Q fever. A call to heighten our index of suspicion.

The prevalence of Q fever infection is probably underestimated. In Michigan, the first two reported human cases of Q fever occurred in 1984. The case-patients lived in adjacent, rural counties and had multiple exposures to goats. We conducted a serosurvey of goat owners and a reference population to compare the prevalence of Q fever antibodies in the two-county area. Goat owners were almost three times more likely to be seropositive with Q fever antibodies than the reference population (43% vs 15%). Among goat owners, individual and household seropositivity prevalences were positively correlated with the number of goats, the number of positive goats, and the number of goat births on the farm. Q fever should be considered more often in the differential diagnosis of patients with compatible illness, especially those with frequent animal contact.

Ketanserin analogues: structure-affinity relationships for 5-HT2 and 5-HT1C serotonin receptor binding.

Ketanserin is the prototypic 5-HT2 serotonin antagonist; although it has been an important tool for the study of serotonin pharmacology, it has had relatively little impact on drug design because remarkably little is known about its structure-affinity relationships. Furthermore, ketanserin also binds at 5-HT1C receptors and even less is known about the influence of its structural features on 5-HT1C receptor affinity. The present study reveals that the fluoro and carbonyl groups of the 4-fluorobenzoyl portion of ketanserin make small contributions to 5-HT2 binding and that the intact benzoylpiperidine moiety is an important feature. Ring-opening of the piperidine ring reduces affinity. Although the quinazoline-2,4-dione moiety also contributes to binding, it appears to play a smaller role and can be structurally simplified with retention of 5-HT2 affinity. N-(4-Phenylbutyl)-4-(4-fluorobenzoyl)piperidine (39), for example, binds with nearly the same affinity (Ki = 5.3 nM) as ketanserin (Ki = 3.5 nM). All of the compounds examined bind at 5-HT1C sites with lower affinity than ketanserin, and some of the simplified analogues bind with nearly 10 times the 5-HT2 versus 5-HT1C selectivity of ketanserin; however, none displays > 120-fold selectivity. Several of the compounds, such as the amide 32 and the urea 33 represent examples of new structural classes of 5-HT2 ligands.

Novel 1-phenylpiperazine and 4-phenylpiperidine derivatives as high-affinity sigma ligands.

sigma receptors may represent an exciting new approach for the development of novel psychotherapeutic agents. Unfortunately, many of the commonly used sigma ligands lack selectivity (e.g., many bind at phencyclidine or dopamine receptors) or suffer from other serious drawbacks. Recently, we described a series of 2-phenylaminoethanes that bind at sigma receptors with high affinity and selectivity. Because there is evidence that 1-phenylpiperazines can structurally mimic the 2-phenylaminoethane moiety, we prepared a series of 1-phenylpiperazines and related analogues and incorporated structural features already shown to enhance the sigma binding of the 2-phenylaminoethanes. Several of these derivatives bind at sigma receptors with high affinity (Ki = 1-10 nM) and lack appreciable affinity for phencyclidine and dopamine receptors. In as much as certain of these agents structurally resemble the high-affinity, but nonselective, sigma ligand haloperidol, and because they bind with 10 times the affinity of haloperidol, we have apparently identified what appears to be the primary sigma pharmacophore of that agent.

Binding of substituted and conformationally restricted derivatives of N-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane at sigma-receptors.

Certain benzomorphans, such as N-allylnormetazocine, are classical "sigma-opiates" that bind both at sigma and phencyclidine (PCP) binding sites with modest affinity. Recently, we identified N-substituted 2-phenylaminoethane as being the primary sigma-pharmacophore of the benzomorphans and demonstrated that 1-phenyl-2-aminopropane (2) derivatives, depending upon their terminal amine substituents, constitute a novel class of high-affinity sigma-selective agents. With this pharmacophore, it is shown in the present investigation that the aromatic hydroxyl group (a prime feature of all the sigma-opiates) contributes little to the binding of 2 at sigma-sites. It is also demonstrated that an N-substituted aminotetralin moiety (such as 17, a conformationally restricted analogue of 2) may also be considered a sigma-opiate pharmacophore. Unlike the sigma-opiates, derivatives of 2 and 17 display no affinity for PCP sites and must consequently lack those structural features important for the binding of benzomorphans at PCP sites. Because 3-phenylpiperidines and related sigma-ligands also possess a phenylalkylamine imbedded within their structures, we propose that the 2-phenylaminoethane moiety is a common sigma-pharmacophore for derivatives of 2, the 3-phenylpiperidines, and the sigma-opiates.

