Mammographic density and candidate gene variants: a twins and sisters study.

BACKGROUND: Mammographic density, the light/white radiographic appearance on a mammogram that represents connective and epithelial tissue, is a strong risk factor for breast cancer which seems to be highly heritable. Little is known about its genetic determinants. METHODS: We studied 457 women from 207 sisterhoods (104 monozygotic twins, 182 dizygotic twins, and 171 singletons). Percentage mammographic density (PMD) as well as dense area and nondense area were calculated using a computer-assisted method. We measured six single nucleotide polymorphisms from six candidate genes (COMT, HSD3B1, IGFBP3, HER2, XPD, and XRCC3). Associations between genotypes and mammographic measures were tested (a) cross-sectionally using a multivariate normal model fitted using FISHER that allowed separate correlations for monozygotic, dizygotic, and nontwin pairs and (b) within sister pairs using paired t tests. RESULTS: Cross-sectionally, each additional copy of the HSD3B1 Asn(367)Thr variant allele was associated with lower PMD (-3.47% per allele; SE = 1.65; P = 0.035). Within-pair regression estimates confirmed this association. There was no evidence for an association between the mammographic density measures and any of the other variants studied. CONCLUSION: We have replicated an association between a variant in the HSD3B1 gene and PMD, which suggests that HSD3B1 may be genetic determinant of mammographic density.     

The common variant rs1447295 on chromosome 8q24 and prostate cancer risk: results from an Australian population-based case-control study.

A recent study from deCode reported an association between common variants in the region 8q24 and prostate cancer risk. The strongest association was found with the single nucleotide polymorphism rs1447295. We genotyped 821 prostate cancer cases and 732 population controls for rs1447295 to test the association between this common variant and prostate cancer risk, and examine whether this association depends on Gleason score. Our case-control study confirmed the association between rs1447295 and prostate cancer risk (P = 0.0005). The odds ratio (OR) for prostate cancer was 1.52 [95% confidence interval (CI), 1.20-1.93] for carriers of any A allele compared with noncarriers. The OR for Gleason score 5 to 6 prostate cancer (1.48; 95% CI, 1.13-1.95) was similar to the OR for Gleason score 7 to 10 prostate cancer (1.58; 95% CI, 1.18-2.11, P for heterogeneity = 0.7). We conclude that the A allele of rs1447295 is associated with a higher risk of prostate cancer regardless of tumor aggressiveness, suggesting that such a variant, or a variant in linkage disequilibrium with it, plays a role early in prostate carcinogenesis.     

Vasopressin levels and pediatric head trauma

The syndrome of inappropriate secretion of antidiuretic hormone is associated with head trauma; however, there are no reports concerning vasopressin levels in pediatric patients with head trauma. Urine vasopressin in eight children (mean +/- SEM, age 7.5 +/- 1.6 years, range 1 to 15 years) was measured by radioimmunoassay during their hospitalization for head trauma. Urine vasopressin values for ten healthy children (mean age 5.4 +/- 1.3 years) and for eight children hospitalized for systemic antibiotic treatment of infections (age 5.9 +/- 1.8 years) also were obtained. Urine vasopressin, urine and serum sodium concentration and osmolality, urea nitrogen, creatinine, and fluid intake were measured within 24 hours of admission and daily for the following two days. For the first three days following head trauma, mean urine vasopressin levels in pediatric patients with head trauma were increased (P less than .05) compared with those of healthy children. Despite fluid restriction to 85% of maintenance level, 25% of patients with head trauma exhibited the clinical syndrome of inappropriate secretion of antidiuretic hormone (hyponatremia, increased urinary sodium, diminished serum osmolality, and urine osmolality greater than serum osmolality). Urine osmolality greater than 800 mosm/kg was associated with markedly increased urine vasopressin levels (200 to 1,650 pg/mL); children with this finding may be at particular risk for the syndrome of inappropriate secretion of anti-diuretic hormone without restrictive water intake.     

Follicular phase gonadotropin-releasing hormone agonist and human gonadotropins: a better alternative for ovulation induction in in vitro fertilization

Leuprolide acetate was used in 189 in vitro fertilization (IVF) cycles. Patients were allocated prospectively into two groups: In group A (96 cycles), leuprolide acetate was started on the 2nd menstrual cycle day of the actual IVF attempt. In group B (93 cycles), leuprolide acetate was started on the 3rd luteal phase day of the preceding IVF cycle. Ovulation was induced with a combination of pure follicle-stimulating hormone (FSH) and human menopausal gonadotropins (hMG), starting on or before the 5th cycle day, respectively. Leuprolide acetate and gonadotropins were continued until the day of human chorionic gonadotropin (hCG) administration. Follicular aspiration was carried out either by laparoscopy or by transvaginal ultrasound guidance. Group A required a lower number of FSH and hMG ampules than group B; nevertheless, there was no difference in the number of follicles, percentage of preovulatory oocytes or fertilization rate between the groups. The number of embryos transferred was 3.3 and 3.4, respectively. A significantly higher pregnancy rate was observed in group A (40.6% versus 27.7%) and a lower miscarriage rate (22.8% versus 36%) than in group B. In short, this study suggests that there is no need to administer leuprolide acetate routinely during the luteal phase of the preceding IVF cycle.     

