Identification of viral genomic elements responsible for rabies virus neuroinvasiveness

Attenuated tissue culture-adapted and natural street rabies virus (RV) strains differ greatly in their neuroinvasiveness. To identify the elements responsible for the ability of an RV to enter the CNS from a peripheral site and to cause lethal neurological disease, we constructed a full-length cDNA clone of silver-haired bat-associated RV (SHBRV) strain 18 and exchanged the genes encoding RV proteins and genomic sequences of this highly neuroinvasive RV strain with those of a highly attenuated nonneuroinvasive RV vaccine strain (SN0). Analysis of the recombinant RV (SB0), which was recovered from SHBRV-18 cDNA, indicated that this RV is phenotypically indistinguishable from WT SHBRV-18. Characterization of the chimeric viruses revealed that in addition to the RV glycoprotein, which plays a predominant role in the ability of an RV to invade the CNS from a peripheral site, viral elements such as the trailer sequence, the RV polymerase, and the pseudogene contribute to RV neuroinvasiveness. Analyses also revealed that neuroinvasiveness of an RV correlates inversely with the time necessary for internalization of RV virions and with the capacity of the virus to grow in neuroblastoma cells.     

Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference

Ghrelin is a recently identified growth hormone (GH) secretogogue whose administration not only induces GH release but also stimulates food intake, increases adiposity, and reduces fat utilization in mice. The effect on food intake appears to be independent of GH release and instead due to direct activation of orexigenic neurons in the arcuate nucleus of the hypothalamus. The effects of ghrelin administration on food intake have led to the suggestion that inhibitors of endogenous ghrelin could be useful in curbing appetite and combating obesity. To further study the role of endogenous ghrelin in appetite and body weight regulation, we generated ghrelin-deficient (ghrl(-/-)) mice, in which the ghrelin gene was precisely replaced with a lacZ reporter gene. ghrl(-/-) mice were viable and exhibited normal growth rates as well as normal spontaneous food intake patterns, normal basal levels of hypothalamic orexigenic and anorexigenic neuropeptides, and no impairment of reflexive hyperphagia after fasting. These results indicate that endogenous ghrelin is not an essential regulator of food intake and has, at most, a redundant role in the regulation of appetite. However, analyses of ghrl(-/-) mice demonstrate that endogenous ghrelin plays a prominent role in determining the type of metabolic substrate (i.e., fat vs. carbohydrate) that is used for maintenance of energy balance, particularly under conditions of high fat intake.     

PTSD in Latino Patients: Illness Beliefs, Treatment Preferences, and Implications for Care

Background  Little is known about how Latinos with post-traumatic stress disorder (PTSD) understand their illness and their preferences for mental health treatment. Objective  To understand the illness beliefs and treatment preferences of Latino immigrants with PTSD. Design  Semi-structured, face-to-face interviews. Participants  Sixty foreign-born, Latino adults recruited from five primary care centers in New York and New Jersey and screened for PTSD. Approach  Content analytic methods identified common themes, their range, and most frequent or typical responses. Results  Participants identified their primary feelings as sadness, anxiety, nervousness, and fear. The most common feeling was “sad” (triste). Other words frequently volunteered were “angry” (enojada), “nervous” (nerviosa), and “scared” (miedo). Participants viewed their PTSD as impairing health and functioning. They ascribed their somatic symptoms and their general medical problems to the “stress” from the trauma and its consequences on their lives. The most common reason participants volunteered for their work and school functioning being impaired was their poor concentration, often due to intrusive thoughts. Most expressed their desire to receive mental health treatment, to receive it within their primary care center, and preferred psychotherapy over psychotropic medications. Among participants who did not report wanting treatment, most said it was because the trauma was “in the past.” Conclusions  Clinicians may consider enquiring about PTSD in Latino patients who report feeling sad, anxious, nervous, or fearful. Our study suggests topics clinicians may include in the psychoeducation of patients with PTSD.     

