The use of on-line and off-line chromatographic extraction techniques coupled with mass spectrometry for support of in vivo and in vitro assays in drug discovery.

We have investigated various sample chromatographic extraction and sample preparation methods for liquid chromatography mass spectrometry analysis in order to increase the throughput of various in vivo and in vitro assays in support of drug discovery. The results indicated that direct plasma injection, although certainly faster than conventional protein precipitation for sample preparation, had problems associated with column longevity and overall robustness. Frequently a single study could not be completed without column replacement. On-line solid phase extraction, on the other hand, compared well with off-line solid phase extraction, using our LC extraction column design, as contamination of the extraction column was minimized by back flushing using the Gilson syringe pump. Finally, on-line solid phase extraction for support of Caco-2 permeability studies worked very well for both single components and mixtures as the matrix was much simpler, presenting fewer contamination problems.

Quality improvement in the diagnosis and treatment of heart failure by participating Indiana and Kentucky hospitals.

Acute-care hospitals in Kentucky and Indiana collaborated with Health Care Excel, the Medicare peer review organization, to improve the care of patients admitted with heart failure. Current guidelines for the treatment of heart failure support a focus on quality indicators including confirmation of diagnosis, choice of therapeutic agents, education of patients and their caregivers, and discharge planning. Significant improvement occurred in use of diagnostic tests to confirm diagnosis and in patient education and discharge planing. Improvement in use of therapeutic agents was minimal or lacking in most hospitals. This project demonstrated an opportunity and need for continued improvement efforts in the care of heart failure patients.

Shigella in Tulsa County, 1993: epidemiology, day care center association, and control.

Tulsa County experienced an epidemic of Shigella sonnei infection and diarrheal disease during 1993. Of the 298 cases documented, 262 occurred in day care centers. There were 227 epidemiologically-linked secondary cases, primarily in parents and siblings. The mode of transmission was primarily person-to-person among family members and children in day care centers. In addition, transmission may also have occurred as the result of fomities in some day care centers. Control was achieved by antibiotic therapy, inspection, and retraining all day care centers' staffs in hand washing techniques and infection control concepts.

Tuberculosis in a Tulsa high school.

Following the discovery of a high school student with communicable tuberculosis, the Tulsa City-County Health Department skin tested 1,005 persons in the family, community, and school. Of the 931 persons tested at the school, 10 were reactors in March and 33 more were reactors in May. All 5 family members and 4 community contacts were tuberculin reactive. In all, 52 new tuberculin reactors were identified, evaluated, and considered for treatment or prophylaxis. This situation illustrates the conundrum that tuberculosis remains an important public health issue because of the possibility of transmission from small pockets of diseased persons to the larger community, especially in institutions of all kinds. Physicians and public health agencies must be vigilant and identify new cases for treatment and begin contact tracing to minimize the spread of tuberculosis.

Assessment of the spatial occurrence of childhood leukaemia mortality using standardized rate ratios with a simple linear Poisson model.

Reports of a suspected cluster of childhood leukaemia cases in West Central Phoenix have led to a number of epidemiological studies in the geographical area. We report here on a death certificate-based mortality study, which indicated an elevated rate ratio of 1.95 during 1966-1986, using the remainder of the Phoenix standard metropolitan statistical area (SMSA) as a comparison region. In the process of analysing the data from this study, a methodology for dealing with denominator variability in a standardized mortality ratio was developed using a simple linear Poisson model. This new approach is seen as being of general use in the analysis of standardized rate ratios (SRR), as well as being particularly appropriate for cluster investigations.

Twenty-two years of cancer cluster investigations at the Centers for Disease Control.

Beginning in 1961, the Centers for Disease Control investigated 108 cancer clusters and reported the findings in Epidemic Aid Reports. The clusters studied were of leukemia (38%), leukemia and lymphoma (30%), leukemia and other cancer combinations (13%), and all other cancer or combinations (19%). These clusters occurred in 29 states and five foreign countries, with the largest numbers from Connecticut (11), California (eight), Illinois (eight), New York (eight), Georgia (seven), Pennsylvania (six), and Iowa (five). All other states reported less than five. Eight different data collection methods were used, often in combinations, and four types of laboratory methods on four different specimen types. Although 14 different categories of associations were reported, no clear cause was found for any cluster. Nonetheless, concern about clusters by the public and media, and the need to investigate them, warrants the development of a uniform approach for use by local health departments.

