Incidence of breast cancer in first-degree female relatives of men with newly diagnosed prostate cancer

Prostate cancer is the most common incident cancer and the second leading cause of death in men in the United States. Although numerous attempts have been made to identify risk factors associated with prostate cancer, the results have been inconsistent and conflicting. The only established risk factors are age and ethnicity. A positive family history of prostate cancer has also been shown to increase the risk two- to three-fold among close relatives.^ There are several similarities between breast and prostate cancer that make the relationship between the two of interest. (1) Histologically, both cancers are predominantly adenocarcinomas, (2) both organs have a sexual and/or reproductive role, (3) both cancers occur in hormone-responsive tissue, (4) therapy often consists of hormonal manipulation, (5) worldwide distribution patterns of prostate and breast cancer are positively correlated.^ A family history study was conducted to evaluate the aggregation of prostate cancer and co-aggregation of breast cancer in 149 patients referred to The University of Texas, M.D. Anderson Cancer Center with newly diagnosed prostate cancer. All patients were white, less than 75 years of age at diagnosis and permanent residents of the United States. Through a personal interview with the proband, family histories were collected on 1,128 first-degree relatives. Cancer diagnoses were verified through medical records or death certificate. Standardized incidence ratios were calculated using a computer program by Monson incorporating data from Connecticut Tumor Registry.^ In this study, familial aggregation of prostate cancer was verified only among the brothers, not among fathers. Although a statistically significant excess of breast cancer was not found, the increased point estimates in mothers, sisters and daughters are consistent with a co-aggregation hypothesis. Rather surprising was the finding of a seven-fold increased risk of prostate cancer and a three-fold increased risk of breast cancer among siblings in the presence of a maternal history of any cancer. Larger family history studies including high risk (African-Americans) and lower-risk groups (Hispanics) and incorporating molecular genetic evaluations should be conducted to determine if genetic differences play a role in the differential incidence rates across ethnic groups. ^

Risk factors associated with first symptomatic infection of {\it Cryptosporidium parvum\/} in an infant population in Bilbeis, Egypt

Diarrhea disease is a leading cause of morbidity and mortality, especially in children in developing countries. An estimate of the global mortality caused by diarrhea among children under five years of age was 3.3 million deaths per year. Cryptosporidium parvum was first identified in 1907, but it was not until 1970 that this organism was recognized as a cause of diarrhea in calves. Then it was as late as 1976 that the first reported case of human Cryptosporidiosis occurred. This study was conducted to ascertain the risk factors of first symptomatic infection with Cryptosporidium parvum in a cohort of infants in a rural area of Egypt. The cohort was followed from birth through the first year of life. Univariate and multivariate analyses of data demonstrated that infants greater than six months of age had a two-fold risk of infection compared with infants less than six months of age (RR = 2.17; 95% C.I. = 1.01-4.82). When stratified, male infants greater than six months of age were four times more likely to become infected than male infants less than six months of age. Among female infants, there was no difference in risk between infants greater than six months of age and infants less than six months of age. Female infants less than six months of age were twice more likely to become infected than male infants less than six months of age. The reverse occurred for infants greater than six months of age, i.e., male infants greater than six months of age had twice the risk of infection compared to females of the same age group. Further analysis of the data revealed an increased risk of Cryptosporidiosis infection in infants who were attended in childbirth by traditional childbirth attendants compared to infants who were attended by modern childbirth attendants (nurses, trained midwives, physicians) (RR = 4. 18; 95% C.I. = 1.05-36.06). The final risk factor of significance was the number of people residing in the household. Infants in households which housed more than seven persons had an almost two-fold risk of infection compared with infants in homes with fewer than seven persons. Other risk factors which suggested increased risk were lack of education among the mothers, absence of latrines and faucets in the homes, and mud used as building material for walls and floors in the homes. ^

Effect of Acute Administration of Angiopoietin-1 in Experimental Traumatic Spinal Cord Injury: Magnetic Resonance Imaging and Neurobehavioral Studies

