Gitelman syndrome: an analysis of the underlying pathophysiologic mechanisms of acid-base and electrolyte abnormalities.

Gitelman syndrome is the most common inherited tubular disease resulting from mutations of the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter in the early distal convoluted tubules. The review presents the underlying pathophysiologic mechanisms of acid-base and electrolyte abnormalities observed in patients with Gitelman syndrome. The syndrome is usually characterized by hypokalemic metabolic alkalosis in combination with hypomagnesemia and hypocalciuria. Additionally, increased chloride excretion and renin/aldosterone levels, hypophosphatemia (occasionally), hyponatremia (rarely) and glucose intolerance/insulin resistance have been reported. The knowledge of the pathophysiologic mechanisms is useful for the treatment of patients with Gitelman syndrome as well as for the understanding of other tubular diseases.

L-Carnitine/Simvastatin Reduces Lipoprotein (a) Levels Compared with Simvastatin Monotherapy: A Randomized Double-Blind Placebo-Controlled Study.

Lipoprotein (a) [Lp(a)] is an independent risk factor for cardiovascular disease. There are currently limited therapeutic options to lower Lp(a) levels. L-Carnitine has been reported to reduce Lp(a) levels. The aim of this study was to compare the effect of L-carnitine/simvastatin co-administration with that of simvastatin monotherapy on Lp(a) levels in subjects with mixed hyperlipidemia and elevated Lp(a) concentration. Subjects with levels of low-density lipoprotein cholesterol (LDL-C) >160 mg/dL, triacylglycerol (TAG) >150 mg/dL and Lp(a) >20 mg/dL were included in this study. Subjects were randomly allocated to receive L-carnitine 2 g/day plus simvastatin 20 mg/day (N = 29) or placebo plus simvastatin 20 mg/day (N = 29) for a total of 12 weeks. Lp(a) was significantly reduced in the L-carnitine/simvastatin group [-19.4%, from 52 (20-171) to 42 (15-102) mg/dL; p = 0.01], but not in the placebo/simvastatin group [-6.7%, from 56 (26-108) to 52 (27-93) mg/dL, p = NS versus baseline and p = 0.016 for the comparison between groups]. Similar significant reductions in total cholesterol, LDL-C, apolipoprotein (apo) B and TAG were observed in both groups. Co-administration of L-carnitine with simvastatin was associated with a significant, albeit modest, reduction in Lp(a) compared with simvastatin monotherapy in subjects with mixed hyperlipidemia and elevated baseline Lp(a) levels.

Proton pump inhibitors and statins: a possible interaction that favors low-density lipoprotein cholesterol reduction?

BACKGROUND: Proton pump inhibitors (PPIs) might influence the metabolism of cholesterol and statins in the liver. AIM: The impact of PPIs on low-density lipoprotein cholesterol (LDL-C) levels in statin-treated patients. METHODS: Retrospective observational study including consecutive statin-treated individuals followed for ≥3 years in a university hospital lipid clinic. Demographic characteristics as well as clinical and laboratory data were recorded at baseline and the most recent visit. High, moderate and low-intensity statin therapy was defined according to the expected LDL-C reduction (≥50%, 30-50%, and <30%, respectively). We compared the LDL-C reduction in subjects receiving statin + PPI with those on statin alone and assessed the overall effect of PPI administration on LDL-C lowering. RESULTS: Of 648 statin-treated subjects, 7% were also taking a PPI. There was no difference between PPI vs. non-PPI group regarding baseline characteristics and intensity of lipid-lowering therapy. Stepwise linear regression analysis showed that PPI use was significantly associated with LDL-C reduction (b =0.104, p =0.005) along with baseline LDL-C levels (b =0.482, p <0.001), treatment with ezetimibe (b =0.198, p <0.001), presence of diabetes (b =0.168, p <0.001), compliance with treatment (b =0.205, p <0.001), intensity of statin treatment (b =0.101, p =0.005) and cardiovascular risk (b =0.082, p =0.049). Subjects receiving statin + PPI had a higher LDL-C reduction by 6.4% compared with those taking a statin alone (fully adjusted p =0.005). CONCLUSIONS: PPIs may modestly boost the statin-mediated LDL-C reduction. This effect should be confirmed by prospective clinical studies. Hippokratia 2015; 19 (4): 332-337.

