Inhibition of αvß5 Integrin Attenuates Vascular Permeability and Protects against Renal Ischemia-Reperfusion Injury.

Ischemia-reperfusion injury (IRI) is a leading cause of AKI. This common clinical complication lacks effective therapies and can lead to the development of CKD. The αvß5 integrin may have an important role in acute injury, including septic shock and acute lung injury. To examine its function in AKI, we utilized a specific function-blocking antibody to inhibit αvß5 in a rat model of renal IRI. Pretreatment with this anti-αvß5 antibody significantly reduced serum creatinine levels, diminished renal damage detected by histopathologic evaluation, and decreased levels of injury biomarkers. Notably, therapeutic treatment with the αvß5 antibody 8 hours after IRI also provided protection from injury. Global gene expression profiling of post-ischemic kidneys showed that αvß5 inhibition affected established injury markers and induced pathway alterations previously shown to be protective. Intravital imaging of post-ischemic kidneys revealed reduced vascular leak with αvß5 antibody treatment. Immunostaining for αvß5 in the kidney detected evident expression in perivascular cells, with negligible expression in the endothelium. Studies in a three-dimensional microfluidics system identified a pericyte-dependent role for αvß5 in modulating vascular leak. Additional studies showed αvß5 functions in the adhesion and migration of kidney pericytes in vitro Initial studies monitoring renal blood flow after IRI did not find significant effects with αvß5 inhibition; however, future studies should explore the contribution of vasomotor effects. These studies identify a role for αvß5 in modulating injury-induced renal vascular leak, possibly through effects on pericyte adhesion and migration, and reveal αvß5 inhibition as a promising therapeutic strategy for AKI.

JC Polyomavirus Abundance and Distribution in Progressive Multifocal Leukoencephalopathy (PML) Brain Tissue Implicates Myelin Sheath in Intracerebral Dissemination of Infection.

Over half of adults are seropositive for JC polyomavirus (JCV), but rare individuals develop progressive multifocal leukoencephalopathy (PML), a demyelinating JCV infection of the central nervous system. Previously, PML was primarily seen in immunosuppressed patients with AIDS or certain cancers, but it has recently emerged as a drug safety issue through its association with diverse immunomodulatory therapies. To better understand the relationship between the JCV life cycle and PML pathology, we studied autopsy brain tissue from a 70-year-old psoriasis patient on the integrin alpha-L inhibitor efalizumab following a ~2 month clinical course of PML. Sequence analysis of lesional brain tissue identified PML-associated viral mutations in regulatory (non-coding control region) DNA, capsid protein VP1, and the regulatory agnoprotein, as well as 9 novel mutations in capsid protein VP2, indicating rampant viral evolution. Nine samples, including three gross PML lesions and normal-appearing adjacent tissues, were characterized by histopathology and subject to quantitative genomic, proteomic, and molecular localization analyses. We observed a striking correlation between the spatial extent of demyelination, axonal destruction, and dispersion of JCV along white matter myelin sheath. Our observations in this case, as well as in a case of PML-like disease in an immunocompromised rhesus macaque, suggest that long-range spread of polyomavirus and axonal destruction in PML might involve extracellular association between virus and the white matter myelin sheath.

Small molecule mediated inhibition of RORγ-dependent gene expression and autoimmune disease pathology in vivo.

Retinoic acid receptor-related orphan nuclear receptor γ (RORγ) orchestrates a pro-inflammatory gene expression programme in multiple lymphocyte lineages including T helper type 17 (Th17) cells, γδ T cells, innate lymphoid cells and lymphoid tissue inducer cells. There is compelling evidence that RORγ-expressing cells are relevant targets for therapeutic intervention in the treatment of autoimmune and inflammatory diseases. Unlike Th17 cells, where RORγ expression is induced under specific pro-inflammatory conditions, γδ T cells and other innate-like immune cells express RORγ in the steady state. Small molecule mediated disruption of RORγ function in cells with pre-existing RORγ transcriptional complexes represents a significant and challenging pharmacological hurdle. We present data demonstrating that a novel, selective and potent small molecule RORγ inhibitor can block the RORγ-dependent gene expression programme in both Th17 cells and RORγ-expressing γδ T cells as well as a disease-relevant subset of human RORγ-expressing memory T cells. Importantly, systemic administration of this inhibitor in vivo limits pathology in an innate lymphocyte-driven mouse model of psoriasis.

