Disparate results between proliferation rates of surgically excised prostate tumors and an in vitro bioassay using sera from a positive randomized controlled trial.

In vitro bioassay has been used extensively to test the effects of culturing cancer cells in sera from humans participating in dietary interventions, i.e, studies of modified intake of nutrients for the purpose of reducing cancer risk or progression. It has been hypothesized that cell proliferation rates determined by the in vitro bioassay indicate whether modification of dietary intake could decrease cancer cell growth in vivo. It has been suggested, however, that the in vitro bioassay may not correlate with tumor cell proliferation rates in prostate cancer. We investigated the concordance of cell proliferation rates from surgically excised prostate tumor tissue with the in vitro bioassay using sera from matched patients. We used samples from an earlier randomized clinical trial that showed that supplementation with flaxseed significantly inhibited prostate cancer cell proliferation rates in vivo as indicated by Ki67 staining in tumor specimens. Proliferation rates of LNCaP, DU145 and PC3 cell lines cultured in 10% human sera from participants in the flaxseed trial were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Spearman's Rho correlation coefficients (ρ) indicated no association between Ki67 staining in prostate tumors and the in vitro bioassay for the three cell lines. These disparate findings suggest that the in vitro bioassay may not provide an accurate assessment of the environment in vivo.

Twelve months of isoniazid compared with four months of isoniazid and rifampin for persons with radiographic evidence of previous tuberculosis: an outcome and cost-effectiveness analysis.

Isoniazid taken daily for 12 mo and isoniazid and rifampin taken daily for 4 mo are both recommended options for patients with radiographic evidence of previous tuberculosis and positive tuberculin skin tests who have not had prior treatment. We compared the completion rates, number of adverse effects, and cost effectiveness of these two regimens. Patients were treated at the San Francisco Tuberculosis Clinic from 1993 through 1996. A Markov model was developed to assess impact on life expectancy and costs. One thousand twenty-two patients, with a mean age of 52 yr, and > 90% foreign born, were treated; 545 received isoniazid and 477 received isoniazid and rifampin. For isoniazid, 79.8% completed 12 mo of therapy and 4.9% had adverse effects versus 83.6% completion, 6.1% adverse effects for isoniazid and rifampin (p > 0.05 for all between-group comparisons). Both regimens increased life expectancy by 1.4-1.5 yr. Compared with isoniazid, isoniazid and rifampin produced net incremental savings of $135 per patient treated. In patients with radiographic evidence of prior tuberculosis who have not been previously treated, isoniazid for 12 mo and isoniazid and rifampin for 4 mo have similar rates of completion and adverse effects, and both increase life expectancy compared with no treatment. Isoniazid and rifampin for 4 mo is cost saving compared with isoniazid alone. This advantage was maintained even when compared with 9 mo of isoniazid, the new American Thoracic Society/Centers for Disease Control (ATS/CDC) recommendation for treatment with isoniazid alone.

Progress and problems in achieving the United States national target for completion of antituberculosis treatment.

SETTING: The target for antituberculosis treatment in the United States is for 90% of patients to complete therapy within 12 months. OBJECTIVE: To assess progress in achieving the US national target for tuberculosis treatment. DESIGN: A comparison of treatment outcome in two cohorts of patients with drug-susceptible tuberculosis in California-those reported in 1993-1994 (8488 patients) and 1995-1996 (7823 patients). Risk factors for delay in treatment completion (more than 12 months) were assessed. RESULTS: The percentage of cases completing treatment within 12 months increased in the 1995-1996 cohort (to 68.2%), primarily due to concomitant reductions in delays in treatment completion (to 11.1%) and defaulting (to 2.4%). Disparities in timely treatment completion narrowed over time and in nearly all subpopulations, especially in groups with lowest treatment completion in the 1993-1994 cohort. Remaining risk factors for delay in treatment completion included AIDS and older ages. A substantial percentage of patients died or moved before treatment completion. CONCLUSIONS: Despite recent improvements, completion of antituberculosis treatment in California has not reached the national target. Reaching this target will require further reductions in delays in treatment completion and deaths during treatment, and ensuring that patients who move eventually complete treatment.

