RESUMEN

Organic and inorganic colloids play important roles governing the speciation, transport, and bioaccessibility of trace elements in aquatic systems. These carriers are especially important in the boreal zone, where rivers that contain high concentrations of iron and organic matter are prevalent. The distribution of trace elements amongst different colloidal species (or "speciation profile") can therefore be useful as a fingerprint to detect different trace element sources and for tracking colloid transformations, with implications for bioaccessibility. Asymmetrical flow field-flow fractionation coupled to an inductively coupled plasma mass spectrometer was applied to detect the source of trace elements based on their speciation profile along a 125-km stretch of a large river in the Canadian boreal forest. Both the concentration and proportion of bound trace elements were increased by tributary inputs: bound As, Co, Fe, Mn, Pb, U, and Zn increased monotonically from upstream to downstream, increasingly resembling the speciation profile of tributaries. Principal component (PC) analysis also revealed tributary contributions of bound Cu, Ni, Th, V, and Y reflecting their higher concentrations in tributaries, and PC scores also increased monotonically from upstream-downstream. Monotonically decreasing concentrations of mainly ionic and small (i.e.

RESUMEN

AIMS: To investigate the incidence of all-cause mortality, composite mortality and morbidity in people with Type 1 diabetes formerly randomized in the Stockholm Diabetes Intervention Study. METHODS: A total of 102 people with Type 1 diabetes were randomized in the period 1982-1984 to intensified conventional treatment or standard treatment with insulin for a mean of 7.5 years. We prospectively re-evaluated this cohort for the period until 2011 with regard to all-cause mortality and composite mortality, which consisted of myocardial infarction, stroke and end-stage renal disease as primary endpoints. Secondary endpoints were first-time hospitalization for myocardial infarction and stroke or end-stage renal disease. Data on HbA1c levels (mean of 22 values/person) were retrospectively collected between 1996 and 2011. RESULTS: During the median follow-up of 28 years, 22 people died: seven in the intensified conventional insulin group compared with 15 in the standard treatment group (P = 0.30). With regard to composite mortality, six people in the intensified conventional insulin group died compared with 11 in the standard treatment group (P = 0.56). For the secondary endpoints, 11 people in the intensified conventional insulin group developed myocardial infarction or stroke compared with 17 in the standard treatment group (P = 0.72), and one person in the intensified conventional insulin compared with seven people in the standard treatment group developed end-stage renal disease (P = 0.09). Mean HbA1c levels did not differ between groups during the follow-up years. CONCLUSIONS: All-cause mortality, cardiovascular morbidity and progression to end-stage renal disease did not differ in people with Type 1 diabetes earlier randomized to intensified insulin treatment.

Asunto(s)

Diabetes Mellitus Tipo 1/tratamiento farmacológico , Angiopatías Diabéticas/prevención & control , Nefropatías Diabéticas/prevención & control , Hemoglobina Glucada/análisis , Hiperglucemia/prevención & control , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Adulto , Estudios de Cohortes , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/mortalidad , Angiopatías Diabéticas/epidemiología , Angiopatías Diabéticas/mortalidad , Nefropatías Diabéticas/epidemiología , Nefropatías Diabéticas/mortalidad , Monitoreo de Drogas , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Incidencia , Insulina/uso terapéutico , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/mortalidad , Fallo Renal Crónico/prevención & control , Estudios Longitudinales , Masculino , Mortalidad , Infarto del Miocardio/complicaciones , Infarto del Miocardio/epidemiología , Infarto del Miocardio/mortalidad , Infarto del Miocardio/prevención & control , Riesgo , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/mortalidad , Accidente Cerebrovascular/prevención & control , Análisis de Supervivencia , Suecia/epidemiología

RESUMEN

Urea cycle defects belong to the most common metabolic disorders with a cumulative incidence of 1:8000. A common trait of urea cycle defects is a disturbed detoxification of ammonia leading to hyperammonemia in the event of a high nitrogen load. Most patients develop symptoms in the neonatal period or in infancy, e. g. vomiting, seizures and disturbed consciousness. Depending on the affected enzyme and its residual activity, patients differ in the age at first presentation, the character and severity of symptoms and in the susceptibility to metabolic derangement. The presence of hyperammonemia and an altered plasma amino acid profile give the essential diagnostic clues. Since modern therapeutic measures have prolonged the life expectancy of these patients and provided the possibility of a first presentation in adulthood, patients with urea cycle defects have become an increasing challenge in internal medicine. The reported case series illustrates the heterogeneous clinical course of these disorders from childhood to adulthood.