The use of immunohistochemistry for biomarker assessment--can it compete with other technologies?

A morphology-based assay such as immunohistochemistry (IHC) should be a highly effective means to define the expression of a target molecule of interest, especially if the target is a protein. However, over the past decade, IHC as a platform for biomarkers has been challenged by more quantitative molecular assays with reference standards but that lack morphologic context. For IHC to be considered a "top-tier" biomarker assay, it must provide truly quantitative data on par with non-morphologic assays, which means it needs to be run with reference standards. However, creating such standards for IHC will require optimizing all aspects of tissue collection, fixation, section thickness, morphologic criteria for assessment, staining processes, digitization of images, and image analysis. This will also require anatomic pathology to evolve from a discipline that is descriptive to one that is quantitative. A major step in this transformation will be replacing traditional ocular microscopes with computer monitors and whole slide images, for without digitization, there can be no accurate quantitation; without quantitation, there can be no standardization; and without standardization, the value of morphology-based IHC assays will not be realized.

The association between church attendance and psychological health in Northern Ireland: a national representative survey among adults allowing for sex differences and denominational difference.

This study extends previous research concerning the association between religion and psychological health in six ways: (1) by focusing clearly on religious attendance (church attendance); (2) by employing a robust measure of psychological distress (GHQ-12); (3) by studying a highly religious culture (Northern Ireland); (4) by taking sex differences into account (male or female); (5) by taking denominational differences into account (Catholic or Protestant); (6) and by obtaining a national representative sample (N = 4,281 adults aged 16 and above). Results from a 2 (sex) by 2 (denomination) ANCOVA demonstrated that Catholics recorded significantly lower levels of psychological health compared to Protestants, and that females showed significantly lower levels of psychological health compared to males. In addition, females reported higher frequency of religious service attendance than males, and Catholics reported higher attendance rates than Protestants. A significant positive association was found between frequency of religious attendance and GHQ-12 scores, and this association was moderated by sex and denomination. In conclusion, the results suggest that there may be sex and denominational differences in further understanding the relationship between frequency of religious attendance and psychological health.

Norovirus outbreak in a cruise ship sailing around the British Isles: investigation and multi-agency management of an international outbreak.

OBJECTIVE: Managing an outbreak of gastroenteritis (GI) on board a cruise ship while minimising disruption to passengers' on board and shore visit activities is difficult. For this reason it is important to understand the complex patterns of transmission in a closed community. We describe the epidemiological investigation of an outbreak of norovirus during an international cruise. METHODS: A retrospective cohort study was conducted using information from lists routinely maintained by the travel company, including the passenger manifest, and organised coach tour lists. Information on air-conditioning (AC) systems was used to assess the possible sources of exposures. FINDINGS: Of the 1194 passengers 191 (16%) and 5 crew (<1%) became ill with GI symptoms. The attack rate was higher amongst passengers whose cabin was on the main deck (RR 3.41, 95% CI 1.47-7.94) that houses both passengers' cabins and leisure facilities including shops. Passengers who went on one of the organised coach tours where there were symptomatic passengers were at an increased risk of infection (RR 2.14, CI 1.51-3.03). Analysis of the 56 AC sections on the ship and did not detect an association with infection. CONCLUSIONS: Patterns of transmission of norovirus on a cruise ship are complex. Our study suggests infections are more likely among those passengers staying in areas of the ship that are highly transited or used for communal activities and more difficult to clean. Emphasis on the importance of early reporting of symptoms can help minimise transmission. Internationally agreed guidelines on the management of outbreaks on cruise ships are needed.

The theory of planned behavior and binge drinking: assessing the impact of binge drinker prototypes.

