Heritability of the symptoms of benign prostatic hyperplasia and the roles of age and zonal prostate volumes in twins

OBJECTIVES: Both benign prostatic hyperplasia and lower urinary tract symptoms (LUTS) have been shown to increase with age in men, but a causal relationship between prostate volume and symptoms has not been established. This study had two aims, to investigate the inter-relationships of age, symptoms, and various zonal measurements in the prostate and to assess the impact of heritable influences on symptom score. METHODS: Eighty-three monozygotic twin pairs and 83 dizygotic twin pairs were studied to determine age and LUTS as assessed by the American Urological Association symptom score. Their prostate volumes (total, transition zone, and peripheral zone) were measured by transrectal ultrasound. RESULTS: There was significant evidence of pairwise correlation between transition zone and symptom score (P = 0.04) and between age and symptom score (P = 0.03). Age also showed significant correlation with all volume measurements. Heritability appears to account for 82.6% of the variability in symptom score in men older than 50 years. CONCLUSIONS: This study provides evidence that age and transition zone volume play a role in LUTS, but also that their influence is not strong. Estimates of heritability suggest that hereditary factors contribute substantially to LUTS.     

Inhibition of allergen-induced pulmonary responses by the selective tryptase inhibitor 1,5-bis-[4-[(3-carbamimidoyl-benzenesulfonylamino)-methyl]-phenoxy]-pen tane (AMG-126737)

Emerging evidence suggests that mast cell tryptase is a therapeutic target for the treatment of asthma. The effects of this serine protease are associated with both pathophysiologic pulmonary responses and pathologic changes of the asthmatic airway. In this study, the tryptase inhibitor 1,5-bis-[4-[(3-carbamimidoyl-benzenesulfonylamino)-methyl]-p henoxy]-pentane (AMG-126737) was evaluated for its pharmacologic effects against allergen-induced airway responses. AMG-126737 is a potent inhibitor of human lung mast cell tryptase (Ki = 90 nM), with greater than 10- to 200-fold selectivity versus other serine proteases. Intratracheal administration of AMG-126737 inhibited the development of airway hyperresponsiveness in allergen-challenged guinea pigs with an ED50 of 0.015 mg/kg. In addition, the compound exhibited oral activity in the guinea pig model. The in vivo activity of AMG-126737 was confirmed in a sheep model of allergen-induced airway responses, where the compound inhibited early and late phase bronchoconstriction responses and the development of airway hyperresponsiveness. These results support the proposed role of tryptase in the pathology of asthma and suggest that AMG-126737 has potential therapeutic utility in this pulmonary disorder.     

Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency—diagnosis,plasma carnitine fractions and management in a further patient

Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD), the third enzyme of the mitochondrial -oxidation pathway, carries out the dehydrogenation of 3-hydroxyacyl-CoA compounds of 12–18 carbon length. To date only nine cases of LCHAD deficiency have been documented. We report a further patient who as a neonate developed non-specific gastro-intestinal symptoms and at 5 months of age cardiomyopathy, recurrent hypoketotic hypoglycaemia and gross alterations of plasma carnitine fractions. Dietary management with medium chain triglycerides led rapidly to clinical improvement. There was a close correlation between the clinical condition, plasma carnitine fractions and cardiac function. At 2 years of age she is developing normally.     

Rights and respect. Legal and ethical issues challenge today's mental healthcare professionals

The special circumstances of patients in mental health facilities often make questions concerning patient autonomy, freedom of choice, and consent to treatment even more complex than they are in other contexts. Individual facilities need to identify the ethical issues they are likely to encounter and create policies that address them effectively. The advent of managed care has created unprecedented access problems for mental healthcare providers. In many cases patients must be proven dangerous to themselves or others before they can be admitted for emergency care; because it is difficult to prove this, many persons go without needed treatment. The high costs of care and prejudices against persons with mental illness also create ethical problems. The necessity of performing clinical evaluations raises important ethical issues as well. Care givers evaluating someone at the request of a school, employer, or court should be sensitive to the possible consequences of their evaluation. They should also restrict their diagnoses to their area of competency and inform clients of the purpose of the evaluation, its possible consequences, and the limits of its confidentiality. Mental health professionals must also respect patients' rights to informed consent and understand the issues of voluntary or involuntary admissions. In addition, care givers should be aware of the various issues created by the need to occasionally control patients' behavior. Finally, for mental healthcare facilities, it is essential to establish an ethics committee to address these issues.     