Spinal cord injury (SCI) is a devastating condition that affects people in the prime of their lives. A myriad of vascular events occur after SCI, each of which contributes to the evolving pathology. The primary trauma causes mechanical damage to blood vessels, resulting in hemorrhage. The blood-spinal cord barrier (BSCB), a neurovascular unit that limits passage of most agents from systemic circulation to the central nervous system, breaks down, resulting in inflammation, scar formation, and other sequelae. Protracted BSCB disruption may exacerbate cellular injury and hinder neurobehavioral recovery in SCI. In these studies, angiopoietin-1 (Ang1), an agent known to reduce vascular permeability, was hypothesized to attenuate the severity of secondary injuries of SCI. Using longitudinal magnetic resonance imaging (MRI) studies (dynamic contrast-enhanced [DCE]-MRI for quantification of BSCB permeability, highresolution anatomical MRI for calculation of lesion size, and diffusion tensor imaging for assessment of axonal integrity), the acute, subacute, and chronic effects of Ang1 administration after SCI were evaluated. Neurobehavioral assessments were also performed. These non-invasive techniques have applicability to the monitoring of therapies in patients with SCI. In the acute phase of injury, Ang1 was found to reduce BSCB permeability and improve neuromotor recovery. Dynamic contrast-enhanced MRI revealed a persistent compromise of the BSCB up to two months post-injury. In the subacute phase of injury, Ang1’s effect on reducing BSCB permeability was maintained and it was found to transiently reduce axonal integrity. The SCI lesion burden was assessed with an objective method that compared favorably with segmentations from human raters. In the chronic phase of injury, Ang1 resulted in maintained reduction in BSCB permeability, a decrease in lesion size, and improved axonal integrity. Finally, longitudinal correlations among data from the MRI modalities and neurobehavioral assays were evaluated. Locomotor recovery was negatively correlated with lesion size in the Ang1 cohort and positively correlated with diffusion measures in the vehicle cohort. In summary, the results demonstrate a possible role for Ang1 in mitigating the secondary pathologies of SCI during the acute and chronic phases of injury.

Estimation of male-to-female ratios of mutation rate in primates and rodents

Haldane (1935) developed a method for estimating the male-to-female ratio of mutation rate ($\alpha$) by using sex-linked recessive genetic disease, but in six different studies using hemophilia A data the estimates of $\alpha$ varied from 1.2 to 29.3. Direct genomic sequencing is a better approach, but it is laborious and not readily applicable to non-human organisms. To study the sex ratios of mutation rate in various mammals, I used an indirect method proposed by Miyata et al. (1987). This method takes advantage of the fact that different chromosomes segregate differently between males and females, and uses the ratios of mutation rate in sequences on different chromosomes to estimate the male-to-female ratio of mutation rate. I sequenced the last intron of ZFX and ZFY genes in 6 species of primates and 2 species of rodents; I also sequenced the partial genomic sequence of the Ube1x and Ube1y genes of mice and rats. The purposes of my study in addition to estimation of $\alpha$'s in different mammalian species, are to test the hypothesis that most mutations are replication dependent and to examine the generation-time effect on $\alpha$. The $\alpha$ value estimated from the ZFX and ZFY introns of the six primate specise is ${\sim}$6. This estimate is the same as an earlier estimate using only 4 species of primates, but the 95% confidence interval has been reduced from (2, 84) to (2, 33). The estimate of $\alpha$ in the rodents obtained from Zfx and Zfy introns is ${\sim}$1.9, and that deriving from Ube1x and Ube1y introns is ${\sim}$2. Both estimates have a 95% confidence interval from 1 to 3. These two estimates are very close to each other, but are only one-third of that of the primates, suggesting a generation-time effect on $\alpha$. An $\alpha$ of 6 in primates and 2 in rodents are close to the estimates of the male-to-female ratio of the number of germ-cell divisions per generation in humans and mice, which are 6 and 2, respectively, assuming the generation time in humans is 20 years and that in mice is 5 months. These findings suggest that errors during germ-cell DNA replication are the primary source of mutation and that $\alpha$ decreases with decreasing length of generation time. ^