Effects of thyroid dysfunction on lipid profile.

Thyroid dysfunction has a great impact on lipids as well as a number of other cardiovascular risk factors. Hypothyroidism is relatively common and is associated with an unfavorable effect on lipids. Substitution therapy is beneficial for patients with overt hypothyroidism, improving lipid profile. However, whether subclinical hypothyroidism should be treated or not is a matter of debate. On the other hand, hyperthyroidism can be associated with acquired hypocholesterolemia or unexplained improvement of lipid profile. Overall, thyroid dysfunction should be taken into account when evaluating and treating dyslipidemic patients.

Rosuvastatin treatment is associated with an increase in insulin resistance in hyperlipidaemic patients with impaired fasting glucose.

AIM OF THE STUDY: The increase in physician-reported diabetes following rosuvastatin treatment in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin study has raised concerns whether this statin exerts a detrimental effect on glucose metabolism. We assessed the effect of rosuvastatin treatment across dose range on glucose homeostasis in hyperlipidaemic patients with impaired fasting glucose (IFG), who are at high risk to develop diabetes mellitus. METHODS: The medical records of 72 hypelipidaemic patients with IFG on rosuvastatin 10 (RSV10 group), 20 (RSV20 group) and 40 mg/day (RSV40 group) were reviewed. The median follow up was 12.4 weeks. At the first visit, prior to rosuvastatin prescription and at the latest visit, serum lipid profile and indices of glucose metabolism, including fasting glucose, insulin and HOmeostasis Model Assessment (HOMA(IR)) index levels, were assessed. RESULTS: Rosuvastatin treatment improved lipid profile and was associated with a dose-dependent significant increase in HOMA(IR) values by 25.4%, 32.3% and 44.8% at the dose of 10, 20 and 40 mg/day (p < 0.01 for all, p < 0.05 for the comparison between groups), respectively, mirrored by correspondent increase in plasma insulin levels [by 21.7%, 25.7% and 46.2% in the RSV10, RSV20 and RSV40 group (p < 0.001 for all) respectively]. Baseline HOMA(IR) levels was the most important contributor (R(2) = 68.1%, p < 0.001), followed by the dose of rosuvastatin treatment (R(2) = 23.7%, p < 0.01), in a model that explained 91.8% of the variability in HOMA(IR) increase. CONCLUSION: In patients with IFG and hyperlipidaemia, rosuvastatin treatment was associated with a dose-dependent increase in insulin resistance.

Are the pleiotropic effects of telmisartan clinically relevant?

Hypertension is one of the major risk factors for cardiovascular disease. Angiotensin receptor blockers (ARBs) are a class of antihypertensive drugs with established efficacy and favorable safety profile. Telmisartan, a member of the ARB family, holds some additional traits which differentiate it from the rest ARBs. A pivotal role in these characteristics plays its ability to partially activate the peroxisome proliferator activated receptor-gamma, which in turn controls a number of metabolism-related genes. Indeed, telmisartan has shown a number of pleiotropic effects in experimental and clinical studies. These include the amelioration of insulin resistance, improvement of lipid profile and favorable fat redistribution. Moreover, telmisartan has been associated with beneficial effects on vascular function, cardiac remodeling and renal function. However, do all these pleiotropic effects translate into clinical benefit? Recent studies have tried to answer this question with promising but not definitive results.

How safe is the use of thiazolidinediones in clinical practice?

