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Biomedical subjects

B Kohl

Publications and source records attributed to B Kohl.

At least 19 recordsLinked to original sources

Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model.

Although hyperhomocysteinemia (HHcy) is a well-known risk factor for the development of cardiovascular disease, the underlying molecular mechanisms are not fully elucidated. Here we show that induction of HHcy in apoE-null mice by a diet enriched in methionine but depleted in folate and vitamins B6 and B12 increased atherosclerotic lesion area and complexity, and enhanced expression of receptor for advanced glycation end products (RAGE), VCAM-1, tissue factor, and MMP-9 in the vasculature. These homocysteine-mediated (HC-mediated) effects were significantly suppressed, in parallel with decreased levels of plasma HC, upon dietary supplementation with folate and vitamins B6/B12. These findings implicate HHcy in atherosclerotic plaque progression and stability, and they suggest that dietary enrichment in vitamins essential for the metabolism of HC may impart protective effects in the vasculature.

Animals↗

Elevated plasma concentrations of lipoprotein(a) in medicated epileptic patients.

Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for vascular diseases. There are no data on Lp(a) levels in patients on long-term medication with carbamazepine, phenytoin, phenobarbital, or valproate. To investigate the effects of such treatment on Lp(a) levels and common carotid artery intima media thickness we studied 51 epileptic outpatients on long-term antiepileptic medication and 51 age-and sex-matched controls. Lp(a) levels above 45 mg/dl were found in 11 of 50 patients, but in only 4 of 51 controls (P < 0.05). The mean serum concentration of Lp(a) was 33.0+/-7.0 mg/dl in patients and 16.9+/-2.7 mg/dl in controls (P < 0.05). Epileptic patients also had a thicker intima media of the common carotid artery (0.79+/-0.04 mm) than controls (0.69+/-0.02 mm, P < 0.05) as measured by B-mode ultrasonography. Our results suggest an untoward effect of long-term antiepileptic medication on Lp(a) serum concentrations. Elevated Lp(a) levels might be a risk factor for arteriosclerosis in epileptic patients.

Adult↗

Probucol for treatment of hyperlipidemia in persistent childhood nephrotic syndrome. Report of a prospective uncontrolled multicenter study.

In a prospective, uncontrolled multicenter study, we have evaluated the effects of probucol on hyperlipidemia, proteinuria, and glomerular filtration rate (GFR) in hyperlipidemic children with persistent nephrotic syndrome. Probucol was started for a total of 12 weeks in 8 children and for 24 weeks in 14 children. Lipoprotein profiles, serum malondialdehyde (MDA) levels, proteinuria, renal function, and electrocardiogram were monitored every 4 weeks. Side effects were recorded by questionnaire. Treatment was completed by 7 of 8 patients for 12 weeks and by 7 of 14 children for 24 weeks. After 12 weeks, the mean serum concentrations of triglycerides (-15%), total cholesterol (-25%), very low-density lipoprotein-cholesterol (-27%), low-density lipoprotein-cholesterol (-23%), and high-density lipoprotein-cholesterol (-24%), as well as apolipoprotein (apo) A-I (-19%), apo B (-21%), and MDA (-32%) were reduced. The positive effects of probucol on the lipoprotein profile persisted over 24 weeks; however, there was no significant effect on either proteinuria or GFR. In conclusion, probucol had beneficial effects on lipoproteins and lipid peroxidation, but improved neither proteinuria nor GFR. The drug was generally tolerated well, but had to be discontinued because of a prolonged QT interval in 4 of 22 patients.

Adolescent↗

Elevated plasma concentrations of homocysteine in antiepileptic drug treatment.