Cost-effectiveness analysis of directly observed therapy for patients with tuberculosis at low risk for treatment default.

To determine the incremental cost of directly observed therapy (DOT) for patients with tuberculosis at low risk for treatment default, we applied a model of DOT effectiveness to 1,377 low-risk patients in California during 1995. The default rate for this cohort, which consisted of those with no recent history of substance abuse, homelessness, or incarceration, was 1.7%. The model predicted that DOT and self-administered therapy (SAT) cured 93.1 and 90.8% of these patients, respectively. DOT would initially cost $1.83 million more than SAT, but avert $569,191 in treatment cost for relapse cases and their contacts, for a net incremental cost of $1.27 million ($919 per patient treated), or $40,620 per additional case cured. The cost-effectiveness of DOT was sensitive to the default rate and relapse rate after completing SAT. DOT would generate cost savings only when the default and relapse rates were more than 32.2 and 9.2%, respectively. Given the low default rate and resulting high incremental cost of DOT, provision of DOT to low-risk patients in California should be evaluated in the context of resource availability, competing program priorities, and program success in completing self-administered therapy with a low relapse rate.

Tuberculosis prevention in methadone maintenance clinics. Effectiveness and cost-effectiveness.

To determine the effectiveness and cost-effectiveness of a program to provide screening for tuberculosis infection and directly observed preventive therapy (DOPT) in methadone maintenance clinics, we determined completion rates of screening for tuberculosis infection, medical evaluation, and preventive therapy, as well as the number of active tuberculosis cases and tuberculosis-related deaths prevented, in five clinics in San Francisco, California. Between 1990 and 1995, a total of 2,689 clients (of whom 18% were HIV-seropositive) were screened at least once. Of eligible clients, 99% received tuberculin skin tests, 96% received a medical examination, 91% began isoniazid preventive therapy, and 82% completed preventive therapy. Program effectiveness was enhanced by close collaboration between public health and methadone maintenance programs and the use of incentives and enablers. Over a 3-yr follow-up period, only one verified case of tuberculosis was reported among clients with a positive tuberculin skin test, thereby preventing as much as 95% of expected tuberculosis cases. Over 10 yr, we estimate the program would prevent 30.0 (52%) of 57.7 expected cases of tuberculosis, and 7.6 (57%) of 13.4 expected tuberculosis-related deaths. The program cost $771,569, but averted an estimated $876,229, for a net savings of $104,660 (average of $3, 724 per case prevented). Our study demonstrates that when effectively implemented, screening for tuberculosis infection and DOPT in methadone maintenance clinics is a highly cost-effective approach to prevent tuberculosis.

A population-based study determining the incidence of tuberculosis attributable to HIV infection.

Although the tuberculosis (TB) epidemic has been attributed in part to the AIDS epidemic, few studies in the United States have measured the risk attributable to HIV infection. We linked the TB registry of Alameda County, California, 1985 to 1994, with the AIDS registry, 1982 to 1994. We defined a person with TB and HIV infection as a patient in the TB registry with the same name, race/ethnicity, gender, and date of birth as a patient in the AIDS registry. We used population and HIV seroprevalence estimates to determine the HIV-seropositive and -seronegative population at risk of TB in 1994. Of 1990 TB cases reported by Alameda County from 1985 to 1994, 116 (5.8%) had an AIDS diagnosis. Among 25- to 44-year-old TB patients, 25.2% of U.S.-born men and 8.4% of U.S.-born women had an AIDS diagnosis. In 1994, the estimated TB incidence rate in persons with HIV infection was 198.1 per 100,000 versus a rate of 13.9 of 100,000 among persons without HIV infection (rate ratio, 13.8; 95% confidence interval, 8.0, 23.8). In 1994, 93% of TB cases among HIV seropositive persons, 6.4% of all TB cases, and 16.7% of TB cases aged 25 to 44 years were attributable to HIV infection. The high attributable risk underscores the impact of HIV on the TB epidemic. All persons with HIV infection should be screened for TB, and persons with TB infection should be screened for HIV infection. TB/HIV coinfected patients should be provided with TB preventive therapy.