BACKGROUND: Thiazolidinediones (TZDs) are widely used antidiabetic drugs with proven efficacy regarding mainly surrogate markers of diabetes management. However, efficacy on surrogate markers may not always translate into benefits in clinical outcomes. Thiazolidinediones are usually well tolerated; however, their use may be associated with several adverse effects. The first TZD, troglitazone, was withdrawn from the market owing to serious hepatotoxicity. However, this does not seem to be the case with newer TZDs. OBJECTIVE: The aim of the present review is to discuss the safety profile of this drug class. METHODS: We searched PubMed up to July 2008 using relevant keywords. CONCLUSIONS: Common side effects associated with TZDs include edema, weight gain, macular edema and heart failure. Moreover, they may cause hypoglycemia when combined with other antidiabetic drugs as well as decrease hematocrit and hemoglobin levels. Increased bone fracture risk is another TZD-related side effect. Thiazolidinediones tend to increase serum low density lipoprotein cholesterol levels, with rosiglitazone having a more pronounced effect compared with pioglitazone. Moreover, rosiglitazone increases low density lipoprotein particle concentration in contrast to pioglitazone where a decrease is observed. Rosiglitazone has been associated with an increase in myocardial infarction incidence. On the other hand, pioglitazone may reduce cardiovascular events. Overall, TZDs are valuable drugs for diabetes management but physicians should keep in mind that they are associated with several adverse events, the most prominent of which is heart failure.

Alterations in the high density lipoprotein phenotype and HDL-associated enzymes in subjects with metabolic syndrome.

Patients with metabolic syndrome (MetS) usually have low high density lipoprotein cholesterol (HDL-C) levels. We determined the HDL distribution profile as well as the HDL-related lipoprotein associated phospholipase A(2) (HDL-LpPLA(2)) and paraoxonase-1 (PON1) activities in subjects with MetS (n = 189) but otherwise healthy. Age and sex-matched individuals (n = 166) without MetS served as controls. The lower HDL-C concentration in MetS patients was due to a reduction in both large and small HDL subclasses (P < 0.001 and P < 0.05, respectively). As the number of MetS components increased, the HDL phenotype comprised of a greater percentage of small HDL-3 and less large HDL-2 subclasses, resulting in a decreased HDL-2/HDL-3 ratio (P < 0.001 for all trends). Multivariate analysis revealed that HDL-2 levels and the HDL-2/HDL-3 ratio significantly and independently correlated with HDL-C (positively) and TG (negatively) levels. HDL-3 concentration significantly and independently positively correlated with HDL-C and TG levels. HDL-LpPLA(2) activity was decreased in MetS patients (P < 0.01), a phenomenon that may contribute to the defective antiatherogenic activity of HDL in MetS. PON1 activity did not differ between groups. We conclude that MetS, in addition to the decrease in HDL-C concentration, is associated with alterations in the HDL phenotype, which is comprised of a greater percentage of small HDL subclasses. Furthermore, HDL-LpPLA(2) activity is decreased in MetS patients.

Pleiotropic effects of thiazolidinediones.

BACKGROUND: Insulin resistance and hyperglycemia characterize type 2 diabetes mellitus. Type 2 diabetes mellitus is usually accompanied by concomitant disorders, such as dyslipidemia, hypertension and atherosclerosis. Thiazolidinediones are antidiabetic drugs that increase insulin sensitivity by activating the peroxisome proliferator-activated receptor gamma. There is evidence that thiazolidinediones exert a number of pleiotropic effects that may play an important role in the treatment of type 2 diabetes mellitus. OBJECTIVE: The purpose of the present article was to review the 'pleiotropic' effects of thiazolidinediones (i.e., their effects beyond glucose lowering). METHODS: The study involved searching PubMed up to February 2008 using relevant keywords. CONCLUSIONS: Thiazolidinediones favorably alter fat distribution and improve cardiovascular risk factors, such as blood pressure, inflammation markers and uric acid and they may also delay the progression of atherosclerosis. The effects on the lipid profile differ between the two thiazolidinediones studied with pioglitazone having more positive effects compared with rosiglitazone. Furthermore, thiazolidinediones improve diabetic complications, such as diabetic nephropathy and non-alcoholic fatty liver disease. Thiazolidinediones may also play a role in other diseases, such as polycystic ovary syndrome. These pleiotropic effects may prove to be clinically relevant. There has been recent debate about the possible differences between the two thiazolidinediones in terms of cardiovascular disease outcome. In this context, differences in the lipid effects between the two drugs may be relevant.

