Transmission routes of HIV-1 gp120 from brain to lymphoid tissues

The blood-brain barrier (BBB) restricts the entry of antiviral agents into the CNS thereby facilitating the creation of a reservoir of HIV that could potentially reinfect peripheral tissues. We characterized the efflux from brain of radioactively labeled viral coat HIV-1 gp120 (I-gp120) after intracerebroventricular (i.c.v.) injection. The half-time disappearance rate of I-gp120 from brain was 12.6 min, which was faster than could be explained by the reabsorption of cerebrospinal fluid into blood but could not be explained by a saturable transporter. After i.c.v. injection, I-gp120 appeared in the serum and was sequestered by spleen and the cervical nodes, demonstrating a potential for virus within the CNS to reinfect peripheral tissues. However, the amount of I-gp120 appearing in serum was less than that expected based on the efflux rate, whereas uptake by the cervical nodes was much greater after i. c.v. than after i.v. injection of I-gp120. These findings were explained by drainage from the brain directly to the cervical lymph nodes through the brain's primitive lymphatic system. These lymphatics potentially provide a pathway through which CNS reservoirs of HIV-1 could directly reinfect lymphoid tissue without being exposed to circulating antiviral agents.     

Preliminary report of mortality among workers compensated for work-related asthma

BACKGROUND: Although fatalities due to asthma have been reported among subjects with occupational asthma (OA) associated with re-exposure, groups of subjects with work-related asthma have not been systematically followed up for mortality. During a review of compensation claims for asthma in Ontario, we identified 3 respiratory deaths among subjects previously compensated for OA for whom their surviving spouses received death benefits. This suspected "cluster" prompted us to undertake an investigation to examine mortality pattern among workers compensated for work-related asthma. METHODS: Subjects receiving compensation for OA or aggravation of asthma (AA) between 1980 and 1993, and a comparison sample of workers with claims for musculoskeletal injuries during the same period were identified from the Ontario Workers' Compensation Board. We also identified another comparison group of non-compensated asthmatic patients seen at a hospital clinic during the same period. The files of those with work-related asthma were reviewed to determine if OA or AA was adequately documented. Mortality was ascertained by linkage with the Mortality Database at the Ontario Cancer Registry through 1996. We compared the mortality of the three groups with that expected in the general population of Ontario using SMRs, and directly by proportional-hazards regression. RESULTS: The study included 3,070 subjects: 1,112 with work-related OA/AA with adequate documentation, 1,556 with work-related injuries, and 402 patients with non-work-related asthma. Of the 66 deaths identified, only 2 deaths were due to asthma, both in the work-related asthma group: one from the index cluster and one not previously identified. A second index death was coded as dying from COPD not elsewhere classified (ICD9 496), while the third index death also died of asthma but there was not sufficient information documenting OA to include the subject in the analyses. As compared with the general population, there were fewer deaths than expected from most causes, except for deaths among the work-related asthma claimants and the nonwork-related asthma patients from respiratory diseases (SMRs 1.3 and 5.9, respectively; 0.5 among injury claimants), all chronic obstructive lung disease (ICD9 490-496; SMRs 2.3 and 7.7, respectively), and asthma (SMRs 18.2 and 0, respectively). In direct comparison of the work-related asthma claimants with the injury claimants, the risk of death appeared elevated from respiratory disease (RR 2.6) and ischemic heart disease (IHD) (RR 2.8) but the confidence intervals included unity. CONCLUSIONS: This preliminary report raises the possibility that serious outcomes, including excess deaths from respiratory disease, in particular asthma, may occur among those with work-related asthma even in the absence of re-exposure. However, the findings are inconclusive given that the number of deaths was small and we identified only one new asthma death in addition to the index cluster. We also observed for the first time that deaths due to circulatory disease, particularly IHD, may also be increased among such workers; this needs to be confirmed elsewhere.     

