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Biomedical subjects

K Jacob

Publications and source records attributed to K Jacob.

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

Erythrocyte protoporphyrins in hepatitis C viral infection.

OBJECTIVES: Protoporphyrin is the immediate precursor of the heme molecule. Due to a spillover from hemaotopoietic tissue it is regularly found in small amounts in erythrocytes and excreted into the bile. In hereditary erythropoietic protoporphyria excess protoporphyrin accumulates and can cause severe liver damage both by crystallization and induction of oxidative stress. The aim of this investigation was to study protoporphyrin concentrations in other liver disorders. DESIGN AND METHODS: Erythrocyte protoporphyrin and zinc protoporphyrin concentrations were studied in 50 patients with chronic hepatitis C infection and various degrees of liver damage. High-performance liquid chromatographic analysis with fluorescence detection was used. RESULTS: Erythrocyte protoporphyrin was increased in 32% of the patients studied; in 12 patients up to two-fold higher than the maximum of the reference range, in 4 up to three-fold higher (median concentration 98 nmol/L, interquartile range 68-142; maximum 379 nmol/L (reference range: <125 nmol/L)). In 6 of the 10 patients in the subgroup with signs of severe liver dysfunction (decreased serum albumin and prolonged thromboplastin time, elevated serum bilirubin), protoporphyrin was elevated. Erythrocyte zinc protoporphyrin was increased in 7 cases out of all 50 studied; in these seven cases, erythrocyte protoporphyrin was also elevated (median concentration of zinc protoporphyrin in the whole study group: 232 nmol/L, interquartile range 182-342; maximum 827 nmol/L (reference range <464 nmol/L). CONCLUSIONS: Elevated erythrocyte protoporphrin levels are frequently found in patients with advanced chronic hepatitis C infection. Because protoporphyrin is well known to be hepatotoxic, these findings warrant further investigation.

Adult↗
PubMed1999

Osteonectin promotes prostate cancer cell migration and invasion: a possible mechanism for metastasis to bone.

The mechanism underlying the "organ-specific" metastasis of prostate cancer cells to the bone is still poorly understood. It is not clear whether the cells only invade the bone and proliferate there or whether they invade many tissues but survive mainly in the bone ("seed and soil"). Extracts from various organs were used as chemoattractants in the in vitro chemotaxis and invasion assays. Results show that, in comparison with extracts of other tissues, bone extracts promote a 2- to 4-fold increase in chemotaxis by human prostate epithelial cells and a 4-fold increase in the invasive ability of human prostate carcinoma cells. The purified active factor from bone and from marrow stromal-cell-conditioned medium is a low glycosylated osteonectin that specifically promotes the invasive ability of bone-metastasizing prostate (and breast) cancer cells but not that of non-bone-metastasizing tumor cells. It does not stimulate the growth of prostate cancer cells in vitro or in vivo. Because osteonectin specifically enhances matrix metalloprotease activity in prostate and breast cancer cells (and not in other tumor cell types), we conclude that prostate cancer cell metastasis to the bone is, in part, mediated by the ability of osteonectin to promote migration, protease activity, and invasion.

Bone Neoplasms↗
PubMed1999

Studies on coproporphyrin isomers in urine and feces in the porphyrias.