PURPOSE: Homocysteine is an experimental convulsant and an established risk factor in atherosclerosis. A nutritional deficiency of vitamin B6, vitamin B12, or folate leads to increased homocysteine plasma concentrations. During treatment with carbamazepine (CBZ), phenytoin, or phenobarbital, a deficiency in these vitamins is common. The objective of the study was to test the hypothesis that antiepileptic drug (AED) treatment is associated with increased homocysteine plasma concentrations. METHODS: A total of 51 consecutive outpatients of our epilepsy clinic receiving stable, individually adjusted AED treatment and 51 sex- and age-matched controls were enrolled in the study. Concentrations of total homocysteine and vitamin B6 were measured in plasma; vitamin B12 and folate were measured in the serum of fasted subjects. RESULTS: Patients and controls differed significantly in concentrations of folate ( 13.5+/-1.0 vs. 17.4+/-0.8 nM and vitamin B6 (39.7+/-3.4 vs. 66.2+/-7.5 nM), whereas serum concentrations of vitamin B12 were similar. The homocysteine plasma concentration was significantly increased to 14.7+/-3.0 microM in patients compared with controls (9.5+/-0.5 microM; p < 0.05, Wilcoxon rank-sum test). The number of patients with concentrations of >15 microM was significantly higher in the patient group than among controls. The same result was obtained if only patients with CBZ monotherapy were included. Patients with increased homocysteine plasma concentrations had lower folate concentrations. CONCLUSIONS: These data support the hypothesis that prolonged AED treatment may increase plasma concentrations of homocysteine, although the alternative explanation that increased homocysteine plasma concentrations are associated with the disease and not the treatment cannot be completely excluded at the moment.

Age Factors↗

Translated anti-sense product of the Na/phosphate co-transporter (NaPi-II).

The homeostasis of Pi in marine teleosts is maintained by renal Pi secretion as well as by Pi reabsorption. A Na/Pi co-transport system belonging to the NaPi-II protein family is instrumental in tightly controlled renal Pi handling in mammals and fish. We have isolated an NaPi-II related cDNA from winter flounder. It was cloned from a female gonad cDNA library and is 624 bp long. The transcript is expressed in female and male flounder gonads as well as in kidney and intestine, although at very low levels. RNase H digestion experiments revealed an opposite orientation of the transcript with regard to NaPi-II-related mRNA. The anti-sense orientation was confirmed by genomic sequence analysis and Southern blotting. Alluding to the sense transcript, the anti-sense transcript was denoted IPAN. The open reading frame of IPAN encodes a basic protein of 68 amino acid residues. Immunohistochemistry confined the anti-sense related protein, Ipan, to a submembranous compartment of immature oocytes, suggesting a role in oocyte development. In kidney and intestine Ipan is partly co-localized with the Na/Pi co-transporter, implying a regulatory function for the anti-sense protein. However, direct protein-protein interaction could not be established. The existence of a putative open reading frame in other species extends the biological significance of the novel protein.

Amino Acid Sequence↗

The Na+-phosphate cotransport system (NaPi-II) with a cleaved protein backbone: implications on function and membrane insertion.

1. Renal handling of inorganic phosphate (Pi) involves a Na+-Pi cotransport system which is well conserved between vertebrates. The members of this protein family, denoted NaPi-II, share a topology with, it is thought, eight transmembrane domains. The transporter is proposed to be proteolytically cleaved within a large hydrophilic loop in vivo. 2. The consequences of an interrupted backbone were tested by constructing cDNA clones encoding different N- (1-3 and 1-5) and C-terminal (4-8 and 6-8) complementary fragments of NaPi-II from winter flounder. When the cognate fragments were used in combination (1-3 plus 4-8; 1-5 plus 6-8) they comprised the full complement of the putative transporter domains. 3. None of the four individual fragments or the 1-5 plus 6-8 combination when expressed in Xenopus oocytes increased Pi flux. Coexpression of fragments 1-3 plus 4-8 stimulated transport activity identical to that for expressed wild-type NaPi-II with regard to pH dependency and Km for Na+ and Pi binding; however, the maximal transport rate (vmax) was lower. 4. Immunohistochemistry on cryosections confined the functionally active 1-3 plus 4-8 combination to the oocyte membrane. This was not the case for the 1-5 plus 6-8 combination or any of the individual fragments, all of which failed to induce fluorescence. 5. A second immunohistochemical approach using intact oocytes allowed determination of the extracellular regions of the protein. Epitopes within the loop between transmembrane domains 3 and 4 enhanced fluorescence. Neither N- nor C-terminal tags induced fluorescence.

Animals↗

Are psychoactive-drug-induced changes in plasma lipid and lipoprotein levels of significance for clinical remission in psychiatric disorders?

In the present pilot study, our aim was to investigate whether associations could be demonstrated in psychiatric patients between the changes in plasma lipid and lipoprotein levels expected during treatment with psychoactive drugs and the changes in the patients' depressive and hostile behavior. One hundred and fourteen patients with various psychiatric disorders (depressive episode in bipolar affective disorder, depressive episode or recurrent depressive disorder, paranoid schizophrenia, and schizoaffective disorders) were included in the study. The following examinations were carried out in each patient on admission and at discharge: (1) the plasma lipid parameters total cholesterol (TC), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), high-density lipoprotein (HDL), and triglycerides (TRI) were determined, and (2) the psychopathological features were recorded employing the AMDP system and the AMDP Syndrome Scales. Within the context of a naturalistic clinical setting with a choice of psychoactive drugs available, patients were subdivided at the end of treatment into eight treatment groups, as follows: group 1, treatment with butyrophenones; group 2, treatment with tricyclics; group 3, treatment with butyrophenones and tricyclics; group 4, treatment with butyrophenones, tricyclics and selective serotonin reuptake inhibitors; group 5, treatment with butyrophenones and lithium; group 6, treatment with tricyclics and lithium; group 7, treatment with butyrophenones, tricyclics and lithium; and group 8, treatment with butyrophenones, tricyclics, selective serotonin reuptake inhibitors and lithium. To compare the changes in the eight treatment groups, mixed general linear models including diagnosis, gender, age, body mass index changes, and baseline values were applied using proc GLM of SAS. Butyrophenones induce an increase in TC, LDL, and TC/TRI ratio, whereas tricyclics lead to an increase in TC, LDL, VLDL, and TRI. In combined medication of butyrophenones and tricyclics the effects of tricyclics predominate. Comedication of lithium inhibits the increase in TC and LDL induced by butyrophenones and/or tricyclics. Treatment groups with lipid changes of the same type (decrease, no change, or increase) were combined in "lipid change groups". Analyses of variance or covariance (with psychopathological admission value as covariate where there were significant differences in psychopathological admission mean values between the groups) of these lipid change groups with regard to the changes in the Depressive Syndrome Scale and the Hostility Syndrome Scale gave results which are interpreted as follows: an increase in TC or LDL inhibits the remission of hostility, whereas an increase in TRI with concomitant decrease in TC, or else a relatively greater increase in TRI than in TC promotes the remission of hostility. A decrease in TRI or VLDL promotes the remission of depression. Our data and findings published in the literature may suggest that systemic changes in plasma lipid parameters, at the cellular level, induce changes in the fluidity of brain cell membranes. We hypothesize that an increase in plasma TC or LDL and/or a decrease in plasma TRI or VLDL may induce a relative decrease in brain cell membrane fluidity with decreased presynaptic serotonin reuptake and increased postsynaptic serotonin function. This proposed increase in brain serotonin function would finally result in an anti-depressive, aggression-promoting effect. Conversely, a decrease in plasma TC or LDL and/or an increase in plasma TRI or VLDL may induce a relative increase in brain cell membrane fluidity with increased presynaptic serotonin reuptake and decreased postsynaptic serotonin function. This proposed decrease in brain serotonin function would result in an anti-aggressive, depression-promoting effect.

Adult↗

Na-P(i) cotransport sites in proximal tubule and collecting tubule of winter flounder (Pleuronectes americanus).