An outbreak of non-A, non-B hepatitis associated with the infusion of a commercial factor IX complex during cardiovascular surgery.

An outbreak of non-A, non-B hepatitis was recognized among cardiovascular surgical patients from one hospital in June 1985. Illness was found to be significantly associated with a commercial brand of factor IX complex given to patients because of intraoperative bleeding. A change in the commercial brand of factor IX stocked by the hospital pharmacy had occurred in October 1984 and coincided with the onset of the outbreak. A retrospective study of cardiovascular surgery patients identified 23 cases and 7 probable cases of non-A, non-B hepatitis among patients who had received infusions of brands A and B factor IX complex. Three cases were in brand A recipients and 27 were in brand B recipients. Respective brand-specific attack rates were 5 and 42% (relative risk = 7.7; p less than 2 x 10(-5); chi 2 test). Nineteen of 30 case patients (63%) were jaundiced, including 2 brand A recipients and 17 brand B recipients. Median peak serum aminotransferase was 690.5 IU (range 27-2,824). The incubation period for cases in brand B recipients was a median of 7 weeks (range 2-17 weeks). Prevention of non-A, non-B hepatitis in this population requires adhering to strict indications for the use of clotting factor preparations and avoiding these products when at all possible. Heat treatment of clotting factor products may reduce the risk of viral disease transmission, but certain methods may not inactivate the causative agents of non-A, non-B hepatitis.

Childhood leukemia in Woburn, Massachusetts.

Possible associations between environmental hazards and the occurrence of childhood leukemia were investigated in Woburn, MA, for the period 1969-79. Residents of Woburn were concerned over what they perceived to be a large number of childhood leukemia cases; at the same time there was extensive publicity about uncontrolled hazardous waste sites in Woburn, which resulted in its being placed on the Superfund list. Many believed that the elevated rate of childhood leukemia was related to these sites or to two city water wells that had been closed in 1979 when they were found to be contaminated by organic chemicals. An occurrence was defined as childhood leukemia when it was diagnosed in a Woburn resident less than 20 years old between 1969 and 1979 and confirmed by review of hospital and pathology records. This investigation confirmed an increase in incidence which was distributed uniformly over the 11-year period. Six of the persons with leukemia were located close to each other in one census tract, 7.5 times the expected number. Parents of the children and of two matched control groups were interviewed about medical history, mother's pregnancy history, school history, and environmental exposures. There were no significant differences between the leukemia victims and persons in the control groups. No leukemia sufferer had contact with a hazardous waste site. While the contaminants of Wells G and H, which had been closed, are not known leukemogens, it is not possible to rule out exposure to this water as a factor, particularly in the eastern Woburn residents.

Life-style factors among patients with melanoma.

For the period 1975 to 1980, melanoma incidence in persons 10 through 49 years of age in a southwest Georgia town was significantly increased compared with US rates (expected = 9; observed = 41) and Atlanta rates (expected = 13; observed = 41). We surveyed 36 white patients with melanoma and 74 unaffected control subjects to identify risk factors possibly associated with melanoma in this population. When compared with the controls, the patients more often had a history of melanoma in family members [odds ratio (OR) = 8.00; 95% confidence limits (CL) = 0.89 to 71.6; P = .063]; skin sensitivity to sun exposure (OR = 1.63; CL = 1.04 to 2.56; P = 0.016); or preexisting pigmented nevi (OR = infinity; one-sided 95% lower limit = 1.94, P = .005). More male patients had melanomas on covered body sites, though 67% of melanomas in both sexes occurred on normally covered sites. Patients in our study also had been exposed more often than controls to sick animals in the year before onset (OR = 3.18; CL = 0.92 to 11.0; P = .055) and to pesticides in nonoccupational settings (OR = 3.56; CL = 0.87 to 14.5; P = .059).