The urinary and fecal distribution and the relative proportions of the four coproporphyrin (copro) isomers I-IV were analysed in 20 healthy subjects and in patients suffering from one of the seven common types of hepatic or erythropoietic hereditary porphyrias. The ratios of copro isomers I-IV were analyzed by ion-pair high-performance liquid chromatography (HPLC). Observations showed significantly increased proportions of fecal copro isomer I and decreased proportions of copro isomers III, II and IV in erythropoietic porphyrias. In acute hepatic porphyrias the excretion of fecal copro isomer III is dominant (isomer III = 58.4+/-24.0%; x+/-S.D.) and significantly higher (P < 0.001) than in erythropoietic porphyrias (isomer III = 15.3+/-7.7%; x+/-S.D.) and chronic hepatic porphyrias (isomer III = 25.8+/-7.6%; x+/-S.D.). The increased proportions of fecal copro isomer III proved to be important for the diagnosis of hereditary coproporphyria and porphyria variegata independent of the clinical phase existing. These last two acute hepatic porphyrias also showed markedly elevated percentages of the fecal atypical isomers II and IV. In urine significantly decreased proportions of copro isomer I in acute hepatic porphyrias (isomer I = 12.3+/-6.0%; x+/-S.D.) could be observed as compared with non-acute porphyrias (isomer I = 53.7+/-15.2%; x+/-S.D.). Conversely, the proportion of urinary copro isomer III was significantly higher in acute hepatic porphyrias (isomer III= 81.4+/-6.4%; x+/-S.D.). As expected, the greatest amounts of urinary copro isomer I were found in congenital erythropoietic porphyria (isomer I =92.0+/-3.3; x+/-S.D.) and protoporphyria with hepatobiliary complications (isomer I = 81.3+/-10.7; x+/-S.D.). The atypical urinary copro isomers I1 and IV were detected in all types of porphyrias ranging from 0.1 to 11.5%. The combined amounts of copro isomers II and IV show a significantly decreased percentage in congenital erythropoietic porphyria as compared with all other types of hereditary porphyrias. In conclusion, we demonstrate that the characteristic pattern of the copro isomer constellations I-IV in the various types of porphyrias are of differential diagnostic importance. The inversion of the I to III ratio in feces in hereditary coproporphyria and porphyria variegata allows the recognition of gene carriers.

Chromatography, High Pressure Liquid↗
PubMed1999

Investigations on the formation of urinary coproporphyrin isomers I-IV in 5-aminolevulinic acid dehydratase deficiency porphyria, acute lead intoxication and after oral 5-aminolevulinic acid loading.

OBJECTIVES: Investigation of the metabolism of the four urinary coproporphyrin isomers I-IV in the extremely rare 5-aminolevulinic acid dehydratase (ALAD) deficiency porphyria (syn.: Doss porphyria), in acute lead intoxication, and after oral 5-aminolevulinic acid (ALA) loading. DESIGN AND METHODS: We analyzed the excretion of total urinary coproporphyrins and the composition of the respective isomers I-IV with ion-pair HPLC methods in these conditions. RESULTS: The concentration of total coproporphyrins was about 30-fold increased in patients with ALAD deficiency porphyria and acute lead intoxication as compared with controls. In addition, the proportion of coproporphyrin III as well as that of the atypical isomers II and IV were significantly elevated at the expense of isomer I. After oral ALA administration to normal volunteers, a 10- to 15-fold increase in the maximal concentration of total urinary coproporphyrins was observed within 12 to 24 h. Urinary levels were back to normal after another 24 h. The excretion pattern of the individual urinary coproporphyrin isomers I-IV after ALA ingestion revealed a dynamic process: initially isomer III was preferentially formed, followed by a 3-fold increase of isomers II and IV via non-enzymatic rearrangement of isomer III, and finally normalization of all four isomers occurred within 48 h. CONCLUSIONS: These results demonstrate that oral ALA loading can be used as an in vivo model to study the metabolism of the four urinary coproporphyrin isomers I-IV especially in ALAD deficiency porphyria and in acute lead poisoning.

Administration, Oral↗
PubMed1999

Corticosteroid-binding globulin and free cortisol in the early postoperative period after cardiac surgery.

OBJECTIVES: To characterize concentrations of corticosteroid-binding globulin (CBG), total and free serum cortisol, and free urinary cortisol in patients during the postoperative period of cardiac surgery. DESIGN AND METHODS: In 24 patients serum was sampled on the first and second postoperative day after cardiac surgery (21 procedures with thoracotomy, 3 thoracoscopic procedures); urine was collected for two 10-h periods (8 P.M. until 6 A.M.) on the respective postoperative days. Total serum cortisol and free urinary cortisol were measured with an automated chemiluminescence assay (analysis of urine after extraction with dichloromethane), and CBG using a coated-tube RIA. Free serum cortisol was calculated from the concentrations of total serum cortisol and CBG as described previously. Thirty healthy volunteers were studied as controls. RESULTS: CBG was reduced to about one-half of the normal concentration on both postoperative days. Whereas total cortisol was about two-fold increased on the first postoperative day compared to controls extremely high concentrations of free serum cortisol were calculated from CBG and total cortisol [median 136 nmol/L (interquartile range 100-185); controls 21.8 nmol/L (interquartile range 16.9-29.8)]. On the second postoperative day, median total serum cortisol was within the interquartile range of the controls, free serum cortisol in contrast was still two-fold increased. Free serum cortisol and free urinary cortisol were significantly correlated (r = 0.60). CONCLUSIONS: Extremely high concentrations of free serum cortisol are typically found in the postoperative period of cardiac surgery; under these conditions the mere consideration of total cortisol does not appropriately display the activation of the adrenal cortex.

Adult↗
PubMed1999

Cortisol metabolism in the postoperative period after cardiac surgery.

Relative 11beta-hydroxysteroid dehydrogenase deficiency has been shown previously to arise from endogenous hypercortisolism in diseases of the hypothalamic/pituitary/adrenocortical system; whether stress induced hypercortisolism may also result in substrate overload of 11beta-hydroxysteroid dehydrogenase has not yet been studied. We therefore studied the characteristics of cortisol metabolisation during the postoperative period of cardiac surgery, representing a well standardized surgical procedure. In a prospective, observational, consecutive case study, 14 patients undergoing cardiac surgery were investigated. During the first two days after cardiac surgery urine was collected from the patients during two 10 hour overnight periods (8 p.m. (day of surgery) until 6 a.m., and during the following night). Using capillary gas-chromatography, main urinary cortisol metabolites were quantified (tetrahydrocortisone, tetrahydrocortisol, allo-tetrahydrocortisol, cortolones, cortols as sum of cortisol metabolites (CM)). Free urinary cortisol (FUC) was determined by an automated immunoassay after extraction. The ratio of cortisol metabolites (tetrahydrocortisol, allo-tetrahydrocortisol, cortols) to cortisone metabolites (tetrahydrocortisone, cortolones) was calculated to characterize the overall activity of 11beta-hydroxysteroid dehydrogenase, an enzyme system catalyzing the conversion of cortisol to inactive cortisone (CMR, cortisol metabolisation ratio). Total cortisol metabolisation (including hepatic ring A-reduction and conjugation) was estimated by a cortisol turnover quotient (CM/FUC). In all urinary samples the ratio of cortisol to cortisone metabolites was markedly elevated compared to controls (patients: median 1.9, interquartile range 1.5-2.4, absolute range 1.0-3.2; controls: median 0.45, interquartile range 0.36-0.52); this ratio was positively correlated to FUC (r2 = 0.30; p = 0.003). The cortisol turnover quotient was markedly reduced (patients: median 38.0, interquartile range 20.0-103.9, absolute range 8.3-211.9; controls: median 259, interquartile range 176-415) and inversely correlated to FUC (r2 = 0.64, p < 0.001). It is concluded that major surgical trauma results in a marked relative reduction of cortisol inactivation probably consequent to substrate overload of the metabolizing enzymes; as the activity of these enzymes (mainly 11beta-hydroxysteroid dehydrogenase) is crucial for the modulation of cortisol receptor access, tissue corticoid sensitivity in the postoperative period may vary substantially from physiological conditions.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1999

Evaluation of the first automated thyroglobulin assay.

The aim of this study was to investigate technical and analytical performance of the first automated thyroglobulin (Tg) assay (DPC-Immulite; Diagnostic Products Corporation, Los Angeles, USA). In imprecision studies using several human serum pools ranging from 21 to 58 replicates, a coefficient of variation of 9.0% was obtained at a mean Tg concentration of 0.84 ng/ml and of 6.1% at a Tg concentration of 62.1 ng/ml. In a method comparison with a non-automated assay (BRAHMS LUMItest Tg, BRAHMS, Berlin, Germany) using 383 sera of 303 patients with thyroid carcinoma, regression analysis according to Passing and Bablock yielded in the following equation: Immulite Tg = 1.6 x BRAHMS Tg-0.1 ng/ml (Pearson's r = 0.979). Sera obtained from 59 patients with thyroid carcinoma enabled comparative follow-up studies; in all cases qualitative agreement was found with regard to increase or decrease of serum Tg; in eight cases, however, Tg was detected with the Immulite assay but not with the BRAHMS assay. Further follow-up proved the presence of thyroid tissue in these patients. From these and further methodological data (dilution linearity, interference studies, carry-over study, high-dose hook properties, and short report time) it is concluded that the DPC-Immulite Tg assay meets the requirements of routine diagnostic use.

