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Biomedical subjects

J Klein

Publications and source records attributed to J Klein.

At least 505 records · Page 28Linked to original sources
PubMed1991

MHC class II genes of a marsupial, the red-necked wallaby (Macropus rufogriseus): identification of new gene families.

In placental mammals, the class II region of the major histocompatibility complex (Mhc) consists of several gene families which show orthologous relationships in the different species. As these families are not orthologous with the Mhc class II beta-chain-encoding gene families of birds, the different mammalian families must have diverged after the separation of birds and mammals approximately 250 Mya but before the radiation of placental mammals (60-80 Mya). To obtain further information about the origin of the class II genes in mammals, we studied the beta-chain-encoding genes of the wallaby as a representative of marsupials, which split from placental mammals approximately 125 Mya. Three beta-chain-encoding genes were isolated from a red-necked wallaby (Macropus rufogriseus) cDNA library by using a chimpanzee DRB probe, and their nucleotide sequences were determined. The genes are not orthologous to any of the genes in mammals studied thus far but belong to two new families which we designated Maru-DAB and Maru-DBB. One of the three sequences (DAB2) seems to be derived from a transcribed pseudogene; it lacks the codons specifying the first 51 amino acid residues of the beta 2 domain. The fact that the DAB and DBB families have thus far not been found in placental mammals and that none of the DOB, DPB, DQB, or DRB genes seems to be expressed in the one representative marsupial species can be interpreted as suggesting that class II gene families of eutherian and metatherian mammals evolved from different ancestral genes.

Amino Acid Sequence↗
PubMed1991

A high-performance liquid chromatographic method for the measurement of the iron chelator 1,2-dimethyl-3-hydroxypyridin-4-one in human plasma.

1,2-Dimethyl-3-hydroxypyridin-4-one (CP020 or L1) is a novel oral iron chelator that has proved to be effective in animals and humans. A rapid, accurate, and sensitive high-performance liquid chromatography method is described for measuring L1 in human plasma using a Hypercarb 7 microns column and monitoring the column eluent by ultraviolet absorption at 280 nm. CP020 and the internal standard (CP094) were extracted into dichloromethane (2 x 5 ml) from plasma at neutral pH [0.25 ml of plasma + 0.75 ml of 60 mM 3-(N-morpholino)propanesulfonic acid buffer, pH 7.4]. The method proved to be linear (r2 = 0.998) in the clinical range of 0.5-50 micrograms/ml when 0.25 ml of plasma was used, with the coefficient of variation less than 10% even at the lower concentration range.

Adolescent↗
PubMed1991

Failure to demonstrate unconscious perception during balanced anaesthesia by postoperative motor response.

Eighty patients undergoing a standardized balanced anaesthesia were randomly assigned to either a suggestion group (N = 38) or a control group (N = 42), in a double-blind design. Anaesthesia was maintained with nitrous oxide, enflurane and fentanyl. Patients in the suggestion group were played seaside sounds, interrupted by statements of the importance of touching the ear during a postoperative visit, by means of a prerecorded audiotape and headphones. Tapes containing these suggestions were played from 30 min after the first incision, for a duration of 15 min. Patients in the control group were only played seaside sounds. There were no significant differences between the groups in either the number of patients touching their ears postoperatively or the number and duration of ear touches.

Adult↗
PubMed1991

Uptake and storage of choline by rat brain: influence of dietary choline supplementation.

In order to elucidate the regulation of the levels of free choline in the brain, we investigated the influence of chronic and acute choline administration on choline levels in blood, CSF, and brain of the rat and on net movements of choline into and out of the brain as calculated from the arteriovenous differences of choline across the brain. Dietary choline supplementation led to an increase in plasma choline levels of 50% and to an increase in the net release of choline from the brain as compared to a matched group of animals which were kept on a standard diet and exhibited identical arterial plasma levels. Moreover, the choline concentration in the CSF and brain tissue was doubled. In the same rats, the injection of 60 mg/kg choline chloride did not lead to an additional increase of the brain choline levels, whereas in control animals choline injection caused a significant increase; however, this increase in no case surpassed the levels caused by chronic choline supplementation. The net uptake of choline after acute choline administration was strongly reduced in the high-choline group (from 418 to 158 nmol/g). Both diet groups metabolized the bulk (greater than 96%) of newly taken up choline rapidly. The results indicate that choline supplementation markedly attenuates the rise of free choline in the brain that is observed after acute choline administration. The rapid metabolic choline clearance was not reduced by dietary choline load. We conclude that the brain is protected from excess choline by rapid metabolism, as well as by adaptive, diet-induced changes of the net uptake and release of choline.

Animals↗
PubMed1991

Accelerator mass spectrometry: application to study of aluminum kinetics in the rat.

The advent of accelerator mass spectrometry (AMS) now permits the ultrasensitive detection of extremely long-lived isotopes, including 14C, 26Al, and 41Ca. Until now, tracer studies of aluminum kinetics have not been possible because aluminum has only two isotopes, with half-lives of 6.5 min (29Al) and 7 x 10(5) yr (26Al), neither of which is suitable for conventional studies. In a novel experiment we have employed AMS to study aluminum kinetics in a normal rat and a 5/6-nephrectomized rat over a 3-wk period of intravenous injection of a tracer dose of 26Al. Kinetics were similar in the two animals; approximately 75% of intravenously injected tracer 26Al was excreted in the urine in the first 24 h as was approximately 80% after 3 wk. