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Biomedical subjects

R Horn

Publications and source records attributed to R Horn.

At least 37 records · Page 2Linked to original sources
PubMed2000

Free serum leptin but not bound leptin concentrations are elevated in patients with end-stage renal disease.

BACKGROUND: Leptin is a 16-kDa protein that is thought to be a regulator of food intake and body weight. Although total serum leptin levels have been reported to be elevated in obese and normal weight patients with end-stage renal disease (ESRD), it is not known whether serum-free leptin concentrations are also increased in patients with ESRD with no apparent nutritional problems. Furthermore, there are no data on how different dialysis modes (high-flux haemodiafiltration and low-flux dialysis) influence serum leptin subfractions. METHODS: We measured fasting serum free and bound leptin levels in three groups of male subjects: patients on haemodiafiltration with high flux dialysers (n=11), patients on haemodialysis with low-flux dialysers (n=17) and healthy age (61+/-8 years) and BMI (23.8+/-3.1 kg/m(2)) matched control subjects (n=28). Both leptin components were determined before and after a single dialysis session. RESULTS: Body mass indices were correlated with serum free leptin levels in both patients (r=0.69, P<0.001) and controls (r=0.77, P<0.001). Mean (SD) serum free leptin levels were significantly higher in ESRD patients than in control subjects (91+/-33 vs 41+/- 21 pmol/l; P<0.01). Bound leptin levels did not differ in both groups (0.67+/-0.12 vs 0.56+/-0.11 nmol/l, NS). Elevated serum-free leptin levels in ESRD patients could be reduced by haemodiafiltration with high-flux membranes, but not with low-flux haemodialysis membranes. The former led to a reduction of initial serum free leptin values to 76+/-17% (P<0.01), whereas bound leptin remained unaffected. CONCLUSION: Serum-free leptin levels are elevated in ESRD without any apparent effect on body weight. In contrast, serum bound leptin levels remain stable, thus central feedback regulation via the bound form of the hormone may serve as an alternative explanation in the regulation of food intake and energy expenditure in chronic patients on haemodialysis with no apparent nutritional problems.

Body Mass Index↗
PubMed2000

Bone density and metabolism in patients with viral hepatitis and cholestatic liver diseases before and after liver transplantation.

OBJECTIVE: Osteoporosis is frequently found in patients with cholestatic liver disease (primary biliary cirrhosis/primary sclerosing cholangitis) and chronic viral hepatitis. There is limited information about the long-term effect of liver transplantation (OLT) on bone metabolism. The aim of this study was to investigate the effect of liver transplantation on bone metabolism in patients with cholestatic and viral liver diseases. METHODS: We randomly recruited 193 patients with chronic viral hepatitis or cholestatic liver diseases. Bone density (Z-score) and markers of bone metabolism (intact parathyroid hormone [iPTH], PTH 70-84, osteocalcin, procollagen, telopeptide, and vitamin D) were determined before and at time points (< and > 24 months) post-OLT. RESULTS: Before OLT, bone density (Z-score) was decreased in patients with cholestatic (-1) and viral (-0.4) liver diseases. In both groups bone density continued to decrease in the periods up to and more than 24 months after OLT. In the cholestatic group, bone density decreased significantly compared to pre-OLT (p < 0.05) and to the viral hepatitis group (p < 0,001). Markers of bone metabolism showed that after OLT, bone metabolism was enhanced and shifted versus bone resorption. Immunosuppressive drug therapy (glucocorticoids, cyclosporin, FK 506) directly correlated with increased bone metabolism post-OLT. CONCLUSIONS: Bone loss is a long-term problem after OLT, particularly in patients with cholestatic liver diseases. Drug therapy is a main factor of bone loss. Pre- and post-OLT therapy to reduce bone loss is recommended.

Adult↗
PubMed1999

Regional cerebral blood flow single-photon emission tomography with 99mTc-HMPAO and the acetazolamide test in the evaluation of vascular and Alzheimer's dementia.