Cytokines in combination with chemotherapy for advanced renal carcinoma--the importance of patient selection

An outpatient regimen of interferon-alpha (IFN-alpha), interleukin-2 (IL-2) and 5-fluorouracil (5-FU) was previously reported to have significant activity (response rate 48.6%) in patients with advanced renal cell carcinoma (RCC). The patient group reported were generally of good performance status (PS), had undergone previous nephrectomy and would be considered of good prognosis with respect to response and survival after treatment with IL-2. The characteristics of patients with RCC referred to specialist units in the UK differ from that patient group in that many patients present with metastatic disease, are of poor PS and are considered unfit for nephrectomy. We tested the three drug regimen in a representative patient group of 55 patients who had: median PS of 1 (range 0-2); median time from diagnosis to treatment of 2.7 months (0.2-113); and median number of sites of disease 3 (1-5). 22/55 had not had prior nephrectomy and 31 were considered of poor risk, 15 moderate risk and only 9 of good risk. Treatment consisted of an 8 week cycle of IFN-alpha 6 MU/m2 day 1 weeks 1 and 4 and thrice weekly weeks 2-3 and 9 MU/m2 thrice weekly, weeks 5-8. IL-2 20 MU/m2 days 3-5, weeks 1 and 4 and 5 MU/m2 thrice weekly weeks 2-3. 5-FU 750 mg/m2 day 1 of weeks 5-8. There were no complete responses (CR), 9 (17%) partial responses (PR) and 13 patients (24%) had stable disease. Sixteen patients withdrew early from treatment and were not evaluable for response. Amongst 25 evaluable patients who had undergone nephrectomy the response rate was 32% (95% CI: 14-50%). Only 1 response was seen in patients who had not undergone nephrectomy. Survival was predicted by PS, nephrectomy, number of sites of metastasis and risk group. Most patients experienced significant toxicity of grade I/II but few grade III/IV toxicities were seen as compared to intravenous IL-2 regimens. These data are part of a large data set that has been submitted for publication in The British Journal of Urology. The regimen has been shown to have activity but this is seen predominantly in patients of good PS, with prior nephrectomy and limited sites of disease. Patients of poor risk are likely to experience significant toxicity without benefit and should be offered alternative palliative therapies.     

Untersuchung zur Kategorisierung des mandibulären Wachstumspotentials von Petrovic,Lavergne und Stutzmann

Zusammenassung In der vorliegenden Studie sollte untersucht werden, ob die vonPetrovic, Lavergne undStutzmann vorgeschlagene Kategorisierung des mandibulären Wachstumspotentials für die Behandlung mit dem Funktionsregler Geltung hat. Dazu wurden die Fernröntgenaufnahmen von 140 Patienten der Angle-Klasse II nach zirka zweijähriger Behandlung mit Funktionsreglern analysiert. Im Vergleich zu 133 unbehandelten Kindern mit Angle-Klasse II trat in fast allen Rotationsgruppen eine signifikant größere Zunahme der Unterkiefergesamtlänge ein. Zwischen der Kategorie 2 mit niedrigem Wachstumpotential und Kategorie 5 mit hohem Wachstumspotential wurden keine signifikant unterschiedlichen Zunahmen der Unterkieferlänge festgestellt.

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Summary The results of the study show whether the classification of mandibular growth potential, as proposed by Petrovic, Lavergne and Stutzmann has any influence on the treatment with a function regulator. X-rays of 140 class II patients were analysed after a treatment time of approximately 2 years. In comparison with 133 class II children without any treatment, a significant increase of the overall mandibular length was observed in almost all children treated. There was no significant difference in the increase of mandibular length between category 2 (low growth potential) and category 5 (high growth potential).

     

Treatment of hypogonadal adolescent boys with long acting subcutaneous testosterone pellets