Localization of a recently described and cloned Na-Pi cotransport system from flounder was investigated by reverse transcription-polymerase chain reaction (RT-PCR) of microdissected tubules and by immunocytochemistry of kidney of winter flounder. Histological examination showed a small glomerulus, an extremely short proximal tubule PI with a selective affinity to Lens culinaris agglutinin from lentils, and an extensive second proximal tubule segment PII (> 90% of proximal tubules), consisting of cells with numerous apical clear vesicles and extensive amplification of basolateral cell membranes. PII merged with the collecting tubule/ collecting duct (CT/CD) system without a distal segment. By RT-PCR, PII cells revealed high levels of NaPi-II related RNA; low levels were also observed in CTs. Previously characterized antisera against different epitopes of flounder NaPi-II specifically labeled the basolateral regions of PII and the apical cell portion of CT/CD cells and of some PII cells. These results suggest that tubular secretion of P(i) occurs in PII of teleost fish with modulation of urinary P(i) content in the subsequent CT/CD system.

Animals↗

Hyperhomocyst(e)inemia and endothelial dysfunction in IDDM.

OBJECTIVE: Considering that elevated blood levels of homocyst(e)ine represent a known independent risk factor for macrovascular disease, we assessed the link between hyperhomocyst(e)inemia and diabetic microvascular complications. RESEARCH DESIGN AND METHODS: Homocyst(e)ine and thrombomodulin plasma levels, a marker of endothelial cell damage, were measured before and 3 h after oral methionine loading in 75 patients with stable, well-controlled IDDM and 40 healthy control subjects matched for sex and age. Exclusion criteria were hyperlipidemia, hypertension, smoking, or positive family history for cardiovascular disease. RESULTS: IDDM patients had higher pre- and postload homocyst(e)ine plasma levels than did healthy control subjects (12.0 vs. 7.7 mumol/l and 27.6 vs. 16.0 mumol/l; P < 0.001). Of 75 IDDM patients, 26 had homocyst(e)ine plasma levels above the normal range (defined as mean +2 SD of values obtained in the control group). The IDDM patients with hyperhomocyst(e)inemia had higher thrombomodulin plasma levels (62.2 vs. 38.2 ng/ml; P < 0.001), higher albumin excretion rates (485 vs. 115 mg/l; P < 0.005), and a higher prevalence of late diabetic complications (nephropathy, 76 vs. 33%; retinopathy, 69 vs. 51%; neuropathy, 57 vs. 41%; macroangiopathy, 57 vs. 33%) compared with IDDM patients with normal plasma homocyst(e)ine. In vitro experiments with human umbilical vein cells show an increased release of thrombomodulin into the culture supernatant only when endothelial cells were pretreated with advanced glycation end product (AGE)-albumin before L-homocystine was added. A synergistic action of homocyst(e)ine and AGEs might contribute to vascular complications of patients with diabetes. CONCLUSIONS: Hyperhomocyst(e)inemia is common in nephropathic diabetic patients and may contribute to the enhanced morbidity and mortality from cardiovascular diseases characteristically observed in IDDM patients with diabetic nephropathy.

Adult↗

From peptide to non-peptide. 3. Atropisomeric GPIIbIIIa antagonists containing the 3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione nucleus.

The benzodiazepinedione class of non-peptidal GPIIbIIIa antagonists has been modified to allow the isolation of noninterconverting rotational isomers, or atropisomers, with the aim of examining their structure-activity relationships as compared to active RGD-containing peptides and other non-peptidal antagonists. Resolution of these antagonists was accomplished by the introduction of a tert-butyl group at N1 and a chlorine at C9 on the 3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione nucleus and enantiospecific substitution on the beta-alanine side chain attached to N4. The relative configuration was determined by single-crystal X-ray analysis. Further, conformational analyses using ab initio calculations were performed to assess the conformational preferences about the beta-alanine side chain. The data support a good topographical correlation between the benzodiazepinedione class of antagonists and the "cupped" presentation of the RGD tripeptide sequence found in the cyclic peptide G4120. The relationship between these compounds with other peptidal and non-peptidal antagonists is discussed.

Benzodiazepinones↗

Hyperhomocyst(e)inemia and endothelial dysfunction in IDDM.

