High cysteine diet reduces insulin resistance in SHR-CRP rats.

Increased plasma total cysteine (tCys) has been associated with obesity and metabolic syndrome in human and some animal studies but the underlying mechanisms remain unclear. In this study, we aimed at evaluating the effects of high cysteine diet administered to SHR-CRP transgenic rats, a model of metabolic syndrome and inflammation. SHR-CRP rats were fed either standard (3.2 g cystine/kg diet) or high cysteine diet (HCD, enriched with additional 4 g L-cysteine/kg diet). After 4 weeks, urine, plasma and tissue samples were collected and parameters of metabolic syndrome, sulfur metabolites and hepatic gene expression were evaluated. Rats on HCD exhibited similar body weights and weights of fat depots, reduced levels of serum insulin, and reduced oxidative stress in the liver. The HCD did not change concentrations of tCys in tissues and body fluids while taurine in tissues and body fluids, and urinary sulfate were significantly increased. In contrast, betaine levels were significantly reduced possibly compensating for taurine elevation. In summary, increased Cys intake did not induce obesity while it ameliorated insulin resistance in the SHR-CRP rats, possibly due to beneficial effects of accumulating taurine.

The combination of atorvastatin with silymarin enhances hypolipidemic, antioxidant and anti-inflammatory effects in a rat model of metabolic syndrome.

Hypolipidemic and cardioprotective effects of statins can be associated with the development of myopathies and new-onset type 2 diabetes. These adverse effects may be related to increased oxidative stress. The plant extract silymarin (SM) is known for its antioxidant and anti-inflammatory actions. We tested the hypothesis that the combination of atorvastatin (ATV) with SM could improve therapy efficacy and eliminate some negative effects of statin on hypertriglyceridemia-induced metabolic disorders. Hereditary hypertriglyceridemic rats were fed a standard diet for four weeks without supplementation; supplemented with ATV (5 mg/kg b. wt./day) or a combination of ATV with 1 % micronized SM (ATV+SM). ATV treatment elevated plasma levels of HDL-cholesterol (p<0.01), glucose and insulin and decreased triglycerides (p<0.001). The combination of ATV+SM led to a significant reduction in insulin, an improvement of glucose tolerance, and the hypolipidemic effect was enhanced compared to ATV alone. Furthermore, ATV supplementation increased skeletal muscle triglycerides but its combination with SM decreased triglycerides accumulation in the muscle (p<0.05) and the liver (p<0.01). In the liver, ATV+SM treatment increased the activities of antioxidant enzymes, glutathione and reduced lipid peroxidation (p<0.001). The combined administration of ATV with SM potentiated the hypolipidemic effect, reduced ectopic lipid accumulation, improved glucose metabolism, and increased antioxidant and anti-inflammatory actions. Our results show that SM increased the effectiveness of statin therapy in a hypertriglyceridemic rat model of metabolic syndrome.

Metabolic cardio- and reno-protective effects of empagliflozin in a prediabetic rat model.

