Modelling muscle energy-metabolism in anaerobic muscle.

A mathematical model of anaerobic muscle energy-metabolism was developed to predict pH and the concentrations of nine muscle metabolites over time. Phosphorous-31 Nuclear Magnetic Resonance was used to measure time-course data for some phosphate metabolites and pH in anoxic M. semitendinosus taken from three slaughtered sheep. Muscles were held at 35 degrees C during the experiment. Measurement commenced 25 min post mortem and concluded before rigor mortis. The model was fitted to these data within experimental error, by simultaneously varying model parameter values and initial substrate concentrations. The model was used to simulate the period from death until metabolic activity ceased, in order to predict the different stages of metabolic response to anoxia. The model suggested that alkalinisation would occur in all three muscles in the first few minutes after the onset of anoxia, followed by a steady decline in pH. For two of the muscles this decline continued until rigor, with final pH values of 5.60 and 6.07. For the other muscle, pH reached a low of 5.60 near rigor but then increased to a final value of 5.73. A rise in pH after rigor has been observed but not previously explained in the literature. The modelling results suggest it was caused by the alkalising effect of adenosine monophosphate deamination being greater at low pH than the acidifying effect of inosine monophosphate dephosphorylation.

Immune dysfunction in Australian Aborigines.

An examination of the prevalence and phenotype of immune disorders in different ethnic groups may provide important clues to the etiopathogenesis of these disorders. Whilst still conjectural the restricted and somewhat unique polymorphisms of the MHC (and other genetic loci involving host defences) of the Australian Aborigines may provide an explanation for their apparent heightened susceptibility to newly encountered infections and their resistance to many (auto) immune and allergic disorders. In comparison with non-Aboriginal Australians, Australian Aborigines have heightened frequencies of rheumatic fever, systemic lupus erythematosus, various infections and post-streptococcal glomerulonephritis. In contrast various autoimmune disorders (e.g. rheumatoid arthritis, multiple sclerosis, CREST, biliary cirrhosis, coeliac disease, pernicious anaemia, vitiligo), B27 related arthropathies, psoriasis, lymphoproliferative disorders and atopic disorders appear infrequent or absent. Similarly various autoantibodies occur with increased or diminished frequency. With continuing racial admixture, social deprivation and deleterious lifestyles of these people it is likely that further changes in both the frequencies and phenotype of these immune disorders will occur. It is only with a full understanding of the pathogenic mechanisms involved in these immune disorders that meaningful and clinical relevant interventions will be possible.

Delayed hypersensitivity skin testing to mumps and Candida albicans antigens is normal in middle-aged HTLV-I- and-II-infected U.S. cohorts.

It has been reported that human T cell lymphotropic virus (HTLV)-I-infected persons in Japan have decreased delayed hypersensitivity skin test reactivity to tuberculin purified protein derivative (PPD), but HTLV-I- or -II-infected persons do not generally develop opportunistic infections. We administered standardized intradermal testing with PPD, mumps, and Candida albicans antigens to 31 HTLV-I, 48 HTLV-II, and 143 seronegative subjects in the United States. Reactivity at 48 hr was compared among the three groups. Response rates to PPD were very low in all subjects. Fifty-five percent of seronegative subjects did not react to mumps antigen, compared with 55% of HTLV-I [adjusted odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.27-2.33] and 38% of HTLV-II (OR = 0.73, 95% CI 0.33-1.64). Fifty-one percent of seronegatives did not react to Candida albicans antigen, compared with 34% of HTLV-I (OR = 0.37, 95% CI 0.15-0.93) and 46% of HTLV-II (OR = 0.71, 95% CI 0.34-1.52). Anergy was present in 33% of seronegatives, 28% of HTLV-I (OR = 0.60, 95% CI 0.20-1.78), and 19% of HTLV-II (OR = 0.56, 95% CI 0.22-1.44). HTLV-I- and -II-infected persons appear to have intact delayed hypersensitivity skin test responses to mumps and Candida albicans antigens.