Asunto(s)

Trastornos Innatos del Ciclo de la Urea/diagnóstico , Trastornos Innatos del Ciclo de la Urea/terapia , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven

RESUMEN

The phospholipidfloppase MDR3 (gene symbol: ABCB4) is expressed in the canalicular membrane of hepatocytes and mediates the biliary excretion of phosphatidylcholine, which is required for the formation of mixed micelles in bile. Several mutations of ABCB4 have been identified, which cause cholestatic liver diseases of varying severity including progressive familial intrahepatic cholestasis type 3 (PFIC-3), intrahepatic cholestasis of pregnancy (ICP) and the low phospholipid associated cholelithiasis syndrome (LPAC). Here, we report on four new (S1076N; L 23Hfs16X; c.286 + 1G > A; Q 1181E) and one known (S27G) MDR3 mutations in eight patients of three families. The patients presented with a wide spectrum of liver diseases. The clinical presentation and decisive laboratory findings or the association to a trend-setting family history led to the identification of the genetic background in these patients. Even the same mutation may be associated with varying disease progression.

Asunto(s)

Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Envejecimiento/genética , Colestasis Intrahepática/diagnóstico , Colestasis Intrahepática/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Mutación/genética , Adulto , Preescolar , Heterocigoto , Humanos , Lactante , Masculino , Linaje

RESUMEN

The age structures of populations of African annual Nothobranchius spp. were examined for the first time. Daily increments in sagittal otoliths of Nothobranchius furzeri, Nothobranchius kadleci, Nothobranchius orthonotus and Nothobranchius rachovii from southern and central Mozambique were used for age determination. Four hypotheses were tested: (1) timing of hatching is consistent with the calendar onset of the rainy season, (2) hatching is synchronized within a population in a pool, (3) there is a difference in hatching date between geographical regions differing in mean total annual precipitation and (4) sympatric Nothobranchius spp. hatch at the same time. The results show that daily increment analysis represents an applicable method for age determination in Nothobranchius spp. Despite a significant positive relationship between age and size of fishes, a pronounced variation in fish size at an age precluded the use of fish size as a valid age marker. Timing of hatching was not consistent with the calendar onset of the rainy season. Interpopulation variability was observed in the degree of hatching date synchronization within a population. Hatching dates were relatively uniform in some populations, while there was considerable variability in others. Differences in timing of hatching date were found in only 1 of 2 years within the three regions investigated (Chefu, lower Limpopo and Sofala regions), each of which differed in mean total annual rainfall. The hatching dates of sympatric Nothobranchius spp. were marginally different, but further testing on a larger sample is needed for conclusive results.

Asunto(s)

Peces Killi/fisiología , Reproducción/fisiología , Animales , Tamaño Corporal/fisiología , Femenino , Masculino , Mozambique , Membrana Otolítica/anatomía & histología , Estaciones del Año

Asunto(s)

Intolerancia a la Fructosa , Galactosemias , Enfermedad del Almacenamiento de Glucógeno , Porfirias Hepáticas , Intolerancia a la Fructosa/fisiopatología , Intolerancia a la Fructosa/terapia , Galactosemias/fisiopatología , Galactosemias/terapia , Enfermedad del Almacenamiento de Glucógeno/fisiopatología , Enfermedad del Almacenamiento de Glucógeno/terapia , Enfermedad del Almacenamiento de Glucógeno Tipo I/fisiopatología , Enfermedad del Almacenamiento de Glucógeno Tipo I/terapia , Enfermedad del Almacenamiento de Glucógeno Tipo III/fisiopatología , Enfermedad del Almacenamiento de Glucógeno Tipo III/terapia , Humanos , Porfirias Hepáticas/fisiopatología , Porfirias Hepáticas/terapia , Pronóstico

