Polymorphisms and haplotypes of TOLLIP and MUC5B are associated with susceptibility and survival in patients with fibrotic hypersensitivity pneumonitis.

INTRODUCTION AND OBJECTIVES: Hypersensitivity pneumonitis (HP) is an interstitial lung disease with diverse clinical features that can present a fibrotic phenotype similar to idiopathic pulmonary fibrosis (IPF) in genetically predisposed individuals. While several single nucleotide polymorphisms (SNPs) have been associated with IPF, the genetic factors contributing to fibrotic HP (fHP) remain poorly understood. This study investigated the association of MUC5B and TOLLIP variants with susceptibility, clinical presentation and survival in Portuguese patients with fHP. MATERIAL AND METHODS: A case-control study was undertaken with 97 fHP patients and 112 controls. Six SNPs residing in the MUC5B and TOLLIP genes and their haplotypes were analyzed. Associations with risk, survival, and clinical, radiographic, and pathological features of fHP were probed through comparisons among patients and controls. RESULTS: MUC5B rs35705950 and three neighboring TOLLIP variants (rs3750920, rs111521887, and rs5743894) were associated with increased susceptibility to fHP. Minor allele frequencies were greater among fHP patients than in controls (40.7% vs 12.1%, P<0.0001; 52.6% vs 40.2%, P = 0.011; 22.7% vs 13.4%, P = 0.013; and 23.2% vs 12.9%, P = 0.006, respectively). Haplotypes formed by these variants were also linked to fHP susceptibility. Moreover, carriers of a specific haplotype (G-T-G-C) had a significant decrease in survival (adjusted hazard ratio 6.92, 95% CI 1.73-27.64, P = 0.006). Additional associations were found between TOLLIP rs111521887 and rs5743894 variants and decreased lung function at baseline, and the MUC5B SNP and radiographic features, further highlighting the influence of genetic factors in fHP. CONCLUSION: These findings suggest that TOLLIP and MUC5B variants and haplotypes may serve as valuable tools for risk assessment and prognosis in fibrotic hypersensitivity pneumonitis, potentially contributing to its patient stratification, and offer insights into the genetic factors influencing the clinical course of the condition.

The Arg499His gain-of-function mutation in the C-terminal domain of PCSK9.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a monogenic disease characterized by high levels of low-density lipoprotein cholesterol and premature atherosclerotic cardiovascular disease. FH is caused by loss of function mutations in genes encoding LDL receptor (LDLR), and Apolipoprotein B (APOB) or gain of function (GOF) mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9). In this study, we identified a novel variant in PCSK9, p.(Arg499His), located in the C-terminal domain, in two unrelated FH patients from Spain and Italy. METHODS: We studied familial segregation and determined variant activity in vitro. RESULTS: We determined PCSK9 expression, secretion and activity of the variant in transfected HEK293 cells; extracellular activity of the recombinant p.(Arg499His) PCSK9 variant in HEK 293 and HepG2 cells; PCSK9 affinity to the LDL receptor at neutral and acidic pH; the mechanism of action of the p.(Arg499His) PCSK9 variant by co-transfection with a soluble construct of the LDL receptor and by determining total PCSK9 intracellular accumulation when endosomal acidification is impaired and when an excess of soluble LDLr is present in the culture medium. Our results show high LDL-C concentrations and FH phenotype in p.(Arg499His) carriers. In vitro functional characterization shows that p.(Arg499His) PCSK9 variant causes a reduction in LDLr expression and LDL uptake. An intracellular activity for this variant is also shown when blocking the activity of secreted PCSK9 and by inhibiting endosomal acidification. CONCLUSIONS: We demonstrated that p.(Arg499His) PCSK9 variant causes a direct intracellular degradation of LDLr therefore causing FH by reducing LDLr availability.

Real-World Outcomes with Lomitapide Use in Paediatric Patients with Homozygous Familial Hypercholesterolaemia.