Parvovirus B19 in kidney transplant patients

Renal transplant patients were screened for the presence of parvovirus B19, before transplantation and monthly for 4 months after transplantation, by means of a sensitive nested PCR assay. Upon screening plasma from 110 patients, we found that two asymptomatic patients were B19 DNA positive. One of these patients was PCR positive in the plasma sample taken 2 months after transplantation; the plasma contained anti-B19 IgG antibodies before transplant and throughout the follow-up period, with an increase in the IgG level in the second posttransplant sample coinciding with the detection of B19 DNA. IgM antibodies to B19 were not detected in this patient. Because, for this patient, the donor's spleen DNA was also B19 DNA positive, we suspect B19 transmission from the donor and limited B19 replication, inasmuch as this patient already had a primed immune response to B19. The other patient was PCR positive in the pretransplant and in the plasma sample taken 1 month after transplant and contained a strong anti-B19 IgG response in the pretransplant sample and throughout the follow-up period-and anti-B19 IgM antibodies were not detected before or after transplantation. By testing samples taken from this patient at 2 weeks, 2 months, and 3 months before transplantation, we were able to determine that the infection occurred shortly before transplantation. Unexpectedly, this graft failed and was removed 2 days after transplantation despite a negative cross-match. A pathological examination of the kidney indicated acute vascular rejection, suggesting a possible role for B19 in this complication.     

Pleomorphic lobular carcinoma: morphology, immunohistochemistry, and molecular analysis

Infiltrating pleomorphic lobular carcinoma (PLC) is an aggressive variant of infiltrating lobular carcinoma. Recently, in situ changes identical to PLC (PLCIS) have been described. The role of prognostic markers and their correlation with therapeutics, clinical outcome, and genetic changes is not well established in PLC. The authors examined 38 cases of this entity to understand better this tumor's biology. Immunohistochemical (IHC) analysis was performed in 21 specimens for estrogen and progesterone steroid receptors, p53, Her 2 (p185), and GCDFP-15. Genomic deoxyribonucleic acid was obtained from microdissected tumor as well as normal control cells, and loss of heterozygosity was investigated at the ESR (16q24), p53 (TP53 17p), Her 2 (17q 11-12), and BRCA 1 (17q12-25) loci. In this series, the average patient age was 57.5 years (age range, 24-92 years). Twenty-seven women were postmenopausal. Tumor size ranged from 1.2 to 25 cm. Six patients were a pathologic stage I; 19, stage II; 12, stage III; and one, stage IV. Histologically, multifocal nodular aggregates of discohesive pleomorphic tumor cells were seen interspersed in dense and fibrotic breast parenchyma. Twenty-nine percent of the specimens demonstrated associated signet ring cells. The remainder had dishesive, globoid, plasmacytoid cells with high-grade nuclear features. PLCIS was identified in 17 of 38 patients (45%), and lobular carcinoma in situ (LCIS) was noted in 8 patients (21%). IHC analysis showed estrogen immunoreactivity in 81%, progesterone in 67%, GCDFP-15 in 71%, and Her 2 in 81% (2+ to 3+ membranous staining) of specimens. Antibodies to p53 stained the tumor cell nuclei in 48% of the tumors. Loss of heterozygosity was identified in 52% of the specimens at the p53 locus, 18% at the ESR locus, 19% to 24% at the Her 2 loci, and 27% to 32% at the BRCA 1 locus. Follow-up was available in 19 patients and ranged from 12 months to 15 years (mean, 73 months). Seven patients had no evidence of disease at last examination (range, 1-15 years), three patients were alive with disease (range, 2-14 years), and nine patients were dead of disease (range, 2 months-9 years). Six patients had subsequent diagnoses of tumor in the contralateral breast. Analysis shows that PLC tends to appear in older postmenopausal women who present with locally advanced disease. PLCIS was found to be associated with PLC 45% of the time. The aggressive clinical course of patients with PLC is supported by tumor immunoreactivity with unfavorable markers Her 2 and p53. Overexpression of Her 2 in PLC may be therapeutically relevant, enabling the use of novel chemotherapeutic drugs like Herceptin. Interestingly, tumors that were Her 2 immunoreactive also maintained estrogen hormone immunoreactivity.