The present study assessed the value of including prototype perceptions within the theory of planned behavior (TPB) when predicting young people's binge drinking intentions and behavior. Undergraduate students (N=94) completed questionnaires assessing the main constructs of the TPB as well as measures of prototype evaluation and prototype similarity. Binge drinking behavior was assessed at one-week follow-up (N=79). The TPB explained 58% of the variance in binge drinking intentions and 22% of the variance in binge drinking at one-week follow-up. The prototype perception measures explained additional variance in both binge drinking intentions (DeltaR(2)=.04) and behavior (DeltaR(2)=.09), although only prototype similarity emerged as a significant predictor. In addition, a significant interaction was found between prototype similarity and subjective norm in relation to the prediction of binge drinking behavior, suggesting that the perception of supportive norms may enhance the impact of prototype perceptions on health-risk behavior. The implications of the findings for interventions to encourage more appropriate drinking behavior are outlined.

Flu vaccination in nursing homes: a survey of nursing-home managers.

BACKGROUND: This article describes the findings of a survey of nursing-home managers in the Sefton area of Merseyside about flu vaccination in their nursing homes during the 2002/2003 flu vaccination campaign. This followed concerns expressed that significant numbers of nursing-home residents may not have been offered the vaccine during the annual campaign. METHODS: A survey of all nursing homes in Sefton carried out in April 2003. RESULTS: Forty-three nursing homes participated in the study. Survey results showed considerable variation in practice with regard to the organization of flu vaccination and consequently considerable variation in the outcomes achieved with regard to the number of residents vaccinated. Residents are more likely to be offered vaccination in some homes than others. The size of the home and the number of qualified staff may be influential. Some homes report uncertainty related to the issues of consent and anaphylaxis and problems obtaining vaccine prescriptions. However, attitudes of nursing-home managers may also be important.

The General Health Questionnaire and Eysenck's three-dimensional model of personality.

A sample of 115 men and women between the ages of 20 and 60 completed the 30-item General Health Questionnaire together with the short-form Revised Eysenck Personality Questionnaire. The data indicate psychological distress so assessed is correlated .43 (p <.001) with Neuroticism and -.26 (p <.01) with Introversion but is unrelated to Psychoticism scores.

Role for microphthalmia transcription factor in the diagnosis of metastatic malignant melanoma.

Microphthalmia transcription factor (Mitf), a protein critical for the embryonic development and postnatal viability of melanocytes, is a master lineage regulator and modulates extracellular signals. Recently, an anti-Mitf antibody, D5, was shown to be both a sensitive and a specific marker of epithelioid melanoma. Those data suggested that Mitf expression was specific for melanocytic differentiation because it was not detected in six different carcinoma types. To broaden the spectrum of melanomatous and nonmelanomatous tumors tested with this antibody, the authors investigated the sensitivity and specificity of the D5 anti-Mitf antibody in 36 metastatic melanomas and 102 nonmelanomatous tumors. Twenty-nine of 36 (81%) melanomas examined were reactive for D5. Of these, 29 of 32 (91%) epithelioid melanomas were reactive, whereas all 4 melanomas with spindle cell morphology were nonreactive. Six of 102 (5.8%) nonmelanomatous tumors (1 breast carcinoma, 1 malignant mixed mullerian tumor, 2 renal cell carcinomas, and 2 leiomyosarcomas) were reactive for D5. All melanomas were reactive for S-100 protein (a criteria for inclusion in the study), whereas 8 of 102 (7.8%) of nonmelanomatous tumors were reactive. Twenty-five of 36 melanomas (69%) were reactive for HMB-45, whereas no nonmelanomatous tumors were reactive. Twenty-one of 28 (75%) melanomas were reactive for Melan-A. Reactivity for Melan-A was detected in 5 of 102 (4.9%) nonmelanomatous tumors. As with D5, HMB-45 and Melan-A failed to detect all spindle-cell melanomas. Results of this study confirm that D5 is a sensitive marker for epithelioid melanomas; however, the authors found D5 neither quite as sensitive nor quite as specific as in previous studies. Nevertheless, the authors believe that positive staining for D5 when taken in clinical, histologic, and immunohistochemical context may be diagnostically useful. In particular, D5 is helpful in the evaluation of epithelioid neoplasms, but not spindle-cell tumors.