INTRODUCTION: Homozygous familial hypercholesterolaemia (HoFH) is a rare, autosomal disease affecting the clearance of low-density lipoprotein cholesterol (LDL-C) from circulation, and leading to early-onset atherosclerotic cardiovascular disease (ASCVD). Treatment consists mainly of statins, lipoprotein apheresis (LA) and, more recently, the microsomal triglyceride transfer protein inhibitor lomitapide. Lomitapide is not licensed for use in children, but has been made available through an expanded access programme or on a named patient basis. METHODS: This case series includes 11 HoFH patients in 10 different centres in eight countries, less than 18 years of age (mean 11.6 ± 1.1 years, 64% male), with signs of ASCVD, and who have received treatment with lomitapide (mean dose 24.5 ± 4.3 mg/day; mean exposure 20.0 ± 2.9 months). Background lipid-lowering therapy was given according to local protocols. Lomitapide was commenced with a stepwise dose escalation from 2.5 mg or 5 mg/day; dietary advice and vitamin supplements were provided as per the product label for adults. Laboratory analysis was conducted as part of regular clinical care. RESULTS: In the 11 cases, mean baseline LDL-C was 419 ± 74.6 mg/dL and was markedly reduced by lomitapide to a nadir of 176.7 ± 46.3 mg/dL (58.4 ± 6.8% decrease). Six patients achieved recommended target levels for children below 135 mg/dL, five of whom had LA frequency reduced. In one case, LDL-C levels were close to target when lomitapide was started but remained stable despite 75% reduction in LA frequency (from twice weekly to biweekly). Adverse events were mainly gastrointestinal in nature, occurred early in the treatment course and were well managed. Three patients with excursions in liver function tests were managed chiefly without intervention; two patients had decreases in lomitapide dose. CONCLUSIONS: Lomitapide demonstrated promising effectiveness in paediatric HoFH patients. Adverse events were manageable, and the clinical profile of the drug is apparently similar to that in adult patients. FUNDING: Amryt Pharma.

MUSCLE INFARCTION AND SEVERE DETERIORATION OF RENAL FUNCTION IN A PATIENT WITH TYPE 1 DIABETES MELLITUS AND CHRONIC KIDNEY DISEASE.

CONTEXT: Spontaneous muscle infarction is a rare complication of diabetes mellitus, mainly affecting women and patients with long-lasting type 1 diabetes. OBJECTIVE: This report is aimed to describe the case of a patient with type 1 diabetes and diabetic nephropathy in whom a severe deterioration of renal function was triggered by a muscle infarction. SUBJECT AND METHODS: Subject of the study was a 33-years-old woman with an 18 years history of type 1 diabetes mellitus, proliferative diabetic retinopathy, nephropathy at stage 3 chronic kidney disease, somatic sensory-motor polyneuropathy and autonomic neuropathy. RESULTS: The patient presented with severe pain and dysfunction of the left thigh without prior trauma plus progressive deterioration of the renal function. Nuclear magnetic resonance of the thigh showed inflammatory changes in the external vastus with hyperintensity on T2 sequence and edema of the subcutaneous cellular tissue. After other possible etiologies were ruled out, a clinical diagnosis of spontaneous muscle infarction was established. The patient needed hospital admission for two months, during which the renal function worsened until she required hemodialysis. No other possible triggers of kidney injury were identified. CONCLUSIONS: Up to our knowledge, this is the first described case where muscle infarction is suspected to have caused exacerbation of an existing chronic kidney failure. Monitoring the renal function should be considered in patients with diabetic nephropathy presenting with this rare complication of diabetes.

Utilidad de la resonancia magnética en la evaluación del mal alineamiento patelar / Usefulness of magnetic resonance imaging in the evaluation of patellar malalignment