Automation↗
PubMed1999

Urinary porphyrin excretion in hepatitis C infection.

A high prevalence of hepatitis C virus infection in porphyria cutanea tarda in some populations suggests a close link between viral hepatitis and alteration of porphyrin metabolism. Moreover, there is evidence of a role of porphyrinopathies in hepatocarcinogenesis. The aim of our study was to obtain data on the prevalence and patterns of heme metabolism alterations in patients with chronic hepatitis C virus infection. Urinary porphyrin excretion was prospectively studied in 100 consecutive outpatients with chronic hepatitis C infection without signs of photosensitivity, using an ion-pair high-performance liquid chromatography method. Increased total porphyrin excretion was found in 41 patients, with predominant excretion of coproporphyrins (whole study group: mean 146 microg/g creatinine, interquartile range 76-186; normal < 150), in 10 patients excretion exceeded 300 microg/g creatinine. In the majority of all patients studied (75/100) an increased ratio of the relatively hydrophobic coproporphyrin isomer I to isomer III was found. In just one case, urinary porphyrin pattern characteristic for chronic hepatic porphyria was present (uroporphyrin > coproporphyrin, heptacarboxyporphyrin III increased) but the total porphyrin excretion was only slightly elevated in this case. In the whole group, total urinary porphyrin excretion correlated well with serum bilirubin and was inversely correlated with albumin and thrombin time. In conclusion, secondary coproporphyrinuria occurs frequently in heptatitis C infection, whereas in Germany, preclinical porphyria cutanea tarda seems to be rare in these patients.

Chromatography, High Pressure Liquid↗
PubMed1998

Resting metabolic rate in preadolescent girls at high risk of obesity.

OBJECTIVE: To investigate whether children at high risk of obesity have a reduced resting metabolic rate (RMR). DESIGN: Cross-sectional study. SUBJECTS: 93 healthy girls (age: 8-12 y) were allocated to one of four groups, according to the subjects' and their parents' weight status: group 1, overweight children with both parents overweight (OB/OB2; n = 17); group 2, normal weight children with both parents overweight (N/OB2; n = 28); group 3, overweight children of discordant parents (OB/OB1; n = 21) and group 4, normal weight children with both parents normal weight (N/OB0; n = 27). MEASUREMENTS: Weight, height, fat-free mass (FFM) and fat mass (FM) by bioelectrical impedance analysis (BIA), RMR (indirect calorimetry) for the duration of 25 min. RESULTS: Controlling for disparities in body composition, age and physical maturity, significant differences were found in adjusted group means of RMR (OB/OB2 1181 kcal/d; N/OB2 1276 kcal/d; OB/OB1 1234 kcal/d; N/OB0 1199 kcal/d; P < 0.02) with the OB/OB2 girls showing the lowest energy expenditure. CONCLUSION: We found evidence that preadolescent girls at risk of obesity, are not generally predisposed to a higher body weight, because of a greater metabolic efficiency. In fact, our data show that more emphasis should be laid on defining different subgroups of both overweight and normal weight subjects in studies investigating metabolic rate.

Aging↗
PubMed1998

Quantification of cortisol inactivation in cirrhosis of the liver.

Impaired cortisol inactivation in patients with cirrhosis of the liver has been described, but precise data are limited and the pathophysiological significance of this finding has to be elucidated. Therefore, we assessed the main urinary cortisol metabolites using capillary gas chromatography and urinary free cortisol using an enzyme immunoassay in 20 consecutive patients with cirrhosis of the liver and in 28 healthy controls; ratios of cortisol inactivation were calculated (cortisol metabolites/cortisone metabolites, and sum of tetrahydrogenated cortisol metabolites/free urinary cortisol). In patients with cirrhosis free urinary cortisol was normal, whereas the sum of cortisol metabolites was significantly reduced; therefore, cortisol synthesis seems to be adequately adapted to the decreased hepatic inactivation (conjugation, ring A-reduction). A significantly reduced ratio of cortisol metabolites to cortisone metabolites indicating impaired renal 11beta-hydroxysteroid dehydrogenase activity was only found in a subgroup of patients with ascites.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1998

In vitro modulation of human melanoma cell invasion and proliferation by all-trans-retinoic acid.

