Persistence of porcine reproductive and respiratory syndrome virus in serum and semen of adult boars.

Four seronegative adult boars were intranasally inoculated with porcine reproductive and respiratory syndrome virus (PRRSV) isolate VR-2332. Serum and semen were collected 2-3 times weekly for over 100 days postinoculation (DPI). Serum samples were assayed for PRRSV by virus isolation (VI) and a polymerase chain reaction (PCR) and screened for antibodies to PRRSV using the indirect fluorescent antibody (IFA) and virus neutralization (VN) tests. Semen was assayed for PRRSV RNA by PCR. Virus and viral RNA was detected in the serum of all boars within 1 DPI by Vi and/or PCR. However, VI results indicated that viremia was transient and occurred from 1 to 9 DPI. Viral RNA was detected in serum from 1 to 31 DPI. In the acute stage of the infection, PRRSV RNA was detected in serum by PCR prior to the presence of viral RNA in semen. The PRRSV RNA was detected in semen as early as 3 DPI and persisted for 25 DPI in 2 of the boars and 56 and 92 DPI in the remaining 2 boars. Detection of PRRSV RNA in semen occurred 2-8 and 28-35 days prior to the detection of antibodies by IFA and VN, respectively. PRRSV was isolated from the bulbourethral gland of the boar that shed viral RNA in semen for 92 DPI. These results suggest that PRRSV RNA can be detected by PCR in boar serum and semen, and may persist for variable periods of time. Viremia and the serologic status of the boar are not adequate indicators of when PRRSV or PRRSV RNA is being shed in the semen. Preliminary findings also indicated that neither shipping stress nor reinoculation with homologous PRRSV resulted in viremia or viral RNA shedding in semen.

Obesity in heterozygous carriers of the gene for the Bardet-Biedl syndrome.

Obesity and renal failure are common manifestations in the autosomal recessive Bardet-Biedl (BB) syndrome. Because obesity and hypertension have been reported frequently in non-homozygous relatives of BB patients, we hypothesized that BB heterozygotes are predisposed to these conditions. Clinical information was collected from 34 patients of BB homozygotes, who are obligate heterozygotes. The proportion of severely overweight fathers (26.7%) was significantly higher than that in comparably aged United States white males (8.9%). We conclude that the BB gene may predispose male heterozygous carriers to obesity. If BB heterozygotes are 1% of the general population, we estimate that approximately 2.9% of all severely overweight white males carry a single BB gene. The BB parents of both sexes were also significantly taller than U.S. white men and women of comparable age.

Incidence of cancer in 161 families affected by ataxia-telangiectasia.

BACKGROUND: Ataxia-telangiectasia is an autosomal recessive syndrome in which cancers develop in affected homozygotes at a rate approximately 100 times higher than in unaffected age-matched subjects. Retrospective studies have shown that persons heterozygous for the ataxia-telangiectasia gene, who make up about 1 percent of the general population, also have an excess risk of cancer, particularly breast cancer in women. Patients with ataxia-telangiectasia and cells derived from homozygotes and heterozygotes are unusually sensitive to ionizing radiation. METHODS: Cancer incidence and mortality, mortality from ischemic heart disease, and mortality from all causes were compared prospectively for a mean of 6.4 years in 1599 adult blood relatives of patients with ataxia-telangiectasia and 821 of their spouses, who served as controls, in 161 families affected by ataxia-telangiectasia. In a case-control substudy, we compared documented occupational and fluoroscopic diagnostic exposures to radiation in the 19 female blood relatives in whom breast cancer was first diagnosed during the period of prospective observation with the exposures in 57 matched blood relatives who did not have breast cancer. RESULTS: Cancer rates were significantly higher in the group of blood relatives than in their spouses, specifically in the subgroup of 294 blood relatives who were known to be heterozygous for the ataxia-telangiectasia gene. The estimated risk of cancer of all types among heterozygotes as compared with noncarriers was 3.8 in men and 3.5 in women, and that for breast cancer in women was 5.1. Among the blood relatives, women with breast cancer were more likely to have been exposed to selected sources of ionizing radiation than controls without cancer (odds ratio = 5.8, P = 0.005). Male and female blood relatives also had 3-fold and 2.6-fold excess mortality from all causes, respectively, from the ages of 20 through 59 years. CONCLUSIONS: The ataxia-telangiectasia gene predisposes heterozygotes to cancer, particularly breast cancer in women. There is also excess mortality from all causes in adults under the age of 60. Diagnostic or occupational exposure to ionizing radiation probably increases the risk of breast cancer in women heterozygous for ataxia-telangiectasia.