Objetivos. Evaluar la utilidad de la resonancia magnética (RM) tomada en 20° de flexión de rodilla en el diagnóstico del dolor patelofemoral (DPF) causado por mal alineamiento patelar (MAP). Material y método. Se realizaron 25 RM en pacientes con DPF en los cuales se sospechó de MAP como causa y 25 en pacientes sin DPF (grupo control). Se midieron: distancia surco intertroclear-tuberosidad anterior tibial (SIT-TAT) y los ángulos de: Laurin modificado, Merchant y Troclear. Análisis estadístico con los test de ANOVA, Fischer y Pearson. Resultados. Hubo diferencias significativas entre los pacientes con DPF vs. grupo control en relación a: distancia SIT-TAT (11,79 mm vs. 9,35 mm, p = 0,002), ángulo de Laurin modificado (12,17° vs. 15,56°, p = 0,05) y ángulo Troclear (139° vs. 130,02°, p = 0,049). Respecto al ángulo de Merchant no hubo diferencias significativas. La distancia SIT-TAT tuvo un valor predictivo positivo (VPP) del 70% para DPF, con una sensibilidad del 51,61% y una especificidad del 53,33%. El ángulo de Laurin modificado tuvo un VPP del 77,78% para DPF, con una sensibilidad del 28% y una especificidad del 92%. El ángulo Troclear tuvo un VPP del 85,71% para DPF, con una sensibilidad del 24% y una especificidad del 96%. Conclusiones. La RM en 20° de flexión puede confirmar el MAP como causa de DPF. La determinación de alteraciones de la distancia SIT-TAT, báscula patelar y ángulo Troclear se correlaciona positivamente con la presencia del DPF, sugiriendo que este es causado por un mal alineamiento leve (AU)

Objectives. The aim of this study is to evaluate the usefulness of Magnetic Resonance Imaging (MRI) at 20° of knee flexion in patients with patellofemoral pain syndrome (PFPS) caused by suspected patellofemoral malalignment (PFM). Material and method. Fifty MRIs were performed on 25 patients with PFPS secondary to suspected PFM based on clinical examination, and on 25 patients without PFPS (control group). Measurements were made of tibial tuberosity-trochlear groove distance (TTTG) and modified Laurin, Merchant and trochlear angles. The results were analyzed with ANOVA and Fischer tests. Pearson correlation coefficients were used to analyze differences between PFPS and control cases. Specificity, sensitivity, positive predictive value and negative predictive value for knee pain were documented. Results. Significant differences were observed between PFPS and control groups in TTTG (11.79 mm vs. 9.35 mm; P=.002), Laurin angle (12.17° vs. 15.56°; P=.05), and trochlear angle (139° vs. 130.02°; P=.049). No differences were found between groups as regards the Merchant angle (P=.5). TTTG was 70% predictive of PFPS; however, it was only 53.33% specific, with a sensitivity of 51.61% for PFPS. Laurin angle was 77.78% predictive of PFPS, with a specificity of 92% and a sensitivity of 28%. Trochlear angle was 85.71% predictive of PFPS, with a specificity of 96% and a sensitivity of 24%. Conclusions. MRI can confirm clinically suspected PFPS secondary to malalignment. MRI determination of TTTG, patellar tilt, and trochlear angle correlates positively with clinical diagnosis of PFPS, suggesting that PFPS is caused by subtle malalignment (AU)

Characterization of bacterial diversity associated with microbial mats, gypsum evaporites and carbonate microbialites in thalassic wetlands: Tebenquiche and La Brava, Salar de Atacama, Chile.

In this paper, we report the presence of sedimentary microbial ecosystems in wetlands of the Salar de Atacama. These laminated systems, which bind, trap and precipitate mineral include: microbial mats at Laguna Tebenquiche and Laguna La Brava, gypsum domes at Tebenquiche and carbonate microbialites at La Brava. Microbial diversity and key biogeochemical characteristics of both lakes (La Brava and Tebenquiche) and their various microbial ecosystems (non-lithifying mats, flat and domal microbialites) were determined. The composition and abundance of minerals ranged from trapped and bound halite in organic-rich non-lithifying mats to aragonite-dominated lithified flat microbialites and gypsum in lithified domal structures. Pyrosequencing of the V4 region of the 16s rDNA gene showed that Proteobacteria comprised a major phylum in all of the microbial ecosystems studied, with a marked lower abundance in the non-lithifying mats. A higher proportion of Bacteroidetes was present in Tebenquiche sediments compared to La Brava samples. The concentration of pigments, particularly that of Chlorophyll a, was higher in the Tebenquiche than in La Brava. Pigments typically associated with anoxygenic phototrophic bacteria were present in lower amounts. Organic-rich, non-lithifying microbial mats frequently formed snake-like, bulbous structures due to gas accumulation underneath the mat. We hypothesize that the lithified microbialites might have developed from these snake-like microbial mats following mineral precipitation in the surface layer, producing domes with endoevaporitic communities in Tebenquiche and carbonate platforms in La Brava. Whereas the potential role of microbes in carbonate platforms is well established, the contribution of endoevaporitic microbes to formation of gypsum domes needs further investigation.