Repeat whole-blood and plateletpheresis donors:unreported deferrable risks, reactive screening tests, andresponse to incentive programs.

BACKGROUND: Evaluating plateletpheresis (PPH) and repeat community whole-blood (RWB) donors' responses to donation incentive programs is essential for developing effective donor retention programs. STUDY DESIGN AND METHODS: Using data from a 1998 anonymous questionnaire sent to 92,581 US blood donors, the prevalence of unreported deferrable risks, screening test reactivity, and response to incentives were compared in RWB and PPH donors by the use of weighted chi-square tests and logistic regression analyses. RESULTS: From 52,650 respondents, 38,884 RWB and 2,028 PPH donors were identified. Levels of screening test reactivity (1%) and unreported deferrable risks (UDRs, 2-3%) were similar in RWB and PPH donors. RWB and PPH donors were strongly encouraged or discouraged by similar incentives. Of the incentives that would encourage a higher proportion of UDR-free RWB donors to return, cholesterol screening and earning a blood credit appealed to >50 percent. Similar results were obtained for cholesterol screening in PPH donors. Community service or education credits, premarital screening, and cash had limited appeal for PPH and RWB donors, respectively, and would be more likely to differentially encourage donors with a UDR to return. CONCLUSION: Incentives that were associated with the greatest donor appeal and that minimized the potential recruitment of more risky donors were identified.

The potential impact of incentives on future blood donation behavior.

BACKGROUND: It is important to assess the potential efficacy and safety of offering donation incentives as part of recruitment and retention programs. STUDY DESIGN AND METHODS: In 1995, 7489 allogeneic donors responded to an anonymous mail survey that inquired about demographics, donation history, infectious disease risks, and the potential appeal of incentives. RESULTS: The projected net effect of offering blood credits and medical testing would be to motivate, respectively, 58 percent and 46 percent of donors to return, whereas offering an item of limited value would motivate 20 percent to do so. First-time and younger donors reported more frequently than repeat or older donors that incentives would appeal to them. Donors attracted by cash were 60 percent more likely to have a risk for transfusion-transmissible infections (p = 0.03). Although not statistically significant, the odds of being an at-risk donor were higher among individuals attracted by tickets to events (OR 1.5) and extra time off work (OR 1.2). CONCLUSION: These findings suggest that offering blood credits and (though to a lesser extent) items of limited value could be safe and effective strategies for retaining donors. Although medical tests were found to have broad appeal, studies are needed to identify tests in which donors would be most interested.

False-negative testing errors in routine viral marker screening of blood donors. For the Retrovirus Epidemiology Donor Study.

BACKGROUND: The contribution of testing errors to the risk of virus transmission by transfusion depends on the rate of false-negative testing errors and the prevalence of infected seropositive donations. Although the false-negative testing error rate has been estimated at 0.1 to 1 percent on the basis of proficiency studies, it has not previously been measured in routine donor screening. STUDY DESIGN AND METHODS: A 1991 to 1995 database containing 5,153,153 donations from 1.5 x 10(6) donors (including autologous donors) was searched to identify donors who tested seropositive for HIV, HCV, HTLV-I or II and who attempted subsequent donations. The false-negative rate in routinely screened follow-up donations was determined, and false-negative cases were investigated to identify the cause. RESULTS: Subsequent donations (n = 2015) by 1224 donors with confirmed-positive results were identified. Eleven (0.5%) of these donations did not react in EIA. Ten of the 11 false-negative cases were attributable to borderline-reactive donations. On subsequent donations, there were borderline-nonreactive results on HTLV-I (2 cases), first-generation HCV (5 cases), and second-generation HCV (3 cases) EIAs. The final case was strongly reactive for HCV in a second-generation EIA on two donations (signal-to-cutoff [S:C] ratio >3.5), followed by a baseline nonreactive result on a third donation (S:C = 0.05). CONCLUSION: False-negative testing results occur infrequently during routine infectious-disease donor screening. Although most false-negative results occurred with borderline-reactive HTLV-II samples and/or early-generation HCV EIAs, frank technical errors (e.g., sample mixup or failure to add sample to EIA well) also occur at a low rate (0.05%; 95% CI, 0-1.5%). Process enhancements designed to reduce errors (e.g., enhanced automation of data management and testing systems and process controls for EIAs) are warranted to detect and prevent false-negative results.