Fatal injuries and alcohol.

We reviewed fatal injuries in Fulton County, Georgia, in collaboration with the medical examiner's office. This county encompasses most of the city of Atlanta and has a population of approximately 600,000 persons. Information collected for 1981 and 1982 was analyzed; and the results of blood alcohol content (BAC) testing and toxic screens were reviewed for all victims of homicide, suicide, and unintentional fatal injuries who died within six hours of being injured. Seventy-one percent of 271 homicide victims had been drinking, and 51 percent had BACs greater than or equal to 0.1 mg/dL. Of 153 suicide victims, 37 percent had been drinking and 20 percent had BACs greater than or equal to 0.1 mg/dL. Of 54 drivers who died in single-vehicle collisions, 78 percent had been drinking; 54 percent of 162 victims of nonvehicular unintentional fatal injuries had positive blood alcohol levels. There was little evidence of the use of psychotropic drugs among victims of fatal injury. Most of the victims of homicide and unintentional fatal injuries who had positive toxic screens also had a positive blood alcohol tests.

Antagonism of a (+)N-allylnormetazocine stimulus by (-)PPAP and several structurally related analogs.

Employing rats trained to discriminate 5 mg/kg of the benzomorphan opioid (+)N-allylnormetazocine [(+)NANM] from vehicle, tests of stimulus generalization and antagonism were conducted to determine the influence of several potential sigma-receptor ligands. It has been previously suggested that the (+)NANM stimulus may involve concurrent action at sigma- and phencyclidine (PCP) receptors. Although the low-affinity sigma-antagonist rimcazole was without stimulus-attenuating effect, three novel sigma-ligands--(-)PPAP, CNS 3018, and CNS 3093 (ID50 doses = 3.2, 6.7, and 4.5 mg/kg, respectively)--antagonized the (+)NANM stimulus in a dose-related fashion. The nonselective serotonergic agent 1-(3-trifluoromethyl)phenylpiperazine (TFMPP) produced partial generalization in (+)NANM-trained animals whereas buspirone, a 5-hydroxytryptamine1A (5-HT1A) agonist, attenuated (to 27% drug-appropriate responding) the (+)NANM stimulus. Because the prototypic 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) failed to attenuate the (+)NANM stimulus at pharmacologically relevant doses, it seems unlikely that the (+)NANM stimulus involves a 5-HT1A mechanism. TFMPP and buspirone display modest affinity for sigma-receptors and this may account for the present findings with these agents. The present results neither establish a role for sigma involvement in the stimulus properties of (+)NANM nor eliminate a role for PCP receptors. They do, however, demonstrate that sigma-ligands with little to no affinity for PCP receptors are capable of antagonizing the (+)NANM stimulus.

Mechanistic investigation of the stimulus properties of 1-(3-trifluoromethylphenyl)piperazine.

Using a standard two-lever operant procedure with rats trained to discriminate 1-(3-trifluoromethylphenyl)piperazine (TFMPP) (0.5 mg/kg) from saline, tests of stimulus antagonism and stimulus generalization were performed to better understand the stimulus properties of this agent. The agents examined for ability to antagonize the TFMPP stimulus were prazosin, quipazine, zacopride, buspirone, 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), 1-(2-methoxyphenol)-4-[4-(2-phthalimido)butyl]-piperazine (NAN-190), haloperidol, and 1-(2-pyrimidinyl)piperazine (1-PP); only buspirone attenuated the response to TF-MPP. In separate experiments, the lowest nondisrupting dose of buspirone (1.2 mg/kg) caused a rightward shift of the TFMPP dose-response curve (TFMPP alone, ED50 = 0.19 mg/kg; TFMPP + buspirone, ED50 = 0.43 mg/kg). In addition, 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (CP 93, 129), 7-trifluoromethyl-4-(4-methyl-1-piperazinyl)pyrolo[1,2-a]quinox ali ne (CGS 12066B), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), 3-chlorophenylbiguanide (mCPBG), NAN-190, nisoxetine, zacopride, 1-PP, (+)-N-allylnormetazocine ((+)-NANM), and N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) were analyzed in tests of stimulus generalization. The TFMPP stimulus generalized only to CGS 12066B (ED50 = 4.2 mg/kg) and (+)-NANM (ED50 = 8.8 mg/kg). Tests with DOI and MDMA resulted in partial generalization. Up to doses that disrupted behavior, all other agents had little effect on TFMPP-appropriate responding. The results of these and other published studies suggest roles for 5-hydroxytryptamine 1B (5-HT1B), 5-HT1C, and, possibly, sigma-receptors in the mediation of the TFMPP stimulus and indicate a lack of involvement of 5-HT1A, 5-HT2, dopaminergic, and adrenergic mechanisms in this behavior.