[Usefulness of magnetic resonance imaging in the evaluation of patellar malalignment]. / Utilidad de la resonancia magnética en la evaluación del mal alineamiento patelar.

OBJECTIVES: The aim of this study is to evaluate the usefulness of Magnetic Resonance Imaging (MRI) at 20° of knee flexion in patients with patellofemoral pain syndrome (PFPS) caused by suspected patellofemoral malalignment (PFM). MATERIAL AND METHOD: Fifty MRIs were performed on 25 patients with PFPS secondary to suspected PFM based on clinical examination, and on 25 patients without PFPS (control group). Measurements were made of tibial tuberosity-trochlear groove distance (TTTG) and modified Laurin, Merchant and trochlear angles. The results were analyzed with ANOVA and Fischer tests. Pearson correlation coefficients were used to analyze differences between PFPS and control cases. Specificity, sensitivity, positive predictive value and negative predictive value for knee pain were documented. RESULTS: Significant differences were observed between PFPS and control groups in TTTG (11.79 mm vs. 9.35 mm; P=.002), Laurin angle (12.17° vs. 15.56°; P=.05), and trochlear angle (139° vs. 130.02°; P=.049). No differences were found between groups as regards the Merchant angle (P=.5). TTTG was 70% predictive of PFPS; however, it was only 53.33% specific, with a sensitivity of 51.61% for PFPS. Laurin angle was 77.78% predictive of PFPS, with a specificity of 92% and a sensitivity of 28%. Trochlear angle was 85.71% predictive of PFPS, with a specificity of 96% and a sensitivity of 24%. CONCLUSIONS: MRI can confirm clinically suspected PFPS secondary to malalignment. MRI determination of TTTG, patellar tilt, and trochlear angle correlates positively with clinical diagnosis of PFPS, suggesting that PFPS is caused by subtle malalignment.

Association of Taq 1B CETP polymorphism with insulin and HOMA levels in the population of the Canary Islands.

BACKGROUND AND AIMS: Cholesteryl ester transfer protein (CETP) is an enzyme with a key role in lipoprotein metabolism. A common genetic polymorphism, the Taq 1B, influences CETP activity and HDL-cholesterol levels, with individual homozygotes for the B1 allele exhibiting higher enzyme activity and lower HDL-cholesterol levels than carriers of at least one B2 allele. Our aim was to analyze the influence of Taq 1B CETP polymorphism on cardiovascular risk factors in a representative sample of adult subjects from Canary population. METHODS AND RESULT: A total of 518 adult subjects from the Canary Islands, enrolled in a nutritional survey (the ENCA study), were included. The Taq 1B polymorphism was analyzed by PCR-RFLP. Compared with individuals with at least one B2 allele, and after adjusting for age, sex, BMI, waist perimeter, smoking and alcohol intake, carriers of the B1B1 genotype showed lower HDL-cholesterol levels (geometric mean (95% CI): 46.6 (44.5-48.8) vs. 50.6 (49.1-52.9)mg/dl; P=0.003); and higher insulin (geometric mean (95% CI): 11.1 (10.5-11.9) vs. 10.0 (9.5-10.5µU/ml; P=0.008) and HOMA levels (geometric mean (95% CI): 2.3 (2.1-2.5) vs. 2.1 (1.9-2.1); P=0.009). In addition, the B1B1 genotype was more frequent in individuals who had low levels of HDL-cholesterol according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria (Odds Ratio (OR): 1.563; 95% CI: 1.04-2.34; P=0.030), and in those included in the upper quartile of insulinemia (OR: 1.90; 95% CI: 1.20-3.03; P=0.007) and HOMA (OR: 1.61; 95% CI: 1.02-2.57; P=0.043). CONCLUSION: The observed influence of Taq 1B polymorphism on insulin levels and HOMA highlights the possible role of CETP in the regulation of glucose homeostasis.

Insulin resistance explains the relationship between novel cardiovascular risk factors and hypertension. The Telde Study.

