Toxicological safety evaluation of DNA plasmid vaccines against HIV-1, Ebola, Severe Acute Respiratory Syndrome, or West Nile virus is similar despite differing plasmid backbones or gene-inserts.

The Vaccine Research Center has developed a number of vaccine candidates for different diseases/infectious agents (HIV-1, Severe Acute Respiratory Syndrome virus, West Nile virus, and Ebola virus, plus a plasmid cytokine adjuvant-IL-2/Ig) based on a DNA plasmid vaccine platform. To support the clinical development of each of these vaccine candidates, preclinical studies were performed to screen for potential toxicities (intrinsic and immunotoxicities). All treatment-related toxicities identified in these repeated-dose toxicology studies have been confined primarily to the sites of injection and seem to be the result of both the delivery method (as they are seen in both control and treated animals) and the intended immune response to the vaccine (as they occur with greater frequency and severity in treated animals). Reactogenicity at the site of injection is generally seen to be reversible as the frequency and severity diminished between doses and between the immediate and recovery termination time points. This observation also correlated with the biodistribution data reported in the companion article (Sheets et al., 2006), in which DNA plasmid vaccine was shown to remain at the site of injection, rather than biodistributing widely, and to clear over time. The results of these safety studies have been submitted to the Food and Drug Administration to support the safety of initiating clinical studies with these and related DNA plasmid vaccines. Thus far, standard repeated-dose toxicology studies have not identified any target organs for toxicity (other than the injection site) for our DNA plasmid vaccines at doses up to 8 mg per immunization, regardless of disease indication (i.e., expressed gene-insert) and despite differences (strengths) in the promoters used to drive this expression. As clinical data accumulate with these products, it will be possible to retrospectively compare the safety profiles of the products in the clinic to the results of the repeated-dose toxicology studies, in order to determine the utility of such toxicology studies for signaling potential immunotoxicities or intrinsic toxicities from DNA vaccines. These data build on the biodistribution studies performed (see companion article, Sheets et al., 2006) to demonstrate the safety and suitability for investigational human use of DNA plasmid vaccine candidates for a variety of infectious disease prevention indications.     

Absorption, distribution, metabolism, and elimination of 8-2 fluorotelomer alcohol in the rat.

The absorption, distribution, metabolism, and elimination of [3-14C] 8-2 fluorotelomer alcohol (8-2 FTOH, C7F1514CF2CH2CH2OH) following a single oral dose at 5 and 125 mg/kg in male and female rats have been determined. Following oral dosing, the maximum concentration of 8-2 FTOH in plasma occurred by 1 h postdose and cleared rapidly with a half-life of less than 5 h. The internal dose to 8-2 FTOH, as measured by area under the concentration-time curve to infinity, was similar for male and female rats and was observed to increase in a dose-dependent fashion. The majority of the 14C 8-2 FTOH (> 70%) was excreted in feces, and 37-55% was identified as parent. Less than 4% of the administered dose was excreted in urine, which contained low concentrations of perfluorooctanoate (approximately 1% of total 14C). Metabolites identified in bile were principally composed of glucuronide and glutathione conjugates, and perfluorohexanoate was identified in excreta and plasma, demonstrating the metabolism of the parent FTOH by sequential removal of multiple CF2 groups. At 7 days postdose, 4-7% of the administered radioactivity was present in tissues, and for the majority, 14C concentrations were greater than whole blood with the highest concentration in fat, liver, thyroid, and adrenals. Distribution and excretion of a single 125-mg/kg [3-14C] 8-2 FTOH dermal dose following a 6-h exposure in rats was also determined. The majority of the dermal dose either volatilized from the skin (37%) or was removed by washing (29%). Following a 6-h dermal exposure and a 7-day collection period, excretion of total radioactivity via urine (< 0.1%) and feces (< 0.2%) was minor, and radioactivity concentrations in most tissues were below the limit of detection. Systemic availability of 8-2 FTOH following dermal exposure was negligible.     

Issues in Design and Implementation in an Urban Birth Cohort Study: The Syracuse AUDIT Project

The Syracuse AUDIT (Assessment of Urban Dwellings for Indoor Toxics) project is a birth cohort study of wheezing in the first year of life in a low-income urban setting. Such studies are important because of the documented serious risks to children's health and the lack of attention and published work on asthma development and intervention in communities of this size. We studied 103 infants of mothers with asthma, living predominantly in inner-city households. Our study combines measurements of a large panel of indoor environmental agents, in-home infant assessments, and review of all prenatal and postnatal medical records through the first year of life. We found multiple environmental pollution sources and potential health risks in study homes including high infant exposure to tobacco smoke. The prevalence of maternal smoking during pregnancy was 54%; postnatal environmental tobacco smoke (ETS) exposure was nearly 90%. The majority (73%) of homes showed signs of dampness. Participants' lives were complicated by poverty, unemployment and single-parenthood. Thirty-three percent of fathers were not involved with their children, and 62% of subjects moved at least once during the study period. These socioeconomic issues had an impact on project implementation and led to modification of study eligibility criteria. Extensive outreach, follow up, and relationship-building were required in order to recruit and retain families and resulted in considerable work overload for study staff. Our experiences implementing the project will inform further studies on this and other similar populations. Future reports on this cohort will address the role of multiple environmental variables and their effects on wheezing outcome during the first year of life.Crawford, Hargrave, Liu, Anbar, Hall, Naishadham, Czerwinski, Webster, Lane, and Abraham are with the Department of Pathology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Hunt is with the UNYSPEC Ltd., Baldwinsville, NY, USA.     

Impact of postdischarge surveillance on surgical site infection rates for several surgical procedures: results from the nosocomial surveillance network in The Netherlands.