Psychiatric disorders in 36 families with Wolfram syndrome.

OBJECTIVE: The purpose of this study was to test the hypothesis that heterozygous carriers of the gene for the Wolfram syndrome, who constitute about 1% of the population, are predisposed to significant psychiatric illness. The Wolfram syndrome is an autosomal recessive neurodegenerative syndrome in which 25% of the individuals who are homozygous for the condition have severe psychiatric symptoms that lead to suicide attempts or psychiatric hospitalizations. METHOD: The authors collected questionnaires, death certificates, and hospital records for blood relatives and their spouses in 36 families of individuals with the Wolfram syndrome and compared the proportion of blood relatives who had had psychiatric hospitalizations, had committed suicide, or had self-reported mental illness to the proportion of spouses with the same manifestations. RESULTS: The proportion of blood relatives who had had psychiatric hospitalizations, had committed suicide, or had self-reported mental illness significantly exceeded the proportion of spouses with the same manifestations. CONCLUSIONS: Since heterozygous carriers of the gene for the Wolfram syndrome are 50-fold more common among the blood relatives than among the spouses, the larger proportion among blood relatives is evidence that heterozygous carriers of the gene for the Wolfram syndrome are predisposed to significant psychiatric illness.

Cancers in 44 families with ataxia-telangiectasia.

Cancer incidence was measured retrospectively in 574 close blood relatives of white ataxia-telangiectasia (A-T) patients and 213 spouse controls in 44 previously unreported families. The cancer incidence rate in the adult blood relatives was significantly elevated over the rate in the spouse controls (rate ratio = 3.9, p less than 0.01). For heterozygous carriers of the A-T gene, the relative risk of cancer was estimated to be 6.1 (p less than 0.005) as compared with nonheterozygotes. The most frequent cancer site in the blood relatives was the female breast, with nine cancers observed. These findings provide further support for the hypothesis that heterozygotes for the A-T gene are predisposed to cancer.

Effective testing of gene-disease associations.

We propose a method for testing any hypothesized association between a candidate allele, for which there is a specific laboratory test, and a common chronic disease. Families in which this allele is segregating are identified through index individuals who are homozygous or heterozygous for the allele. The sample consists of the subset of identified families who also have at least one member with the common disease of interest. For each independent family in this subset, select one person with the disease and determine if he or she is heterozygous for the allele. The observed proportion of heterozygotes in this sample is compared to the proportion expected on the basis of each diseased relative's null probability of being heterozygous for the allele; this null probability depends only on the relative's relationship to the index individual and the population allele frequency. We provide these null probabilities, develop appropriate inference procedures, discuss sample size requirements, and compare this method to a standard case-control design. Results using this method are unlikely to be influenced by confounders, systematic bias, or genetic heterogeneity.

Cancer predisposition of ataxia-telangiectasia heterozygotes.

Ataxia-telangiectasia (A-T) is a progressive neurologic disorder in which there is varied immune dysfunction, an excess sensitivity to ionizing radiation, and a striking predisposition to cancer. It is the autosomal recessive syndrome for which there is the strongest evidence, derived from retrospective studies of cancer incidence and mortality in A-T families, that the heterozygote is predisposed to cancer. We present, in tabular form, the specific cancer sites or types most likely to be associated with A-T heterozygosity. These include solid tumors of the breast, pancreas, stomach, bladder, and ovary, and chronic lymphocytic leukemia. We also introduce a new method to test these associations. As soon as molecular probes for the A-T allele(s) are available, this new research design will be used to test rigorously each association, hypothesized on the basis of previous data, between a specific cancer site and A-T heterozygosity.

Circulatory disease mortality and diabetes incidence in 27 families with Friedreich ataxia.