Survey of graduates of the Epidemic Intelligence Service as an approach to enhancing ethnic diversity among the nation's epidemiologists.

A survey was conducted to improve the recruitment, training, and retention of epidemiologists in the Epidemic Intelligence Service (EIS) Program of the Centers for Disease Control. The authors compared minority graduates of the program and nonminority graduates in several areas: reasons for application, degree of satisfaction, appropriateness of preparation for epidemiologic practice, and current professional activities. A closed-ended questionnaire was mailed to all 87 minority graduates from the program during the period 1970-88, and to 172 randomly selected nonminority graduates. Of 259 graduates surveyed, 234 or 90.3 percent returned the questionnaire--89.6 percent of minority graduates and 90.7 percent of nonminority graduates. Virtually all graduates were satisfied with their EIS experience (95.2 percent), have encouraged others to apply (96.1 percent), and are the most frequent sources of initial contact of prospective officers (38.2 percent). Most EIS graduates (71.2 percent) were still working in epidemiology. Compared with the nonminority graduates, the minority graduates were more likely to be women and to be single. Minority graduates were less likely than non minorities to hold academic appointments (44.2 percent versus 60.0 percent) and less likely to work in academic settings as their primary job (11.5 percent versus 18.7 percent). At the same time, minority graduates were more likely to have learned of the EIS Program from academic advisors (32.1 percent versus 19.4 percent). Graduates express high levels of satisfaction with the EIS Program and continue to practice epidemiology following graduation. Few differences between the minority and nonminority graduates were found. Because fewer minority graduates are in academic settings to serve as mentors or role models, alternative recruitment methods must be developed to sustain a high level of interest among minority groups in the EIS Program.

Assessing trends in mortality in 121 U.S. cities, 1970-79, from all causes and from pneumonia and influenza.

The Centers for Disease Control receives weekly reports of mortality due to all causes and to pneumonia and influenza from 121 cities and counties in the United States. To assess the epidemiologic applicability of these data, the trends of death rates based on data compiled by the Centers for Disease Control's mortality reporting system (CDC-MRS) from 1970 through 1979 were compared with trends derived from national mortality statistics compiled by the National Center for Health Statistics (NCHS). In general, CDC-MRS trends in death rates from all causes and from pneumonia and influenza followed patterns similar to those shown by mortality statistics for the entire nation. CDC-MRS data were particularly sensitive to annual fluctuations in the nationwide rate of death from pneumonia and influenza among the elderly population. However, because of higher death rates among residents of the CDC-MRS reporting areas, in addition to other ascertainment biases, CDC-MRS death rates--from all causes and from pneumonia and influenza--consistently exceeded NCHS rates for the nation. Moreover, for each age group, trends based on CDC-MRS reflected an underestimate of the rate of decline in mortality observed over time according to NCHS data. It is concluded that despite its limitations, the CDC-MRS provides mortality data that are both timely and useful for epidemiologic purposes.

Alcohol and fatal injuries in Oklahoma.

To assess the usefulness of medical examiner data in describing the relationship between alcohol use and fatal injuries, 1978-84 data from the Office of the Chief Medical Examiner (ME), State of Oklahoma, was examined. In each year in the study period, approximately 1,500 deaths resulted from unintentional injuries (UI) and 800 deaths resulted from intentional injuries (i.e., suicides and homicides). For persons who died on the same day they were injured, testing for blood alcohol ranged from 90% of homicide victims, to 73% of suicide victims and to 66% of UI victims. Alcohol was associated with 52% of homicides, 49% of UI and 40% of suicides. Alcohol was detected most often in samples from Hispanic men and from Native Americans of both sexes. This study suggests that state public health agencies and researchers should consider the use of ME data for epidemiologic information on the relationship between alcohol and injury-related mortality and for surveillance of these problems.

Application of multiple time series analysis to the estimation of pneumonia and influenza mortality by age 1962-1983.