OBJECTIVE: To compare the number of surgical site infections (SSIs) registered after hospital discharge with respect to various surgical procedures and to identify the procedures for which postdischarge surveillance (PDS) is most important. DESIGN: Prospective SSI surveillance with voluntary PDS. Recommended methods for PDS in the Dutch national nosocomial surveillance network are addition of a special registration card to the outpatient medical record, on which the surgeon notes clinical symptoms and whether a patient developed an SSI according to the definitions; an alternative method is examination of the outpatient medical record. SETTING: Hospitals participating in the Dutch national nosocomial surveillance network between 1996 and 2004. RESULTS: We collected data on 131,798 surgical procedures performed in 64 of the 98 Dutch hospitals. PDS was performed according to one of the recommended methods for 31,134 operations (24%) and according to another active method for 32,589 operations (25%), and passive PDS was performed for 68,075 operations (52%). Relatively more SSIs were recorded after discharge for cases in which PDS was performed according to a recommended method (43%), compared with cases in which another active PDS method was used (30%) and cases in which passive PDS was used (25%). The highest rate of SSI after discharge was found for appendectomy (79% of operations), followed by knee prosthesis surgery (64%), mastectomy (61%), femoropopliteal or femorotibial bypass (53%), and abdominal hysterectomy (53%). CONCLUSIONS: For certain surgical procedures, most SSIs develop after discharge. SSI rates will be underestimated if no PDS is performed. We believe we have found a feasible and sensitive method for PDS that, if patients routinely return to the hospital for a postdischarge follow-up visit, might be suitable for use internationally.     

Part-time and full-time medical specialists, are there differences in allocation of time?

Background  

An increasing number of medical specialists prefer to work part-time. This development can be found worldwide. Problems to be faced in the realization of part-time work in medicine include the division of night and weekend shifts, as well as communication between physicians and continuity of care. People tend to think that physicians working part-time are less devoted to their work, implying that full-time physicians complete a greater number of tasks. The central question in this article is whether part-time medical specialists allocate their time differently to their tasks than full-time medical specialists.     

Who is at risk of osteoporosis?

This contribution assesses who is at risk of osteoporosis, by delineating the key risk factors involved in the condition. Osteoporosis represents a major public health problem through its association with fragility fractures, primarily of the hip, spine and distal forearm. Some risk factors for fragility fracture act through bone mineral density (BMD), for example female gender, asian or Caucasian race, premature menopause, primary or secondary amenorrhoea, primary and secondary hypogonadism in men, prolongued immobilisation, low dietary calcium intake, vitamin D deficiency. However, a number of others contribute significantly to fracture risk over and above their association with BMD (age, high bone turnover, poor visual acuity, neuromuscular disorders, previous fragility fracture, glucocorticoid therapy, family history of hip fracture, low body weight, cigarette smoking, excess alcohol consumption).     

Functional neuroimaging in child psychiatry

Functional neuroimaging in child psychiatry presents unique scientific, ethical, and technical challenges. The study of childhood disorders presupposes knowledge of neurodevelopment and brain maturation. However, much of human brain science is based on inferences from animal work and indirect neurochemical measures from body fluids. Neuroimaging can examine brain development directly in humans. The benefits can be enormous for learning how and when to intervene to prevent or treat a disorder. These unprecedented potential gains are countered by complex and difficult ethical issues. Technical advances can reduce ethical concerns by minimizing risks. They also promise to enhance the sensitivity and specificity of the measures (eg, by improving spatial and temporal resolution). Judiciously designed investigations will permit the testing of a priori hypotheses built on rational models of neuropathology. Finally, it is the integration of scientific knowledge across the various fields of neuroscience and clinical research that will push the limits of our understanding of health and disease.     

A comparison of HIV seropositive and seronegative young adult heroin- and cocaine-using men who have sex with men in New York City, 2000–2003

The purpose of this analysis was to determine the prevalence and correlates of HIV infection among a street-recruited sample of heroin-and cocaine-using men who have sex with men (MSM). Injection (injecting ≦3 years) and non-injection drug users (heroin, crack, and/or cocaine use<10 years) between 18 and 40 years of age were simultaneously street-recruited into two cohort studies in New York City, 2000–2003, by using identical recruitment techniques. Baseline data collected among young adult men who either identified as gay/bisexual or reported ever having sex with a man were used for this analysis. Nonparametric statistics guided interpretation. Of 95 heroin/ cocaine-using MSM, 25.3% tested HIV seropositive with 75% reporting a previous HIV diagnosis. The majority was black (46%) or Hispanic (44%), and the median age was 28 years (range 18–40). HIV-seropositive MSM were more likely than seronegatives to be older and to have an HIV-seropositive partner but less likely to report current homelessness, illegal income, heterosexual identity, multiple sex partners, female partners, and sex for money/drug partners than seronegatives. These data indicate high HIV prevalence among street-recruited, drug-using MSM compared with other injection drug use (IDU) subgroups and drug-using MSM; however, lower risk behaviors were found among HIV seropositives compared with seronegatives. Large-scale studies among illicit drug-using MSM from more marginalized neighborhoods are warranted.     

Journey of Hope Program Outcomes

Families of persons with mental illness often benefit from participating in interventions which provide education and support. The present study describes outcomes reported by 424 families who participated in one such intervention, the Journey of Hope (JOH) program. Hierarchical regression analyses found that program outcomes—increased knowledge of the causes and treatment of mental illness, increased understanding of the mental health service system, and improved morale—were predictive of one another. JOH therefore may provide families with the knowledge and support they need to strengthen their ability to cope with their relative's mental illness.