Effect of haemodialysis on serum levels of tumour markers in patients with end-stage renal failure

SUMMARY: We studied the effect of haemodialysis on the serum levels of tumour markers in 78 patients, 49 men and 29 women with a mean age of 61 ± 2 years, who had been undergoing haemodialysis for 39 ± 10 months. No patient had any clinical evidence of malignancy. Serum values of carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), squamous-cell-carcinoma-related antigen (SCC), neuron-specific enolase (NSE), tissue polypeptide antigen (TPA), CA 15-3, CA 19–9, and among males prostate-specific antigen (PSA) were determined before and after dialysis. Postdialysis values, after being corrected for haemoconcentration, were compared with predialysis values. A significant increase of 32% was observed in NSE levels ( P <0.001) and of 21% in CA 15-3 ( P <0.001) after haemodialysis. A lesser, but still statistically significant, increase (8-12%) was observed in SCC, AFP and CEA levels ( P <0.05), while the values of the remaining three markers remained unchanged. In conclusion, an increase in some tumour markers was found in our patients after dialysis, a finding which requires further investigation.     

Effects of antiandrogen-estrogen treatment on sexual and endocrine parameters in hirsute women

Sexual activity was evaluated in 51 women with hirsutism associated with increased levels of circulating androgens before and while on combined treatment with the antiandrogen cyproterone acetate (CA) and ethinyl estradiol (EE₂) and compared to a reference group of 52 subjects. The percentage of unbound testosterone (T) was higher (p < 0.001), the coital frequency lower (p < 0.05), and the masturbation frequency higher (p< 0.04) in hirsute women. Mean frequency of total activity (coitus plus masturbation) was similar in the two groups. Treatment with combination of CA and EE₂ resulted in a decline of unbound T (p< 0.001). There was no change of total sexual activity, but coital frequency increased (p < 0.05) and masturbation frequency declined (p < 0.04). It is concluded that raised levels of circulating androgens, as judged by free T concentration, are not of crucial importance in the expression of sexual behavior in hirsute women.     

An association between variants in the IGF2 gene and Beckwith-Wiedemann syndrome: interaction between genotype and epigenotype

Beckwith-Wiedemann syndrome (BWS) is a fetal overgrowth disorder involving the deregulation of a number of genes, including IGF2 and CDKN1C, in the imprinted gene cluster on chromosome 11p15.5. In sporadic BWS cases the majority of patients have epimutations in this region. Loss of imprinting of the IGF2 gene is frequently observed in BWS, as is reduced CDKN1C expression related to loss of maternal allele-specific methylation (LOM) of the differentially methylated region KvDMR1. The causes of epimutations are unknown, although recently an association with assisted reproductive technologies has been described. To date the only genetic mutations described in BWS are in the CDKN1C gene. In order to screen for other genetic predispositions to BWS, the conserved sequences between human and mouse differentially methylated regions (DMRs) of the IGF2 gene were analyzed for variants. Four single nucleotide polymorphisms (SNPs) were found in DMR0 (T123C, G358A, T382G and A402G) which occurred in three out of 16 possible haplotypes: TGTA, CATG and CAGA. DNA samples from a cohort of sporadic BWS patients and healthy controls were genotyped for the DMR0 SNPs. There was a significant increase in the frequency of the CAGA haplotype and a significant decrease in the frequency of the CATG haplotype in the patient cohort compared to controls. These associations were still significant in a BWS subgroup with KvDMR1 LOM, suggesting that the G allele at T382G SNP (CAGA haplotype) is associated with LOM at KvDMR1. This indicates either a genetic predisposition to LOM or interactions between genotype and epigenotype that impinge on the disease phenotype.     

Aneuploidy of chromosome 20 in invasive breast cancer correlates with poor outcome

Breast carcinoma is a genetically and phenotypically heterogeneous disease and is frequently associated with nonrandom chromosomal alterations. The aim of this study was to investigate the numerical aberrations of chromosome 20 in breast cancer. The observed chromosome-specific numerical abnormalities were evaluated along with the established clinicopathological parameters, the immunohistochemical expression of ER, PR, p53, c-erbB-2, Ki-67 and patients' survival. Nonisotopic in situ hybridization was applied to interphase cell nuclei on paraffin embedded tissue sections. Polysomy of chromosome 20 was the prevalent alteration in 45 of 50 (90%), monosomy in 2 of 50 (4%) and disomy in 3 of 50 (6%) cases. Invasive ductal carcinomas displayed a higher percentage of polysomy than lobular ones. A statistical significant association was demonstrated between Ki-67 immunohistochemical expression and polysomy of chromosome 20. Disomy was inversely correlated with Ki-67, while monosomy was suggestively associated with PR positive expression. Among the patients, those with the highest levels of polysomy showed the worst survival. In conclusion, the gain of chromosome 20 is the prevalent aberration in patients with breast carcinomas and may be useful prognostic marker in breast cancer.     