Coexistence of spinal intramedullary teratoma and diastematomyelia in an adult.

STUDY DESIGN: A case report of intramedullary spinal cord teratoma with remote diastematomyelia in a female adult. OBJECTIVE: To present a rare case of a dysembryogenic spinal tumor with concurrent split cord malformation and to define the importance of early surgical removal of the tumor. SETTING: A department of neurosurgery in Greece. METHODS: A 44-year old woman, presented with progressive lower limb muscle weakness, gait disturbances and dysesthesias in the trunk and lower extremity. She underwent plain radiographs, CT and MRI scan, which revealed an exophytic intramedullary spinal cord tumor at the level of T8-T10 and distant diastematomyelia in the upper lumbar spine (L2-L3). She underwent surgical intervention. The tumor was subtotally removed. No attempt was made to treat diastematomyelia. RESULTS: Postoperatively, the patient's neurological status started to improve gradually. After 1 year she exhibited better strength in the lower limb muscles and improved sensation. The histological examination demonstrated mature spinal teratoma consisting of ectodermal, mesodermal and endodermal elements. CONCLUSIONS: In adult patients with intramedullary masses of possible dysembryogenic origin, the whole spine must be examined for additional dysraphic lesions. The choice and the timing of a surgical intervention are strongly dependent on the clinical picture.

Hepatitis E virus antibodies in hemodialysis patients: an epidemiological survey in central Greece.

Hepatitis E virus (HEV) is the causative agent for enteric non-A, non-B hepatitis. Transmission is mainly via the fecal-oral route but the possibility of an additional parenteric transmission has been raised. Patients undergoing chronic hemodialysis (HD) have an increased risk of exposure to blood transmitted agents. Previous studies concerning prevalence of antibodies to HEV (anti-HEV) among HD patients gave conflicting results. The aim of the study presented here was to determine the prevalence of anti-HEV among HD patients of a well-defined semi-rural region in central Greece (Thessalia region). All patients (n=351, 234 males, mean age 60+/-14 years) who were being treated in the HD units of central Greece (n=5) during 2001 were tested for anti-HEV antibody. Two commercially available specific solid-phase enzyme-linked immunoassays were applied for anti-HEV detection. Hepatitis B virus markers, antibodies to HCV, HIV and HTLV were also screened in all patients by commercially available assays. Serum aminotransferase (AST, ALT) levels were measured by spectrophotometry. 17 anti-HEV-positive patients were found and prevalence was 4.8%, varying from 1.8 - 9.8% in the various HD units. Prevalence of HBsAg and anti-HCV was 5.7% (2.9 - 15%) and 23.6% (11.5 - 36.2%) respectively. The anti-HEV prevalence was increased compared to healthy blood donors in Greece (0.26%, p < 0.01). The highest prevalence of anti-HEV was seen at the HD unit of the General Hospital of Karditsa (9.8%). Risk factors for anti-HEV antibody were not identified: no association was found between anti-HEV positivity and age or sex, duration of HD, hepatitis B or C virus infection markers, previously elevated aminotransferase levels or history of transfusion. Our investigation of HEV infection in the cohort of HD patients in central Greece showed that the prevalence of anti-HEV was greater than in healthy blood donors. There was no association to blood borne infections (HBV, HCV). The high prevalence of anti-HEV we found in one HD unit was probably related to a local infection in the past. However, long-term prospective studies are needed in an attempt to identify whether intra-unit factors are also responsible for the increased prevalence of serologic markers of HEV infection among HD patients.

Residues of aldicarb in oranges: a unit-to-unit variability study.