The mechanisms behind the cardiovascular and renal benefits of empagliflozin is not fully understood. The positive impact of the medication on cardiovascular mortality can not be solely attributed to its antidiabetic effect, with a metabolic mechanism possibly involved. To investigate the metabolic effects of empagliflozin treatment (10 mg/kg/day for 6 weeks), we used an adult male rat model with serious vascular complications associated with metabolic syndrome and prediabetes. Impaired glucose tolerance, severe albuminuria and impaired insulin sensitivity were induced by intragastric administration of methylglyoxal and high sucrose diet feeding for four months. Although empagliflozin decreased body weight, non-fasting glucose and insulin, glucagon levels remained unchanged. In addition, empagliflozin increased adiponectin levels (+40%; p < 0.01) and improved skeletal muscle insulin sensitivity. Increased non-esterified fatty acids (NEFA) in empagliflozin-treated rats is understood to generate ketone bodies. Empagliflozin increased ß-hydroxybutyrate levels in serum (+66%; p < 0.05) and the myocardium (30%; p < 0.01), suggesting its possible involvement as an alternative substrate for metabolism. Empagliflozin switched substrate utilisation in the myocardium, diverting glucose oxidation to fatty acid oxidation. Representing another favorable effect, empagliflozin also contributed to decreased uric acid plasma levels (-19%; p < 0.05). In the kidney cortex, empagliflozin improved oxidative and dicarbonyl stress parameters and increased gene expression of ß-hydroxybutyrate dehydrogenase, an enzyme involved in ketone body utilisation. In addition, empagliflozin decreased microalbuminuria (-27%; p < 0.01) and urinary neutrophil gelatinase-associated lipocalin (NGAL) excretion (-29%; p < 0.01). Our results reveal the important systemic metabolic effect of empagliflozin on alterations in substrate utilisation and on increased ketone body use in prediabetic rats. Improved oxidative and dicarbonyl stress and decreased uric acid are also possibly involved in the cardio- and reno-protective effects of empagliflozin.

First-trimester screening for preeclampsia.

DESIGN: Review article. SETTING: Department of Clinical Biochemistry, University Hospital Olomouc; Department of Obstetrics and Gynecology, Palacky University Olomouc, Faculty of Medicine and Dentistry, University Hospital Olomouc; The Institute for the Care of Mother and Child and 3rd Faculty of Medicine Charles University, Prague; G-CENTRUM Olomouc, Olomouc; Genetika Plzeň, Pilsen. Methods, results: Preeclampsia (PE) is a multisystem disorder complicating pregnancy. It is the leading cause of maternal and perinatal mortality and morbidity worldwide. Recent studies have shown that high-risk pregnant women may benefit from low-dose acetylsalicylic acid early therapy in prevention of the development of severe forms of the disease. The risk group of pregnant women should be identified in 11-13 gestational week for effective prevention. The only procedure validated in many studies for performing PE screening with sufficient diagnostic accuracy in the first trimester of pregnancy is given by The Fetal Medicine Foundation (FMF) and has been adopted and published in a new recommendation by The International Federation of Gynecology and Obstetrics (FIGO). CONCLUSION: This article summarizes the recent findings and recommendation for performing screening of preeclampsia in 1st trimester of pregnancy and how to prevent the development of severe forms of PE by low-dose acetylsalicylic acid therapy.

The effect of combined diet containing n-3 polyunsaturated fatty acids and silymarin on metabolic syndrome in rats.

The risk of development of metabolic syndrome can be increased by hypertriglyceridemia. A search for effective therapy is a subject of considerable attention. Therefore, our hypothesis is that the fish oil (containing polyunsaturated fatty acids; n-3 PUFA) in a combination with silymarin can more effectively protect against hypertriglyceridemia-induced metabolic disturbances. The study was conducted using a unique non-obese strain of rats with hereditary hypertriglyceridemia an accepted model of metabolic syndrome. Adult male rats were treated with n-3 PUFA (300 mg/kg/day) without or with 1 % micronized silymarin in a diet for 4 weeks. The treatment with the diet containing n-3 PUFA and silymarin significantly reduced concentrations of serum triglycerides (-45 %), total cholesterol (-18 %), non-esterified fatty acids (-33 %), and ectopic lipid accumulation in skeletal muscle (-35 %) compared to controls. In addition, an increase in Abcg5 and Abcg8 mRNA expression (as genes affecting lipid homeostasis) as well as in protein content of ABCG5 (+78 %) and ABCG8 (+232 %) transporters have been determined in the liver of treated rats. Our findings suggest that this combined diet could be used in the prevention of hypertriglyceridemia-induced metabolic disorders.

Dissecting the role of Folr1 and Folh1 genes in the pathogenesis of metabolic syndrome in spontaneously hypertensive rats.