Cellular and molecular correlates to plasticity during recovery from injury in the developing mammalian brain.

In summary, our studies indicate that the perinatal mammalian brain shows considerable plasticity in response to trauma. Studies carried out both in vivo in the perinatal mouse brain and in vitro in cell line culture and organotypic slice cultures of developing brain tissue, indicate that the cytokine, interleukin-1 beta (IL-1 beta) regulates early healing responses that restore the integrity of the damaged structure and create conditions conducive to the sprouting of new connections involved in plasticity. In response to a lesion placed in the cerebral cortex in a late third trimester embryo, astrocytes form a line that delimits damaged tissue being removed by phagocytic macrophages from tissue that will remain part of the neural parenchyma. By six days after birth, this line of delimiting astrocytes (LDA) appears to become the new glial limiting membrane or glial limitans at the lesion site. A gliotic scar covers the new glial limitans, but no gliosis appears within the neural parenchyma itself. The expression of IL-1 beta is upregulated in astrocytes that form the LDA and is also upregulated in the parenchyma internal to the LDA. Experiments done in vivo where the type 1 interleukin-1 receptor was blocked via injection of interleukin-receptor antagonist protein (IL-ra) indicated that both LDA formation and wound closure were dependent upon interleukin type 1 receptor activation. To test the idea that IL-1 beta could directly influence astrocyte shape and orientation, in vitro studies were carried out on astrocytic C6 glioma cells in culture. IL-1 beta induced changes in cell shape and orientation similar to those seen in in vivo formation of the LDA. Addition of IL-1ra blocked IL-1 beta induced changes in C6 cells. IL-1 beta, then, acting upon its type 1 receptor, regulates astrocytic activities that, in vivo, produce successful healing in the perinatal brain. Studies in organotypic slice cultures of early postnatal mouse hippocampus parallel in vivo studies. Phagocytic cells, in this case, "reactive/activated" microglia, reach peak numbers immediately after injury induced by culture preparation. The round microglia were replaced over 10 days in culture by "resting/ramified" microglia. Over the first 2 days of culture, astrocytes appeared thin and elongated, resembling cells that form the LDA in vivo. Over the next 8 days in cultures, astrocytes underwent hypertrophy to form a gliotic scar over the surface of the culture. The scar resembled that seen external to the LDA after healing in in vivo experiments. IL-1 beta was abundantly expressed throughout the culture period by cells showing a variety of morphologies. Finally, neurite sprouting, an indicator of circuit reorganization and plasticity, occurred rapidly in the hippocampal dentate gyrus in both in vivo and in vitro paradigms. A prenatally placed lesion in the entorhinal cortex that partially deafferents the developing dentate gyrus, induced novel sprouting of the axons of dentate granule cells, the mossy fibers, into the dentate molecular layer. Similar sprouting occurred in vitro in organotypic slice culture of deafferented hippocampus. In culture, sprouting was first observed at the time of onset of astrocyte hypertrophy, indicating that astrocyte derived factors may play a role in regulating circuit reorganization. Viewed together, in vivo and in vitro studies indicate that IL-1 beta upregulation in neural tissue correlates with glial activities that underlie rapid healing and repair in the perinatal brain, and that glial activities associated with deafferentation may play a role in inducing compensatory neurite sprouting and cicuit reorganization.

Development of a population-specific risk assessment to predict elevated blood lead levels in Santa Clara County, California.