BACKGROUND: Most studies describing an association between hypertension and an inflammatory/pro-thrombotic state do not assess insulin resistance. AIM: To examine the association between hypertension and new cardiovascular risk factors when considering both classical risk factors and insulin resistance. METHODS: In a population-based sample of 1030 subjects, clinical information and blood samples were obtained. Subjects were classified according to the presence or absence of hypertension, and insulin resistance was estimated using the homeostasis model of assessment (HOMA). To identify variables independently associated with hypertension, a four-model multiple logistic regression was performed: model 1 included novel risk factors (Plasminogen Activator Inhibitor- 1 [PAI-1], fibrinogen, von Willebrand Factor [vWF], lipoprotein(a), homocysteine and C-reactive Protein [CRP]); model 2, novel risk factors plus HOMA; model 3 included both classical (smoking, triglycerides, HDL cholesterol, total cholesterol, waist circumference and diabetes) and novel risk factors and model 4, model 3 plus HOMA. All were adjusted for age, BMI and gender and compared using Akaike's Information Criterion (AIC). RESULTS: In model 1, only PAI-1, age and BMI showed association with hypertension.When HOMA and classical risk factors were also included, PAI-1 was replaced by triglyceride, smoking and diabetes. The lowest AIC value (best adjustment) was displayed by model 4, comprising all of the variables. Only age, BMI, HOMA and smoking remained significantly associated with hypertension. CONCLUSIONS: The novel cardiovascular risk factors assessed do not add information as markers of hypertension when classical risk factors or insulin resistance are included in the evaluation.

Thyrotropin levels and their relationship with cardiovascular risk factors in the island of Gran Canaria, Spain. Implications of lowering the upper reference limit of thyrotropin stimulating hormone.

OBJECTIVE: To characterize the cardiovascular risk profile of subjects with high and normal-high concentrations of serum TSH in a sample of adult Spanish subjects from the island of Gran Canaria. DESIGN: Cross-sectional population-based study. SUBJECTS: After excluding 28 individuals on current treatment with levothyroxine and 9 others with TSH levels below the range of normality (0.3-4.9 mU/l), 704 randomly selected subjects (412 women; age range: 30-82 yr) belonging to the Telde Study were assessed. MEASUREMENTS: Participants underwent physical examination and fasting blood analyses to determinate TSH, serum lipids, homocysteine, fibrinogen, von Willebrand factor, plasminogen activator inhibitor- 1, C-reactive protein, and insulin. RESULTS: Twenty-nine participants had serum TSH concentrations above the normal range of normality. Among all the studied variables, only female sex and diastolic blood pressure were significantly associated with TSH levels > or =5 mU/l in a multivariate logistic regression analysis. If the upper normal limit of TSH was reduced up to 2.4 mU/l, an additional group of 106 subjects would be considered to have elevated TSH levels. A serum TSH > or =2.5 mU/l was positive and independently associated with female sex, body mass index, total cholesterol, and homocysteine, and negatively associated with smoking. CONCLUSIONS: Although the impact of serum TSH levels on cardiovascular risk cannot be established from these findings, TSH values within the upper part of the usually accepted normal range were demonstrated to be associated with well-recognized risk factors for cardiovascular disease.

Differences in traditional and emerging cardiovascular risk factors of subjects discordantly classified by metabolic syndrome definitions of the International Diabetes Federation and the National Cholesterol Education Program.

BACKGROUND AND AIM: Several working definitions of metabolic syndrome have been proposed for clinical use. However, individuals can be discordantly classified as having or not having metabolic syndrome depending on the choice of one or another definition. This study compared the cardiovascular risk profile of subjects concordantly and discordantly diagnosed by the criteria of the National Cholesterol Education Program (NCEP) and the criteria of the International Diabetes Federation (IDF). METHODS AND RESULTS: Nine hundred and twenty-nine non-diabetic adult subjects belonging to a cross-sectional population-based study in Gran Canaria island (Spain) were assessed. Participants completed a questionnaire and underwent physical examination, fasting blood analyses, and a standardized oral glucose tolerance test. Two hundred and four subjects (22%) had metabolic syndrome according to both definitions, 31 (3.3%) only by the IDF criteria, and 5 (0.5%) only by the NCEP criteria. Participants fulfilling both proposals showed more adverse age and sex-adjusted measures of BMI, waist, HDL cholesterol, triglycerides, post-load glucose, HOMA-IR and plasminogen inhibitor activator-1 (PAI-1) than individuals exclusively satisfying the IDF criteria. Moreover, in contrast to subjects meeting both criteria, those that fulfilled only the IDF criteria had levels of BMI, waist, total and HDL cholesterol, post-load glucose, glycated HbA1c, C-reactive protein, PAI-1 and fibrinogen not significantly different from those observed in subjects without metabolic syndrome. CONCLUSION: The IDF definition identifies a surplus of individuals whose cardiovascular risk profile, particularly regarding to some non-traditional cardiovascular risk factors, is less adverse than that observed in subjects also diagnosed by the NCEP definition.