Increased frequency of the rare PstI allele (P2) in a population of CAD patients in Northern Greece

Restriction fragment length polymorphisms (RFLPs) at the apolipoprotein AI-CIII-AIV gene cluster and their association with coronary artery disease (CAD) and lipid levels were studied in a Northern Greek population. Ninety-five patients with CAD and fifty-four normal controls, angio-graphically proven, were included in this study. Using genomic hybridization techniques, three polymorphic restriction sites were identified at this locus: the PstI at the 3' end of the apoAI gene, the SacI at the 3' non-coding region of the apoCIII gene and the PvuII at the intergenic region between the apoCIII-AIV genes. The rare allele (P2) arising from the absence of the PstI restriction site was observed with a significantly higher frequency (p<0.01) in patients compared to normals (0.11 vs 0.02). In contrast, the rare allele for the SacI polymorphic site had a similar distribution among patients and controls (0.12 vs 0.16). The same was observed for the PvuII RFLP (0.04 vs 0.05). Correlation of lipid and apolipoprotein AI levels with the three RFLPs revealed no significant association, although apo AI and HDL were lower in patients with the P2 allele. Thus, in this Greek population, only the PstI polymorphism, among the polymorphic restriction sites examined, appears to be associated with CAD.     

Supernumerary marker chromosomes (SMCs) in Turner syndrome are mostly derived from the Y chromosome

DNA and FISH (fluorescence in situ hybridization) analysis were carried out in 12 patients with stigmata of Turner syndrome to determine whether the Supernumerary M arker C hromosome (SMC) found cytogenetically in each of these patients was derived from the Y chromosome. The presence of a Y chromosome in these patients may predispose them to develop gonadoblastoma. PCR-Southern blot analysis, followed by FISH, was used to detect the presence of Y chromosome material. The S ex determining R egion Y (SRY), T estis S pecific P rotein Y -encoded (TSPY) and Y -chromosome R NA R ecognition M otif (YRRM) genes, which map at Yp11.31, Yp11.1–11.2 and Yp11.2/Yq11.21–11.23, respectively, were selected as markers, because they span the whole Y chromosome, and more importantly, they are considered to be involved in the development of gonadoblastoma. It was shown that in 12 patients, all of whom had an SMC, the SMC of 11 was derived from the Y chromosome. Furthermore, the presence of the SRY, TSPY and YRRM gene sequences was determined and FISH analysis confirmed the Y origin of the SMCs. The methodology described in this report is a rapid, reliable and sensitive approach which may be easily applied to determine the Y origin of an SMC carried in Turner syndrome. The identification of an SMC is important for the clinical management and prognostic counseling of these patients with Turner syndrome.     

Disease prevention and health promotion in medical education: reflections from an academic health center.

PURPOSE: It is unclear whether academic health centers are successfully addressing societal needs and expectations by preparing students with knowledge and skills in disease prevention and health promotion. The authors assessed whether students were exposed to key content in these areas and whether they felt this exposure was adequate. METHOD: All components of the first three years of the Case Western Reserve University (Case) curriculum were examined in 2001 to create a curricular map, using competencies in disease prevention and health promotion identified by the Association of Teachers of Preventive Medicine (ATPM) as a template to assess the scope of instruction. Case students' United States Medical Licensing Examination (USMLE) Step 2 subscores in preventive medicine and health maintenance from 1994 to 2000 and graduating seniors' assessment of the adequacy of their training were compared to national data from the Association of American Medical Colleges' 2000 Graduation Questionnaire (GQ). RESULTS: Most content areas identified by ATPM were present in the Case curriculum and were offered frequently in a variety of educational venues over the first three years. USMLE scores increased nationally and at Case from 1994 to 2000 and Case students' perception of training adequacy in preventive medicine and health promotion was comparable to national ratings from the 2000 GQ. CONCLUSIONS: Broad and frequent exposure to disease prevention and health promotion core competencies has value, but may not sufficiently prepare students to deliver health-promoting services confidently. Creative curricula highlighting prevention's relevance throughout clinical practice and incorporating formal opportunities to apply knowledge and build experience may result in greater success.     