Invasive growth and formation of metastases involve complex interactions between tumour cells, host cells and components of the extracellular matrix. Retinoids, a group of vitamin A derivatives, modulate cell growth and differentiation and have been found to suppress tumour cell invasion in vitro and formation of metastases in vivo. The aim of our study was to investigate changes in proliferation and invasion through membrane barriers in vitro of seven human melanoma cell lines, established from human primary melanomas or metastases, in response to treatment with retinoic acid (RA). These changes were compared with the expression regulation of molecules that have been identified as targets of RA-mediated signal pathways. Invasiveness in vitro was correlated with the origin of the cell lines and was significantly higher in the lines derived from metastases. In all the cell lines proliferation and chemotaxis were inhibited by 10(-5) M RA, but the cell lines established from metastases were significantly more sensitive with respect to inhibition of invasion by RA. The specific expression patterns of MMP-1 and TIMP-2 were detected and regulated by RA in almost all cell lines, whereas expression of MMP-2 and TIMP-1 was not influenced by RA treatment. The most striking difference between the cell lines was a strong downregulation of transforming growth factor-beta (TGF-beta) expression in cell lines derived from metastases when treated with RA in contrast to cell lines from primary melanomas. These data provide evidence that RA modulates growth, chemotaxis and invasion in a broad panel of melanoma cell lines derived both from primary non-metastasized melanomas and metastases. However, distinct molecular mechanisms are involved in mediating these effects.

Antineoplastic Agents↗
PubMed1998

5-Aminolevulinic acid dehydratase deficiency porphyria: a twenty-year clinical and biochemical follow-up.

5-Aminolevulinic acid dehydratase (ALAD) activity in two patients with compound heterozygous 5-aminolevulinic acid dehydratase deficiency porphyria was studied over the last 20 years. The patients' enzyme activity was <10% from 1977 to 1997. An acute crisis in each patient was successfully treated by infusion of glucose and heme arginate. After this therapy both urinary 5-aminolevulinic acid (ALA) and total porphyrins were diminished to 65% in patient B. In patient H, ALA was decreased to 80%, and total porphyrins were reduced to 15% after treatment with heme arginate and glucose. The patients remained free of symptoms after this therapy. Family studies of patient B showed cross-reactive immunological material (CRIM), in which the maternal mutation is CRIM(+), whereas the paternal mutation is CRIM(-). Incubation of erythrocyte lysates with ALA decreased porphyrin formation, whereas incubation with porphobilinogen produced porphyrin concentrations within reference values in both patients, confirming that ALAD activity is rate-limiting in these cells.

Adolescent↗
PubMed1997

Interdependence between degree of porphyrin excess and disease severity in congenital erythropoietic porphyria (Günther's disease).

Various clinical and biochemical observations point to a relationship between degree of disease expression and metabolic disturbance in autosomal recessive congenital erythropoietic porphyria (Günther's disease). Although the clinical manifestations have been well described since Günther's fundamental observations, an interdependence between disease severity and porphyrin excess has yet to be elucidated. We investigated porphyrin metabolism in nine Indian patients suffering from the characteristic clinical symptoms: skin photosensitivity, red-colored urine as a sign of extremely elevated porphyrinuria and mild to severe hemolytic anemia. Porphyrins in urine, feces and blood were analysed by HPTLC and HPLC in conjunction with spectrophotometry and spectrofluorometry. Uroporphyrinogen III synthase activities in red blood cells were determined using a coupled-enzyme assay. Biochemical studies revealed varying degrees of porphyrinuria with total urinary porphyrins between 23 and 102 mumol/24 h (normal < 0.2 mumol/24 h) and uroporphyrin predominance. Urinary and fecal coproporphyrin isomer I were markedly elevated to 87-97% and 81-93% (normal < 31%, < 75%), respectively. Overproduction of porphyrins led to a considerable porphyrinemia with mainly copro- and protoporphyrin. A hitherto undescribed fecal porphyrin pattern with increased protoporphyrin levels was found in three patients. This atypical finding was probably related to severe hemolysis since protoporphyrin can be excreted only via the liver with bile in the feces. High porphyrin levels in urine, feces and blood were associated with worse cutaneous symptoms. Activities of uroporphyrinogen III synthase in red blood cell lysates were decreased to between 9% and 30% of controls. Patients showed increased porphobilinogen deaminase activities, up to 190% of control. Deficiency of uroporphyrinogen III synthase activity was reflected by inversion of the relationship between and isomer III leading to dominance of isomer I. Elevation of porphobilinogen deaminase activities is related to hemolysis and, additionally, to regulatory compensation for the enzyme deficiency. Variations in both the severity of photosensitivity and the enhancement of porphyrin production and excretion indicate the molecular heterogeneity of this disease. These findings suggest a close relationship between the metabolic disturbance reflected by porphyrin excess and the severity of disease expression.