The diagnostic potential of technetium-99m hexamethylpropylene amine oxime (HMPAO) following systemic administration of the cerebral vasodilator acetazolamide (acetazolamide test) was evaluated by regional cerebral blood flow (rCBF) single-photon emission tomography (SPET) in patients with Alzheimer's disease (AD) or vascular dementia (VD). An initial, high-resolution SPET study was performed with 99mTc-HMPAO, and after 2 days the patients were re-evaluated with 99mTc-HMPAO following systemic administration of acetazolamide. Reconstructed SPET slices were evaluated visually and semiquantitatively by a semi-automatic rCBF map method. When 99mTc-HMPAO alone was used, bilateral hypoperfusion was found in the temporal and/or parietal regions in 33% (6/18) of the VD patients and in 70% (23/33) of the AD patients. The corresponding data obtained by quantitative evaluation were 41% (7/17) and 71% (15/21), respectively. The vascular reserve capacity, as determined with the acetazolamide test, was preserved visually in 22% (4/18) and quantitatively in 29% (5/17) of the VD patients, but in 73% (24/33) and 76% (16/21) of the AD patients. The differences in the perfusion patterns between the VD and AD patients were statistically significant (P<0.01, Fischer's exact test). Of the VD patients with hypoperfusion (bilateral temporal and/or parietal), 4/6 (67%, visual evaluation) and 4/7 (57%, quantitative evaluation) had a decreased vascular reserve capacity as determined with the acetazolamide test. In the AD group of patients the corresponding results were 3/23 (13%) and 4/15 (27%). It is concluded that the acetazolamide test is promising in rCBF SPET to differentiate VD from AD.

Acetazolamide↗
PubMed1999

Relation of free and specifically bound leptin to insulin secretion in patients with impaired glucose tolerance (IGT).

Impaired glucose tolerance (IGT) is frequently associated with an increased fat mass and an altered fat distribution. The adipocyte derived hormone, leptin has been shown to interact with insulin at various levels and may be intimately involved in this process. However, only limited data concerning the interaction of insulin, glucose tolerance and leptin are available and no data exist on the potential influence of bound vs. free circulating leptin. We therefore studied free and bound leptin in 136 patients (77 males, 59 females) with IGT, in relation to plasma glucose, insulin, proinsulin and C-peptide levels as well as serum free and bound leptin concentrations during an oral glucose tolerance test (oGTT). The expected positive relation of free serum leptin levels with body mass index (BMI) was found. Free leptin concentrations were higher in women than in men. Analysis in tertiles revealed a significant relation between free leptin (16-58, 60-160, and 169-932 pmol/l) and mean fasting insulin levels (65, 93, and 100 pmol/l). This relationship remained significant in a multiple regression analysis with BMI and gender as covariates. Similar independent relationships to leptin serum levels were observed for HbA1c and plasma C peptide levels and the proinsulin/insulin ratio but not for plasma glucose and proinsulin levels. These data suggest a fine tuning of leptin by small changes in circulating insulin levels observed in impaired glucose tolerance.

Blood Glucose↗
PubMed1999

Interaction between the pore and a fast gate of the cardiac sodium channel.

Permeant ions affect a fast gating process observed in human cardiac sodium channels (Townsend, C., H.A. Hartmann, and R. Horn. 1997. J. Gen. Physiol. 110:11-21). Removal of extracellular permeant ions causes a reduction of open probability at positive membrane potentials. These results suggest an intimate relationship between the ion-conducting pore and the gates of the channel. We tested this hypothesis by three sets of manipulations designed to affect the binding of cations within the pore: application of intracellular pore blockers, mutagenesis of residues known to contribute to permeation, and chemical modification of a native cysteine residue (C373) near the extracellular mouth of the pore. The coupling between extracellular permeant ions and this fast gating process is abolished both by pore blockers and by a mutation that severely affects selectivity. A more superficial pore mutation or chemical modification of C373 reduces single channel conductance while preserving both selectivity of the pore and the modulatory effects of extracellular cations. Our results demonstrate a modulatory gating role for a region deep within the pore and suggest that the structure of the permeation pathway is largely preserved when a channel is closed.

Algorithms↗
PubMed1999

Free leptin, bound leptin, and soluble leptin receptor in normal and diabetic pregnancies.

