Vitamin D levels and insulin resistance in children born with severe growth restriction.

This study was designed to examine differences in serum 25(OH)D levels between small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) prepubertal children in correlation with birth weight and indices of insulin resistance and ß-cell function. Sixty-five nonobese children were examined at age 5-7.5 years; 27 born SGA and 38 matched AGA. Body weight, height, BMI, and waist circumference were recorded and fasting serum levels of glucose, insulin, 25(OH)D, and parathyroid hormone (PTH) were measured. The homeostasis model assessment for insulin resistance (HOMA-IR) and the ß-cell function index (HOMA-ß%) were estimated. The mean level of 25(OH)D was higher in the SGA group (26.2±10 vs. 17.2±7 ng/ml, p<0.01) but that of PTH was no different. The insulin resistance and ß-cell function indices were higher in the SGA group: HOMA-IR 1.34±0.67 vs. 0.99±0.53, and HOMA-ß% 135±56 vs. 97±60 in the SGA and AGA groups, respectively. In the SGA group, 25(OH)D was correlated with HOMA-ß% but not with HOMA-IR or insulin. In multiple regression, in the total cohort 25(OH)D and HOMA-IR were independently negatively correlated with birth weight (ß= - 0.31, ß= - 0.36, p<0.05) respectively. In conclusion, at prepuberty severely in utero growth restricted children have increased birth weight dependent levels of 25(OH)D, which might exert a regulatory role on ß-cell function.

Effect of rosuvastatin monotherapy or in combination with fenofibrate or ω-3 fatty acids on lipoprotein subfraction profile in patients with mixed dyslipidaemia and metabolic syndrome.

BACKGROUND: Raised triglycerides (TG), decreased high-density lipoprotein cholesterol (HDL-C) levels and a predominance of small dense low density lipoproteins (sdLDL) are characteristics of the metabolic syndrome (MetS). OBJECTIVE: To compare the effect of high-dose rosuvastatin monotherapy with moderate dosing combined with fenofibrate or ω-3 fatty acids on the lipoprotein subfraction profile in patients with mixed dyslipidaemia and MetS. METHODS: We previously randomised patients with low-density lipoprotein cholesterol (LDL-C) > 160 and TG > 200 mg/dl to rosuvastatin monotherapy 40 mg/day (R group, n = 30) or rosuvastatin 10 mg/day combined with fenofibrate 200 mg/day (RF group, n = 30) or ω-3 fatty acids 2 g/day (Rω group, n = 30). In the present study, only patients with MetS were included (24, 23 and 24 in the R, RF and Rω groups respectively). At baseline and after 12 weeks of treatment, the lipoprotein subfraction profile was determined by polyacrylamide 3% gel electrophoresis. RESULTS: The mean LDL size was significantly increased in all groups. This change was more prominent with RF than with other treatments in parallel with its greater hypotriglyceridemic capacity (p < 0.05 compared with R and Rω). A decrease in insulin resistance by RF was also noted. Only RF significantly raised HDL-C levels (by 7.7%, p < 0.05) by increasing the cholesterol of small HDL particles. The cholesterol of larger HDL subclasses was significantly increased by R and Rω. CONCLUSIONS: All regimens increased mean LDL size; RF was the most effective. A differential effect of treatments was noted on the HDL subfraction profile.

Visfatin levels in prepubertal children born small or large for gestational age.

Children born small (SGA) or large (LGA) for gestational age are prone to develop insulin resistance (IR) during childhood. Visfatin, a hormone with insulin-mimetic actions, has been associated with IR. This study was designed to examine whether serum level of visfatin is correlated with metabolic indices of IR, in prepuberty in association with the intrauterine growth pattern. The following parameters were evaluated at a mean age of 6.5±1.2 years in 155 prepubertal children born appropriate for the gestational age (AGA) (n=63), or SGA (n=42), or LGA (n=50): serum levels of visfatin, adiponectin, leptin, fasting glucose (G(F)) and insulin (I(F)), the homeostasis model assessment IR index (HOMA-IR), plasma lipids, anthropometric indices at birth and the time of evaluation, and obesity indices [waist circumference (WC), body mass index (BMI) and skinfold thickness]. The mean serum level of visfatin was lower in the SGA than in the AGA and the LGA children (9±5.2 vs. 11.8±5.1 and 12.7±5.6 ng/ml, respectively, p<0.01). Girls had lower visfatin levels than boys (10.4±4.3 ng/ml vs. 12.5±6.7 ng/ml, p<0.05). Visfatin was not correlated with IR indices. In multiple regression analysis visfatin level was positively correlated with birth weight z-score (t=2.56, beta=0.24, p<0.01) and crown to heel z-score (t=2.46, beta=0.22, p=0.014), independent of age, gender, maternal weight before pregnancy, maternal weight gain during pregnancy, BMI z-score, WC z-score, serum leptin and adiponectin, and HOMA-IR. In conclusion serum visfatin level was lower in prepubertal SGA children but not correlated with IR indices. Low birth weight was an independent predictor of visfatin level.

BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients' outcome.

BACKGROUND: The significance of BRAF mutations, microsatelite instability (MSI) status and cyclin D1 expression in patients with metastatic colorectal cancer (mCRC) was evaluated. METHODS: Primary tumours from 144 patients treated for mCRC were assessed for BRAF (V600E) mutation, MSI status and cyclin D1. The data were correlated with progression-free survival (PFS) and overall survival (OS). RESULTS: BRAF mutations were detected in 10 (out of 22, 45%) patients with MSI-H tumours compared with 2 (out of 122, 1.6%) in those with microsatellite stable tumours (P<0.001). The presence of BRAF mutations was correlated with cyclin D1 overexpression (7 out of 26 patients, 58% vs 5 out of 118 patients, 14%; P=0.001). Patients with BRAF-mutated primary tumours had a significantly decreased PFS (2.7 vs 9.8 months; P<0.001) and median OS (14 vs 30 months; P<0.001) than patients with wild-type (wt) tumours. Patients with MSI-H and BRAF-mutated tumours experienced significantly lower PFS (3.1 vs 11.4 months; P=0.008) and OS (14.5 vs 35.5 months; P=0.004) than patients with MSI-H and BRAF wt tumours. Similarly, BRAF mutations and cyclin D1 overexpression were correlated with decreased PFS (3.1 vs 8.6 months; P=0.03) and OS (17.8 vs 39.2 months; P=0.01). CONCLUSION: BRAF V600E mutations are associated with MSI-H status and cyclin D1 overexpression and characterize a subgroup of patients with poor prognosis.

The effects of ezetimibe and/or orlistat on triglyceride-rich lipoprotein metabolism in obese hypercholesterolemic patients.

We investigated the factors influencing triglycerides (TG) reduction during ezetimibe, alone or combined with orlistat, administration. Eighty-six obese hypercholesterolemic subjects were prescribed a low-fat diet and were randomized to ezetimibe (E group), orlistat (O group), or both (OE group) for 6 months. Plasma TG and apolipoprotein (apo) C-III reduction was significantly greater in the combination group compared with monotherapy. Multivariate analysis showed that in E group apoC-III reduction and baseline TG levels were independently positively correlated, whereas baseline apoC-II levels were negatively correlated, with TG lowering. In OE group apoC-III reduction was the only independent contributor to TG reduction.

Absence of SLC22A12 gene mutations in Greek Caucasian patients with primary renal hypouricaemia.

OBJECTIVE: Primary renal hypouricaemia is a hereditary clinical disorder characterized by increased renal urate clearance due to isolated renal tubular defect of uric acid transport. There have been only a few studies on primary renal hypouricaemia in Caucasian populations. Defects in the SLC22A12 gene, which encodes the renal urate transporter URAT1, have been reported to be related to the disease pathogenesis. This study was undertaken to elucidate whether SLC22A12 gene mutations are responsible for low serum uric acid levels in Greek people. MATERIAL AND METHODS: Nine Greek Caucasian subjects with primary renal hypouricaemia were included in the study. All had serum uric acid less than 2.5 mg dL(-1) (0.14 mmol L(-1)), fractional excretion of uric acid more than 10% and no other known causes of hypouricaemia. Mutation analysis of the SLC22A12 gene was performed. RESULTS: No mutation was found--only the previously reported silent polymorphism 1246T > C (His 42His) in exon 2 of the SLC22A12 gene. CONCLUSIONS: No previously reported mutation of URAT1 was associated with primary renal hypouricaemia in Greek subjects.

Genetic polymorphisms of the apolipoprotein A-IV in a Greek population and their relation to plasma lipid and lipoprotein levels.

Apolipoprotein (apo) A-IV is a protein component of triglyceride-rich lipoproteins and high-density lipoproteins (HDL). In this study, two common genetic polymorphisms of the apoA-IV gene [codons 347(allele A and T) and 360 (allele 1 and 2)] were investigated in Greek patients with hyperlipidaemia and in healthy individuals matched for age, sex and smoking habits. In both study populations we evaluated the effect of these polymorphic sites on lipid and lipoprotein plasma levels and the body mass index (BMI). The frequencies of the 1/1 and 1/2 genotypes in codon 360 were 0.94 and 0.06 in hyperlipidemic patients and 0.92 and 0.08 in the control population, respectively. The frequencies of the A/A, A/T and T/T genotypes in codon 347 were 0.62, 0.34 and 0.04 in hyperlipidemic patients and 0.59, 0.33 and 0.08 in the control population, respectively. None of the above genotype frequency differences between the study populations reached statistical significance. The control population was not affected by any polymorphism of the apo A-IV gene. Hyperlipidaemic patients, carriers of the allele 2 (1/2 genotype), had significantly lower plasma triglyceride levels than carriers of the allele 1 (p = 0.03). Genetic variation in codon 347 had no influence on lipid and lipoprotein plasma levels. None of the polymorphisms at codons 360 and 347 affected the BMI. In conclusion, this study describes for the first time the genotype frequencies for polymorphic sites in codons 360 and 347 of the apo A-IV gene in a Greek population and suggests that the presence of the allele 2 is associated with lower plasma triglyceride levels in hyperlipidaemic patients.

Lipid profile in subclinical hypothyroidism: is L-thyroxine substitution beneficial?

OBJECTIVE: The significance of dyslipidemia in subclinical hypothyroidism (SH) and the effect of thyroid substitution on lipids remain controversial. The present study aimed to assess the association of SH with lipid abnormalities and to quantify the effect of L-thyroxine therapy on serum lipid profiles. DESIGN: Serum lipid parameters of 66 patients with SH and 75 age- and sex-matched euthyroid controls were evaluated in a cross-sectional study. RESULTS: Patients with SH had higher total cholesterol (TC) (222+/-45 (s.d.) vs 190+/- 32 mg/dl), low-density lipoprotein cholesterol (LDL-C) (139+/-28 vs 118+/-39 mg/dl), apolipoprotein B (149+/-21 vs 139+/-18 mg/dl) and lipoprotein (a) (Lp(a)) (median 12.5 (0.8-101) mg/dl vs 7 (0.8-44) mg/dl) levels compared with euthyroid controls (P<0.05 for all comparisons). In a follow-up study including 37 patients with SH, all measurements were repeated after restoration of a euthyroid state with incremental doses of l-thyroxine. No significant changes in serum lipid profiles were observed except for a decrease in high-density lipoprotein cholesterol (59+/-15 to 55+/-14 mg/dl, P<0.05). However, patients with high pre-treatment TC (> or =240 mg/dl) showed a significant reduction in both TC (278+/-28 vs 257+/-36 mg/dl, P<0.05) and LDL-C (192+/-23 vs 173+/-28 mg/dl, P<0.01) levels. Similar but more pronounced changes were observed in a subgroup of patients with pre-treatment levels of TSH > or =10 microU/ml. Thyroid autoimmunity had no effect on either the baseline or the post-treatment lipid profile. CONCLUSION: Although patients with subclinical hypothyroidism exhibit increased levels of the atherogenic parameters (mainly LDL-C and Lp(a)), thyroid substitution therapy does not seem to significantly improve dyslipidemia in the whole group of patients.

Routine differential diagnosis of proteinurias by capillary electrophoresis.

Capillary electrophoresis is a relatively new analytical technique that begins to have an impact on both routine and research in clinical laboratories. Recently, a fully automated system has become commercially available (Paragon CZE 2000, Beckman, USA) for the analysis of human serum proteins. Urine protein analysis, on the other hand, is currently accomplished by electrophoresis of concentrated urine specimens. The method is used to distinguish the glomerular from the tubular proteinuria and for the identification of Bence-Jones proteins. The procedure is labor-intensive and technically demanding. We developed a technique for the serum capillary electrophoresis instrument that can also be applied routinely to the differential diagnosis of proteinurias. Overriding the programmed dilution step of the instrument, we were able to distinguish different types of proteinurias without concentration of specimens with a total protein content of 150-200 mg/l as determined by sulfosalicylic acid. The different electrophoretic patterns obtained by the capillary electrophoresis system for various specimens correlated well with established techniques (Hydragel Proteinurie Kit, Sebia, France). The method is applicable for routine analysis of urinary proteins. It is reliable, less expensive and faster than the conventional methods (electrophoretic or immunonephelometric) used today for the differentiation of proteinurias, and it can be used as a quick screening test.