Increased levels of plasma cysteine predispose to obesity and metabolic disturbances. Our recent genetic analyses in spontaneously hypertensive rats (SHR) revealed mutated Folr1 (folate receptor 1) on chromosome 1 as a quantitative trait gene associated with reduced folate levels, hypercysteinemia and metabolic disturbances. The Folr1 gene is closely linked to the Folh1 (folate hydrolase 1) gene which codes for an enzyme involved in the hydrolysis of dietary polyglutamyl folates in the intestine. In the current study, we obtained evidence that Folh1 mRNA of the BN (Brown Norway) origin is weakly but significantly expressed in the small intestine. Next we analyzed the effects of the Folh1 alleles on folate and sulfur amino acid levels and consecutively on glucose and lipid metabolism using SHR-1 congenic sublines harboring either Folr1 BN and Folh1 SHR alleles or Folr1 SHR and Folh1 BN alleles. Both congenic sublines when compared to SHR controls, exhibited significantly reduced folate clearance and lower plasma cysteine and homocysteine levels which was associated with significantly decreased serum glucose and insulin concentrations and reduced adiposity. These results strongly suggest that, in addition to Folr1, the Folh1 gene also plays an important role in folate and sulfur amino acid levels and affects glucose and lipid metabolism in the rat.

Metformin attenuates myocardium dicarbonyl stress induced by chronic hypertriglyceridemia.

Reactive dicarbonyls stimulate production of advanced glycation endproducts, increase oxidative stress and inflammation and contribute to the development of vascular complications. We measured concentrations of dicarbonyls - methylglyoxal (MG), glyoxal (GL) and 3-deoxyglucosone (3-DG) - in the heart and kidney of a model of metabolic syndrome - hereditary hypertriglyceridemic rats (HHTg) and explored its modulation by metformin. Adult HHTg rats were fed a standard diet with or without metformin (300 mg/kg b.w.) and dicarbonyl levels and metabolic parameters were measured. HHTg rats had markedly elevated serum levels of triacylglycerols (p<0.001), FFA (p<0.01) and hepatic triacylglycerols (p<0.001) along with increased concentrations of reactive dicarbonyls in myocardium (MG: p<0.001; GL: p<0.01; 3-DG: p<0.01) and kidney cortex (MG: p<0.01). Metformin treatment significantly reduced reactive dicarbonyls in the myocardium (MG: p<0.05, GL: p<0.05, 3-DG: p<0.01) along with increase of myocardial concentrations of reduced glutathione (p<0.01) and glyoxalase 1 mRNA expression (p<0.05). Metformin did not have any significant effect on dicarbonyls, glutathione or on glyoxalase 1 expression in kidney cortex. Chronically elevated hypertriglyceridemia was associated with increased levels of dicarbonyls in heart and kidney. Beneficial effects of metformin on reactive dicarbonyls and glyoxalase in the heart could contribute to its cardioprotective effects.

Mutant Wars2 gene in spontaneously hypertensive rats impairs brown adipose tissue function and predisposes to visceral obesity.

Brown adipose tissue (BAT) plays an important role in lipid and glucose metabolism in rodents and possibly also in humans. Identification of genes responsible for BAT function would shed light on underlying pathophysiological mechanisms of metabolic disturbances. Recent linkage analysis in the BXH/HXB recombinant inbred (RI) strains, derived from Brown Norway (BN) and spontaneously hypertensive rats (SHR), identified two closely linked quantitative trait loci (QTL) associated with glucose oxidation and glucose incorporation into BAT lipids in the vicinity of Wars2 (tryptophanyl tRNA synthetase 2 (mitochondrial)) gene on chromosome 2. The SHR harbors L53F WARS2 protein variant that was associated with reduced angiogenesis and Wars2 thus represents a prominent positional candidate gene. In the current study, we validated this candidate as a quantitative trait gene (QTG) using transgenic rescue experiment. SHR-Wars2 transgenic rats with wild type Wars2 gene when compared to SHR, showed more efficient mitochondrial proteosynthesis and increased mitochondrial respiration, which was associated with increased glucose oxidation and incorporation into BAT lipids, and with reduced weight of visceral fat. Correlation analyses in RI strains showed that increased activity of BAT was associated with amelioration of insulin resistance in muscle and white adipose tissue. In summary, these results demonstrate important role of Wars2 gene in regulating BAT function and consequently lipid and glucose metabolism.