We measured serum levels of free leptin, bound leptin, and soluble leptin receptor by specific RIA methods in 20 normal and 19 insulin-dependent diabetes mellitus subjects at 20 and 30 weeks gestation and postpartum, and analyzed the data using hierarchical statistical models. Total leptin levels rise from 20-30 weeks gestation (688 +/- 58 to 785 +/- 62 pmol/L, mean +/- SEM; P = 0.009). There is a significant postpartum fall to 445 +/- 47 pmol/L (P < 0.001). This rise is caused by the rise in the bound leptin levels, as there is no significant change in free leptin levels between 20 and 30 weeks (P = 0.17). There is a significant postpartum fall in free leptin levels (P < 0.001). Insulin requirements rise in the third trimester, but despite this there was no significant difference in free or bound leptin levels between the normal and diabetic subjects at any stage [free leptin, 223 +/- 35 and 266 +/- 24, 237 +/- 45 and 223 +/- 27, and 109 +/- 16 and 104 +/- 24 (P = 0.34); bound leptin, 410 +/- 73 and 428 +/- 54, 501 +/- 78 and 562 +/- 71, and 330 +/- 47 and 271 +/- 46 (P = 0.84); for normals and diabetics at 20 and 30 weeks gestation and postpartum, respectively]. Diabetic subjects, however, had significantly higher soluble leptin receptor levels at all stages (P << 0.001), which rose further in the third trimester from 3742 +/- 268 (mean +/- SEM) to 4134 +/- 239 pmol/L, whereas in the normal group there was a fall from 3149 +/- 169 to 2712 +/- 123 (P = 0.05). There is a linear relationship between the soluble leptin receptor levels and the body mass index in the diabetic group only. We conclude that there is no significant difference in free or bound leptin levels between the normal and insulin-dependent diabetic subjects either during pregnancy or postpartum, but female insulin-dependent diabetic subjects have significantly higher soluble leptin receptor levels. We speculate that high soluble leptin receptor levels might be implicated in the development of the leptin resistance in this group.

Adult↗
PubMed1998

Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans.

Sequential cleavage of the precursor protein pre-pro-opiomelanocortin (POMC) generates the melanocortin peptides adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (MSH) alpha, beta and gamma as well as the opioid-receptor ligand beta-endorphin. While a few cases of isolated ACTH deficiency have been reported (OMIM 201400), an inherited POMC defect has not been described so far. Recent studies in animal models elucidated a central role of alpha-MSH in the regulation of food intake by activation of the brain melanocortin-4-receptor (MC4-R; refs 3-5) and the linkage of human obesity to chromosome 2 in close proximity to the POMC locus, led to the proposal of an association of POMC with human obesity. The dual role of alpha-MSH in regulating food intake and influencing hair pigmentation predicts that the phenotype associated with a defect in POMC function would include obesity, alteration in pigmentation and ACTH deficiency. The observation of these symptoms in two probands prompted us to search for mutations within their POMC genes. Patient 1 was found to be a compound heterozygote for two mutations in exon 3 (G7013T, C7133delta) which interfere with appropriate synthesis of ACTH and alpha-MSH. Patient 2 was homozygous for a mutation in exon 2 (C3804A) which abolishes POMC translation. These findings represent the first examples of a genetic defect within the POMC gene and define a new monogenic endocrine disorder resulting in early-onset obesity, adrenal insufficiency and red hair pigmentation.

Adrenal Insufficiency↗
PubMed1998

Independent versus coupled inactivation in sodium channels. Role of the domain 2 S4 segment.

The voltage sensor of the sodium channel is mainly comprised of four positively charged S4 segments. Depolarization causes an outward movement of S4 segments, and this movement is coupled with opening of the channel. A mutation that substitutes a cysteine for the outermost arginine in the S4 segment of the second domain (D2:R1C) results in a channel with biophysical properties similar to those of wild-type channels. Chemical modification of this cysteine with methanethiosulfonate-ethyltrimethylammonium (MTSET) causes a hyperpolarizing shift of both the peak current-voltage relationship and the kinetics of activation, whereas the time constant of inactivation is not changed substantially. A conventional steady state inactivation protocol surprisingly produces an increase of the peak current at -20 mV when the 300-ms prepulse is depolarized from -190 to -110 mV. Further depolarization reduces the current, as expected for steady state inactivation. Recovery from inactivation in modified channels is also nonmonotonic at voltages more hyperpolarized than -100 mV. At -180 mV, for example, the amplitude of the recovering current is briefly almost twice as large as it was before the channels inactivated. These data can be explained readily if MTSET modification not only shifts the movement of D2/S4 to more hyperpolarized potentials, but also makes the movement sluggish. This behavior allows inactivation to have faster kinetics than activation, as in the HERG potassium channel. Because of the unique properties of the modified mutant, we were able to estimate the voltage dependence and kinetics of the movement of this single S4 segment. The data suggest that movement of modified D2/S4 is a first-order process and that rate constants for outward and inward movement are each exponential functions of membrane potential. Our results show that D2/S4 is intimately involved with activation but plays little role in either inactivation or recovery from inactivation.

Amino Acid Substitution↗
PubMed1998

rCBF SPECT and the acetazolamide test in the evaluation of dementia.