Risk factors for hepatitis C virus infection in United States blood donors. NHLBI Retrovirus Epidemiology Donor Study (REDS)

Injection drug use (IDU) is a known risk factor for hepatitis C virus (HCV) infection, but the strength of other parenteral and sexual risk factors is unclear. In 1997, we performed a case-control study of 2,316 HCV-seropositive blood donors and 2,316 seronegative donors matched on age, sex, race/ethnicity, blood center, and first-time versus repeat-donor status. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Questionnaires were returned by 758 (33%) HCV(+) and 1,039 (45%) control subjects (P =.001). The final multivariate model included only the following independent HCV risk factors: IDU (OR = 49.6; 95% CI: 20.3-121.1), blood transfusion in non-IDU (OR = 10.9; 95% CI: 6.5-18.2), sex with an IDU (OR = 6.3; 95% CI: 3.3-12.0), having been in jail more than 3 days (OR = 2.9; 95% CI: 1.3-6.6), religious scarification (OR = 2.8; 95% CI: 1.2-7. 0), having been stuck or cut with a bloody object (OR = 2.1; 95% CI: 1.1-4.1), pierced ears or body parts (OR = 2.0; 95% CI: 1.1-3.7), and immunoglobulin injection (OR = 1.6; 95% CI: 1.0-2.6). Although drug inhalation and a high number of lifetime sex partners were significantly more common among HCV seropositives, they were not associated with HCV after controlling for IDU and other risk factors. IDU, blood transfusion among non-IDU, and sex with an IDU are strong risk factors for HCV among United States blood donors. Weaker associations with incarceration, religious scarification, being stuck or cut with a bloody object, pierced ears or body parts, and immunoglobulin injection must be interpreted with caution.

Rheumatic disease and the Australian aborigine.

OBJECTIVE: To document the frequency and disease phenotype of various rheumatic diseases in the Australian Aborigine. METHODS: A comprehensive review was performed of the archaeological, ethnohistorical, and contemporary literature relating to rheumatic diseases in these indigenous people. RESULTS: No evidence was found to suggest that rheumatoid arthritis (RA), ankylosing spondylitis (AS), or gout occurred in Aborigines before or during the early stages of white settlement of Australia. Part of the explanation for the absence of these disorders in this indigenous group may relate to the scarcity of predisposing genetic elements, for example, shared rheumatoid epitope for RA, B27 antigen for AS. In contrast, osteoarthritis appeared to be common particularly involving the temporomandibular joint, right elbow and knees and, most probably, was related to excessive joint loading in their hunter gatherer lifestyle. Since white settlement, high frequency rates for rheumatic fever, systemic lupus erythematosus, and pyogenic arthritis have been observed and there are now scanty reports of the emergence of RA and gout in these original Australians. CONCLUSION: The occurrence and phenotype of various rheumatic disorders in Australian Aborigines is distinctive but with recent changes in diet, lifestyle, and continuing genetic admixture may be undergoing change. An examination of rheumatic diseases in Australian Aborigines and its changing phenotype may lead to a greater understanding of the aetiopathogenesis of these disorders.

Retention of "safe" blood donors. The Retrovirus Epidemiology Donor Study.