Treatment of cirrhosis caused by hepatitis C

There are real concerns about patients with cirrhosis after HCV infection and their outcome because the survival rate after 5 years in the group with descompensated liver disease (Child-Pugh C) is very poor, it's only 50%. Likewise, it's possible that these patients develop another feared complication, hepatocellular carcinoma. This tumor can appear even in patients with compensated cirrhosis. Prevalence varies according to the geographic region. In the occidental countries, prevalence is 7-11% in the 5 year follow-up (1.6-3.2 cases for every 100 persons each year). On the other hand, oriental series report a prevalence of 30% in the 5 year follow-up (6-7 cases for every 100 persons each year). The quality of available information leads us to suggest that therapy with pegylated interferon and ribavirin is clearly indicated for patients with compensated cirrhosis as long as the white cell and platelet counts allow the reduction induced by the therapy. This scheme is contraindicated in cirrhotic patients with a Child-Pugh score of 10 points or more. Available data about therapeutic effect on cirrhosis progression suggest that an effective scheme based on interferon is able to induce a sustained viral response, and is related with a lesser risk of complications secondary to liver failure. The survival rate is better in these patients. Clinical observations suggest that interferon may prevent hepatocellular carcinoma in cirrhotic patients after HCV infection, especially in Oriental countries which have a high incidence of this carcinoma. Because of geographical and racial differences between East and West, it's inadequate to extrapolate information from one of these regions to the other.     

Seroprevalence and risk factors for Trypanosoma cruzi infection in the Amazon region of Ecuador

Trypanosoma cruzi infection in the Ecuadorian Amazon region has recently been reported. A seroepidemiologic survey conducted in four provinces in this region indicates a seroprevalence rate of 2.4% among the 6,866 samples collected in 162 communities. Among children < OR = 10 years of age, 1.2% were seropositive. Risk factors for T. cruzi seropositivity were having been born and remaining in the Ecuadorian Amazon provinces, age, living in a house with a thatch roof and open or mixed wall construction, recognizing the vector insects, and reporting being bitten by a triatomine bug. These data suggest active transmission of Chagas' disease in the Ecuadorian Amazon region is associated with poor housing conditions, and highlight the need for further studies aimed at understanding the biology of the insect vectors, reservoir species, and the clinical impact of T. cruzi infection as the basis for future educational and control programs in this region.     

Hyperphenylalaninemia in the Philippines

To present patients with hyperphenylalaninemia (HPA) diagnosed by routine newborn screening and to discuss the principles in managing hyperphenylalaninemia, retrospective clinical chart review was conducted. Newborn screening for phenylketonuria (PKU) was performed using the Guthrie Test or Bacterial Inhibition Assay, utilizing dried blood spots on special filter cards. Positive screens were confirmed through plasma amino acid determination, urinary pterins for tetrahydrobiopterin deficiency, enzyme analysis. Once confirmed, the patients were kept on low-phenylalanine diet and regularly monitored for blood phenylalanine levels and developmental profile. A total of 189,720 newborns were screened from 1996--2001. Seventy five screened positive for PKU; 41 returned for retest; 3 were confirmed positive for HPA. This paper presents the first two cases of HPA detected by the Philippine Newborn Screening Program. The management of each case upon diagnosis is discussed. The significance of early detection and treatment of HPA is emphasized.     

Cost-benefit analysis of newborn screening for galactosemia in the Philippines

To determine the incidence of galactosemia (GAL) in the Philippines and to determine whether newborn screening for GAL is cost-beneficial from a societal perspective, cost-benefit analysis was performed. Newborn screening for GAL was done after the 24th hour of life using the Beutler test. Patients screened positive were recalled for confirmatory testing. Using incidence rates obtained from the different participating hospitals of the Philippine Newborn Screening Program (PNSP), the costs for the detection and treatment of GAL were compared to the expected benefits by preventing mental retardation, cataracts and other physical disabilities caused by the disorder that would lead to a loss of productivity for the individual. Sensitivity analyses for incidence and discount rates were also included. Of the 157,186 newborns screened by the PNSP since its inception in 1996, 8 screened positive results. Confirmatory testing of these patients showed that 2 had galactosemia. The incidence of galactosemia in this population therefore, is 1 in 106,006 (95% CI= 1:44,218 - 1:266,796). Projecting the figures to the actual birth rate (1.5M newborns/year), the total costs of the screening program amounted to $1.1M, while the total benefits amounted only to $0.2M, yielding net cost of $0.9M. A cost-benefit analysis of the screening program for galactosemia using the incidence 1 in 106,006 demonstrated that the costs of the program outweigh the benefits. The true incidence of galactosemia in the Philippine population may yield an incidence rate that will result in greater net benefits for the program.