BACKGROUND: The diagnostic potential of 99mTc-HMPAO following systemic administration of the cerebral vasodilator acetazolamide (acetazolamide test) was evaluated using regional-cerebral-blood-flow (rCBF) SPECT in patients with Alzheimer's disease (AD) or with vascular-type of dementia (VD). METHODS: An initial, high-resolution SPELT study was performed with 99mTc-HMPAO, and after 2 days patients were re-evaluated with 99mTc-HMPAO following systemic administration of acetazolamide. Reconstructed SPELT slices were evaluated visually and semiquantitatively by a semiautomatic rCBF map method. RESULTS: Using 99mTc-HMPAO alone, a bilateral hypoperfusion was found in the temporal and/or parietal regions in 33% (6/18) of VD patients and in 70% (23/33) of AD patients. The vascular reserve capacity, as determined with the acetazolamide test, was not impaired in 22% of the VD patients but in 76% of the AD patients. The differences in the perfusion patterns between VD and AD patients were statistically different (p < 0.01, Fischer's exact test). Of the 6 VD patients with hypoperfusion (bilateral temporal and/or parietal), 4 had a decreased vascular reserve capacity as determined in the acetazolamide test. Decreased reserve capacity was found in only 4 out of 25 patients with AD. CONCLUSIONS: The acetazolamide test is helpful in rCBF SPECT to differentiate VD from AD.

Journal Article↗
PubMed1998

[Total illness costs of schizophrenia and monetary evaluation of prevention of recurrence exemplified by a standard depot neuroleptic (flupenthixol decanoate)].

Treatment of patients suffering from schizophrenia is very expensive. However, by consistently and methodically performed medical prophylaxis the disease can be controlled sufficiently well. Regular prophylactic treatment compared to repeated treatment of acute episodes has both medical advantages and reduces cost by reducing the rate of hospitalisation. Prophylactic treatment with Flupentixoldecanoat can save up to 68% of costs.

Adult↗
PubMed1997

Thia fatty acids, metabolism and metabolic effects.

(1) The chemical properties of thia fatty acids are similar to normal fatty acids, but their metabolism (see below: points 2-6) and metabolic effects (see below: points 7-15) differ greatly from these and are dependent upon the position of the sulfur atom. (2) Long-chain thia fatty acids and alkylthioacrylic acids are activated to their CoA esters in endoplasmatic reticulum. (3) 3-Thia fatty acids cannot be beta-oxidized. They are metabolized by extramitochondrial omega-oxidation and sulfur oxidation in the endoplasmatic reticulum followed by peroxisomal beta-oxidation to short sulfoxy dicarboxylic acids. (4) 4-Thia fatty acids are beta-oxidized mainly in mitochondria to alkylthioacryloyl-CoA esters which accumulate and are slowly converted to 2-hydroxy-4-thia acyl-CoA which splits spontaneously to an alkylthiol and malonic acid semialdehyde-CoA ester. The latter presumably is hydrolyzed and metabolized to acetyl-CoA and CO2. (5) Both 3- and 4-thiastearic acid are desaturated to the corresponding thia oleic acids. (6) Long-chain 3- and 4-thia fatty acids are incorporated into phospholipids in vivo, particularly in heart, and in hepatocytes and other cells in culture. (7) Long-chain 3-thia fatty acids change the fatty acid composition of the phospholipids: in heart, the content of n-3 fatty acids increases and n-6 fatty acids decreases. (8) 3-Thia fatty acids increase fatty acid oxidation in liver through inhibition of malonyl-CoA synthesis, activation of CPT I, and induction of CPT-II and enzymes of peroxisomal beta-oxidation. Activation of fatty acid oxidation is the key to the hypolipidemic effect of 3-thia fatty acids. Also other lipid metabolizing enzymes are induced. (9) Fatty acid- and cholesterol synthesis is inhibited in hepatocytes. (10) The nuclear receptors PPAR alpha and RXR alpha are induced by 3-thia fatty acids. (11) The induction of enzymes and of PPAR alpha and RXR alpha are increased by dexamethasone and counteracted by insulin. (12) 4-Thia fatty acids inhibit fatty acid oxidation and induce fatty liver in vivo. The inhibition presumably is explained by accumulation of alkylthioacryloyl-CoA in the mitochondria. This metabolite is a strong inhibitor of CPT-II. (13) Alkylthioacrylic acids inhibits both fatty acid oxidation and esterification. Inhibition of esterification presumably follows accumulation of extramitochondrial alkylthioacryloyl-CoA, an inhibitor of microsomal glycerophosphate acyltransferase. (14) 9-Thia stearate is a strong inhibitor of the delta 9-desaturase in liver and 10-thia stearate of dihydrosterculic acid synthesis in trypanosomes. (15) Some attempts to develop thia fatty acids as drugs are also reviewed.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed1997

Rey Auditory-Verbal Learning Test: structure of a modified German version.