Asunto(s)

Enfermedad de Gaucher , Hemocromatosis , Degeneración Hepatolenticular , Deficiencia de alfa 1-Antitripsina , Enfermedad de Gaucher/diagnóstico , Enfermedad de Gaucher/fisiopatología , Enfermedad de Gaucher/terapia , Hemocromatosis/diagnóstico , Hemocromatosis/genética , Hemocromatosis/terapia , Degeneración Hepatolenticular/diagnóstico , Degeneración Hepatolenticular/genética , Degeneración Hepatolenticular/terapia , Humanos , Deficiencia de alfa 1-Antitripsina/diagnóstico , Deficiencia de alfa 1-Antitripsina/fisiopatología , Deficiencia de alfa 1-Antitripsina/terapia

RESUMEN

Aflatoxins are highly toxic carcinogens produced by several species in Aspergillus section Flavi. Strains of A. flavus that do not produce aflatoxins, called atoxigenic strains, have been used commercially in North America as tools for limiting aflatoxin contamination. A similar aflatoxin management strategy is being pursued in Nigeria. In the current study, loci across the 68 kb aflatoxin biosynthesis gene cluster were compared among 18 atoxigenic and two aflatoxin-producing vegetative compatibility groups (VCGs) from Nigeria and an atoxigenic VCG used commercially in North America. Five of the atoxigenic VCGs had large deletions (37-65 kb) extending from the teleomeric side of the aflatoxin biosynthesis cluster. In one VCG (AV0222) the deletion extended through the cluster to the adjacent sugar cluster. The remaining twelve atoxigenic VCGs, including the VCG used for aflatoxin management in North America, contained all the aflatoxin pathway genes, but with defects. Two observations support the long-term persistence of atoxigenicity within A. flavus: first, a comparison of pathway genes revealed more changes in atoxigenic than in aflatoxin-producing isolates relative to the aflatoxin-producing strain NRRL 3357; and second, several non-synonymous changes are unique to atoxigenics. Atoxigenic VCG diversity was assessed with phylogenetic analyses. Although some atoxigenics share relatively recent ancestry, several are more closely related to aflatoxin producers than to other atoxigenics. The current study demonstrates VCGs of A. flavus in West Africa with diverse mechanisms of atoxigenicity and potential value in aflatoxin management programmes.

Asunto(s)

Aflatoxinas/biosíntesis , Aflatoxinas/genética , Aspergillus flavus/genética , Aspergillus flavus/metabolismo , Carcinógenos/metabolismo , Variación Genética , Control Biológico de Vectores , Aflatoxinas/metabolismo , Aspergillus flavus/aislamiento & purificación , Productos Agrícolas/química , Productos Agrícolas/microbiología , Bases de Datos de Ácidos Nucleicos , Contaminación de Alimentos/prevención & control , Eliminación de Gen , Genes del Tipo Sexual de los Hongos , Isoenzimas/genética , Familia de Multigenes , Nigeria , Filogenia , Poligalacturonasa/genética , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple , Especificidad de la Especie , Zea mays/microbiología , alfa-Amilasas/genética , alfa-Glucosidasas/genética

Asunto(s)

Caracteres Sexuales , Muerte Súbita del Lactante/epidemiología , Muerte Súbita del Lactante/genética , Animales , Sesgo , Modelos Animales de Enfermedad , Femenino , Ligamiento Genético , Humanos , Recién Nacido , Masculino , Ratones , Resucitación