Residues of aldicarb and its sulphoxide and sulphone oxidative metabolites in individual Navelino orange trees were determined at several time intervals after soil application of TEMIK 10G at 200 g formulated material per tree. Analysis was by HPLC with postcolumn derivatization giving average recoveries of 98% for aldicarb (RSD 6%), 34% for aldicarb sulphoxide (RSD 5%) and 77% for aldicarb sulphone (RSD 5%). Lowest calibrated levels (LCLs) were 0.02 mg/kg for aldicarb and aldicarb sulphone and 0.04 mg/kg for aldicarb sulphoxide. At the recommended preharvest interval (PHI) of 120 days no detectable residues of any compound, including the parent compound, were found in and of the samples analysed. In mature fruits (PHI of 88 days) detectable residues at the LCL for aldicarb sulphoxide and 0.03 or 0.04 mg/kg for aldicarb sulphone were found in only three of the 18 samples analYsed. In immature fruits detectable residues of aldicarb sulphoxide at concentrations ranging between 0.04 (LCL) and 0.51 mg/kg were detected in 70 out of 88 samples analysed, while residues of aldicarb sulphone at concentrations 0.02 (LCL) to 0.8 mg/kg were detected in 73 out of 88 samples. Indicative variability factors for sulphoxide and sulphone were estimated for immature fruits.

Determination of residues of endosulfan and five pyrethroid insecticides in virgin olive oil using gas chromatography with electron-capture detection.

A simple, fast and economical method has been developed for the determination of endosulfan and five pyrethroid insecticides, cypermethrin, deltamethrin, fenvalerate, lambda-cyhalothrin and permethrin, in virgin olive oil. The method uses a Sep-Pak alumina-N column cleanup after a liquid-liquid extraction or low-temperature precipitation step, and gas chromatography (GC) with electron-capture detection. The matrix effect was assessed for the GC systems used. Recoveries were 71-91% with RSD values of 6-17%. The method was applied to 338 virgin olive oil samples for monitoring of residues of these pesticides. Cypermethrin and lambda-cyhalothrin were detected at the limit of quantification in one sample each, while 22% of samples contained endosulfan residues, mostly at very low levels ranging from 0.02 to 0.57 mg/kg.

Low-temperature clean-up method for the determination of organophosphorus insecticides in olive oil.

A simple, extremely low-cost method using low-temperature lipid precipitation has been developed for the rapid analysis of virgin olive oil for organophosphorus insecticides and triazine herbicides commonly used in olive groves. The method gives good clean-up for GC analysis with nitrogen-phosphorus detection and recoveries between 77 and 104%, with RSD values of 7-16%. Matrix enhancement was observed for some pesticides and metabolites.

Residue levels of chlorpropham in individual tubers and composite samples of postharvest-treated potatoes.

Chlorpropham, a herbicide and sprout suppressant, is used on stored potatoes to prolong the storage period without deterioration of produce quality. Data for residue concentrations on an individual tuber basis are required by WHO for the estimation of the variability factor. In this study, the levels of chlorpropham in individual tubers and in composite samples were determined. The distribution of chlorpropham between the peel and the tuber flesh was examined, and the fate during the cooking process (washing, boiling, frying) was studied. The concentrations in individual tubers ranged from 1.8 to 7.6 mg/kg 10 days postapplication (mean 3.8 mg/kg, RSD 39%), from 0.7 to 4.0 mg/kg 28 days postapplication (mean 2.9 mg/kg, RSD 28%), and from 0.8 to 3.8 mg/kg 65 days postapplication (mean 2.2 mg/kg, RSD 48%). The calculated residues in composite samples 10 days postapplication ranged from 4.3 to 6.1 mg/kg (mean 4.9 mg/kg, RSD 20%). Those in samples taken 28 days postapplication ranged from 3.1 to 4.2 mg/kg (mean 3.8 mg/kg, RSD 15%). The concentrations determined in composite samples of whole tubers 65 days postapplication ranged between 2.6 and 3.2 (mean 2.9 mg/kg, RSD 11%). Peeling removed 91-98% of the total residue; washing reduced residues by 33-47%. Detectable residues were found in boiled potatoes and the boiling water, and in french fries and the frying oil. Monitoring data on commercial prefried frozen french fries are reported.

Field trials to determine residues of chlozolinate in table grapes.