OBJECTIVES: To determine: (1) the prevalence of a blood lead level (PbB) of 10 micrograms/dL or greater and 20 micrograms/dL or greater among children aged 6 to 72 months attending the Santa Clara County (SCC), California, public clinics, (2) risk factors for elevated PbB in this population, and (3) whether an SCC public clinic population-specific risk-assessment tool and a five-question lead poisoning questionnaire developed by the Centers for Disease Control and Prevention are useful for prospectively identifying children at higher risk for elevated PbB. METHODS: We tested for PbB 3630 children aged 6 to 72 months attending SCC public outpatient clinics between August 8, 1991, and September 1, 1992. We then conducted two matched case-control studies. Five local risk-factor questions were combined with the CDC's five-question lead poisoning questionnaire, and from May 1, 1993, to June 30, 1993, we conducted risk assessments on 247 children tested for PbB. RESULTS: Two hundred twenty-two of 3630 children (6.1%) had a PbB of 10 micrograms/dL or greater. Thirty-nine (1.1%) had a PbB at least 20 micrograms/dL. Seventy-nine percent of the children screened and 91.0% of the children with PbB at least 10 micrograms/dL were Hispanic. Twenty percent of Mexican-born Hispanic children had a PbB of 10 micrograms/dL or greater, versus 7% of U.S.-born Hispanic children. Several factors were associated with elevated PbB among Hispanic children. For identifying children with a PbB of at least 10 micrograms/dL, the sensitivity and predictive value negative for the CDC's "high risk" definition were 30% and 93%, respectively, whereas for the SCC population-specific high-risk definition, the sensitivity was 90% and the predictive value negative was 98%. CONCLUSIONS: Hispanic children attending SCC public clinics have risk factors for elevated PbB that were not included in the CDC's lead poisoning questionnaire. Methods for prioritizing the frequency of lead screening may be improved by combining the CDC's questions with a population-specific risk assessment.

Integrating voice, data, and paging technologies to enhance information services.

The University of California at San Francisco Medical Center has made a commitment to upgrade its information and telecommunications systems infrastructure. One of the several projects being undertaken by the Medical Center, the Intelligent Console Project, demonstrates how integrating different systems, databases and technologies can improve the quality and accessibility of information, while reducing costs and stream-lining administrative activities. The Intelligent Console acts as an interface mechanism for the several constituent systems and data-bases of the Medical Center and provides a single, front-end control console by which operators can support communications using standardized procedures. Much paperwork has been eliminated and operator training and scheduling streamlined. Equipment consolidation has also freed up space at the Medical Center.

Mapping the early development of projections from the entorhinal cortex in the embryonic mouse using prenatal surgery techniques.

The purpose of this work was to study the development of specific projections from the postero-lateral cortex during the third trimester of gestation in the mouse. To do this, we labeled undifferentiated lateral cortex with the fluorescent carbocyanine dye, Dil, in the embryonic day (E) 16 mouse embryo using exo utero surgical techniques (Muneoka, Wanek, and Bryant, 1986). Embryos were allowed to develop to term (postnatal day 0, P0) at which time the fiber patterns emanating from the marked regions were studied. Dye placement in the undifferentiated postero-ventral cortex produced labeled fibers in the hippocampal formation. A robust projection of the angular bundle into the CA1 region of the hippocampus was heavily labeled. In addition, in some animals, cortical tracts, such as the anterior commissure, corpus callosum, and a corticotectal tract, were labeled. These tracts have been described previously as scaffolding pathways in the fetal cat (McConnell, Ghosh, and Shatz, 1989), and other vertebrates (Wilson, Ross, Parrett, and Easter, 1990). Dye placement in adjacent, more anterior or dorsal areas showed strong labeling in cortical structures but no labeling in the hippocampal formation. These data indicate that, by birth, the temporal cortex is subdivided along the rostro-caudal axis as entorhinal cortex and perirhinal cortex, and along the dorso-ventral axis, as entorhinal cortex and neocortex. Also, these earliest connections are similar to adult connections in their specificity of target area selection. Therefore, these early, yet specific, connections may play a role int he formation of future connections during postnatal development.

Pension status of recently retired workers on their longest job: findings from the New Beneficiary Survey.

Pension coverage among recently retired workers was greater in the early 1980's than it was a decade earlier. Workers whose longest job was with a private employer and women workers were among the groups that experienced the largest increases in coverage by a pension plan other than the social security program. Private pension plan coverage increased from 47 percent to 64 percent for men and from 21 percent to 39 percent for women. The key factors analyzed here include industry, occupation, length of employment, and earnings. Data from the New Beneficiary Survey reveal that a high proportion of covered workers received pension payments at retirement. Pension payments were received by 9 in 10 retirees covered by a government plan and by 3 in 4 retirees covered by a private industry plan on their longest job. In addition, lump-sum payments were received by 12 percent of the men and 21 percent of the women in private pension plans.