Friedreich ataxia (FRA) is an autosomal recessive neuromuscular disorder in which nearly all affected homozygotes eventually develop significant cardiomyopathy and a substantial proportion also develop diabetes mellitus. Diabetes and early heart disease have been observed previously in close blood relatives of FRA patients. To test the hypothesis that FRA heterozygotes may have elevated rates of heart disease mortality and diabetes incidence, we compared the rates of these conditions in 1,191 adult blood relatives to those in 745 nonblood relative spouse controls in 27 families of FRA patients. We found no evidence for an excess of diabetes in the blood relatives. For three broad categories of circulatory disease mortality, the FRA blood relatives had significantly higher rates than the spouse controls. However, when each relative's prior probability of heterozygosity for the FRA gene was taken into account, the resulting estimates of relative risk of dying from circulatory disease for FRA heterozygotes compared to nonheterozygotes were not significantly elevated. Since the latter analysis provides the best test of the hypothesis, our data did not strongly support the hypothesis that FRA heterozygotes are at increased risk of cardiac death.

Breast and other cancers in families with ataxia-telangiectasia.

Patients who are homozygous for ataxia-telangiectasia have an exceptionally high incidence of cancer. In a group of families expected to have a high proportion of heterozygotes for ataxia-telangiectasia, we tested the hypothesis that such heterozygotes, estimated to make up 0.68 to 7.7 percent of the U.S. white population, also have an excess cancer risk. Retrospective cancer incidence rates in adult blood relatives of patients with ataxia-telangiectasia in 110 white non-Amish families were significantly elevated over the incidence rates in spouse controls (rate ratios, 1.6 for men [P = 0.032]; 2.0 for women [P = 0.013]). For persons who are heterozygous for ataxia-telangiectasia, the relative risk of cancer was estimated to be 2.3 for men (P = 0.014) and 3.1 for women (P = 0.004). Breast cancer in women was the cancer most clearly associated with heterozygosity for ataxia-telangiectasia (rate ratio, 3.0 [P = 0.028]; heterozygote relative risk, 6.8 [P = 0.006]). On the basis of this estimated relative risk of 6.8 and an estimated heterozygote frequency in the general population of 1.4 percent, 8.8 percent of patients with breast cancer in the U.S. white population would be heterozygous for ataxia-telangiectasia. We conclude that heterozygous carriers of the gene for ataxia-telangiectasia have an excess risk of cancer, particularly breast cancer in women.

Cancer in families with severe combined immune deficiency.

Cancer incidence and mortality were analyzed in 1,181 blood relatives and 558 spouse controls in 24 families of severe combined immune deficiency (SCID) patients, to test the hypothesis that heterozygous carriers of a gene for an autosomal recessive form of SCID are predisposed to cancer. Since at least 1 patient in each family was female and there were no cases outside the probands' sibships, the pattern of occurrence of SCID within the families was compatible with autosomal recessive inheritance. The observed numbers of cancer cases and deaths did not exceed the expected numbers derived from population-based rates; and there was no cancer excess when incidence rates in blood relatives were compared directly to those in spouse controls, since the rate ratios were 1.2 and 1.0 for males and females, respectively. In addition, cancer rate ratios were not significantly elevated when calculated separately for the 9 families of adenosine deaminase (ADA)-deficient SCID patients and for the 15 families without evidence of ADA deficiency.

Diabetes mellitus in ataxia-telangiectasia, Fanconi anemia, xeroderma pigmentosum, common variable immune deficiency, and severe combined immune deficiency families.

The hypothesis that heterozygous carriers of genes for certain autosomal recessive syndromes may be predisposed to diabetes was tested by comparing diabetes incidence from age 20 to 69 yr in blood relatives to that in spouse controls among 7999 adult family members of patients with one of five autosomal recessive syndromes: ataxia-telangiectasia (A-T), Fanconi anemia (FA), xeroderma pigmentosum (XP), common variable immune deficiency (CVID), and severe combined immune deficiency (SCID). FA and A-T families were studied because earlier findings in family members and the frequency of diabetes in homozygotes suggested that heterozygotes might also be predisposed to diabetes. The XP, CVID, and SCID families were included to see what analysis of family data would reveal when there was no prior evidence for a gene-diabetes association. The diabetes rate ratios of 2.6 and 4.2 among FA and SCID females, respectively, were significantly elevated. For female FA heterozygotes specifically, the estimated relative risk of 5.1 for developing diabetes was also significantly elevated. Among males, the most pronounced, although not statistically significant, findings were an elevated rate ratio of 2.2 for A-T males and a low-rate ratio of 0.5 for CVID males. The results suggest that heterozygotes for some of the diabetes-associated autosomal recessive syndromes may themselves be predisposed to diabetes.