RESUMEN

Genotoxicity evaluations have been proposed as regulatory requirements for establishing German MAK values for inhaled fibrous dusts. The objective of this in vitro assay was to assess the potential for para-aramid (p-aramid) respirable-sized, fiber-shaped particulates (RFP) to induce chromosomal aberrations in cultured human peripheral blood lymphocytes without metabolic activation. The highest concentration tested in this assay was limited by the physical characteristics of p-aramid RFP. The test substance was suspended in fully supplemented RPMI culture medium with 1% Pluronic F68. All dosing was achieved using a dosing volume of 90% (900 microl/ml), and the vehicle control cultures were treated with 900 microl/ml of fully supplemented RPMI culture medium with 1% Pluronic F68. In the chromosomal aberrations assay, the treatments were either 3 or 19 h without metabolic activation. Cultures were harvested 22 h from the initiation of treatment. Replicated cultures of human whole blood lymphocytes were incubated with p-aramid RFP concentrations of 6.30, 12.6, 25.2, 50.4, 101, 201, and 401 microg/ml. Cultures treated with concentrations to 50.4 microg/ml for 3 h and 6.30, 12.6, 25.2, and 201 microg/ml for 19 h were analyzed for structural and numerical chromosomal aberrations. No significant increase in cells with chromosomal aberrations, polyploidy, or endoreduplication was observed in the cultures analyzed. The results demonstrated that p-aramid RFP was negative for inducing chromosomal aberrations in cultured human peripheral blood lymphocytes without metabolic activation. In addition, we conclude that the utility of these tests for evaluating the genotoxicity of fibrous or particulate materials is questionable.

Asunto(s)

Aberraciones Cromosómicas , Linfocitos/efectos de los fármacos , Mutágenos/toxicidad , Polímeros/toxicidad , Adulto , Células Cultivadas , Humanos , Técnicas In Vitro , Linfocitos/ultraestructura , Microscopía Electrónica de Rastreo , Mitomicina/toxicidad , Pruebas de Mutagenicidad , Inhibidores de la Síntesis del Ácido Nucleico/toxicidad

RESUMEN

Cholestasis induces down-regulation of multidrug resistance protein 2 (Mrp2, symbol Abcc2), which is localized to the canalicular membrane. Given the overlapping substrate specificities of Mrp2 and multidrug resistance protein 3 (Mrp3, symbol Abcc3), we examined the hypothesis of a different subcellular and lobular localization of these members of the Mrp family in rat liver after bile duct ligation. We raised a polyclonal antibody against rat Mrp3 and detected this protein in the basolateral plasma membrane of hepatocytes surrounding the central veins and of cholangiocytes. The Mrp3 protein level was less than 2% of the expression observed after 72 hours of obstructive cholestasis. After 48 hours of bile duct ligation, the Mrp3 protein was increased and was further enhanced after 72 hours. In 72-hour-cholestatic rat liver Mrp3 was expressed, in addition, in periportal hepatocytes. However, there was a preponderance of Mrp3 in the pericentral area of the liver lobule. In Mrp2-deficient mutant rat liver, the Mrp3 protein expression was most enhanced and its zonation was lost. The Mrp3 immunostaining of cholangiocytes was preserved in cholestatic and in Mrp2-deficient mutant liver. Canalicular Mrp2 decreased and amounted to 34% of normal after bile duct ligation for 72 hours. We conclude that the hepatocellular up-regulation of Mrp3 in cholestasis together with cholangiocellular Mrp3 may compensate for the biliary obstruction and impaired canalicular Mrp2 function by clearing cholephilic anionic substances into the blood.

Asunto(s)

Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Transportadoras de Casetes de Unión a ATP/metabolismo , Colestasis/metabolismo , Membranas Intracelulares/metabolismo , Hígado/metabolismo , Animales , Proteínas Portadoras/metabolismo , Técnica del Anticuerpo Fluorescente Indirecta , Immunoblotting , Masculino , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba

RESUMEN

We recently demonstrated that the sphingomyelin (SM) content of adipocyte membranes was negatively correlated with the expression of peroxisome proliferator-activated receptor-gamma (PPARgamma) in the subcutaneous adipose tissue of obese women with variable degrees of insulin resistance. We have now investigated whether SM really does have an impact on the expression of PPARgamma in 3T3-F442A adipocytes. Adding SM to the culture medium for 24 h caused a significant increase in SM content of adipocyte membranes and an acyl chain length-dependent decrease in the levels of PPARgamma mRNA and protein. The longer the acyl chain of the fatty acid of SM, the greater was the decrease in PPARgamma. These data suggest that the nature of the fatty acid is important in the regulation of PPARgamma by the SM pathway.