Hepatotoxic effects of fenofibrate in spontaneously hypertensive rats expressing human C-reactive protein.

Dyslipidemia and inflammation play an important role in the pathogenesis of cardiovascular and liver disease. Fenofibrate has a well-known efficacy to reduce cholesterol and triglycerides. Combination with statins can ameliorate hypolipidemic and anti-inflammatory effects of fibrates. In the current study, we tested the anti-inflammatory and metabolic effects of fenofibrate alone and in combination with rosuvastatin in a model of inflammation and metabolic syndrome, using spontaneously hypertensive rats expressing the human C-reactive protein transgene (SHR-CRP transgenic rats). SHR-CRP rats treated with fenofibrate alone (100 mg/kg body weight) or in combination with rosuvastatin (20 mg/kg body weight) vs. SHR-CRP untreated controls showed increased levels of proinflammatory marker IL6, increased concentrations of ALT, AST and ALP, increased oxidative stress in the liver and necrotic changes of the liver. In addition, SHR-CRP rats treated with fenofibrate, or with fenofibrate combined with rosuvastatin vs. untreated controls, exhibited increased serum triglycerides and reduced HDL cholesterol, as well as reduced hepatic triglyceride, cholesterol and glycogen concentrations. These findings suggest that in the presence of high levels of human CRP, fenofibrate can induce liver damage even in combination with rosuvastatin. Accordingly, these results caution against the possible hepatotoxic effects of fenofibrate in patients with high levels of CRP.

[Spontaneous antepartal RhD alloimmunization]. / Spontánní antepartální RhD aloimunizace.

AIM OF THE STUDY: Assess the incidence of spontaneous antepartal RhD alloimmunization in RhD negative pregnant women with an RhD positive fetus. DESIGN: Clinical study. SETTING: Department of Obstetrics and Gynecology, Medical School and University Hospital Olomouc. METHODS: A total of 906 RhD negative women with an RhD positive fetus and without the presence of anti-Dalloantibodies at the beginning of pregnancy were examined. Always it was a singleton pregnancy, RhD blood group of the pregnant women was assessed in the 1st trimester of pregnancy, RhD status of the fetus was determined after delivery. Screening for irregular antierythrocyte antibodies was performed in all women in the 1st trimester of pregnancy, at 28-32 weeks gestation and immediately prior to delivery at 38-42 weeks gestation. Screening for irregular antierythrocyte antibodies was performed also at 6 months following delivery in all cases of positive antibodies before delivery. Antibody screening was performed using the indirect antiglobulin (LISS/NAT) and enzyme (papain) test with their subsequent identification using a panel of reference erythrocytes by column agglutination method Dia-Med. After delivery, the volume of fetomaternal hemorrhage was assesed in all RhD negative women and RhD alloimmunization prophylaxis was performed by administering the necessary IgG anti-D dose; none of the women were administered IgG anti-D antepartally. RESULTS: During screening for irregular antierythrocyte antibodies at 28-32 weeks gestation, anti-D alloantibodies were diagnosed in 0.2% of the women (2/906); immediately prior to the delivery at 38-42 weeks gestation, anti-D alloantibodies were diagnosed in 2.3% of the women (21/906) and repeatedly even at 6 months following delivery (21/157). In 82.7% of the women (749/906), examination at 6 months following delivery was not performed, therefore in these women spontaneous antepartal RhD alloimmunization cannot reliably be ruled out. Alloimmunization may not be diagnosed yet at term of delivery. If anti-D alloantibodies were not present prior to the delivery, these women were all administered IgG anti-D in a dose of at least 125 µg after delivery. CONCLUSION: In RhD negative women with an RhD positive fetus, the incidence of spontaneous antepartal RhD alloimmunization was at least 2.3%. Most cases may theoretically be prevented by prophylactic administration of 250 µg of IgG anti-D to all RhD negative women at 28 weeks gestation.

