Molecular biology and pathogenesis of the human T-cell leukaemia/lymphotropic virus Type-1 (HTLV-1)

Retroviruses are associated with a variety of diseases, including immunological and neurological disorders, and various forms of cancer. In humans, the Human T-cell Leukaemia/Lymphotropic virus type 1 (HTLV-1), which belongs to the Oncovirus family, is the aetiological agent of two diverse diseases: Adult T-cell leukaemia/lymphoma (ATLL) (Poiesz et al. 1980; Hinuma et al. 1981; Yoshida et al. 1982), as well as the neurological disorder tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM) (Gessain et al. 1985; Rodgers-Johnson et al. 1985; Osame et al. 1986). HTLV-1 is the only human retrovirus known to be the aetiological agent of cancer. A genetically related virus, HTLV-2, has been identified and isolated (Kalyanaraman et al. 1982). However, there has been no demonstration of a definitive aetiological role for HTLV-2 in human disease to date. Simian T-cell lymphotropic viruses types 1 and 2 (STLV-1 and -2) and bovine leukaemia virus (BLV) have also been classified in same group, Oncoviridae, based upon their similarities in genetic sequence and structure to HTLV-1 and -2 (Burny et al. 1988; Dekaban et al. 1995; Slattery et al. 1999). This article will focus on HTLV-1, reviewing its discovery, molecular biology, and its role in disease pathogenesis.     

Genetic heterogeneity in spondyloepiphyseal dysplasia congenita

Two unrelated infants seen for evaluation of short stature at 14 and 27 months, respectively, had clinical and radiographic findings consistent with the diagnosis of spondyloepiphyseal dysplasia congenita (SED congenita). No other anomalies were noted. Both sets of parents were normal, both family histories were unremarkable, and neither couple was consanguineous. Both families were counseled that SED congenita is an autosomal dominant disorder and that sporadic cases probably result from new mutations; a low recurrence risk was given. Both families subsequently produced a second affected child. Our experiences suggest that genocopies of autosomal dominant SED congenita exist that are clinically and radiographically indistinguishable, at least within the first 3 years. Autosomal recessive inheritance seems most likely, although alternative explanations are possible. Genetic heterogeneity should be considered when providing genetic counseling for sporadic SED congenita in young children.     

Increased susceptibility to RSV infection by exposure to inhaled diesel engine emissions

Although epidemiologic data strongly suggest a role for inhaled environmental pollutants in modulating the susceptibility to respiratory infection in humans, the underlying cellular and molecular mechanisms have not been well studied in experimental systems. The current study assessed the impact of inhaled diesel engine emissions (DEE) on the host response in vivo to a common pediatric respiratory pathogen, respiratory syncytial virus (RSV). Using a relatively resistant mouse model of RSV infection, prior exposure to either 30 microg/m3 particulate matter (PM) or 1,000 microg/m3 PM of inhaled DEE (6 h/d for seven consecutive days) increased lung inflammation to RSV infection as compared with air-exposed RSV-infected C57Bl/6 mice. Inflammatory cells in bronchoalveolar lavage fluid were increased in a dose-dependent manner with regard to the level of DEE exposure, concomitant with increased levels of inflammatory mediators. Lung histology analysis indicated pronounced peribronchial and peribronchiolar inflammation concordant with the level of DEE exposure during infection. Mucous cell metaplasia was markedly increased in the airway epithelium of DEE-exposed mice following RSV infection. Interestingly, both airway and alveolar host defense and immunomodulatory proteins were attenuated during RSV infection by prior DEE exposure. DEE-induced changes in inflammatory and lung epithelial responses to infection were associated with increased RSV gene expression in the lungs following DEE exposure. These findings are consistent with the concept that DEE exposure modulates the lung host defense to respiratory viral infections and may alter the susceptibility to respiratory infections leading to increased lung disease.     

Familial pseudomembranous colitis and its relation to lincomycin therapy

Severe pseudomembranous colitis was observed in 3 members of a single family: the father and 2 of his children. 2 of the affected family members received the antibiotic lincomycin prior to the onset of their symptoms. The findings in this family raise the possibility that antibiotic-induced pseudomembranous colitis in some patients may be the result of a pharmacogenetic interaction.Supported by grants from the National Institutes of Health (GM 19258) and from the Upjohn Co. Dr. Brown is an Established Investigator of The American Heart Association. Dr. Goldstein is the recipient of USPHS Research Career Development Award 5 KO4 GM 70277.     

Effects of low sulfur fuel and a catalyzed particle trap on the composition and toxicity of diesel emissions

In this study we compared a "baseline" condition of uncontrolled diesel engine exhaust (DEE) emissions generated with current (circa 2003) certification fuel to an emissions-reduction (ER) case with low sulfur fuel and a catalyzed particle trap. Lung toxicity assessments (resistance to respiratory viral infection, lung inflammation, and oxidative stress) were performed on mice (C57Bl/6) exposed by inhalation (6 hr/day for 7 days). The engine was operated identically (same engine load) in both cases, and the inhalation exposures were conducted at the same exhaust dilution rate. For baseline DEE, this dilution resulted in a particle mass (PM) concentration of approximately 200 microg/m3 PM, whereas the ER reduced the PM and almost every other measured constituent [except nitrogen oxides (NOx)] to near background levels in the exposure atmospheres. These measurements included PM, PM size distribution, PM composition (carbon, ions, elements), NOx, carbon monoxide, speciated/total volatile hydrocarbons, and several classes of semivolatile organic compounds. After exposure concluded, one group of mice was immediately sacrificed and assessed for inflammation and oxidative stress in lung homogenate. Another group of mice were intratracheally instilled with respiratory syncytial virus (RSV), and RSV lung clearance and inflammation was assessed 4 days later. Baseline DEE produced statistically significant biological effects for all measured parameters. The use of low sulfur fuel and a catalyzed trap either completely or nearly eliminated the effects.     

Cold tolerance: behavioral differences following single or multiple cold exposures

Previous research has demonstrated that repeated exposure to cold water results in cold tolerance. The present set of experiments examined whether spontaneous behavioral activity and the rate of rewarming differed between cold tolerant and nontolerant rats. Animals receiving six cold exposures (one per day) were compared to subjects receiving a single cold exposure but cooled to match the final day temperature of the six-exposure group. Immediately following the final or only cold exposure, activity was measured by an activity monitor (Exp. 1) or was videotaped and scored by an independent observer (Exp. 2). Furthermore, rats' temperatures were monitored for 90 min (Exp. 2) and 60 min (Exp. 3) following the activity measurement. The results indicated that cold-tolerant rats exhibited activity similar to normal, noncooled subjects, whereas the activity in the single exposure group was impeded. Moreover, rats in the multiple exposure groups rewarmed more quickly than subjects in the single exposure condition. The third experiment also examined if the procedures of Experiments 1 and 2 resulted in associative cold tolerance. Experiment 3 replicated earlier findings, which have shown that exposure to the same cold stimulus in an altered context resulted in a loss of tolerance. These findings suggest that the processing of contextual stimuli is necessary for the acquisition of cold tolerance and that behavioral activity and rewarming rates can be used as alternative measures of cold tolerance.