Cardiovascular diseases risk factors during the first year of life

The pattern of change in cardiovascular risk factors, blood pressure (SBP and DBP) and plasma total cholesterol (TC), over time, their tracking and their relation to anthropometric measurements during the first year of life were investigated. Also, the effect of breast feeding on TC and the relationship of blood pressure measurements and family history of CVD risk factors were examined. One hundred five newborn term, healthy infants who were seen at a pediatric clinic in The Woodlands, Texas were followed longitudinally from 2 weeks to 1 year of age. TC, blood pressure, weight and length of the infants were measured at age 2 weeks, and again at 2, 4, 6, 9 and 12 months. In addition, family history, maternal and paternal, of CVD risk factors was obtained. Data analyses included only 40 infants who completed one year of follow up.^ At 2 weeks of age, the median value for TC was 23 mg/dl higher for females than for males. This difference disappeared as infants got older. For males, most of the increase in TC median levels, from 114 to 137 mg/dl, occurred between the ages of 2 weeks and 2 months, whereas for the female group, TC levels increased moderately, about 10 mg/dl, between 9 and 12 months of age. Tracking of TC was examined by using Spearman's correlation analysis. There were strong correlations between measurements taken as early as 2 weeks of age with later measurements. These correlations were stronger and more significant for males than for females (for males, r varied between 0.51 to 0.70, whereas for females, r varied between 0.11 to 0.70). The association of body measurements with TC is no more than modest and is closer for female infants than for male infants. Analysis, also, showed that infants who received breast milk had a TC mean value 47 mg/dl higher than that for infants who received formula milk only during the period of breast feeding and this difference disappeared by age 12 months.^ In both genders, most of the increase in blood pressure (about 10-15 mmHg in both SBP and DBP) occurred during the first 4 months of life. Most of the increase for male infants occurred during the first 2 months of life, while for females, the increase in SBP and DBP was between the age of 2 and 4 months. Neither SBP nor DBP track well during the first year of life and most of the correlations between measurements at different ages were not significant for either gender. The cross-sectional relationship of blood pressure measurements and selected body measurements was assessed. For females, only at age of 12 months did DBP have positive and significant correlations with weight, length and Quetelet index (r = 0.57, 0.60 and 0.57, respectively). There were no significant correlations between blood pressure and body measurements for males. Finally, analysis showed that maternal history of CV risk factors was significantly related to SBP in the female infant group, but not for males. For DBP, neither maternal nor paternal history was related. ^

Predictors of benzodiazepine self -administration behavior in anxious patients

The purpose of this study was to examine factors that may be associated with benzodiazepine (BZ) self-administration and risks of dependence in anxious patients. Preliminary work included examination of psychosocial characteristics and subjective drug response as potential predictors of medication use. Fifty-five M, F patients with generalized anxiety or panic disorder participated in a 3-week outpatient Choice Procedure in which they self-medicated “as needed” with alprazolam (Alz) and placebo. Findings showed that a large amount of variance in alprazolam preference, frequency, and quantity of use could be predicted by measures of anxiety, drug liking, and certain personality characteristics. The primary study extended this work by examining whether individual differences in Alz sensitivity also predict patterns of use. Twenty anxious patients participated in the study, which required 11 weekly clinic visits. Ten of these also participated in a baseline assessment of HPA-axis function that involved 24-hour monitoring of cortisol and ACTH levels and a CRH Stimulation Test. This assessment was conducted on the basis of prior evidence that steroid metabolites exert neuromodulatory effects on the GABA A receptor and that HPA-axis function may be related to BZ sensitivity and long-term disability in anxious patients. Patients were classified as either HIGH or LOW users based on their p.r.n. patterns of Alz use during the first 3 weeks of the study. They then participated in a 4-week dose response trial in which they received prescribed doses of medication (placebo, 0.25, 0.5, and 1.0mg Alz), each taken TID for 1 week. The dose response trial was followed by a second 3-week Choice Procedure. Findings were not indicative of biological differences in Alz sensitivity between the HIGH and LOW users. However, the HIGH users had higher baseline anxiety and greater anxiolytic response to Alz than the LOW users. Anxiolytic benefits of p.r.n. and prescribed dosing were shown to be comparable, and patients' conservative patterns of p.r.n. medication use were not affected by the period of prescribed dosing. Although there was not strong evidence to suggest relationships between HPA-axis function and Alz use or sensitivity, interesting findings emerged about the relationship between HPA-axis function and anxiety. ^