OBJECTIVE: While elevated blood levels of homocyst(e)ine represent an independent risk factor for macrovascular disease, we assessed the link between hyperhomocyst(e)inemia and diabetic microvascular diseases. RESEARCH DESIGN AND METHODS: Plasma levels of homocyst(e)ine and thrombomodulin (TM), markers of endothelial cell damage, were measured before and 3 h after oral methionine loading in 75 patients with IDDM and 40 healthy control subjects matched for sex and age. Exclusion criteria were hyperlipidemia, hypertension, smoking, or positive family history for cardiovascular disease. RESULTS: IDDM patients had higher pre- and postload plasma levels of homocyst(e)ine than did healthy control subjects (12.0 vs. 7.7 mumol/l and 27.6 vs. 16.0 mumol/l; P < 0.001). Of 75 IDDM patients, 26 had plasma homocyst(e)ine levels above the normal range (means +/- 2 SD of values obtained in the control group). These IDDM patients with hyperhomocyst(e)inemia had higher plasma TM levels (62.2 vs. 38.2 ng/ml, P < 0.001), higher albumin excretion rates (485 vs. 115 mg/l, P < 0.005), and a higher prevalence of late diabetic complications (nephropathy, 76 vs. 33%; retinopathy, 69 vs. 51%; neuropathy, 57 vs. 41%; and macroangiopathy, 57 vs. 33%) compared with IDDM patients with normal plasma homocyst(e)ine. In vitro experiments with human umbilical vein cells showed an increased release of TM into the culture supernatant only when endothelial cells were pretreated with advanced glycation end product (AGE)-albumin before L-homocystine was added. A synergistic action of homocyst(e)ine and AGEs might contribute to vascular complications in patients with diabetes. CONCLUSIONS: Hyperhomocyst(e)inemia is common in nephropathic diabetic patients and may contribute to the enhanced morbidity and mortality from cardiovascular diseases characteristically observed in IDDM patients with diabetic nephropathy.

Administration, Oral↗

Glucocorticoids decrease the production of parathyroid hormone-related protein in vitro but not in vivo in the Walker carcinosarcoma 256 rat model.

In 50-90% of cases, humoral hypercalcemia of malignancy (HHM) is due to tumor secretion of parathyroid hormone-related protein (PTHrP). Glucocorticoids are sometimes used as calcium lowering agents and there are in vitro results showing that glucocorticoids diminish PTHrP production. In this study we tested whether the serum-calcium-lowering effect of glucocorticoids is due to decreased PTHrP production by the tumor. As an animal and cell culture model we used the Walker carcinosarcoma (WCS) 256, a rat mammary carcinoma cell line producing PTHrP. In vitro, dexamethasone caused a dose-dependent inhibition of PTHrP production, whereby already 1-5 nmol/L revealed a significant decrease by WCS 256 cells. In contrast to these in vitro results, in WCS 256 tumor-bearing rats, dexamethasone (4 mg/kg body weight on day 4, and 1 mg/kg body weight from day 5 until day 7 after WCS transplantation; circulating dexamethasone levels > 20 nmol/L) did not decrease PTHrP production, PTHrP secretion, serum calcium, or tumor weight in vivo. We conclude that, in this PTHrP-mediated model of humoral hypercalcemia of malignancy, glucocorticoids do not decrease PTHrP production and secretion in vivo and do not show a calcium-lowering effect.

Analysis of Variance↗

Na-Pi cotransport in flounder: same transport system in kidney and intestine.

The cloning of a renal Na-Pi contransport in system from winter flounder (P eudopleuronectes americanus) has recently been reported. We used this information to answer the questions 1) what is the distribution of the transport protein along the nephron? and 2) how are renal and intestinal transporters related? The distribution of the flounder NaPi-II protein was tested using two antisera raised against partial sequences (amino acids 1-14 and 388-441) of the transporter. Antibody-specific fluorescence was detected at the basolateral membrane of epithelial cells in the proximal tubular segment PII. Two clones corresponding to the renal Na-Pi cotransporter were isolated from a flounder intestinal cDNA library. Their functional properties were determined using Xenopus laevis oocytes. The apparent affinities for Pi [Michaelis constant (K(m)) = 0.063 mM] and Na (K(m) = 45.3 mM), as well as the pH dependency (increasing transport activity with increasing pH), showed the same characteristics in both intestinal and the renal systems. Sequence analysis revealed that the two intestinal clones were 100% homologous to the renal cDNA, Flounder NaPi-II-specific immunofluorescence was observed predominantly at the apical membrane on intestinal cross sections. We report the cloning and expression of the first intestinal Na-Pi cotransport system. This transporter belongs to the small group of proteins that exhibit the same function in the apical and the basolateral membranes of different cells.