AIMS: Long acting subcutaneous testosterone pellets are of proved efficacy for the treatment of hypogonadal men, but have not been reported as a treatment modality in adolescent boys. Pharmacodynamic studies of subcutaneous testosterone release have shown prolonged normalisation of testosterone levels for at least four months. Administration of a long acting, safe, effective, and convenient form of treatment is desirable when life-long treatment is indicated. PATIENTS AND METHODS: Eighteen boys (aged 13.9-17.5 years at the start of treatment)-seven with primary hypogonadism, nine with secondary hypogonadism, and two boys being treated with testosterone for tall stature--were given testosterone pellets (8-10 mg/kg) every six months for 18 months. Height, weight, pubertal status, and psychosocial parameters were assessed and follicle stimulating hormone, luteinising hormone, testosterone, prolactin, and lipids were measured at 0, 1, 3, 6, 12, and 18 months. Bone age was measured at 0 and 12 months. RESULTS: In all boys growth velocity continued appropriately for bone age. Puberty continued to progress in all boys and in two boys the amount of virilisation exceeded that seen with previous treatment with intramuscular testosterone. After testosterone administration, follicle stimulating hormone and luteinising hormone suppressed incompletely in the boys with primary hypogonadism. Serum testosterone ranged from 4.3 to 26.7 nmol/l at three months to less than 10 nmol/l at six months after implantation. Prolactin and lipid levels were normal throughout the study. By report, there was an improvement in mood and emotional wellbeing. No pellet extrusions occurred in a total of 156 pellet insertions. CONCLUSIONS: All boys preferred this mode of testosterone administration to intramuscular injections. Long acting subcutaneous testosterone pellets are safe, efficacious, well tolerated, and convenient, and result in normal physical growth and improved psychological outlook in adolescent hypogonadal boys.     

Reduction of atherosclerosis in cholesterol-fed rabbits and decrease of expressions of intracellular adhesion molecule-1 and vascular endothelial growth factor in foam cells by a water-soluble fraction of Polygonum multiflorum

Polygonum multiflorum stilbeneglycoside （PMS） is a water-soluble fraction of Polygonum multiflorum Thunb. , one of the most famous tonic traditional Chinese medicines, that has protective effects on the cardiovascular system. The purpose of the present study is to elucidate the effects of PMS on macrophage-derived foam cell functions and the reduction of severity of atherosclerosis in hypercholesterolemic New Zealand White （NZW） rabbits. NZW rabbits were fed for 12 weeks with a normal diet, a high cholesterol diet, or a high cholesterol diet associated with irrigation with different doses of PMS （25, 50, or 100 mg/kg）. Treatment of NZW rabbits fed with high cholesterol diet with 100 mg/kg PMS attenuated the increase in plasma cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and plasma triglyceride. Treatment with 50 and 100 mg/kg PMS caused 43% and 60% decrease in atherosclerotic lesioned area ratio to total surface area, respectively. In U937 foam cells, PMS could decrease the high expression of intercellular adhesion molecule （ICAM）-1 protein and the vascular endothelial growth factor （VEGF） protein levels in the medium induced by oxidized lipoprotein when analyzed by flow cytometry. The results proved that PMS is a powerful agent against atherosclerosis and that PMS action could possibly be through the inhibition of the expression of ICAM-1 and VEGF in foam cells.     

Resistance to the tubulin-binding agents in renal cell carcinoma: no mutations in the class I beta-tubulin gene but changes in tubulin isotype protein expression.

PURPOSE: The primary purpose of this study was to determine whether mutations of the class I beta-tubulin gene may be implicated in the inherent resistance to tubulin-binding agents (TBA) in renal cancer, with a small number of samples and cell lines also being examined for class I and III beta-tubulin isotype protein expression. EXPERIMENTAL DESIGN: DNA was extracted from 90 renal tumors and the class I beta-tubulin gene analyzed for mutations. For each sample, eight PCRs were used to cover the complete coding sequence with intronic primers ensuring highly homologous pseudogenes were not coamplified. Additionally, expression levels of class I and III beta-tubulin isotypes in 17 matched normal and malignant renal samples and a panel of renal cell carcinoma cell lines with differing intrinsic resistance to the TBAs was examined by Western blotting. RESULTS: Four polymorphic sequence changes of the class I beta-tubulin gene were identified with no mutations. Class I protein expression levels were higher in tumor tissue versus normal tissue, whereas class III expression showed no consistent change. In renal cancer cell lines, a significant correlation between class III isotype expression and vinblastine sensitivity was observed. CONCLUSIONS: These results do not support a role for mutations in the class I beta-tubulin gene in the intrinsic resistance of renal cancer to TBAs. Class III isotype expression may be implicated in resistance in vitro but in vivo, changes in class I isotype expression in renal cell carcinoma tissue may support a role in resistance to the TBAs and warrants further investigation.