The Public Health Service role in the disposal of chemical munitions.

Within the last decade, the Centers for Disease Control (CDC) has increasingly emphasized environmental public health activities. The Center for Environmental Health (CEH), one of nine major units of the CDC, was established as a focus for assessment and prevention of environmentally related diseases. Many new, legislatively mandated programs have been delegated to CEH. One such mandated responsibility in Public Laws 91-121 and 91-441 directs the Department of Health and Human Services or its designee to review the Department of Defense (DOD) plans to dispose of or to transport chemical warfare agents. The Chemical Munitions Demilitarization Program, CEH, reviews DOD plans and makes recommendations to ensure that hazards to public health and safety have been provided for in the plans. In addition, these CEH staffers periodically review approved activities at DOD facilities, assessing their monitoring and evaluation programs. CEH staffers also contact State and local health and environmental agencies to identify and evaluate any concerns of the agencies or the public relating to these activities.

Polycythemia vera among participants of a nuclear weapons test.

Two cases of polycythemia vera and two cases of suspected polycythemia vera were found among 3,217 nuclear test participants present during the detonation of the nuclear device, "Smoky," on Aug 31, 1957, and traced through December 1981. The observed occurrence of four cases of polycythemia vera in a group this size significantly exceeds that expected. However, the small individual whole-body doses of radiation reported for these four participants makes the association with ionizing radiation tenuous, although this was the only known unusual risk factor.

Childhood cancer and occupational radiation exposure in parents.

To test the hypothesis that a parent's job exposure to radiation affects his or her child's risk of cancer, the authors compared this exposure during the year before the child's birth for parents of children with and without cancer. Parents of children with cancer were no more likely to have worked in occupations, industries, or combined occupations and industries with potential ionizing radiation exposure. Bone cancer and Wilms' tumor occurred more frequently among children of fathers in all industries with moderate potential ionizing radiation exposure. Children with cancer more often had fathers who were aircraft mechanics (odds ratio (OR) = infinity, one-sided 95% lower limit = 1.5; P = 0.04). Although four of these six were military aircraft mechanics, only children whose fathers had military jobs with potential ionizing radiation exposure had an increased cancer risk (OR = 2.73; P = 0.01). Four cancer types occurred more often among children of fathers in specific radiation-related occupations: rhabdomyosarcoma among children whose fathers were petroleum industry foremen; retinoblastoma among children whose fathers were radio and television repairmen; central nervous system cancers and other lymphatic cancers among children of Air Force fathers. Because numbers of case fathers are small and confidence limits are broad, the associations identified by this study need to be confirmed in other studies. Better identification and gradation of occupational exposure to radiation would increase the sensitivity to detect associations.

The Three Mile Island Population Registry.

Shortly after the March 28, 1979, accident at the Three Mile Island (TMI) nuclear plant outside Harrisburg, Pa., the Pennsylvania Department of Health, in conjunction with the Centers for Disease Control and the U.S. Bureau of the Census, conducted a census of the 35,930 persons residing within 5 miles of the plant. With the help of 150 enumerators, demographic and health-related information was collected on each person to provide baseline data for future short- and long-term epidemiologic studies of the effects of the accident. Individual radiation doses were estimated on the basis of residential location and the amount of time each person spent in the 5-mile area during the 10 days after the accident. Health and behavioral resurveys of the population will be conducted approximately every 5 years. Population-mobility, morbidity, and mortality will be studied yearly by matching the TMI Population Registry with postal records, cancer registry records, and death certificate data. Because the radiation dose from TMI was extremely small, any increase in morbidity or mortality attributable to the accident would be so small as not to be measurable by present methods; however, adverse health effects as a result of psychological stress may occur. Also, a temporary increase in reporting of disease could occur because of increased surveillance and attention to health.

Mortality and cancer frequency among military nuclear test (Smoky) participants, 1957 through 1979.

