Steroid receptors and hormone responsiveness of human prostatic carcinoma

Androgen (AR), estrogen (ER), and progesterone (PR) receptors have been found in human prostatic hyperplasia (BPH) and prostatic carcinoma (PC) (AR mainly in the epithelial compartment and ER in the stromal compartment). These steroid receptors have been studied in the cytosol of 59 prostatic cancers in order to select patients to be treated with endocrine therapy (orchiectomy, administration of antiandrogens). Tissues were collected through transvesical resection and needle biopsy. Tritiated metribolone (R1881), 17b-estradiol and promegestone (R5020) with the use of exchange assay and a dextran-coated charcoal method have been usually employed. In some specimens receptor content was also analyzed in the nuclear fraction. AR was found in the cytosol of 47 of 59 (79.66%), ER in 14 of 26 (53.85%), and PR in 13 of 15 (86.67%) tumors examined. AR was detected in the nuclear fraction of 11 of 26, ER in nine of 13, and PR in two of four tumors examined. AR was found to correlate with the histological grade of the cancers, whereas no correlation could be demonstrated between the histological grade and cytoplasmic or nuclear ER. On the basis of receptor studies, hormonal treatment was started with orchiectomy followed by the administration of cyproterone acetate (CPA) 50 mg twice a day in 26 eligible out of 38 patients available for follow-up with tumors examined for cytoplasmic AR. The response to hormonal therapy depended strictly on the presence of AR. The endocrine treatment used seems, in our opinion, to be the most advisable form of therapy, and is capable of blocking the uptake of androgens of extratesticular origin by prostatic cells. Although the clinical advantages of progestational therapy for human PC are not yet established, the presence of PR in prostatic carcinoma leads us to believe that progestational compounds as well as the progestational activity of CPA may be effective on tumor growth of tissues that are positive for PR.     

Vitamin D Receptor Polymorphisms and Falls Among Older Adults Living in the Community: Results From the ilSIRENTE Study

Vitamin D receptor (VDR) genotypes were associated with cognitive status, depressive symptoms, strength, and sarcopenia, but, thus far, no study has assessed their relationship with falls. The objective of this study is to evaluate whether, in a population of older adults living in the community, VDR FokI and BsmI genotypes are associated with falls. To this aim, we used data from the baseline evaluation of the ilSIRENTE study, which enrolled older adults ≥80 yr of age living in the community in Italy. Falls occurring within 90 days of assessment were assessed by study personnel. The mean age of 259 study participants was 85.0 ± 4.5 (SD) yr; 172 (66.4%) were women. Overall, 33 (12.7%) participants reported one or more falls. The rate of falls was 19.5% in participants with the BB genotype, 11.1% in those with Bb genotype, and 5.9% in those with bb genotype (p for linear trend = 0.02). After adjusting for potential confounders, compared with participants with the BB genotype, those with the bb genotype had a significantly lower OR for falls 0.14 (95% CI, 0.03–0.66). Rate of falls did not differ significantly across FokI genotypes (FF: 14.4%, Ff: 11.9%, ff: 9.1%; p = 0.43). In conclusion, the VDR bb genotype of the BsmI gene is associated with a reduced rate of falls compared with the BB genotype, whereas no effect on falls was shown for FokI polymorphism. Further studies conducted in larger population are needed to confirm the association of BsmI genotype and falls and to understand reasons for these findings.     

Functional analysis of two rare CYP21A2 mutations detected in Italian patients with a mildest form of congenital adrenal hyperplasia

Background  More than 90% of all cases of congenital adrenal hyperplasia (CAH) result from steroid 21-hydroxylase gene ( CYP21A2 ) mutations. Most of these mutations result from intergenic recombinations between CYP21A2 and closely linked CYP21A1P pseudogene. Rare mutations not generated by gene conversion account for 5–10% of 21-hydroxylase deficiency alleles.
Objective  Functional analysis of two novel CYP21A2 missense mutations (p.R224W and p.D407N) was performed.
Design  Our study was composed of two Italian patients suffering from a very mild form of nonclassic CAH (NC-CAH). To assay the enzymatic activity of mutants, the in vitro analysis was performed in transiently transfected COS-1 cells.
Results  The residual activities obtained for p.R224W and p.D407N mutants allow their classification as NC-CAH mutations. These results correlate with the rate of severity of the patients' disease.
Conclusions  In this paper, we report two novel CYP21A2 mutations in two Italian individuals affected by 21-hydroxylase deficiency. Based on the functional in vitro analysis we can classify these mutations as NC-CAH variants.     