Is glucose self-monitoring beneficial in non-insulin-treated diabetic patients? Results of a randomized comparative trial

To study if self-monitoring of glucose, urinary or capillary, could help them to improve their metabolic control through better compliance to diet and/or hypoglycaemic agents, 208 non-insulin-treated poorly controlled diabetic patients were randomized to: group A--regular HbA1c determinations but no self-monitoring, group B--self-urine glucose monitoring, twice every other day, group C--self blood glucose monitoring, twice every other day, and followed six months. At the end of the study period, the decrease of HbA1c over six months--main endpoint--was not significantly different between the three groups (mean +/- SEM; group A: -0.5 +/- 0.2%; group B: -0.1 +/- 0.3%; group C: -0.4 +/- 0.3%). However, the degree of compliance to blood glucose self-monitoring in group C appeared to relate to the outcome: a significant correlation was found between the number of blood glucose strips used and the decrease of HbA1c (r = .36, p less than .02). We conclude that regular self-monitoring has no definite advantage over the usual management for improving metabolic control in non-insulin-treated diabetic patients, though it may possibly help patients ready to comply with its use.     

Proton Pump Inhibitors Independently Protect Against Early Allograft Injury or Chronic Rejection After Lung Transplantation

Background

Acid reflux has been associated with poor outcomes following lung transplantation. Unlike surgical fundoplication, the role of noninvasive, pharmacologic acid suppression remains uncertain.

Aims

To assess the relationship between post-transplant acid suppression with proton pump inhibitors (PPI) or histamine-2 receptor antagonists (H2RA) and onset of early allograft injury or chronic rejection following lung transplantation.

Methods

This was a retrospective cohort study of lung transplant recipients at a tertiary center in 2007–2014. Patients with pre-transplant antireflux surgery were excluded. Time-to-event analysis using the Cox proportional hazards model was applied to assess acid suppression therapy and onset of acute or chronic rejection, defined histologically and clinically. Subgroup analyses were performed to assess PPI versus H2RA use.

Results

A total of 188 subjects (60% men, mean age 54, follow-up 554 person-years) met inclusion criteria. During follow-up, 115 subjects (61.5%) developed rejection, with all-cause mortality of 27.6%. On univariate analyses, acid suppression and BMI, but not other patient demographics, were associated with rejection. The Kaplan–Meier curve demonstrated decreased rejection with use of acid suppression therapy (log-rank p = 0.03). On multivariate analyses, acid suppression (HR 0.39, p = 0.04) and lower BMI (HR 0.67, p = 0.04) were independently predicted against rejection. Subgroup analyses demonstrated that persistent PPI use was more protective than H2RA or no antireflux medications.

Conclusions

Post-lung transplant exposure to persistent PPI therapy results in the greatest protection against rejection in lung transplant recipients, independent of other clinical predictors including BMI, suggesting that PPI may have antireflux or anti-inflammatory effects in enhancing allograft protection.

     

The diagnostic laboratory tests for histoplasmosis: analysis of experience in a large urban outbreak

Of 495 patients reported in a large urban histoplasmosis outbreak, we studied 276 whose serologic tests were done in a single laboratory. Serologic test results were positive in 96% of these patients (compared with less than 5% of controls from an endemic area), cultures were positive in 22%, and special stains in 19%. The immunodiffusion test results were negative in 13% of patients who had positive findings by complement fixation, and 1% had positive results only by immunodiffusion. The complement fixation test was almost twice as sensitive as the immunodiffusion test in patients with subclinical infection. The serologic response differed significantly among the clinical syndromes with higher titers in cavitary and lower titers in disseminated disease. Factors associated with titers of 1:64 or greater to both antigens were black race and immunocompetence. High mycelial titers were also associated with more intense exposure, and high yeast titers were associated with age less than 36 years. No prognostic significance could be proved for fourfold titer rises or falls or persistence of precipitins.     