Use of confirmatory factor analysis for the identification of new components of the metabolic syndrome: the role of plasminogen activator inhibitor-1 and Haemoglobin A1c.

BACKGROUND AND AIM: This study was aimed to identify additional components of metabolic syndrome from a set of cardiovascular risk markers. METHODS AND RESULTS: The homeostasis model assessment of insulin resistance (HOMA-IR), C-reactive protein, fibrinogen, plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor, homocysteine, Haemoglobin A1c (HbA1c), and lipoprotein(a) were assessed in a population-based sample of 902 nondiabetic adult subjects. Those biomarkers that were associated with metabolic syndrome were evaluated by multiple regression analysis, along with other traditional cardiovascular risk factors. Confirmatory factor analysis (CFA) was used to test the hypothesis that both the established components of metabolic syndrome and the novel variables identified by the regression analysis were associated with a single underlying factor. HOMA-IR, PAI-1 and HbA1c were the only biomarkers independently related to metabolic syndrome. CFA validated a one-factor model that included these variables. Moreover, the indices of goodness of fit were better for this expanded model than those obtained for a previously validated one-factor model that was restricted to the conventional elements of the syndrome. CONCLUSIONS: These findings show that PAI-1 and HbA1c are singularly linked to metabolic syndrome. Their elevation is presumably another manifestation of the same pathophysiological mechanism that underlies the recognized traits of the syndrome.

Diabetes mellitus and impaired glucose regulation in the Canary Islands (Spain): prevalence and associated factors in the adult population of Telde, Gran Canaria.

AIMS: To estimate the prevalence and the determinants of diabetes mellitus and impaired glucose regulation (IGR) in an adult Canarian population. METHODS: Cross-sectional study. One thousand and thirty subjects aged 30-82 years were randomly selected. Participants completed a survey questionnaire and underwent blood pressure measurements, anthropometry, blood samples, and a 75-g standardized oral glucose tolerance test. RESULTS: The age-standardized prevalence of diabetes was 15.8% (95% confidence interval: 11.8-19.8) in men and 10.6% (7.1-14.1) in women. Total prevalence was 13.2% (11.1-15.2). Among individuals with diabetes, 55.4% of men and 38.2% of women were not previously diagnosed. The age-standardized prevalences of impaired glucose tolerance and impaired fasting glycaemia were 11.4% (9.5-13.4) and 2.8% (1.8-3.8), respectively. In multivariate analyses, age, waist circumference, serum triglycerides, and familial history of diabetes were independently associated with diabetes in both sexes, while a value of C-reactive protein (CRP) >/= 1 mg/l showed an association with diabetes, but only in men. Age and triglycerides were related to impaired glucose regulation (IGR) in both sexes, waist circumference was related to IGR exclusively in men, and familial diabetes exclusively in women. Statistically significant interactions between gender and both CRP and triglycerides were found with respect to diabetes, and between gender and both waist circumference and triglycerides for IGR. CONCLUSIONS: Compared with the rest of Spain, the prevalence of diabetes is moderately increased in this area of the Canary Islands. Along with other well-established risk factors, CRP was independently associated with diabetes, but only in the male population.

Prevalence of the metabolic syndrome in the island of Gran Canaria: comparison of three major diagnostic proposals.