Amino Acid Sequence↗

Review article: the continuing development of proton pump inhibitors with particular reference to pantoprazole.

Inhibition of the gastric proton pump is gaining acceptance as the treatment of choice for severe gastrooesophageal reflux disease, and for treatment of duodenal and gastric ulceration. Three of these drugs are now available (omeprazole, lansoprazole and pantoprazole) and more are being developed. Proton pump inhibitors share the same core structure, but differ in terms of substituents on this core. The substitutions are able to modify some important chemical properties of the compounds. For example, pantoprazole is significantly more acid-stable than omeprazole or lansoprazole. E3810 is significantly less stable than the other compounds. We present an explantation for this finding that depends on the relative pK values for the pyridine and benzimidazole nitrogens, especially the former. Pantoprazole formulated in an enteric-coated tablet displays high bioavailability and linear pharmacokinetics whether on single or multiple dose regimens. Although all three proton pump inhibitors provide a similar chemical conversion to sulphenamides, which are highly reactive cysteine reagents, these reagents derivatize different cysteines in the extracytoplasmic or membrane domain of the pump and inhibit the pump at different rates. Whereas the differences in chemical reactivity can be explained by the solution chemistry of the compounds, selective derivatization of different cysteines on the protein argues for an involvement of pump structure in response to the presence of the proton pump inhibitor on its luminal surface. This suggests that the proton pump inhibitors, which were originally designed to take advantage of only the highly acidic space generated in the parietal cell by the production of the sulphenamide, are made even more selective by the protein they target. Pantoprazole is metabolized by a combination of phase I and phase II metabolism, and has also been shown to have a very low potential for drug interaction. Studies of acid secretion in man have shown this compound to be an effective and long lasting inhibitor of acid secretion. The pharmacodynamics explain the cumulative effect of repeated doses and maximal acid secretory capacity with a once daily dosage.

2-Pyridinylmethylsulfinylbenzimidazoles↗

The effect of dietary salt on insulin sensitivity.

Acute reduction of salt intake causes an increase in serum lipid and insulin levels in healthy volunteers and patients with essential hypertension, suggesting induction of insulin resistance by salt restriction. Direct measurements of insulin sensitivity using the euglycaemic clamp showed no significant change after 7 days of salt restriction. Our previous study showed a time dependent course of dyslipidaemia after institution of a low salt diet. We therefore assessed insulin sensitivity (M-value) under euglycaemic conditions (clamp technique) at discrete time points using a parallel group design. Two groups of healthy males were examined on high (200 mmol d-1) and low (20 mmol d-1) salt intake. One group (n = 7, 25 +/- 3 years, BMI 22.4 +/- 2.1 kg m-2) received high and low salt diet in random order each for 7 days. The other group (n = 7, 26 +/- 3 years, 22.1 +/- 1.9 kg m-2) received the respective diet in random order for 3 days. A significantly (P < 0.01) different mean M-value was noted in the group receiving the diets for 3 days, i.e. after low salt intake it was 7.4 +/- 1.2 mg kg-1 min-1 and after high salt intake 8.6 +/- 1.1 mg kg-1 min-1. In contrast, the mean M-value was similar after low and high salt periods in the group of individuals who had been studied after 7 days on either salt take (7.8 +/- 1.8 on low salt vs. 7.6 +/- 1.3 mg kg-1 min-1 on high salt).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Porphyrinogenic effects of atracurium, vecuronium, and pancuronium in a primed rat model.