Association between cutaneous melanoma, Breslow thickness and vitamin D receptor BsmI polymorphism

BACKGROUND: Literature data report an association between some vitamin D receptor (VDR) polymorphisms and different kinds of tumours, including malignant melanoma (MM). Only three VDR polymorphisms (FokI, TaqI and A-1012G) have been investigated in association with the presence of cutaneous MM or the development of metastases. OBJECTIVES: The present paper analyses for the first time the association between BsmI polymorphism and MM prevalence together with Breslow thickness. In addition, the FokI single nucleotide polymorphism was also determined. METHODS: One hundred and one patients with MM and 101 healthy donors matched for age and sex were enrolled. Molecular VDR typing was performed by means of restriction fragment length polymorphism analysis. RESULTS: All cases and controls were in Hardy-Weinberg equilibrium for BsmI, FokI and A-1012G. Significant associations were found between the BsmI bb genotype frequency and MM (P = 0.02) along with Breslow thickness (P = 0.001). This same behaviour was not observed for the FokI or A-1012G polymorphisms. Multivariate logistic regression analysis confirmed these significant results after correction for age, gender, skin type and MM localization. CONCLUSIONS: Although the biological meaning of the effects exerted by BsmI polymorphism is still under debate, the statistical association found in the present study suggests that further work should be done to verify this variant as a possible risk marker for MM and its aggressiveness, also considering that the real association may be due to other unknown genes linked to the BsmI b allele.     

Early detection of podiatric anomalies in children with Down syndrome

Aims: To verify the importance of podiatric evaluation in patients with Down syndrome for the early diagnosis and treatment of minor orthopaedic problems. Methods: Case-control study of 50 children affected by Down syndrome (aged 4-10 y) without major orthopaedic malformations compared to 100 healthy children. A complete podiatric examination was performed on all patients and controls. Results: Children with Down syndrome showed several orthopaedic anomalies including bony deformity of the forefoot (90%), flat foot (60%), isolated calcaneal valgus (24%), knee valgus (22%) and pronated flat foot (16%). These abnormalities were responsible for postural alterations as confirmed by baropodometric examination.

Conclusion: The data demonstrated a greater incidence of minor orthopaedic alterations and suggest the necessity of regular podiatric examinations in the follow-up of this syndrome.     

A prolonged neonatal jaundice associated with a rare G6PD mutation

Glucose‐6‐phosphate dehydrogenase (G6PD), a X‐linked hereditary deficiency, is one of most common clinically significant enzyme defects. Despite its largely known role in acute and life‐threatening haemolytic crises, G6PD deficiency may be also associated with neonatal jaundice that, when severe and untreated, may lead to the potential of bilirubin encephalopathy. A prolonged neonatal jaundice was found to be associated with a rare G6PD mutation (c.383T>G; p.L128R), the latter simply annotated in literature database. In this article, we clinically and phenotipically describe a case of an Italian neonate carrying the c.383T>G G6PD mutation. Finally, we named this variant “G6PD Salerno.” Pediatr Blood Cancer 2009;53:475–478. © 2009 Wiley‐Liss, Inc.     

GSTM1-null polymorphism as possible risk marker for hypertension: results from the aging and longevity study in the Sirente Geographic Area (ilSIRENTE study)

BACKGROUND: Involvement of various gene mutations in hypertension have been already reported, including GST (detoxification Phase II enzymes), with contrasting results. This study analyzes a possible association between GSTM1-null and GSTT1-null polymorphisms and the hypertension status in a very old population (>80 years). METHODS: 354 old patients were collected (255 were hypertensive and 99 were not). RESULTS: GSTM1-null individuals (n=156) were significantly associated with increased risk of hypertension [OR=2.25 (1.36-3.72); p=0.005]. This association was confirmed both in 115 male and 239 female subjects. In contrast, no significant association was observed [p=0.52, OR=1.24 (0.67-2.29)] in the 57 hypertensive GSTT1-null genotypes vs 198 wild-type individuals. The above mentioned significances were obtained by multivariate logistic regression analysis after adjusting for confounder variables. Alcohol consumption and/or smoke habits were not significantly different between the two groups, as well as gender, marital status, education, number of concomitant diseases, and presence of cardiovascular diseases. No synergistic association was observed for the combined null genotypes of GSTT1 and GSTM1. CONCLUSIONS: The knowledge of GSTM1 variant status seems to be potentially useful to predict a possible hypertensive status after 80 years of age. This study underlines a possible importance of the GSTM1 enzyme for blood pressure regulation.     

Slight association between type 1 diabetes and "ff" VDR FokI genotype in patients from the Italian Lazio Region. Lack of association with diabetes complications

BACKGROUND: Vitamin D receptor (VDR) mediates the effects of vitamin D. Our paper evaluates the FokI and BsmI VDR genotypes in 246 Caucasian (Italian from Lazio Region) T1DM patients compared with 246 Caucasian healthy controls, sharing age and gender and regional provenience with the patients. In addition, T1DM patients without complications were compared with those carrying three complications. METHODS: Genotyping has been obtained by RFLP-PCR technique. RESULTS: A slight significant association of T1DM with FokI homozygous "f" genotype was observed. No association was observed with the presence of multiple complications by a multivariate analysis. CONCLUSION: T1DM patients showed slightly increased prevalence of "ff" VDR genotype.