BACKGROUND: There are obvious advantages to increasing donor retention. However, for reasons of blood safety, certain donors may, in fact, be more desirable to retain than others. "Safe" donors are defined as those who provided a blood donation that was negative on all laboratory screening tests and who subsequently reported no behavioral risks in response to an anonymous survey. This study identifies the most important factors affecting the intention of "safe" donors to provide another donation. STUDY DESIGN AND METHODS: An anonymous survey asking about donation history, sexual history, injecting drug use, and recent donation experience was mailed to 50,162 randomly selected allogeneic donors (including directed donors) who gave blood from April through July or from October through December 1993 at one of the five United States blood centers participating in the Retrovirus Epidemiology Donor Study. Before mailing, questionnaires were coded to designate donors with nonreactive laboratory screening tests at their most recent donation. RESULTS: A total of 34,726 donors (69%) responded, with substantially higher response among repeat donors. According to reported intentions only, the vast majority of "safe" donors indicated a high likelihood of donating again within the next 12 months. Only 3.4 percent reported a low likelihood of donating again. A comparison of those likely to return and those unlikely to return reveals significant differences in demographics and in ratings of the donation experience. A higher proportion of those unlikely to return were first-time donors, minority-group donors, and donors with less education. The highest projected loss among "safe" donors was seen for those who gave a fair to poor assessment of their treatment by blood center staff or of their physical well-being during or after donating. CONCLUSION: These data suggest that efforts to improve donors' perceptions of their donation experience, as well as attention to the physical effects of blood donation, may aid in the retention of both repeat and first-time donors.

Estimates of infectious disease risk factors in US blood donors. Retrovirus Epidemiology Donor Study.

OBJECTIVE: Individuals who do not respond accurately to questions about infectious disease risk factors at the time of blood donation represent a potential threat to the safety of the blood supply. This study was designed to estimate the prevalence of undetected behavioral and other risks in current blood donors. DESIGN: Anonymous mail surveys to collect demographic, medical, and behavioral information were administered to individuals who had donated blood within the previous 2 months. Sampling weights were used in the analysis to adjust for differential sampling and response rates among demographic groups to provide prevalence estimates for the donor population. SETTING: Five geographically and demographically diverse US blood centers. PARTICIPANTS: A stratified probability sample of 50,162 allogeneic blood donors. MAIN OUTCOME MEASURES: Estimated prevalence rates for risk behaviors that would have been a basis for deferral if reported at the time of the donor screening interview (deferrable risk). RESULTS: Completed questionnaires were received for 34,726 donors (69.2% of the sample). A total of 186 per 10,000 respondents (1.9%) reported a deferrable risk that was present at the time of their past donation, while 39 per 10,000 (0.4%) reported this behavior within the 3 months prior to donation. Rates (with 95% confidence intervals [CIs]) of deferrable risk behaviors were 1.4 (95% CI, 1.2-1.6) times higher for men than women, 1.6 (95% CI, 1.3-2.0) times higher for first-time vs repeat donors, 2.7 (95% CI, 2.0-3.6) times higher for donors with reactive screening tests, and 7.6 (95% CI, 3.6-15.8) times higher for donors who used the confidential unit exclusion option. CONCLUSIONS: Despite the high degree of transfusion safety in the United States today, a measurable percentage of active blood donors when assessed by anonymous survey report risks for human immunodeficiency virus and other infections not reported at the time of screening, suggesting the need for further refinements in the blood donor qualification process.

Tolypodiol, an antiinflammatory diterpenoid from the cyanobacterium Tolypothrix nodosa.

A new diterpenoid, tolypodiol (1), has been isolated from the terrestrial cyanobacterium Tolypothrix nodosa (HT-58-2) and identified by NMR and mass spectral analysis. The monoacetate derivative 2 was prepared. Tolypodiol (1) and its monoacetate derivative 2 show potent antiinflammatory activity in the mouse ear edema assay.

Demographic determinants of hepatitis C virus seroprevalence among blood donors.