Asunto(s)

Receptores Citoplasmáticos y Nucleares/genética , Esfingomielinas/farmacología , Factores de Transcripción/genética , Células 3T3 , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Animales , Secuencia de Bases , Colesterol/metabolismo , Cartilla de ADN/genética , Regulación hacia Abajo/efectos de los fármacos , Femenino , Humanos , Resistencia a la Insulina , Lípidos de la Membrana/metabolismo , Ratones , Obesidad/metabolismo , Fosfolípidos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Citoplasmáticos y Nucleares/biosíntesis , Esfingomielinas/química , Esfingomielinas/metabolismo , Factores de Transcripción/biosíntesis

RESUMEN

BACKGROUND: The cell functions involved in the action of insulin--receptor binding, enzyme and transporter activities--are controlled by membrane properties. We have previously shown that the fasting plasma insulin (FPI) concentration and the homeostasis model assessment (HOMA) estimate of insulin resistance are associated with the sphingomyelin concentration in the erythrocyte membranes of obese women. OBJECTIVES: (1) To study the distribution of phospholipid classes in the plasma membrane and their association with insulin resistance markers in the adipocyte, an insulin-sensitive cell in obese women. (2) To investigate the influence of diabetes in a small group of obese women treated by diet alone. (3) To compare the distribution of phospholipids in erythrocyte membranes in a subgroup of obese nondiabetic and diabetic women. SUBJECTS: Subcutaneous fat biopsies were taken from the abdominal region of 19 obese non-diabetic and seven obese type 2 diabetic women. Erythrocyte membrane assessment was performed in a subgroup of 10 of the 19 obese nondiabetic and in the seven diabetic patients. METHODS: The phospholipid composition of adipocyte and erythrocyte plasma membranes was analyzed by high performance liquid chromatography. RESULTS: FPI was positively correlated with the adipocyte membrane contents of sphingomyelin (P < 0.001), phosphatidylethanolamine (P < 0.05), and phosphatidylcholine (P < 0.01) in the obese nondiabetic women. Similar correlations were obtained with HOMA. A stepwise multiple regression analysis indicated that sphingomyelin accounted for 45.6 and 43.8% of the variance in FPI and HOMA values as an independent predictor. There was a similar positive independent association between FPI and SM in the erythrocyte membranes of the studied subgroup. Diabetes per se did not influence the independent association between SM membrane contents and FPI in both cell types. CONCLUSION: These results suggest a link between membrane phospholipid composition, especially SM, and hyperinsulinemia in obese women.

Asunto(s)

Adipocitos/ultraestructura , Diabetes Mellitus/metabolismo , Membrana Eritrocítica/química , Hiperinsulinismo/metabolismo , Obesidad/metabolismo , Fosfolípidos/análisis , Adulto , Índice de Masa Corporal , Membrana Celular/química , Cromatografía Líquida de Alta Presión , Diabetes Mellitus/sangre , Diabetes Mellitus/patología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Ayuno , Femenino , Homeostasis , Humanos , Hiperinsulinismo/sangre , Hiperinsulinismo/patología , Insulina/sangre , Resistencia a la Insulina , Persona de Mediana Edad , Obesidad/sangre , Obesidad/patología , Fosfatidilcolinas/análisis , Fosfatidiletanolaminas/análisis , Análisis de Regresión , Esfingomielinas/análisis

RESUMEN

We have shown that membrane sphingomyelin (SM) is an independent predictor of the variance of fasting plasma insulin (FPI) concentrations and the homeostasis model assessment (HOMA) estimate of insulin resistance in obese women. The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a key component in adipocyte differentiation that may also contribute to the sensitivity of cells to insulin. PPAR-gamma is activated by fatty acids, and the membrane composition may have an impact on the activity of PPAR-gamma and thus on the sensitivity of adipocytes to insulin. We investigated these possible links by determining the phospholipid contents of adipocyte membranes, the mRNA expression of PPAR-gamma, and the FPI and HOMA estimate of insulin resistance in obese women. The mRNA levels of tumor necrosis factor-alpha (TNF-alpha), which is suspected to play a role in insulin resistance and which downregulates PPAR-gamma expression, were also quantified. FPI and HOMA were strongly positively correlated with membrane SM (P < 0.005) and cholesterol (P < 0.005). PPAR-gamma mRNA levels were negatively correlated with FPI (P < 0.05) and HOMA (P < 0.05) and positively correlated with high-density lipoprotein (HDL) cholesterol (P < 0.05), membrane SM (P < 0.05), and cholesterol contents (P < 0.05). TNF-alpha mRNA levels were not correlated with membrane parameters. In stepwise multiple regression analysis, the variations in PPAR-gamma mRNA levels were mainly explained by HDL cholesterol (31.9%) and membrane SM (17.7%). Our study shows that the expression of PPAR-gamma, a major factor controlling adipocyte functions, the lipid composition of the membrane, and insulin sensitivity are probably closely associated in the adipose tissue of obese women.

