Diminished spontaneous apoptosis in lymphocytes from human immunodeficiency virus-infected long-term nonprogressors

The relationship between peripheral lymphocyte apoptosis and human immunodeficiency virus disease progression was studied in infected subgroups with distinct profiles of progression. Long-term nonprogressors (LTNP) and seronegative controls had levels of spontaneous apoptosis significantly lower than those for recent seroconverters who had CD4 cell counts similar to those of nonprogressors but with a high likelihood of disease progression. Lymphocytes from nonprogressors and seronegative controls also showed negligible spontaneous caspase-3 activity, a biochemical indicator for apoptosis, whereas early progressors exhibited substantial activity. In contrast, when activated with mitogens, the lymphocytes from both LTNP and progressors displayed indistinguishable levels of heightened apoptosis. Spontaneous apoptosis and plasma viremia levels correlated positively in progressors, but not in LTNP. These findings demonstrate that increased lymphocyte apoptosis is evident prior to CD4 T cell decline and that LTNP are relatively resistant to the factors that induce accentuated levels of spontaneous but not mitogen-induced cell death.     

The association between cigarette smoking and selected HIV-related medical conditions

OBJECTIVE: To clarify the effect of cigarette smoking on the development of conditions associated with HIV infection. DESIGN: Prospective and retrospective cohort study, with interview and examination twice a year since 1988. METHODS: Data on 516 HIV-infected men from cohorts of homosexual and bisexual men in San Francisco, Denver and Chicago, who were repeatedly interviewed and examined between 1988 and 1992, were analysed. After excluding men who did not have well-defined dates of seroconversion and those who were classified as ex- or intermittent smokers, 232 men remained for analysis: 106 were smokers and 126 were non-smokers. Univariate and Kaplan-Meier survival analyses were performed to assess the relationship between cigarette smoking and loss of CD4+ T-lymphocytes, diagnosis of any AIDS-defining illness, and specific diagnosis of Kaposi's sarcoma, Pneumocystis carinii pneumonia (PCP), oral candidiasis, hairy leukoplakia, and community-acquired pneumonia. RESULTS: By univariate analyses, cigarette smoking was not associated with clinical AIDS, loss of CD4+ cells, Kaposi's sarcoma or PCP, but was significantly associated with oral candidiasis [relative risk (RR), 1.32; 95% confidence interval (CI), 1.02-1.70], hairy leukoplakia (RR, 1.51; 95% CI, 1.15-1.99), and community-acquired pneumonia (RR, 2.62; 95% CI, 1.30-5.27). Dose-response effect was also evident for these three conditions (all P < 0.01). Kaplan-Meier survival analysis indicated no association between cigarette smoking and time of progression to clinical AIDS, Kaposi's sarcoma (KS), or PCP (P = 0.62, 0.54 and 0.11, respectively) but showed that cigarette smokers developed oral candidiasis, hairy leukoplakia, and pneumonia more quickly than non-smokers (P = 0.031, 0.006 and 0.009, respectively). CONCLUSIONS: Cigarette smoking was not associated with an increased likelihood or rate of developing KS, PCP or AIDS, but was associated with developing community-acquired pneumonia, oral candidiasis, and hairy leukoplakia in these HIV-infected men.     

Thrombosis of tibial arteries in a patient receiving tamoxifen therapy

BACKGROUND: Tamoxifen has been used extensively as adjuvant therapy in the treatment of pre- and post-menopausal patients with breast cancer. One of its known complications is venous thromboembolism. However, arterial thrombosis has been reported rarely. METHODS: A 49-year-old patient with breast cancer had had a total mastectomy 3 years earlier. She was receiving tamoxifen therapy when she developed a sudden onset of pain and numbness of the left foot and calf. An arteriogram showed thrombosis of her tibial arteries. RESULTS: This thrombosis was lysed successfully with urokinase therapy, and tamoxifen therapy was discontinued. At follow-up 4 months later, the patient had normal circulation to both legs. CONCLUSIONS: Patients receiving tamoxifen should be monitored closely for the development of venous or arterial thromboembolism.     