Chlozolinate (Serinal) is a dicarboximide fungicide used in southern European countries principally on grapes. Maximum residue levels have not yet been set by FAO/WHO and are under evaluation in the EU. Field trials have been carried out in Greece on two varieties of table grapes (Cardinal and Victoria) during two consecutive years to assess residues remaining after application according to good agricultural practice. Analysis using a multiresidue method with gas chromatography (ECD) showed that the parent compound decays with a first-order rate constant of 0.057 +/- 0.011 day(-)(1) and that residues had fallen below the proposed MRL of 5 mg/kg in all samples by 21 days postapplication (the proposed PHI). The contribution of the main metabolite, S1, to the total residue is generally <20%. Washing removes a substantial amount (up to 80%) of chlozolinate, which appears to be nonsystemic on grapes, thus reducing real consumer exposure to this pesticide.

Inclusion of the fungicide chlozolinate in a multiresidue method.

A multiresidue GC method for the monitoring of electron-capturing compounds has been validated for the fungicide chlozolinate in the four crops with uses to be supported during re-evaluation procedures within the European Union. The method was also tested for a further eight crops. Matrix-matching of standards was found to be desirable to avoid the random occurrence of artificially high recoveries. The high accuracy and precision of the method, with a mean recovery of 94% and an RSD of +/-5%, shows it to be suitable for routine residue control in a wide range of crops.

Residues of dicloran in clingstone peaches after pre- and postharvest application.

Trials were carried out over a period of several years in order to test the efficacy of pre- and postharvest treatments against fungi causing postharvest rots of stored clingstone peaches destined to canning. Among the fungicides tested, dicloran (2, 6-dichloro-4-nitroaniline) was applied against Botrytis cinerea, Monilia cinerea and Rhizopus stolonifer. The purpose of this work was to determine the residues of this fungicide in fresh, washed, peeled and canned fruits. No relevant data are reported in the open literature to our knowledge. Some residue data, most of them produced by the manufacturer of the compound, were evaluated by the FAO/WHO Joint Meeting on Pesticide Residues (JMPR) and are summarized in the 1974 and 1977 monographs (FAO/WHO 1975 and 1978).

Pesticide residues in olive oil.

The attacks of pests and diseases and the presence of weeds make it necessary to apply pesticides to olive trees to ensure crop protection. Residues of these compounds may remain and contaminate the oil produced. For the analysis of pesticide residues in olive oil, the most common methods are multiresidue methods for fatty substrates, based on partitioning between hexane or light petroleum and acetonitrile. Recently, other methods have been applied, such as ready-to-use, disposable minicolumns or direct injection of oil into a capillary gas chromatograph equipped with a precolumn with an oil recovery tank. Although several pesticides are registered in oil-producing countries for use on olive trees, available literature on the level and fate of residues is very limited. However, it is clear that fat-soluble pesticides tend to concentrate in the oil, both after full coverage and bait spraying, and their use close to harvest should therefore be avoided. Because it is sometimes necessary to use such pesticides late in autumn because of their effectiveness in cases of severe attack, residue trials should be carried out to determine the residue concentration in oil and to set a reasonable preharvest safety interval. Data produced by such trials would permit the establishment of MRLs (tolerances) in olive oil to cover cases where the residues, although relatively high, are not of toxicological significance for consumers (risk assessment). Such is the case with corn oil and the fat-soluble insecticide methyl pirimiphos, registered in the U.S. for use on corn. The U.S. EPA tolerance for methyl pirimiphos in corn is 8 mg/kg, whereas it is 11 times higher (88 mg/kg) for corn oil because it is known to concentrate in the oil. Similar provisions for olive oil, based on data from residue trials according to Good Agricultural Practice, the long-term toxicity of each pesticide as expressed by its ADI for man, and olive oil consumption patterns, would facilitate international trade of this commodity. On the other hand, because of the high dietary and health value of olive oil, it is desirable that toxic pesticide residues be kept as low as possible. Therefore, it would be preferable not to rely only on chemical pest control treatments but to develop and apply alternative plant protection techniques such as Integrated Pest Management (IPM).(ABSTRACT TRUNCATED AT 400 WORDS)