Asunto(s)

Adipocitos/química , Hiperinsulinismo/sangre , Obesidad/metabolismo , Fosfolípidos/análisis , Receptores Citoplasmáticos y Nucleares/biosíntesis , Factores de Transcripción/biosíntesis , Adipocitos/ultraestructura , Tejido Adiposo/química , Tejido Adiposo/patología , Adulto , Biopsia , Índice de Masa Corporal , Membrana Celular/química , Colesterol/análisis , Femenino , Homeostasis , Humanos , Hiperinsulinismo/etiología , Hiperinsulinismo/patología , Insulina/sangre , Resistencia a la Insulina , Obesidad/sangre , Obesidad/complicaciones , Obesidad/patología , ARN Mensajero/análisis , Receptores Citoplasmáticos y Nucleares/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/genética , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

Low-density lipoprotein (LDL) apheresis is a treatment option in patients with coronary artery disease and elevated LDL cholesterol concentrations if maximal drug therapy fails to achieve adequate LDL cholesterol reduction. This therapy is more effective when combined with strong lipid-lowering drugs, such as atorvastatin. However, conflicting data have been published concerning the effect of atorvastatin on fibrinogen concentration. Therefore, we investigated the effect of atorvastatin compared to simvastatin on fibrinogen concentration and other hemorheological parameters in patients treated by weekly LDL apheresis. Hemorheological parameters were, studied twice in 9 patients (4 female, 5 male, 54.0+/-8.9 years) with coronary artery disease treated by weekly LDL immunoadsorption, once during concomitant simvastatin therapy (40 mg daily) and once during atorvastatin therapy (40 mg daily). Fibrinogen concentration, plasma and blood viscosity at different shear rates, parameters of red cell aggregation at stasis and shear rate 3/s, and erythrocyte filterability were determined 7 days after the last LDL apheresis after each drug had been given for a minimum for 8 weeks. Fibrinogen concentration did not show any statistically significant difference during therapy with atorvastatin (3.09+/-0.36 g/L) compared to simvastatin (3.13+/-0.77 g/L). Plasma and blood viscosity as well as erythrocyte filterability were also unchanged. The increase in red cell aggregation at stasis during atorvastatin treatment (5.82+/-1.00 U versus 4.89+/-0.48 U during simvastatin; p < 0.05) was inversely correlated with a lower high-density liprotein (HDL) cholesterol concentration (1.17+/-0.21 mmol/L versus 1.31+/-0.30 mmol/L during simvastatin; p < 0.05). LDL cholesterol showed a strong trend to lower concentrations during atorvastatin (4.14+/-0.61 mmol/L versus 4.56+/-0.66 mmol/L during simvastatin; p = 0.07), despite a reduced plasma volume treated (3,547+/-1,239 ml during atorvastatin versus 3,888+/-1,206 mL during simvastatin; p < 0.05). In conclusion, fibrinogen concentration and other hemorheological parameters were unchanged during atorvastatin compared to simvastatin therapy with the exception of a higher red cell aggregation at stasis. Therefore, with respect to hemorheology, we conclude that atorvastatin should not be withheld from hypercholesterolemic patients regularly treated with LDL immunoadsorption.