Enhanced mRNA expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in breast carcinomas is correlated with adverse prognosis

Tissue inhibitor of metalloproteinase-1 (TIMP-1) has emerged as a multifunctional protein with the contrasting activities of inhibiting tissue-degrading enzymes and promoting cellular growth. In an attempt to elucidate the clinical significance of TIMP-1 in breast cancer, the expression of TIMP-1 mRNA was evaluated in 117 invasive breast carcinomas by mRNA in situ hybridization, in correlation with clinicopathological parameters, immunohistochemical prognostic factors (Ki-67, c-erb-B-2, bcl-2) and clinical outcome. TIMP-1 was detected in stromal cells in areas within the tumours and at the tumour margin. High TIMP-1 mRNA expression in the marginal portion of the tumours was significantly correlated with lymph node metastasis (p<0.05) and c-erbB-2 expression (p<0.05). On the other hand, increased TIMP-1 mRNA expression within the tumours showed a statistically significant correlation with ER detection (p<0.01). Multivariate analysis revealed worse survival for patients with high TIMP-1 mRNA expression in the marginal portion of the tumours; the subgroup of these patients co-expressing high levels of TIMP-1 mRNA within the tumours as well had even worse survival (p=0.042). In conclusion, our data support the multifunctional role of TIMP-1, particularly its growth-promoting activity, on the basis of its significant correlation with lymph node metastasis and adverse prognosis. In addition to the latter property, a probable association of TIMP-1 with tumour cell differentiation is suggested by its topographical correlation with ER detection.     

The efficacy in Navajo infants of a conjugate vaccine consisting of Haemophilus influenzae type b polysaccharide and Neisseria meningitidis outer-membrane protein complex

BACKGROUND AND METHODS. Several conjugate vaccines against Haemophilus influenzae type b have been developed in the search for one that induces protection even in young infants. We evaluated the safety and efficacy of a conjugate vaccine that links the H. influenzae type b capsular polysaccharide to the outer-membrane protein complex (OMPC) of Neisseria meningitidis serogroup B. We conducted a double-blind, placebo, controlled trial in Navajo infants, who are at high risk for systemic infections caused by H. influenzae type b. The infants were randomly assigned to receive the first dose of vaccine or placebo at 42 to 90 days of age and the second at 70 to 146 days of age. RESULTS. Of the infants in the trial, 2588 were assigned to receive the vaccine and 2602 to receive placebo. The mean follow-up was 269 days in the vaccine group and 267 days in the placebo group. Before the age of 18 months, there was 1 systemic H. influenzae type b infection in the vaccine group, as compared with 22 in the placebo group (P less than 0.001; point estimate of efficacy, 95 percent; 95 percent confidence interval, 72 to 99 percent). Of the 22 H. influenzae type b infections in the placebo group, 13 were meningitis. Among the children who received both doses, there was 1 H. influenzae type b infection in the vaccine group (n = 2056) and 14 in the placebo group (n = 2105) (P less than 0.001; point estimate of efficacy, 93 percent; 95 percent confidence interval, 53 to 98 percent). The single infection in the vaccine group occurred at 15 1/2 months of age in an infant with osteomyelitis. Between the first and second doses there were no H. influenzae type b infections in the vaccine group and eight in the placebo group (P less than 0.005; point estimate of efficacy, 100 percent; 95 percent confidence interval, 41 to 100 percent). CONCLUSIONS. The H. influenzae type b OMPC vaccine, administered at 2 and 4 months of age, is safe and induces a high rate of protection against invasive disease caused by H. influenzae type b in infants under the age of 18 months. Protection begins after the first dose.     

Lymphocytic Hypophysitis Presenting as a Pituitary Tumor in a 63-Year-Old Man

This report describes a case of lymphocytic hypophysitis in a 63-year-old man who presented with symptoms of a pituitary mass lesion associated with hypothyroidism and hypogonadism. Postoperative endocrinological testing demonstrated gonadotropic, thyrotropic, and corticotropic hypopituitarism, and the patient was commenced on replacement therapy with hydrocortisone and levothyroxine. Histological examination of the pituitary tissue obtained by transsphenoidal surgery revealed lymphocytic hypophysitis without evidence of a pituitary adenoma. The vast majority of patients with lymphocytic hypophysitis are women particularly during pregnancy and the puerperium. Until recently only four men were reported in the literature. The pathogenesis of lymphocytic hypophysitis is uncertain but autoimmune mechanisms are possibly involved.