pattern in response to the treatments across mines. More encouragingly, treatments did not impact non-target fungi or bacteria. Our results could reflect aspects of our experimental design, including relatively small treatment cells and the lack of an available assay to assess viability of P. destructans from swab samples. Among-site variation we observed, combined with positive results of these treatments in other studies, suggest that site-specific management responses may be important for reducing impacts of white-nose syndrome on bat populations.

Mitochondria are critical for respiration in all tissues; however, in liver, these organelles also accommodate high-capacity anaplerotic/cataplerotic pathways that are essential to gluconeogenesis and other biosynthetic activities. During nonalcoholic fatty liver disease (NAFLD), mitochondria also produce ROS that damage hepatocytes, trigger inflammation, and contribute to insulin resistance. Here, we provide several lines of evidence indicating that induction of biosynthesis through hepatic anaplerotic/cataplerotic pathways is energetically backed by elevated oxidative metabolism and hence contributes to oxidative stress and inflammation during NAFLD. First, in murine livers, elevation of fatty acid delivery not only induced oxidative metabolism, but also amplified anaplerosis/cataplerosis and caused a proportional rise in oxidative stress and inflammation. Second, loss of anaplerosis/cataplerosis via genetic knockdown of phosphoenolpyruvate carboxykinase 1 (Pck1) prevented fatty acid-induced rise in oxidative flux, oxidative stress, and inflammation. Flux appeared to be regulated by redox state, energy charge, and metabolite concentration, which may also amplify antioxidant pathways. Third, preventing elevated oxidative metabolism with metformin also normalized hepatic anaplerosis/cataplerosis and reduced markers of inflammation. Finally, independent histological grades in human NAFLD biopsies were proportional to oxidative flux. Thus, hepatic oxidative stress and inflammation are associated with elevated oxidative metabolism during an obesogenic diet, and this link may be provoked by increased work through anabolic pathways.

Observational epidemiological studies have shown a positive association between hypertension and risk of incident dementia; however, the effects of antihypertensive therapy on cognitive function in controlled trials have been conflicting, and meta-analyses of the trials have not provided clear evidence of whether antihypertensive treatment reduces dementia incidence. The Hypertension in the Very Elderly trial (HYVET) was designed to assess the risks and benefits of treatment of hypertension in elderly patients and included an assessment of cognitive function. Patients with hypertension (systolic pressure 160–200 mm Hg; diastolic pressure <110 mm Hg) who were aged 80 years or older were enrolled in this double-blind, placebo-controlled trial. Participants were randomly assigned to receive 1·5 mg slow release indapamide, with the option of 2–4 mg perindopril, or placebo. The target systolic blood pressure was 150 mm Hg; the target diastolic blood pressure was 80 mm Hg. Participants had no clinical diagnosis of dementia at baseline, and cognitive function was assessed at baseline and annually with the mini-mental state examination (MMSE). Possible cases of incident dementia (a fall in the MMSE score to <24 points or a drop of three points in 1 year) were assessed by standard diagnostic criteria and expert review. The trial was stopped in 2007 at the second interim analysis after treatment resulted in a reduction in stroke and total mortality. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00122811. 3336 HYVET participants had at least one follow-up assessment (mean 2·2 years) and were included: 1687 participants were randomly assigned to the treatment group and 1649 to the placebo group. Only five reports of adverse effects were attributed to the medication: three in the placebo group and two in the treatment group. The mean decrease in systolic blood pressure between the treatment and placebo groups at 2 years was systolic −15 mm Hg, p<0·0001; and diastolic −5·9 mm Hg, p<0·0001. There were 263 incident cases of dementia. The rates of incident dementia were 38 per 1000 patient-years in the placebo group and 33 per 1000 patient-years in the treatment group. There was no significant difference between treatment and placebo groups (hazard ratio [HR] 0·86, 95% CI 0·67–1·09); however, when these data were combined in a meta-analysis with other placebo-controlled trials of antihypertensive treatment, the combined risk ratio favoured treatment (HR 0·87, 0·76–1·00, p=0·045). Antihypertensive treatment in elderly patients does not statistically reduce incidence of dementia. This negative finding might have been due to the short follow-up, owing to the early termination of the trial, or the modest effect of treatment. Nevertheless, the HYVET findings, when included in a meta-analysis, might support antihypertensive treatment to reduce incident dementia. The British Heart Foundation; the Institute de Recherches Internationales Servier.

Background The loss occasioned through miscarriage, stillbirth or neonatal death is recognised as a traumatic event causing grief and sorrow in fathers. While the rate of Indigenous perinatal deaths is almost twice that of non‐Indigenous, there is little support available for Aboriginal and Torres Strait Islander grieving fathers. Objective The SMS4DeadlyDads team partnered with Red Nose, the national charity supporting grieving parents, to co‐design text‐based support for grieving fathers with community representatives and clinicians. Design A 2‐year consultation process with Indigenous services and stakeholders took place in urban and remote locations in Australia. The support for fathers following perinatal loss was assessed, and messages were adapted from those for non‐Indigenous fathers and evaluated. Final messages were reviewed by Red Nose clinicians for optimal delivery timing. Results Community representatives noted the lack of support for new fathers. The culturally appropriate SMS4Deadlydads service delivering text messages to new fathers' mobile phones was welcomed as ‘something for dads’ and the potential to provide confidential support in cases of perinatal loss was recognised. The resulting set of messages was acceptable to indigenous and non‐Indigenous stakeholders. Conclusions The successful development of the messages for Indigenous fathers demonstrates that respectful consultation led by experienced Indigenous leaders can ensure cultural safety and gain community commitment to address highly sensitive topics. Public Contribution Indigenous community representatives and stakeholder service were involved in deciding on the value of the text messaging approach to fathers' grief, the identification of message topics, the wording used in the texts and the linked resources.