Asunto(s)

Anticolesterolemiantes/uso terapéutico , Eliminación de Componentes Sanguíneos , Fibrinógeno/análisis , Fibrinógeno/efectos de los fármacos , Hemorreología/efectos de los fármacos , Ácidos Heptanoicos/uso terapéutico , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/terapia , Técnicas de Inmunoadsorción , Lipoproteínas LDL/sangre , Pirroles/uso terapéutico , Simvastatina/uso terapéutico , Atorvastatina , Eliminación de Componentes Sanguíneos/métodos , Viscosidad Sanguínea/efectos de los fármacos , Terapia Combinada , Agregación Eritrocitaria/efectos de los fármacos , Deformación Eritrocítica/efectos de los fármacos , Femenino , Humanos , Hiperlipoproteinemia Tipo II/fisiopatología , Masculino , Persona de Mediana Edad , Volumen Plasmático/efectos de los fármacos

RESUMEN

The membrane fluidity of reduced-amphotericin B (AmB)-sensitivity Kluyveromyces lactis mutant strain is higher than that of the wild-type K. lactis strain. After culture of the K. lactis and K. lactis mutant cells in the presence of subinhibitory doses of AmB (10 and 125 mg/liter, respectively), the plasma membranes of both yeast strains also showed a higher fluidity than did those of control cells. High membrane fluidity was associated with changes in the structural properties of the membranes. Culture of the K. lactis and K. lactis mutant cells in the presence of AmB induced changes in membrane lipid contents. In particular, phospholipid contents were increased in both strains treated with AmB, compared with their corresponding counterparts. As a result, the sterol/phospholipid ratio decreased. The relative proportion of monounsaturated fatty acids also increased after AmB treatment. The saturated fatty acid/monounsaturated fatty acid ratio decreased in K. lactis and K. lactis mutant cells treated with AmB but also in K. lactis mutant control cells compared to that in the K. lactis wild strain. These changes in lipid composition explain the higher fluidity, which could represent a process of metabolic resistance of the yeasts to AmB.

Asunto(s)

Anfotericina B/farmacología , Antifúngicos/farmacología , Kluyveromyces/efectos de los fármacos , Fluidez de la Membrana/efectos de los fármacos , Tampones (Química) , Farmacorresistencia Microbiana/fisiología , Cinética , Kluyveromyces/fisiología , Lípidos de la Membrana/análisis , Concentración Osmolar , Esferoplastos/efectos de los fármacos , Esferoplastos/fisiología , Factores de Tiempo

RESUMEN

BACKGROUND: An association with subcutaneous adipose tissue TNFalpha expression and insulin resistance has been suggested in obesity/type-2 diabetes, but this has not been examined directly. In the first part of the study we investigated whether this association is present in 7 lean, 10 obese nondiabetic and 9 type-2 diabetic men. In the second part of the study we examined the relationship between adipose tissue TNFalpha mRNA levels and BMI in 81 nondiabetic subjects spanning a wide range of BMIs. METHODS: Subcutaneous adipose tissue TNFalpha mRNA levels and insulin sensitivity were determined with quantitative RT-competitive PCR and hyperinsulinaemic clamp, respectively. RESULTS: Subcutaneous adipose tissue TNFalpha mRNA levels were similar in 7 lean and 10 obese nondiabetic and 9 type-2 diabetic men (P = 0.68), and did not change in response to 240-min hyperinsulinaemia. TNFalpha mRNA levels and insulin sensitivity were not correlated. Unexpectedly, no correlation between TNFalpha mRNA and BMI was found. The relationship between adipose tissue TNFalpha mRNA and BMI was examined further in 31 male and 50 female nondiabetic subjects. The subcutaneous adipose tissue TNFalpha mRNA level correlated with BMI in all subjects (rS = 0.32, P < 0.01), and in a subgroup analysis in men (rS = 0.55, P < 0.01) but not in women (rS = - 0.08). The correlation in men was dependent on a fourfold higher TNFalpha mRNA level in 5 morbidly obese men while there was no difference in TNFalpha mRNA levels in lean or obese men. CONCLUSIONS: Subcutaneous adipose tissue TNFalpha expression does not correlate with insulin sensitivity in nondiabetic or type-2 diabetic men; is not regulated by acute hyperinsulinaemia; and is increased only in morbidly obese men.