[Preliminary results of fetal fibronectin testing in twin pregnancies].

OBJECTIVES: Purpose of this study is to investigate accuracy of fetal fibronectin testing (fFN test) as a means to predict preterm birth in twin gestations without symptoms of preterm labour as well as to compare the results with the world trends. MATERIAL AND METHODS: This study is prospective and comparative. It covers a period from December 2012 to May 2013, includes a total of 43 twin pregnancies--34 bichoriotic biamniotic twin pregnancies, 6 monochoriotic biamniotic twin pregnancies and 3 monochoriotic monoamniotic twin pregnancy A measurement of cervical length by transvaginal ultrasonography is used as well. RESULTS: A total of 43 women had cervico-vaginal fetal fibronectin testing obtained from 24 to 34 weeks of gestation. 31 women had negative fFN test and 12 had positive results. In patiens with negative testing delivery began after a period of 30 days average. In most of the women with negative test result labour occurred after more than 14 days, which means that the test has high specificity. Patients with positive test result had delivery after a mean period of 12 days, which demonstrated that the fetal fibronectin test has high sensitivity The shortest period between the positive testing and delivery was one day A transvaginal ultrasound measurement of the cervical length was performed. Four of our patients had positive test result as well as short cervix and delivery occurred at a mean age of 31 w.g. and 5 days after the test. Four women tested positive for fFNA and had normal cervical length. They had labour at 35+3 w.g. and 23 days after the test. Eight patients tested negative for fFN and had short cervical length, but they had labour after 28 days as well. Most of the researched women (19) had negative test result and normal cervical length and they delivered after average 30 days. CONCLUSIONS: Fetal fibronectin testing used in twin pregnancies as well as in singleton pregnancies proves to have high specificity sensitivity, good positive and negative predictive value. It offers the opportunity for adequate tocolytic therapy once the test comes out to be positive. There is a posibility to decrease the use of corticosteroids. The length of stay in the hospital can also be reduced.

Immunohistochemical evaluation and lymph node metastasis in surgically staged endometrial carcinoma.

OBJECTIVE: To assess the expression of immunohistochemical markers in surgically staged endometrial cancer patients. METHODS: We studied 107 cases of primary untreated endometrial carcinoma in which the p53, bcl-2, her-2/neu, Ki-67, estrogen receptor (ER) and progesterone receptor (PR) antigens were investigated by an immunohistochemical method. In the last 50 consecutive patients immunoreactivity for MMP-7 and MMP-26 was assessed as well. We evaluated the correlations among the immunohistochemical staining assessed by histoscore, and the age, grading, depth of invasion, stage of the neoplasia and extrauterine disease. RESULTS: Mean age was 65 years (range 34-88). All patients were submitted to total abdominal or modified radical vaginal hysterectomy plus bilateral salpingo-oophorectomy and systematic pelvic lymphadenectomy; p53, bcl-2, her-2/neu, Ki-67, MMP-7, MMP-26, estrogen and progesterone receptors were positive in 36 (43%), 71 (86%), 13 (16%), 80 (96%), 65 (78%), 80 (96%), 61 (73%) and 71 (86%) patients, respectively. p53 overexpression was found to be related to poor grade of differentiation and deep myometrial invasion. Immunostaining for ER was inversely related to the histopathological differentiation of the tumors. Decreased expression of PR was related to advanced stage, poor histopathologic differentiation and extrauterine spread of disease. CONCLUSION: The overexpression of p53 seems to indicate more malignant phenotype, while PR expression correlates with parameters of better clinical outcome.