We employed multiple time series analysis to estimate the impact of influenza on mortality in different age groups, using a procedure for updating estimates as current data become available from national mortality data collected from 1962 to 1983. We compared mortality estimates that resulted from a multivariate model for epidemic forecasting with those obtained from univariate models. We found more accurate prediction of deaths from all age groups using the multivarate model. While the univariate models show an adequate fit to the data, the multivariate model often enables earlier detection of epidemics. Additionally, the multivariate approach provides insight into relationships among different age groups at different points in time. For both models, the largest excess mortality due to pneumonia and influenza during influenza epidemics occurred among those 65 years of age and older. Although multiple time series models appear useful in epidemiologic analysis, the complexity of the modelling process may limit routine application.

Breast cancer screening among relatives of women with breast cancer.

BACKGROUND: National surveys indicate that only 15% to 30% of all women in the general population 50 years of age or older have an annual mammogram. METHODS: We studied first-degree female relatives of women with breast cancer, who are at elevated risk of disease, to describe the breast cancer screening practices of these relatives and to improve their practices through a program of intensive education. We report here the screening behaviors of 2471 relatives of women with breast cancer. RESULTS: Self-reported behaviors were as follows: 49% performed monthly breast self-examination and 70% had annual breast examinations by a medical professional. Of 983 women 50 years of age or older, 49% had had a mammogram, but only 14% have a mammogram annually. Of women 50 years of age or older who had never had a mammogram, 92% reported never having had one recommended by a medical professional. CONCLUSIONS: Our findings indicate that screening behaviors in relatives of breast cancer patients are not substantially different from those of women in the general population. Enhanced efforts both to educate medical professionals and to encourage women to demand screening mammography are necessary to reduce breast cancer mortality.

Detection of aberrations in the occurrence of notifiable diseases surveillance data.

The detection of unusual patterns in the occurrence of diseases and other health events presents an important challenge to public health surveillance. This paper discusses three analytic methods for identifying aberrations in underlying distributions. The methods are illustrated on selected infectious diseases included in the National Notifiable Diseases Surveillance System of the Centers for Disease Control. Results suggest the utility of such an analytic approach. Further work will determine the sensitivity of such methods to variations in the occurrence of disease. These methods are useful for evaluating and monitoring public health surveillance data.

Fatal injuries in Oklahoma: descriptive epidemiology using Medical Examiner data.

To characterize mortality associated with injuries and other health problems in Oklahoma, we examined data from the Office of the Chief Medical Examiner of the State of Oklahoma for the years 1978 through 1984. Each year, approximately 1,500 and 800 deaths resulted from unintentional injury (UI) and intentional injury (ie, suicide and homicide), respectively. The medical examiner (ME) data differed substantially from the state's vital statistics (VS); over the seven years, the ME records showed 2,021 (16%) fewer UI deaths than did the VS, as well as 24 (1%) more cases of suicide and 499 (23%) more cases of homicide. Rates for UI and suicide were highest for young adults and for the elderly; in contrast, rates for homicide were highest for young adults, and then decreased with age. For each of the three categories of injury-related deaths, rates for male subjects were approximately three times those for female subjects; rates also varied by race-ethnic group. Deaths due to UI and homicide occurred more often in the summer and on weekends, though suicides did not vary by month and were slightly more common on weekdays. This study indicates that ME data represent an important source of epidemiologic information for the surveillance and study of injury-related mortality.

A cluster of unexplained deaths in a nursing home in Florida.

In the two-week period November 13-27, 1984, 12 patients died in a 54-bed nursing home in Florida; based on previous mortality patterns, 2.5 deaths would have been expected for the whole month. There was no similar increase in deaths in November 1984 and no comparable monthly death rate for any of 69 nursing homes in the same county from 1976-84. Comparison of the 12 deaths in November with 28 deaths that occurred during the previous 10 months and with 31 surviving patients who were continuously present in the nursing home between November 12-28, 1984 revealed that the patients who died in November were more likely to have had onset of the terminal event during the night shift, had a recent visitor, and had an admitting diagnosis of organic brain syndrome. The abrupt increase in the death rate for November 1984 was not associated with a measurable change in population characteristics, an outbreak of infectious disease, or changes in procedures or the environment. Reviews of employee schedules revealed a consistent and strong association between the duty times of two nurses and the onsets of the terminal episode and the times of patient deaths. Continuing epidemiologic surveillance of adverse outcomes in nursing homes is recommended.

Effects of the 65-mph speed limit on rural interstate fatalities in New Mexico.