Asunto(s)

Tejido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus/fisiopatología , Resistencia a la Insulina , Obesidad/fisiopatología , Transcripción Genética , Factor de Necrosis Tumoral alfa/genética , Glucemia/metabolismo , Índice de Masa Corporal , Diabetes Mellitus/genética , Diabetes Mellitus Tipo 2/genética , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Resistencia a la Insulina/genética , Inulina/sangre , Inulina/farmacología , Masculino , Persona de Mediana Edad , Obesidad/genética , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Piel

RESUMEN

Lipoprotein (a) [Lp(a)] is a low-density lipoprotein (LDL) particle with an additional apolipoprotein named apo(a). The concentration of Lp(a) in plasma is determined to a large extent by the size of the apo(a) isoform. Because elevated Lp(a) concentrations in plasma are associated with risk for premature coronary heart disease it is important to determine whether variations in production or catabolism mediate differences in Lp(a) concentration. We determined metabolic parameters of Lp(a) in 17 patients with heterozygous familial hypercholesterolemia or severe mixed hyperlipidemia by fitting a monoexponential function to the rebound of Lp(a) plasma concentration following LDL-apheresis. In 8 of those 17 patients this was done twice following two different aphereses. Although this approach allows one to estimate metabolic parameters without the use of a tracer, it requires several major assumptions such as that apheresis itself does not change production or catabolism of Lp(a) and that Lp(a) metabolism can be described by a single compartment. One apheresis decreased Lp(a) concentration by 59.1+/-8.3%. The fractional catabolic rate (FCR) was 0.16+/-0.12 d(-1) and production rate 6.27+/-5.26 mg x kg(-1) x d(-1). However, observed (concentration before first apheresis) and predicted steady-state concentrations differed considerably (more than 20%) in 9 of 17 patients, indicating that not all assumptions were fulfilled in all patients. Production rate but not FCR was correlated with Lp(a) plasma concentration (r2 = 0.43, P = 0.004) and molecular weight of apo(a) (r2 = 0.48, P = 0.011), which confirms radiotracer experiments showing that variations in Lp(a) plasma concentrations are due to differences in production not catabolism. When parameters were estimated twice in a subgroup of eight patients, satisfactory reproducibility was observed in six patients. Although parameters determined on two occasions correlated well, only FCR was concordant (intraclass correlation coefficient). Thus, despite the limitations arising from the assumptions implicit to this method, metabolic parameters of Lp(a) can be estimated from the rebound of plasma concentration following apheresis.

Asunto(s)

Hiperlipoproteinemia Tipo II/sangre , Lipoproteína(a)/sangre , Adulto , Anciano , Heterocigoto , Humanos , Hiperlipoproteinemia Tipo II/genética , Cinética , Persona de Mediana Edad

RESUMEN

We describe design and baseline data of the Prevention Education Program (PEP), a home-based and family-oriented intervention program, aimed to assess and improve cardiovascular risk factors in school children and their families during an intervention period of 10 years. Started in 1994 in the German town of Nuremberg, currently 37 elementary schools (22 control and 15 intervention schools) are enrolled including 1740 families (1740 first graders, 3046 parents, and 1521 siblings). Major cardiovascular risk factors as well as dietary behavior are evaluated yearly using structured interview, physical examination, laboratory analysis, and seven-day-dietary protocols. The intervention package is applied to all families from intervention schools using regular home visits, health curricula and group sessions. Primary outcome is any reduction in cardiovascular risk factors by dietary intervention and health education compared to the control group getting only written information on the individual risk profile. The presented baseline data showing a high prevalence of cardiovascular risk factors in adults and in their children underline the need for such an intervention program in Germany.

Asunto(s)

Enfermedades Cardiovasculares/prevención & control , Conductas Relacionadas con la Salud , Educación en Salud/métodos , Prevención Primaria , Servicios de Salud Escolar/organización & administración , Adolescente , Adulto , Niño , Colesterol/sangre , Dieta , Familia , Femenino , Alemania , Humanos , Masculino , Estudios Prospectivos , Factores de Riesgo

Asunto(s)

Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Resistencia a la Insulina/genética , Lípidos de la Membrana/metabolismo , Obesidad/genética , Obesidad/metabolismo , Fosfolípidos/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Transcripción Genética , Adulto , Membrana Celular/metabolismo , Humanos , ARN Mensajero/genética