[Immunohistochemical markers expression in hysteroscopy and hysterectomy specimens from endometrial cancer patients: comparison]. / Porovnání exprese imunohistochemických markeru ve vzorcích z hysteroskopie a hysterektomie u pacientek s karcinomem endometria.

OBJECTIVE: To assess the immunohistochemical expression of p53, bcl-2, c-erbB-2, Ki-67, estrogen (ER) and progesterone receptors (PR), MMP-7, MMP-26 in samplex from diagnostic hysteroscopy and therapeutic hysterectomy in endometrial cancer patients. DESIGN: Experimental prospective study. SETTING: Department of Obstetrics and Gynecology, Institute of Human Genetics, Department of Pathology, Palacky University Medical School and University Hospital, Olomouc. METHODS: We studied 43 cases of primary untreated endometrial carcinoma in which the grade and immunomarkers assessed by histoscore were investigated in specimens obtained at hysteroscopy and hysterectomy. RESULTS: Based on hysterosopy, 31 (72.1%) patients were classified as G1, G2 7 (16.3%) and G3 5 (11.6%) respective. In grade 1 the concordance rate was 77.4% of cases, in grade 2 it was in 14.3% of cases and in grade 3 it was in 80.0% of cases. In hysterosocpy samples the p53 expression was found in 23 (53.5%), bcl-2 in 37 (86.0%), c-erbB-2 in 20 (46.5%), Ki-67 in 29 (67.4%), ER in 37 (86.0%), PR in 36 (83.7%), MMP-7 in 25 (58.1%) and MMP-26 in 23 (53.5%) cases. Expression in hysterectomy specimens was p53 positive in 13 (30.2%), bcl-2 positive in 33 (76.7%), c-erbB-2 positive in 24 (55.8%), Ki-67 positive in 25 (58.1%), ER positive in 36 (83.7%), PR positive in 40 (93.0%), MMP-7 positive in 27 (62.8%) and MMP-26 positive in 23 (53.5%) of total 43 cases. CONCLUSION: We found high concordance in expression of p53, bcl-2, PR and MMP-7 in hysteroscopy and hysterectomy samples which could be of importance for therapeutic algorithm in endometrial cancer patients.

[Prognostic significance of clinic pathological and selected immunohistochemical factors in endometrial cancer]. / Prognostický význam klinickopatologických a vybraných imunohistochemických faktoru u karcinomu endometria.

OBJECTIVE: To assess the immunohistochemical expression of p53, bcl-2, c-erbB-2, Ki-67, estrogen (ER) and progesterone (PR) receptors in endometrial cancer patients. To assess the relation between steroid receptors positivity and other markers. To evaluate the prognostic significance of clinicopathologic and immunohistochemical markers on patient disease free survival. DESIGN: Experimental prospective study. SETTING: Department of Obstetrics and Gynaecology, Institute of Human Genetics, Department of Pathology, Department of Biophysics, Palacky University Medical School and University Hospital, Olomouc. METHODS: We studied 144 cases of primary untreated endometrial carcinoma in which the p53, bcl-2, c-erbB-2, Ki-67, ER and PR antigens were investigated with the use of an immunohistochemical method. In a group of 122 patients we assessed disease free survival (DFS) in relation to clinicopathologic and immunohistochemical factors. RESULTS: From the total group of 144 patients, 122 were included for survival analysis. We found 15 (12.3%) patients with recurrence of the disease. Mean age was 64,5 (34-88) years. Immunohistologic expression was p53 positive in 29 (23.8%), bcl-2 positive in 87 (71.3%), c-erbB-2 positive in 34 (27.9%), Ki-67 positive in 56 (45.9%), ER positive in 97 (79.5%) and PR positive in 106 (86.9%) of cases. In the survival analysis significantly shorter DFS was present in tumours with poor differentiation (G3), deep myometrial invasion (M2) and positive lymphoinvasion (N). CONCLUSION: Only poor differentiation (G3) and deep myometrial invasion (M2) are significant independent factors for the length of DFS.