The Auditory Verbal Learning Test (AVLT) is widely used in scientific research as well as in clinical practice. But there exists little research on the structure of the AVLT. We investigated the structure of a German version of the AVLT and VLMT, in 232 patients of a psychiatric clinic and in 872 patients of an epileptologic clinic. First we stated a theoretical LISREL model relating the observed variables of the VLMT to short-term memory (STM) and long-term memory (LTM) as latent variables. Then we estimated the postulated LISREL model in the two samples. The proposed model showed excellent fit in both samples, and there were no significant deviations between the estimated and the observed covariance matrices. Thus, STM and LTM suffice to explain the structure of the VLMT, and the proposed structural equations model can be used to estimate STM and LTM capacity from VLMT data.

Adult↗
PubMed1997

A liquid mixed meal or exogenous glucagon-like peptide 1 (GLP-1) do not alter plasma leptin concentrations in healthy volunteers.

Glucagon-like peptide 1 [7-36 amide] (GLP-1) and the obese gene product (leptin) are thought to be involved in the central regulation of feeding. Both may act from the peripheral circulation to influence brain function. To study potential interactions, GLP-1 ([7-36 amide]: 0.4, 0.8 pmol kg-1 min-1 or placebo on separate occasions) was infused intravenously (from -30 to 240 min) into nine healthy volunteers [age 26 +/- 3 years, body mass index: 22.9 +/- 1.6 kg/m2, glycated haemoglobin HbA1c: 5.0% +/- 0.2% (normal: 4.0%-6.2%), creatinine: 1.1 +/- 0.1 mg/dl], and (at 0 min) a liquid test meal (50 g sucrose in 400 ml 8% amino acid, total amino acids 80 g/l) was administered via a nasogastric tube. Plasma leptin (radioimmunoassay, RIA), glucose, insulin (microparticle enzyme immunoassay), C-peptide (enzyme-linked immunosorbent assay) and GLP-1 (RIA) were measured, and statistical analysis was done with repeated-measures ANOVA and Student's t-test. Plasma leptin concentrations were 31 +/- 6 pmol/l in the basal state. They did not change within 240 min after meal ingestion nor in response to the infusion of exogenous GLP-1 [7-36 amide] (P = 0.99 for the interaction of experiment and time) leading to GLP-1 mean plasma levels of 25 +/- 2 and 36 +/- 3 (basal 6 +/- 1) pmol/l. On the other hand, glucose (from basal 4.7 +/- 0.1 to 6.0 +/- 0.2 mmol/l at 15 min, P < 0.05) and insulin (from basal 28 +/- 2 to 325 +/- 78 pmol/l at 45 min, P < 0.05) increased clearly after the meal with placebo. In conclusion, (1) plasma leptin levels in normal human subjects show no short-term changes after feeding a liquid mixed meal and (2) do not appear to be directly influenced by physiological and pharmacological elevations in plasma GLP-1 [7-36 amide] concentrations. This does not exclude interactions at the cerebral (hypothalamic) level or on more long-term temporal scales.

Adult↗
PubMed1997

Probing the outer vestibule of a sodium channel voltage sensor.

The second and third basic residues of the S4 segment of domain 4 (D4:R2 and D4:R3) of the human skeletal muscle Na+ channel are known to be translocated from a cytoplasmic to an extracellular position during depolarization. Accessibilities of individual S4 residues were assayed by alteration of inactivation kinetics during modification of cysteine mutants by hydrophilic methanethiosulfonate reagents. The voltage dependences of the reaction rates are identical for extracellular application of cationic methanethiosulfonate-ethyltrimethylammonium (MTSET) and anionic methanethiosulfonate-ethylsulfonate (MTSES), suggesting that D4:R3C is situated outside the membrane electric field at depolarized voltages. The absolute rate of R3C modification is 281-fold greater for MTSET than for MTSES, however, suggesting that at depolarized voltages this S4 thiol resides in a negatively charged hydrophilic crevice. The two hydrophobic residues between D4:R2C and D4:R3C in the primary sequence (L1452 and A1453) are not externally exposed at any voltage. An alpha-helical representation of D4/S4 shows that the basic residues D4:R2 and D4:R3 are on the face opposite that of L1452 and A1453. We propose that in the depolarized conformation, the hydrophobic face of this portion of D4/S4 remains in contact with a hydrophobic region of the extracellular vestibule of the S4 channel.

Alkanesulfonates↗