AIMS: The present study was conducted to estimate the prevalence of the metabolic syndrome in a Canarian population, and to compare its frequency as defined by the most commonly used working definitions. METHODS: Cross-sectional population-based study. One thousand and thirty adult subjects were randomly selected from the local census of Telde, a city located on the island of Gran Canaria. Participants completed a survey questionnaire and underwent physical examination, fasting blood analyses, and a 75-g standardized oral glucose tolerance test. The prevalence of the metabolic syndrome was estimated according to the definitions proposed by the World Health Organization (WHO), the European Group for the Study of Insulin Resistance (EGIR) and the National Cholesterol Education Program (NCEP), the latter with the original (6.1 mmol/l) and the revised criterion (5.6 mmol/l) for abnormal fasting glucose. RESULTS: The adjusted prevalence of the metabolic syndrome was 28.0, 15.9, 23.0 and 28.2%, using the WHO, EGIR, NCEP and revised NCEP criteria, respectively. The measure of agreement (kappa statistic) was 0.57 between the WHO and the original NCEP definitions, and 0.61 between the WHO and the revised NCEP definitions. After excluding diabetic subjects, the agreement between the EGIR and WHO proposals was fairly good (kappa=0.70), whereas concordance of the EGIR with the original and the revised NCEP definitions was moderate (kappa=0.47 and 0.46, respectively). CONCLUSIONS: Whichever the considered diagnostic criteria, the prevalence of the metabolic syndrome in this area of the Canary Islands is greater than that observed in most other European populations.

Clinical manifestations and hormonal profile of two women with Cushing's disease and mild deficiency of 21-hydroxylase.

The development of Cushing's disease among patients with deficiency of 21-hydroxylase has not been observed to date. The clinical manifestations and the hormonal profile of this exceptional association are herein described through the study of two cases. The first one was a 39-yr-old woman who had undergone non-curative transsphenoidal surgery for a pituitary-dependent Cushing's syndrome 12 yr before. She showed hypertension, central obesity, severe hirsutism, alopecia and hyperpigmentation. Urinary excretion of cortisol was normal, but ACTH levels were very high and hormonal dynamic studies (cortisol circadian rhythm, insulin-induced hypoglycemia and dexamethasone suppression tests) revealed the qualitative disturbances that characterize Cushing's disease. Serum concentrations of androstenedione, free testosterone and 17-hydroxyprogesterone were clearly increased. Reexamination of the tissue samples from previous surgery confirmed the presence of an ACTH-producing pituitary adenoma. CYP21 gene analysis found the splicing 655G mutation at intron 2 and the V281L mutation at exon 7. The second case was a 21-yr-old woman who was diagnosed with pituitary ACTH-dependent Cushing's syndrome according to unequivocal clinical and laboratory findings. However, hirsutism was particularly severe and both serum androgens and 17-hydroxyprogesterone were elevated. The patient was heterozygote for a large conversion of CYP21 gene. In these cases, the clinical and biochemical expression of Cushing's syndrome was determined by the different severity of 21-hydroxylase deficiency and the subsequent residual ability of adrenal cortex to synthesize cortisol.

Effects of tamoxifen on lipid profile and coagulation parameters in male patients with pubertal gynecomastia.

BACKGROUND/AIM: The estrogenic actions of tamoxifen on lipid profiles and hemostasis have been extensively demonstrated in women. Due to limited experience with this drug in males, it is uncertain whether these effects are also present in men. The aim of our study was to assess the response of blood lipids, lipoproteins, and coagulation parameters in a group of men taking tamoxifen. METHODS: We studied 15 healthy boys with pubertal gynecomastia who were given 10 mg tamoxifen per day. Total testosterone, sex-hormone-binding globulin, estradiol, serum lipids, apolipoprotein B, apolipoprotein A-I, lipoprotein(a), fibrinogen, antithrombin III, von Willebrand factor, and markers of activated coagulation and fibrinolysis were determined at baseline and 1 and 3 months after beginning of the tamoxifen treatment. RESULTS: Total cholesterol and lipoprotein(a) showed moderate but significant decreases from baseline. Low-density lipoprotein and high-density lipoprotein cholesterol concentrations as well as triglyceride and apolipoprotein B levels became lower, but these changes were not statistically significant. Among clotting parameters, antithrombin III was reduced, and von Willebrand factor increased significantly. Markers of activated coagulation and fibrinolysis remained unchanged throughout the period of therapy. CONCLUSIONS: The effects of tamoxifen on blood lipids and hemostasis we found in this group of healthy young men were qualitatively similar, but lesser than those previously described in women.