Steroidal muscle relaxants might theoretically be contraindicated in acute hepatic porphyrias. Atracurium, on the other hand, has been proposed as the muscle relaxant of choice because of its extrahepatic degradation. To further investigate this problem, equipotent doses of atracurium, vecuronium, and pancuronium were determined in male Sprague Dawley rats, using evoked electromyography. After this pilot study, 64 rats were anesthetized, mechanically ventilated, and randomly allocated to eight groups. Animals in groups 1 through 4 received an intraperitoneal injection of arachis-oil 20 h before the experiments. For groups 5 through 8, an experimental porphyria was induced by use of the chemical substance 3,5-dicarbethoxy-1,4-dihydrocollidine (DDC), which was dissolved in arachis-oil and given 20 h prior to the beginning of the study. Rats of groups 1 and 5 served as controls; they received saline and were not given muscle relaxants throughout the experiment. For groups 2 and 6, atracurium was administered at a dosage of 4 mg/kg of body weight, followed by a continuous infusion of 15 mg/kg/h. Animals of groups 3 and 7 received vecuronium at a dosage of 1.5 mg/kg, followed by 7.5 mg/kg/h. For groups 4 and 8, pancuronium was given (0.75 mg/kg and 2.5 mg/kg/h, respectively). At the end of the 3-h study period, the liver was perfused and excised, and urine was obtained. Activity of the hepatic enzyme delta-aminolevulinic acid synthase (ALAS) and urinary concentrations of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) were determined.(ABSTRACT TRUNCATED AT 250 WORDS)

5-Aminolevulinate Synthetase↗

[Diagnostic significance of parathyroid hormone-related protein in tumor patients with hypercalcemia].

The clinical utility of measuring parathormone-related protein (PTHrP) was investigated in 94 patients (48 men, 46 women, mean age 56 [18-82] years) with tumour-associated hypercalcaemia, using a radioimmunoassay directed against the middle portion (53-84) of PTHrP (reference range < 5-21 pmol/l). Increased levels of the middle portion of PTHrP were found in 44 of the 73 patients (60%) with hypercalcaemia associated with solid tumours (median 49 [22-333] pmol/l). There was a positive correlation between the serum calcium concentration and the PTHrP (P = 0.018). The frequency of a raised PTHrP, indicating hormone-induced hypercalcaemia, was similar in patients with and without bone metastases (48% vs 66%). Elevated PTHrP was particularly frequent in patients with squamous cell carcinomas (17 out of 21; 81%), while PTHrP levels were normal in 18 out of the 21 patients with hypercalcaemia associated with haematological malignancies. PTHrP levels were normal in 37 out of 38 normocalcaemic tumour patients and in 30 out of 32 patients with primary hyperparathyroidism. Hypercalcaemia associated with benign disease was found in only one case, a female with marked benign breast hypertrophy.--The measurement of PTHrP allows the demonstration of a pathogenetic factor in tumour-associated hypercalcaemia, and differentiation from other causes of hypercalcaemia, in particular primary hyperparathyroidism.

Adolescent↗

Clinical features of type III hyperlipoproteinemia: analysis of 64 patients.

The clinical and biochemical characteristics of type III hyperlipoproteinemia are described in 64 patients (35 males and 29 females). Homozygosity for apolipoprotein E2, the presence of an abnormally cholesterol-rich very low density lipoprotein fraction (beta-VLDL) and an elevated ratio of very low density lipoprotein cholesterol to plasma triglycerides (> 0.3; normal ratio about 0.2) were the basis for the diagnosis. Mean serum cholesterol and triglyceride concentrations at the first visit in the clinic were 426 +/- 221 and 719 +/- 996 mg/dl, respectively. The mean age at diagnosis of the disorder was 49 years in males and 53 years in females. There was a high prevalence of obesity (72%), xanthomas (42%), and atherosclerosis (39%), especially peripheral vascular disease (31%). Early and correct diagnosis of this familial lipoprotein disorder seems necessary because of the prompt and beneficial response to therapeutic interventions.

Adult↗