Long-term pioglitazone treatment augments insulin sensitivity and PKC-epsilon and PKC-theta activation in skeletal muscles in sucrose fed rats.

It has been suggested that thiazolidinediones (TZDs) ameliorate insulin resistance in muscle tissue by suppressing muscle lipid storage and the activity of novel protein kinase C (nPKC) isoforms. To test this hypothesis, we analyzed long-term metabolic effects of pioglitazone and the activation of nPKC-epsilon and -theta isoforms in an animal model of the metabolic syndrome, the spontaneously hypertensive rat (a congenic SHR strain with wild type Cd36 gene) fed a diet with 60 % sucrose from the age of 4 to 8 months. Compared to untreated controls, pioglitazone treatment was associated with significantly increased basal (809+/-36 vs 527+/-47 nmol glucose/g/2h, P<0.005) and insulin-stimulated glycogenesis (1321+/-62 vs 749+/-60 nmol glucose/g/2h, P<0.0001) in isolated gastrocnemius muscles despite increased concentrations of muscle triglycerides (3.83+/-0.33 vs 2.25+/-0.12 micromol/g, P<0.005). Pioglitazone-treated rats exhibited significantly increased membrane/total (cytosolic plus membrane) ratio of both PKC-epsilon and PKC-theta isoforms compared to untreated controls. These results suggest that amelioration of insulin resistance after long-term pioglitazone treatment is associated with increased activation of PKC-epsilon and -theta isoforms in spite of increased lipid concentration in skeletal muscles.

Differences in hepatic expression of genes involved in lipid homeostasis between hereditary hypertriglyceridemic rats and healthy Wistar rats and in their response to dietary cholesterol.

UNLABELLED: Differences in expression of mRNA of genes regulating lipid and drug metabolism between hereditary hypertriglyceridemic rats (HHTg, accepted model of metabolic syndrome) and healthy Wistar-Kyoto (WKY) rats were studied. Also, differences in expression due to intake of high cholesterol diet (1% w/w) were determined to investigate possible differences in response of the WKY and HHTg rats to increased intake of dietary cholesterol. Levels of ATP-binding cassette transporters (ABCG5, ABCG8), fatty acid synthase (FAS) and cytochrome P450 (CYP2C11) mRNA were significantly lower in HHTg rats on standard laboratory diet; in contrary, CYP7A1, CYP2C6 and CYP2B2 gene expression was significantly higher. The WKY rats responded to high cholesterol diet by an increase in expression of mRNAs for sterol regulatory element binding protein (SREBP1c), CYP2B2 and CYP7A1; lower expression was found in the FAS, ABCG5, ABCG8, CYP4A1, CYP4A2 and acyl-CoA oxidase. HHTg rats responded to cholesterol intake in a similar manner, however, differences were found in expression of the FAS and CYP4A1 mRNA (decrease was not observed), CYP2B2 (decrease instead of an increase). CONCLUSIONS: (i) dietary cholesterol significantly influences expression of genes involved in lipid homeostasis and drug metabolism, and (ii) the HHTg rats responded to dietary cholesterol in a different way.

The impaired response of non-obese hereditary hypertriglyceridemic rats to glucose load is associated with low glucose storage in energy reserves.