Measuring positive affect and well-being after spinal cord injury: Development and psychometric characteristics of the SCI-QOL Positive Affect and Well-being bank and short form

ObjectiveTo develop an item response theory (IRT)-calibrated spinal cord injury (SCI)-specific Positive Affect and Well-being (PAWB) item bank with flexible options for administration.DesignQualitative feedback from patient and provider focus groups was used to expand on the Neurological Disorders and Quality of Life (Neuro-QOL) positive affect & well-being item bank for use in SCI. New items were created and revised based on expert review and patient feedback and were then field tested. Analyses included confirmatory factor analysis, graded response IRT modeling and evaluation of differential item functioning (DIF).SettingWe tested a 32-item pool at several rehabilitation centers across the United States, including the University of Michigan, Kessler Foundation, Rehabilitation Institute of Chicago, the University of Washington, Craig Hospital and the James J. Peters/Bronx Department of Veterans Affairs hospital.ParticipantsA total of 717 individuals with SCI answered the PAWB questions.ResultsA unidimensional model was observed (Confirmatory Fit Index = 0.947; Root Mean Square Error of Approximation = 0.094) and measurement precision was good (reliability in theta of –2.9 to 1.2 is roughly equivalent to classical reliability of 0.95 or above). Twelve items were flagged for DIF, however, after examination of effect sizes, the DIF was determined to be negligible and would have little practical impact on score estimates. The final calibrated item bank resulted in 28 retained itemsConclusionsThis study indicates that the Spinal Cord Injury – Quality of Life PAWB bank represents a psychometrically robust measurement tool. Short form items are also suggested and a computer adaptive test is available.     

Pulmonary arterial hypertension caused by neoplastic thrombosis of the pulmonary artery]

Neoplastic thrombosis of the pulmonary artery is a rare and little known cause of pulmonary arterial hypertension. The clinical picture is one of acute respiratory failure and progressive right ventricular failure caused by pre-capillary pulmonary hypertension. In the living patient there is no way of distinguishing this condition from that of subacute cor pulmonale due to embolism, especially as the primary tumour is not always found either because it is too small or because it has already regressed by the time it has metastasised. The diagnosis usually rests on histological examination of the lungs, and two pathological types can be distinguished: carcinomatous lymphangitis with secondary invasion and thrombosis of the pulmonary arterioles on the one hand, and the neoplastic arterial emboli of a chorio-epithelioma on the other.     

Outcomes of a Behavioral Intervention to Reduce HIV Risk Among Drug-involved Female Sex Workers

Although street-based female sex workers (FSWs) are highly vulnerable to HIV, they often lack access to needed health services and medical care. This paper reports the results of a recently completed randomized intervention trial for FSWs in Miami, Florida, which tested the relative efficacy of two case management interventions that aimed to link underserved FSWs with health services and to reduce risk behaviors for HIV. Participants were recruited using targeted sampling strategies and were randomly assigned to: a Strengths-Based/Professional Only (PO) or a Strengths-Based/Professional-Peer condition (PP). Follow-up data were collected 3 and 6 months post-baseline. Outcome analyses indicated that both intervention groups displayed significant reductions in HIV risk behaviors and significant increases in services utilization; the Professional-Peer condition provided no added benefit. HIV seropositive FSWs responded particularly well to the interventions, suggesting the utility of brief strengths-based case management interventions for this population in future initiatives.     