Cancer and autoimmune disease in families with common variable immune deficiency.

Twenty-five families including 34 individuals with common variable immune deficiency (CVID), with at least one affected female in each family, were studied. The distribution of cases within families was compatible with autosomal recessive inheritance, making it plausible to test hypotheses about the disease risk of heterozygote carriers of putative CVID genes by comparing the frequency of autoimmune disorders and cancer in 1033 adult blood relatives to that in 566 spouse controls. For cancer, observed numbers of cases or deaths were also compared to expected numbers derived from population rates. No single family had an unusual clustering of autoimmune conditions, and, overall, autoimmune disease was not found more frequently in blood relatives than in spouse controls. Blood relatives did have a modest, although not significant, excess of rheumatic heart disease. For cancer analyses, comparisons with general population rates indicated no heterozygote predisposition, while direct comparisons of blood relatives to spouse controls revealed a significantly elevated cancer rate in females (rate ratio = 2.3, P less than 0.003). The estimated relative risk of cancer for female CVID heterozygotes was most elevated in the 45-69-year-old age group. It is arguable whether comparisons with population or spouse controls are the most appropriate for evaluating the cancer risk of CVID heterozygotes. The hypothesis that the CVID gene predisposes heterozygous female carriers to cancer may be evaluated more easily in the future when the genetic basis for CVID is better understood.

Reduction of low birth weight rates by the prevention of unwanted pregnancies.

PIP: It has been claimed that a direct relationship exists between the occurrences of low-birth-weight births and unwanted pregnancies. A strong correlation has been shown between the incidence of low birth weight and the infant mortality rate. Therefore, a reduction in unwanted pregnancies should lead to a reduction in the infant mortality rate. This study was based on interviews with 3030 black and 4891 white postpartum mothers at 60 major hospitals in 17 U.S. cities. Women were questioned about the wantedness of the pregnancy at the time of conception. Low birth weights were 10.6 of black and 5% of white births. Among both groups there was no definite relation between low-birth-weight births and unwanted pregnancies. An exception was that, among women with some college education, unwanted births were more prone to have more frequent low-birth-weight births than women who had wanted the pregnancy. It is concluded that the prevention of unwanted pregnancies will not contribute to the reduction in the occurrence of low-birth-weight births. These results cast doubt on some family planning claims.^ieng

Population growth rates in perfect contraceptive populations.

Abstract Eventually, world population must cease to grow. In many countries attempts are made to decrease population growth by providing family planning services to all who want to prevent pregnancies. In this paper we use the concept 'perfect contraceptive population',(1) - a population in which no unwanted births occur - to derive estimates of the maximum contribution that prevention of unwanted births might make toward attaining a zero rate of natural increase in population.

Can mass media advetising increase contraceptive use?

PIP: A $330,000 multimedia advertising campaign was undertaken in 4 U.S. cities (Columbus, Ohio; Memphis, Tennessee; Altoona, Pennsylvania; Jackson, Mississippi) November 1970-May 1971 by the Family Planning Evaluation project (University of North Carolina) to evaluate the cost and effectiveness of commercial advertising in increasing contraceptive utilization among active fertile individuals. The ads ran on radio, television, in special editions of Life and Look, and in local daily, ethnic, and community newspapers. The level of complaints was below what had been anticipated, and there was no unacceptable community opposition even in the saturation cases. The level of awareness was higher during the campaign for television and radio advertising but not for newspaper and magazine advertising (interviews). The number of "new" patients to family planning clinics was low (ranging from 24 to 444) and it appears that mass media advertising is not an effective recruitment technique. No differences were found in new prescription sales of oral contraceptives or sales of condoms between the media sites and their controls during the 6-month campaign. Mass media campaigns might be more effective in non-US settings where contraceptive knowledge is not great and usage is not widespread.^ieng