Adolescent↗
PubMed1997

Evaluation of a Cys23Ser mutation within the human 5-HT2C receptor gene: no evidence for an association of the mutant allele with obesity or underweight in children, adolescents and young adults.

Serotonin is a neurotransmitter involved in a large number of psychophysiological processes including the regulation of mood, arousal, aggression, sleep, learning, nociceptions, nerve growth and importantly, appetitive functions. Alterations of 5-HT receptor activity have been shown to occur in many psychiatric diseases including depression, anxiety, eating disorders, schizophrenia etc. Hence, genetic variation in genes coding for serotonin receptor proteins might well be involved in the genetic predisposition to these diseases and therefore are of great pharmacogenetic relevance. Knockout mice deficient of a functional 5-HT2C receptor have implicated a potential role of this receptor subtype in the serotonergic control of appetite. A Cys23Ser mutation in the human 5-HT2C receptor gene discovered recently prompted us to investigate this mutation with regard to the development of human obesity. We have evaluated this mutation in 241 obese children and adolescents (mean BMI > or = 97th percentile), 80 normal weight children (BMI 5th-85th percentile) and 92 underweight probands (BMI < or = 15th percentile) for a possible association with obesity. The frequencies of the mutant allele in all three weight groups (obese subjects: 0.1597; normal weight: 0.168; underweight: 0.1575) were very similar. Association as well as linkage studies were negative. Therefore it is unlikely that this receptor mutation plays a direct role in the development of human obesity.

Adolescent↗
PubMed1997

Pharmacokinetics of 5-aminolevulinic acid-induced protoporphyrin IX in skin and blood.

The fluorescence and photosensitivity of endogenously synthesized protoporphyrin IX (PPIX) is increasingly used for the diagnosis and treatment of malignant and certain non-malignant diseases. A selective accumulation of PPIX can be induced by application of 5-aminolevulinic acid (5-ALA), which is a precursor of PPIX in the cellular biosynthetic pathway of heme. The purpose of this study was to monitor the in vivo accumulation of PPIX in different locations of the skin after oral ingestion and to determine the pharmacokinetics of 5-ALA and PPIX in human blood plasma for various routes of application. At the same time we wanted to achieve an optimal treatment scheme but also study possible side-effects of 5-ALA administration. After oral application of 5-ALA in a concentration of 40 mg kg-1 body weight, the fluorescence intensities of PPIX in the skin showed maxima between 6.5 and 9.8 h depending on the location and decreased to values lower than 5% related to the maximum after a mean time of about 40 h. The measured absolute intensities of PPIX fluorescence varied strongly between different patients and different locations on one patient. In the plasma of blood samples, PPIX could be detected via its fluorescence for all studied routes of application with the exception of the ointment, where PPIX levels were below the detection limit of 1 microgram l-1. The highest mean concentration of 742 micrograms l-1 PPIX in the plasma was measured 6.7 h after oral application. For inhalation of 5-ALA, a mean maximum concentration of 12 micrograms l-1 could be detected 4.1 h after application, for intravesical instillation, the mean maximum concentration was found to be 1 microgram l-1 2.9 h after application. The kinetics of 5-ALA in the plasma peaked much earlier with a maximum concentration of 32 mg l-1 about 30 min. after oral administration. The 5-ALA levels did not exceed normal reference values after topical application. The results of our experiments suggest that for a systemic application of 5-ALA side-effects in sensitive patients cannot be excluded.

Aged↗