OBJECTIVE: To measure demographic determinants of hepatitis C virus (HCV) seroprevalence among blood donors in the United States. DESIGN: Cross-sectional epidemiological study. SETTING: Five blood centers in different regions of the United States. SUBJECTS: A total of 862,398 consecutive volunteer blood donors with one or more nonautologous donations from March 1992 through December 1993. METHODS: Demographic data collection, serological screening with second-generation anti-HCV enzyme immunoassay, and confirmation with anti-HCV recombinant immunoblot. RESULTS: There were 3126 donors with at least one blood donation confirmed HCV-seropositive, for a crude prevalence of 3.6 per 1000. Age-specific HCV seroprevalence rose from 0.5 per 1000 donors younger than 20 years to a maximum of 6.9 per 1000 in donors aged 30 to 39 years and declined in older age groups. There was interaction between age and educational attainment, with 30- to 49-year-olds with less than a high school diploma at highest risk of HCV infection (odds ratio [OR], 33.0; 95% confidence interval [CI], 23.0 to 47.2 compared with those younger than 30 years with a bachelor's degree or higher degree). Other independent risk factors for HCV seropositivity included male sex (OR, 1.9; 95% CI, 1.8 to 2.1), black race (OR, 1.7; 95% CI, 1.6 to 1.9), Hispanic ethnicity (OR, 1.3; 95% CI, 1.1 to 1.5), previous blood transfusion (OR, 2.8; 95% CI, 2.5 to 3.1), and first/only time donor status (OR, 4.2; 95% CI, 3.9 to 4.5 compared with repeat donors). Seropositivity for human T-lymphotropic virus types I and II, human immunodeficiency virus, or hepatitis B core antigen was highly associated with HCV seropositivity (OR, 10.4; 95% CI, 9.6 to 11.4 for one vs no marker). CONCLUSIONS: Despite a low overall HCV prevalence in blood donors in the United States, there is a marked variation in HCV seroprevalence by demographic subgroup, even after controlling for prior blood transfusion, a recognized risk factor for HCV. Further study of the prevalence of other parenteral risk factors such as past injection drug use among blood donors is needed.

Status report on the US human growth hormone recipient follow-up study.

Three reported cases of Creutzfeldt-Jakob disease (CJD) in young adults who had received human growth hormone (hGH) raised concerns that pituitary-derived GH had been contaminated. Subsequently reported cases have confirmed this suspicion. The US Public Health Service is conducting an investigation to determine the extent of the problem of CJD in recipients of National Hormone Pituitary Program (NHPP) GH. In addition, other possible adverse effects of GH use including leukemia are being investigated. The design, conduct and current status of the study are the subject of this report. Interview data are now available on 5,240 of the 6,284 subjects treated by the NHPP for growth problems. Analysis is underway.

Influence of 60-Hertz magnetic fields on leukemia.

Female DBA/2 mice at 8 weeks of age were implanted with P388 leukemia cells in groups of ten mice and exposed to a 60-Hz 1.4-microT, 200-microT, or 500-microT magnetic field 2-3 hours after the implant for 6 hours daily, 5 days/week until all the exposed P388-treated and nontreated mice died. Parallel exposed groups of non-P388-treated mice and P388-treated mice exposed at 0 microT were included for study. No statistically significant differences (P greater than .05) in survival, spleen weight, or body weight resulted between P388-treated or nontreated mice from exposure to the magnetic field. No effect on the incidence or progression of P388 leukemia was apparent.

Reversible airway obstruction in cystic fibrosis.

Fourteen (29%) of 48 children with cystic fibrosis had a greater than 15% improvement in forced expiratory volume in one second, or in forced vital capacity after inhalation of salbutamol. All these children were atopic (one or more positive prick tests) and had a significantly higher mean serum IgE than either non-atopic subjects or those atopic subjects without airways reversibility (p less than 0.02). Half of those with airways reversibility had or subsequently developed the clinical picture of allergic bronchopulmonary aspergillosis. Of the whole group 81% were atopic, of whom 77% had a positive reaction to A fumigatus, 64% to housedust, and 56% each to grass pollen and cat hair. Children who were not atopic had significantly better spirometry (p greater than 0.05) than those who were. Children with skin hypersensitivity to A fumigatus had identical spirometry to those who were atopic without reactivity to A fumigatus. Serum precipitins to A fumigatus were present in 48%. Serum precipitins to pancreatin were present in 71%, but the presence of these precipitins did not correlate with atopy, airways reversibility, or serum IgE.