A homozygous mutation in the luteinizing hormone receptor causes partial Leydig cell hypoplasia: correlation between receptor activity and phenotype

Leydig cell hypoplasia (LCH) is characterized by a decreased response of the Leydig cells to LH. As a result, patients with this syndrome display aberrant male development ranging from complete pseudohermaphroditism to males with micropenis but with otherwise normal sex characteristics. We have evaluated three brothers with a mild form of LCH. Analysis of their LH receptor (LHR) gene revealed a homozygous missense mutation resulting in a substitution of a lysine residue for a isoleucine residue at position 625 of the receptor. In vitro analysis of this mutant LHR, LHR(I625K), in HEK293 cells indicated that the signaling efficiency was significantly impaired, which explains the partial phenotype. We have compared this mutant LHR to two other mutant LHRs, LHR(A593P) and LHR(S616Y), identified in a complete and partial LCH patient, respectively. Although the ligand-binding affinity for all three mutant receptors was normal, the hormonal response of LHR(A593P) was completely absent and that of LHR(S616Y) and LHR(I625K) was severely impaired. Low cell surface expression explained the reduced response of LHR(S616Y), while for LHR(I625K) this diminished response was due to a combination of low cell surface expression and decreased coupling efficiency. For LHR(A593P), the absence of a reduced response resulted from both poor cell surface expression and a complete deficiency in coupling. Our experiments further show a clear correlation between the severity of the clinical phenotype of patients and overall receptor signal capacity, which is a combination of cell surface expression and coupling efficiency.     

The specific and sensitive detection of bacterial pathogens within 4 h using bacteriophage amplification

This paper describes a novel approach, termed the 'phage amplification assay', for the rapid detection and identification of specific bacteria. The technique is based on the phage lytic cycle with plaque formation as the assay end-point. It is highly sensitive, quantitative and gives results typically within 4 h. The assay comprises four main stages: (1) phage infection of target bacterium; (2) destruction of exogenous phage; (3) amplification of phage within infected host and (4) plaque formation from infected host with the aid of helper bacteria. A key component of this assay is a potent virucidal agent derived from natural plant extracts, pomegranate rind extract (PRE). In combination with ferrous sulphate PRE can bring about an 11 log-cycle reduction in phage titre within 3 min. This is achieved without any injury to the infected target bacteria. Subsequently, any resulting plaques are derived only from infected target organisms. Data are presented for a range of bacterial hosts including Pseudomonas aeruginosa, Salmonella typhimurium and Staphylococcus aureus. The detection limit for Ps. aeruginosa was 40 bacteria ml-1 in a time of 4 h and 600 bacteria m-1 for Salm. typhimurium. Application of the principles of this technology to other bacterial genera is discussed.     

Eukaryotic and prokaryotic cell functions required for invasion of Staphylococcus aureus into bovine mammary epithelial cells

OBJECTIVE: To investigate patterns of attendance and non-attendance at National Health Service antenatal classes of first-time mothers in the indigenous white population of a large northern city of the UK. DESIGN: Survey using questionnaires, and selected participants were then given an in-depth interview. SETTING: Five maternity wards in two large northern hospitals in the UK. In-depth interviews took place in the respondents' homes. PARTICIPANTS: Fifty newly delivered women were surveyed of whom 18 took part in the follow-up interviews. FINDINGS: There was a clear hierarchy in attendance and non-attendance based on social class, with middle class women being the most regular attenders, closely followed by older, married, working class women. However, overall social class differences were found to be accounted for by the overwhelming non attendance of young, unmarried, working class women. Older, married, working class women were found to have attendance patterns which were close to their middle class counterparts, and what differences there were seemed to be based on material factors. KEY CONCLUSIONS: The majority of women felt that antenatal classes were too technical and did not address emotional and psychological issues. However, young, single unmarried women perceived the classes most negatively. If midwives are to attract such young women, their fears and their need for peer support will have to be recognised.     