Life insurance: genomic stratification and risk classification

With the development and increasing accessibility of new genomic tools such as next-generation sequencing, genome-wide association studies, and genomic stratification models, the debate on genetic discrimination in the context of life insurance became even more complex, requiring a review of current practices and the exploration of new scenarios. In this perspective, a multidisciplinary group of international experts representing different interests revisited the genetics and life insurance debate during a 2-day symposium ‘Life insurance: breast cancer research and genetic risk prediction seminar'' held in Quebec City, Canada on 24 and 25 September 2012. Having reviewed the current legal, social, and ethical issues on the use of genomic information in the context of life insurance, the Expert Group identified four main questions: (1) Have recent developments in genomics and related sciences changed the contours of the genetics and life insurance debate? (2) Are genomic results obtained in a research context relevant for life insurance underwriting? (3) Should predictive risk assessment and risk stratification models based on genomic data also be used for life insurance underwriting? (4) What positive actions could stakeholders in the debate take to alleviate concerns over the use of genomic information by life insurance underwriters? This paper presents a summary of the discussions and the specific action items recommended by the Expert Group.Access to genetic information by life insurers has been a topic of discussion for many years.¹ The possibility of using genetic data to underwrite an applicant''s insurance policy has given rise to concerns about the emergence of ‘genetic discrimination''. Genetic discrimination in the field of life insurance is not necessarily illegal in that in insurance underwriting questions about health, family history of disease, or genetic information may constitute legal exceptions to antidiscrimination legislation.^{2, 3} Nevertheless, the expression ‘genetic discrimination'' has acquired public notoriety⁴ and we will use more neutral language in this paper.Countries including Canada, the United States, Russia, and Japan⁵ have chosen not to adopt laws specifically prohibiting access to genetic data for underwriting by life insurers.⁶ In these countries, life insurance underwriters treat genetic data like other types of medical or lifestyle data. However, a growing number of countries such as Belgium, France, and Norway⁵ have chosen to adopt laws to prevent or limit insurers'' access to genetic data for life insurance underwriting. Other countries including Finland and the United Kingdom have developed voluntary arrangements with the industry (ie moratoria) with similar objectives.⁷Life insurance is a private contract between the policy-holder and the insurer. Its principal role is to provide financial security to the beneficiaries in the event of the insured''s death.⁸ Because of this important role, life insurance is often required, or strongly recommended for those seeking loans to acquire primary social goods, like housing or cars.⁹ In Europe, a consequence of the advent of the welfare state is that private insurance has increasingly played a complementary and supplementary role to social insurance by offering additional security and protection to the population. Thus, in this region, insurance is often considered as a social good that allows individuals to live a comfortable life and as a tool to promote social integration.¹⁰ In other regions of the world, this social role of life insurance is also recognized to a lesser extent. Given this social role, equitable access to life insurance is perceived as a sensitive issue and cases of denial looked upon negatively in popular media. Although documented incidents of denial or of increased premiums on the basis of genetic information have remained limited to the context of a few relatively well known, highly penetrant, familial, adult-onset, genetic conditions,¹¹ they have nevertheless generated significant public concern. Fear that insurers will have access to genetic information generated in a clinical or research setting for use in underwriting has been reported by several studies as a reason for non-participation in genetic research or recommended clinical genetic testing.^{12, 13, 14}The clinical utility of genetic testing for monogenic disorders such as Huntington disease, and hereditary forms of cancer are well established.¹⁵ However, genomic risk profiles based on the known common susceptibility variants have limited utility in risk prediction at the individual level, although they could be used for risk stratification in prevention programmes in populations.¹⁶ Today, a new era of genomic research has made it increasingly affordable to scan the entire genome of an individual. Researchers and physicians can interpret these data together with medical and lifestyle information in the form of sophisticated risk prediction models.¹⁷ Moreover, improvement in computing technologies coupled with the Internet make predictive information increasingly available, whether through direct-to-consumer marketing of genetic tests, genetic data sharing online communities, or international research database projects. Given these important technological and scientific changes, and their impact on various stakeholders. The term ‘stakeholders'' is used in this text to refer to the following groups of individuals: actuaries (person who computes insurance risk and premium rates based on statistical data), academic researchers, community representatives, ethics committees, genetic counsellors, genomic researchers, human rights experts, insurers, governmental representatives, non-governmental organisations, patient representatives, physicians, policy makers, popular media, reinsurers (company in charge of calculating the risk and premium amount for insuring a particular customer), research participants, and underwriters (company or person in charge of calculating the risk involved in providing insurance for a particular customer and to decide how much should be paid for the premium). This list is not meant to be exhaustive as relevant new groups may emerge as this topic further develops in the coming years. A multidisciplinary group of international experts representing different interests (hereinafter ‘the Expert Group'') revisited the genetics and life insurance debate. The following text presents a summary of the issues discussed and the ‘Action Items'' agreed upon by the Expert Group at the ‘Life Insurance, Risk Stratification, and Personalized Medicine Symposium''.