Follow-up of health status has been completed through 1979 for 3,072 (95.5%) of 3,217 nuclear test participants on military maneuvers during the 1957 nuclear test "Smoky." In these participants, 112 cases of cancer were diagnosed, compared with 117.5 cases expected. During the same follow-up period (1957 through 1979), 64 persons died of cancer, compared with an expected 64.3. Statistically significantly increased frequency of occurrence and mortality was found only for leukemia. The amount of cumulative gamma radiation exposure for 1957 ranged from 0 to 10,397 mrem as measured by individual personnel film badges. Although uncertainty remains about the exact amount of radiation exposure, the lack of a significant increase after 22 years in either the incidence of or the mortality from any other cancer and the apparent lack of a dose effect by unit lead to the consideration that the leukemia findings may be attributable either to chance, to factors other than radiation, or to some combination of risk factors possibly including radiation.

Surveillance of infectious mononucleosis cases by use of existing data from state laboratories.

In a pilot study to explore the feasibility of surveillance of cases of infectious mononucleosis, data were collected on 8,258 positive specimens. These specimens had been submitted to six State laboratories--Connecticut, Georgia, Iowa, South Carolina, Virginia, and Wisconsin--during a 2-year period. April 1974-March 1976. Case reporting varied in completeness and geographic coverage. Data concerning case occurrence, by age, sex, and race of patients and month of specimen collection, confirmed previous observations regarding the descriptive epidemiology of the disease. The results indicated that the public health usefulness of extensive surveillance of infections mononucleosis laboratory tests is limited.

Epidemiology of hepatic angiosarcoma in the United States: 1964-1974.

A nationwide survey of hepatic angiosarcoma (HAS) in the United States during the years 1964 through 1974 identified 168 cases. Of these, 42 cases (25%) were associated with known etiologic factors, such as vinyl chloride monomer exposure during preparation of poly(vinyl chloride), use of Thorotrast in angiography, exposure to inorganic arsenic, and treatment with androgenic-anabolic steroids; 126 cases (75%) are of uncertain etiology. HAS most often affects males (ratio of approximately 3:1), peaks in the sixth and seventh decades of life (somewhat earlier than other sarcomas of the liver) and appears to occur more often in the industrialized Northeast and Midwest (although reporting artifact may be a factor). There is an extraordinary relative risk for poly(vinyl chloride) polymerization workers; there may also be other chemical-industrial associations that require further investigation. Prospective epidemiologic studies of HAS should be considered as a means of identifying other causative factors (e.g., chemicals or drugs) related to HAS.

Serum pesticide levels in patients with childhood colorectal carcinoma.

From September 1974 through November 1976, 13 adolescent patients with mucin-producing colorectal adenocarcinoma were treated at a Memphis, Tennessee, pediatric oncology center. Ten of these children were from rural areas of the Mississippi Delta, areas of high pesticide use. None of them had a family history of colorectal cancer, familial polyposis, or ulcerative colitis. Levels of pesticide residues, however, were not generally higher in blood samples from patients and their families than from controls.

Arsenic-related hepatic angiosarcoma.

Data from several small autopsy series in German vintners in the 1940s and 1950s and a number of case reports have previously suggested that arsenic is a cause of hepatic angiosarcoma (HAS). In a nationwide review of deaths from HAS in the United States, we identified seven cases with a history of prolonged use of Fowler's solution (inorganic potassium arsenite), which provide further support for the association of arsenic exposure and HAS. An epidemiologic study of a cohort of individuals treated long-term with Fowler's solution might confirm this association.

Leukemia among participants in military maneuvers at a nuclear bomb test. A preliminary report.

Preliminary studies indicate that nine cases of leukemia have occurred among 3,224 men who participated in military maneuvers during the 1957 nuclear test explosion "Smoky." This represents a significant increase over the expected incidence of 3.5 cases. They included four cases of acute myelocytic leukemia, three of chronic myelocytic leukemia, and one each of hairy cell and acute lymphocytic leukemia. At time of diagnosis, patient ages ranged from 21 to 60 years (mean, 41.8 years) and the interval from time of nuclear test to diagnosis from two to 19 years (mean, 14.2 years). Film-badge records, which are available for eight of the nine men, indicated gamma radiation exposure levels ranging from 0 to 2,977 mrem (mean, 1,033 mrem). Mean film-badge gamma dose for the entire Smoky cohort was 466.2 mrem.