Genetic susceptibility to head and neck cancer: interaction between nutrition and mutagen sensitivity

The development of head and neck cancer may depend not only on exposure to environmental carcinogens but also on a genetically based susceptibility to carcinogen-induced damage. This thesis presents a case-control study that demonstrates the significance of mutagen sensitivity, a measure of an individual's intrinsic DNA repair capacity against free radical damage, as a risk factor for the disease. As part of the case-control analysis, 167 previously untreated patients and 177 age- and sex-matched healthy controls were assessed for various lifestyle factors including tobacco and alcohol habits, occupational exposures, and diet. Mutagen sensitivity expressed by each individual was determined by quantifying bleomycin-induced chromosomal breaks within peripheral blood lymphocytes in vitro. Consistent with our initial observations and those of others, mutagen hypersensitivity was strongly associated with increased risk of head and neck cancer (odds ratio, 4.95; 95% confidence interval, 2.67 to 9.17) after adjusting for age, sex, and race. Low intake of vitamins C and E was also associated with an increased risk of disease and was interactive with mutagen sensitivity in risk estimates. Individuals with both a low intake of various antioxidants and increased chromosomal sensitivity to oxidant-induced DNA damage were at greatest risk. This study supports the concept that the risk of head and neck cancer is determined by a balance of factors that either enhance or protect against free radical oxygen damage, including innate capacities for DNA repair.     

Effect of anatomic distribution of pulmonary emboli on interobserver agreement in the interpretation of pulmonary angiography

OBJECTIVE: This study examines the anatomic distribution of emboli on pulmonary angiography and attempts to determine the relationship of vessel size to interobserver agreement, two factors having important implications in comparing pulmonary angiography with cross-sectional imaging for pulmonary embolism. MATERIALS AND METHODS: One hundred twenty-five consecutive pulmonary angiograms were reviewed retrospectively by three interventional radiologists. Initial interpretations were recorded and compared to determine interobserver agreement on a per-patient and per-embolus basis. Discordant interpretations were reviewed by all radiologists for a consensus interpretation. RESULTS: Unanimous per-patient agreement occurred in 91% (114/125) of initial interpretations. The largest artery containing acute pulmonary embolism was segmental or larger in 24 patients (83% of patients with acute positive findings, 19% of all patients) and subsegmental in only five patients (17% and 4%, respectively). On a per-patient basis, initial interobserver agreement averaged 45% and unanimous consensus agreement was achieved for 79% of patients having isolated subsegmental pulmonary embolism. Consensus readings altered initial per-patient interpretations for 30% of patients having only subsegmental pulmonary embolism; per-embolus interpretations were altered for 37% of all subsegmental emboli. CONCLUSION: Subsegmental emboli occurring as isolated findings are relatively rare. Approximately one third of subsegmental emboli and one third of patients having isolated subsegmental emboli may be initially misdiagnosed on pulmonary angiography. Objections to cross-sectional imaging for pulmonary embolism based on the inability to detect subsegmental pulmonary embolism when compared with pulmonary angiography should be reexamined with this data in mind.     

The sleep of abstinent pure primary alcoholic patients: natural course and relationship to relapse

Sleep in male pure primary alcoholic inpatients was examined at a mean of 16 days (n = 29), 19 weeks (n = 29), 14 months (n = 9), and 27 months (n = 4) of abstinence. Results were as follows: (1) the sleep of abstinent alcoholic patients is short, fragmented, and shallow early in abstinence; (2) a patient's sleep improves slowly over at least the first year of abstinence; however, (3) some facets of a patient's sleep remain abnormal even after 27 months of abstinence; (4) insomnia and sleep fragmentation after approximately 5 months of abstinence may be related to relapse by 14 months. The mechanism underlying the relationship between sleep and withdrawal in alcoholic patients is not well understood, and the issue of treating sleep problems as an adjunct to prevention of relapse warrants further investigation.     

Tracer kinetic modeling of the 5-HT1A receptor ligand [carbonyl-11C]WAY-100635 for PET

[Carbonyl-11C]WAY-100635 is a promising PET radioligand for the 5-HT1A receptor, having demonstrated more favorable characteristics for in vivo imaging than the previously available [O-methyl-11C]WAY-100635. The current study evaluates different tracer kinetic modelling strategies for the quantification of 5-HT1A receptor binding in human brain. Mathematical modelling of the carbonyl-labeled radiotracer is investigated using compartmental structures, including both plasma input and reference tissue approaches. Furthermore, the application of basis function methods allows for the investigation of parametric imaging, providing functional maps of both delivery and binding of the radioligand. Parameter estimates of binding from normal volunteers indicate a low intra- versus a high intersubject variability. It is concluded that a simplified reference tissue approach may be used to quantify 5-HT1A binding either in terms of ROI data or as parametric images.