The aim of the study was to determine the contribution of skeletal muscle, adipose tissue and liver to the impaired glucose clearance manifesting itself during the initial phase of OGTT in a non-obese animal model of insulin resistance, hereditary hypertriglyceridemic (HHTg) rats. Glucose utilisation and storage in insulin target tissues in vivo and in vitro after a glucose load (3 g/kg b. wt.) administered intragastrically following overnight fasting was compared in adult male HHTg rats and Wistar normotriglyceridemic controls after short-term (2 wk) high-sucrose (70 % calories as sucrose) feeding period. In comparison with normotriglyceridemic controls, in HHTg rats the glucose administration did not stimulate GLUT4 translocation to the plasma membrane in skeletal muscle and adipose tissue that was associated with decreased glucose utilisation by these tissues in vitro. The acute glucose supply did not result in increased glycogen synthesis in the liver and fatty acid synthesis de novo in adipose tissue. On the contrary, the serum glucose, triglyceride and free fatty acid levels remained elevated. In conclusion, in the tissues of HHTg rats, despite the increased insulinemia, the processes leading toward increased glucose utilisation and processes transforming glucose into storage forms, such as triglycerides in adipose tissue and glycogen in skeletal muscle and liver, did not start within this time interval. The combination of the impaired glucose utilisation and the impaired glucose storage in energy reserves leads to higher glycaemia following glucose load in HHTg rats.

Coping with social stigma: people with intellectual disabilities moving from institutions and family home.

BACKGROUND: Social stigma and its impact on the life opportunities and emotional well-being of people with intellectual disabilities (IDs) are a subject of both practical and theoretical importance. The disability movement and evolving theories of self, now point to individuals' ability to develop positive identities and to challenge stigmatizing views and social norms. METHOD: This paper presents findings from a phenomenological study of 10 individuals making the transition from their family home to live more independently and 18 individuals moving from a long-stay hospital to live in community housing. It builds on an earlier data set obtained from people living at home with their families and examines: (1) people's awareness of stigma, and (2) their modes of adaptation to stigma. RESULTS: The participants all believed that they faced stigmatized treatment and were aware of the stigma associated with ID. They presented a range of views about self in relation to disability and stigma. These views included regarding themselves as part of a minority group who reject prejudice, and attempts to distance themselves from stigmatizing services and from other individuals with IDs. CONCLUSIONS: The findings are discussed in relation to theories of self and the importance of considering psychosocial factors is stressed in clinical work with people who have IDs.

Psychiatric symptoms in neurologically asymptomatic Huntington's disease gene carriers: a comparison with gene negative at risk subjects.

OBJECTIVE: Psychiatric profiles of two at-risk groups [Huntington's disease (HD) gene carriers and non-carriers] were compared by means of a computerized battery and a structured interview. METHOD: To avoid confounding, only subjects who were free from neurological and cognitive deficits (neurologically asymptomatic) were included in the study. To avoid evaluation biases, all subjects were seen before the genetic testing was undertaken. RESULTS: Gene carriers had significantly worse recognition memory and scored higher in measures of irritability than controls. The groups also differed in terms of the factor structure of their psychiatric symptoms. None of the subjects qualified for a psychiatric diagnosis at the time of assessment. CONCLUSION: The groups differed with respect to their profile of psychiatric symptoms. It is hypothesized that these differences are the expression of different mechanisms, i.e. that cognitive deficits relate more to genetic factors and neurotic complaints more to being brought up in a disturbed family background. Issues concerning instrument sensitivity, selection bias and the advantage of seriatim assessments are discussed.

Psychiatric symptoms and CAG repeats in neurologically asymptomatic Huntington's disease gene carriers.

The putative relationship between the psychiatric profile of a sample of neurologically asymptomatic Huntington's disease gene carriers and CAG repeats was investigated. The psychiatric assessments (by consultant psychiatrist and computerised battery) were undertaken before the genetic testing was carried out. In this way, the informational distortions caused by neurological and cognitive deficits were avoided. The hypothesis that there is a relationship between psychiatric and CAG repeats was tested by seeking direct correlations between psychiatric systems and CAG repeats, and also by correcting the correlation by the number of years above or below the estimated age of onset in Huntington's disease. Scores for irritability and cognitive failures were high in the sample. There was no correlation between any psychiatric variable and CAG repeats. Possible explanations for this lack of correlations are discussed.