As a result of federal legislation passed in April 1987, New Mexico was the first state to resume a 65-mph speed limit on rural Interstate highways. We compared the rates of fatal crashes before and after the speed limit change. The rate of fatal crashes in the 1 year after the speed limit was increased was 2.9 per 100 million vehicle-miles traveled, compared with a predicted rate of 1.5 per 100 million vehicle-miles based on the trend of the 5 previous years. When fatal crashes that occurred after the speed limit change were compared with fatal crashes in the 5 previous years, there was no difference in the mean age and sex of the at-fault drivers, mean age and sex of the victims, seat belt use by the victims, or alcohol involvement of the crashes. The increase in fatal crashes can be attributed to an increase in fatal single-vehicle crashes. Vehicles on rural Interstates are traveling at greater rates of speed and a larger proportion of vehicles are exceeding the 65-mph speed limit. The benefits associated with the 65-mph speed limit should be weighed against the increased loss of lives.

Cryptosporidiosis and surface water.

In the period July through October, 1986, 78 laboratory-confirmed cases of cryptosporidiosis were identified in New Mexico. To determine possible risk factors for development of this disease, we conducted a case-control study; 24 case-patients and 46 neighborhood controls were interviewed. Seventeen (71 per cent) of the 24 case-patients were females, seven (29%) were males; their ages ranged from 4 months to 44 years, median 3 years. There was a strong association between drinking surface water and illness: five of the 24 case-patients, but none of the 46 controls drank untreated surface water. Among children, illness was also associated with attending a day care center where other children were ill (odds ratio = 13.1).

Unexplained deaths in a children's hospital. An epidemiologic assessment.

During a nine-month period, July 1980 through March 1981, the mortality rate for patients on the cardiology ward of a children's hospital was 43.1 deaths per 10,000 patient-days, as compared with 11.0 deaths per 10,000 patient-days during the preceding 54 months. Twenty-five (76 per cent) of 33 infant deaths during this nine-month period occurred between midnight and 6:00 a.m., as compared with 1 of 10 infant deaths during a separate 27-month period (P less than 0.001). Although nearly all deaths occurred in patients with serious congenital heart disease, epidemic-period deaths were more likely to have an unexpected timing and a clinical pattern consistent with digoxin toxicity. In four patients, forensic and clinical digoxin measurements suggested that an intravenous overdose of digoxin had been administered shortly before death. Although a review of nursing schedules revealed a strong association (relative risk, 64.6) between infant deaths and the duty times of a particular nurse, the cause of the epidemic remains unclear. The study led to suggestions that the hospital strengthen central control over procedures for dispensing medicines and implement a system for monitoring the occurrence of deaths by time and place within the hospital.

Endemic giardiasis in New Hampshire: a case-control study of environmental risks.

Giardiasis is the most frequently reported diarrheal disease in northern New England. A case-control study of endemic giardiasis and environmental risk factors among residents of New Hampshire involved 273 cases from the state's 1984 disease registry and 375 controls. Giardiasis was associated with a shallow dug well as a residential water source (odds ratio [OR] = 2.4; 95% confidence interval [CI], 1.3-47.0), a recent history of drinking untreated surface water (OR = 3.4; CI, 2.1-5.5), a history of swimming in a lake or pond (OR = 4.6; CI, 2.4-86.0) or swimming in any natural body of fresh water (OR = 4.0; CI, 2.3-70.0), contact with a person thought to have giardiasis (OR = 2.3; CI, 1.4-36.0), and recent contact with a child in day care (OR = 1.5; CI, 1.0-2.1). Multivariate modeling supported these associations. Shallow wells, relatively common in New Hampshire, have not previously been established as important sources of giardiasis.

Epidemic giardiasis caused by a contaminated public water supply.

In the period November 1, 1985 to January 31, 1986, 703 cases of giardiasis were reported in Pittsfield, Massachusetts (population 50,265). The community obtained its water from two main reservoirs (A and B) and an auxiliary reservoir (C). Potable water was chlorinated but not filtered. The incidence of illness peaked approximately two weeks after the city began obtaining a major portion of its water from reservoir C, which had not been used for three years. The attack rate of giardiasis for residents of areas supplied by reservoir C was 14.3/1000, compared with 7.0/1000 in areas that received no water from reservoir C. A case-control study showed that persons with giardiasis were more likely to be older and to have drunk more municipal water than household controls. A community telephone survey indicated that over 3,800 people could have had diarrhea that might have been caused by Giardia, and 95 per cent of households were either using alternate sources of drinking water or boiling municipal water. Environmental studies identified Giardia cysts in the water of reservoir C. Cysts were also detected in the two other reservoirs supplying the city, but at lower concentrations. This investigation highlights the risk of giardiasis associated with unfiltered surface water systems.