Effect of letrozole on the lipid profile in postmenopausal women with breast cancer.

Hormonal therapy plays a central role in the overall treatment of breast cancer. Aromatase inhibitors can inhibit the aromatase enzyme system resulting in a reduction of oestrogens. Letrozole is a non-steroidal aromatase inhibitor that effectively blocks aromatase activity without interfering with adrenal steroid biosynthesis. The drug can significantly reduce the levels of plasma oestrogens, which remain suppressed throughout the treatment. Data are scarce concerning the influence of these drugs on serum lipid levels. In the present study, we evaluated the effects of letrozole on the serum lipid profile in postmenopausal women with breast cancer. A total of 20 patients with breast cancer were treated with letrozole, 2.5 mg once daily. After an overnight fast, serum lipid parameters (total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides, apolipoproteins A1, B and E and lipoprotein (a)) were measured before treatment and at 8 and 16 weeks afterwards. A significant increase in total cholesterol (P=0.05), LDL cholesterol (P<0.01) and apolipoprotein B levels (P=0.05) in the serum, as well as in the atherogenic risk ratios total cholesterol/HDL cholesterol (P<0.005) and LDL cholesterol/HDL cholesterol (P<0.005) was noticed after letrozole treatment. We conclude that letrozole administration in postmenopausal women with breast cancer has an unfavourable effect on the serum lipid profile.

Partially reversible renal tubular damage in patients with obstructive jaundice.

Decreased serum uric acid levels resulting from renal urate wasting have been occasionally encountered in jaundiced patients. However, in these cases, there are no data concerning the underlying renal tubular defects. In the present study, we investigated the renal tubular function in 35 patients with obstructive jaundice of various severity and causes (11 with lithiasis, 17 with carcinoma, and 7 with intrahepatic cholestasis). A detailed study of the renal tubular function was performed. Beyond the conventional methods, (1)H-NMR spectroscopy of urine was used to evaluate noninvasively renal damage by the characteristic perturbation in the excretion pattern of low-molecular weight endogenous metabolites. On admission, patients with obstructive jaundice had significantly lower serum uric acid and phosphate levels and higher bile acid concentrations compared with 40 age- and sex-matched controls. Serum uric acid levels presented a negative correlation with the total and direct bilirubin as well as the fractional excretion of uric acid. Furthermore, a great number of the patients studied developed one or more proximal tubular dysfunction manifestations beyond uricosuria, such as renal glucosuria, phosphaturia, and increased excretion of alpha(1)-microglobulin. (1)H-NMR spectroscopy of the urine showed decreased levels of citrate and hippurate and increased levels of 3-hydroxybutyrate and acetate. In 12 patients partial or complete remission of jaundice was followed by an improvement of the proximal renal tubular damage. In conclusion, obstructive jaundice can cause a partially reversible generalized proximal tubular dysfunction.

Severe hypomagnesemia and hypoparathyroidism in Kearns-Sayre syndrome.

Kearns-Sayre syndrome (KSS) is a multisystem mitochondrial disorder characterized by the invariant triad: onset before 20, progressive external ophthalmoplegia and pigmentary retinal degeneration, plus at least one of the following: complete heart block, cerebellar dysfunction and CSF protein >100 mg/dl. Autopsies from patients with KSS revealed widespread tissue distribution of mitochondrial (mt) DNA deletions. These deletions result in significantly lower activities of the enzymes of the respiratory chain. KSS has been associated with a variety of endocrine and metabolic disorders in <10% of patients, while renal tubular involvement is extremely rare. We present an 18-year-old girl with KSS who developed hypoparathyroidism and renal tubular dysfunction with inappropriate mangesiuria and kaliuria. We further discuss the renal tubular damage in KSS emphasizing its pathophysiology and clinical phenotype, and review the possible mechanisms of hypoparathyroidism in KSS.

Metabolic abnormalities in patients with primary open-angle glaucoma.

PURPOSE: Although there are few data on the underlying mechanisms of primary open-angle glaucoma (POAG), it has been suggested that metabolic diseases may play a role in the evolution of the disease. We carried out the present study to investigate the involvement of metabolic disturbances in POAG pathogenesis. MATERIAL/METHODS: Serum metabolic parameters were evaluated in 49 POAG patients without a known history of diabetes mellitus and 72 age and sex matched individuals without glaucoma (control group). RESULTS: Among the metabolic parameters examined, only fasting serum glucose and uric acid levels were found significantly higher in patients with glaucoma compared to the control population (117+/-17 mg/dl vs 105+/-11 mg/dl, p=0.05 and 6.2+/-1.9 mg/dl vs 5+/-1.2 mg/dl, p=0.006, respectively). Additionally, a considerably greater proportion of patients had disturbances of the carbohydrate metabolism and hyperuricemia. CONCLUSION: We conclude that disturbances of carbohydrate and uric acid metabolism could play a role in glaucoma damage and pathogenesis.

The effect of atorvastatin on serum lipids, lipoprotein(a) and plasma fibrinogen levels in primary dyslipidaemia--a pilot study involving serial sampling.

We conducted an open-label study to test the effects of atorvastatin on serum lipids, lipoprotein(a) [Lp(a)] and plasma fibrinogen levels. A total of 90 dyslipidaemic, non-smoking patients (45 patients with primary hypercholesterolaemia and 45 patients with primary mixed hyperlipidaemia) aged 48 +/- 11 years were studied. The patients were treated with 20 mg of atorvastatin for 24 weeks, in a single nocturnal dose. At baseline and every eight weeks, the fasting lipid profile, together with serum Lp(a) and plasma fibrinogen levels (Clauss method), were measured. Atorvastatin was highly effective in normalising the serum lipid profile. No significant change in median serum Lp(a) levels was observed in the whole group of patients (0.14 g/l before, vs. 0.16 g/l after, treatment) as well as in patients with raised (> 0.30 g/l) baseline levels (n = 32). A small non-significant increase of plasma fibrinogen was found (3.04 g/l vs. 3.14 g/l) after 24 weeks of atorvastatin administration. The effects of atorvastatin on both these variables did not differ in patients with hypercholesterolaemia or mixed hyperlipidaemia. In conclusion, our findings suggest that the effect of atorvastatin on plasma fibrinogen levels in dyslipidaemic patients without evident vascular disease is not clinically relevant. Furthermore, any rise in fibrinogen levels that may occur is likely to be transient in nature. Further studies are necessary to clarify this issue. There was no evidence that atorvastatin influences serum Lp(a) levels.

G-CSF induces elevation of circulating CA 15-3 in breast carcinoma patients treated in an adjuvant setting.

BACKGROUND: Cancer antigen 15-3 (CA 15-3), a circulating marker that determines secreted products of the polymorphic MUC1 gene, has been established as a convenient tool for monitoring breast carcinoma patients. METHODS: The authors investigated alterations of soluble CA 15-3 in 57 postoperative breast carcinoma patients while they were receiving intensified adjuvant chemotherapy with granulocyte colony stimulating factor (G-CSF) support; 26 patients had American Joint Committee on Cancer (AJCC) Stage II, and 31 patients had AJCC Stage III breast carcinoma. Serial CA 15-3 values recorded thoughout the treatment were compared with baseline values, analyzed for correlation with hematologic and biochemical parameters, and compared with clinicopathologic characteristics and patient outcome. At a median follow-up time of 32 months, 47 of these patients remained relapse-free. RESULTS: A twofold increase of CA 15-3 was detected at the end of the second week of treatment, remained significantly elevated in most patients at above the cutoff level of 30 U/mL throughout the treatment period (P < 0.0001), and subsided to pretreatment values 1-2 months after treatment cessation. CA 15-3 values were found to be associated strongly with absolute neutrophil count, serum lactate dehydrogenase, and alkaline phosphatase. The median values and the kinetics of tumor markers did not differ over time in regard to hormonal receptor status and disease recurrence. CONCLUSIONS: These data provide strong evidence that G-CSF administration can induce elevation of CA 15-3 and indicate that false-positive results should be considered when evaluating CA 15-3 in patients who are receiving G-CSF. It is speculated that this phenomenon occurs through the induction of MUC1 antigen of unknown origin by G-CSF. Experimental investigation of this clinical observation is warranted.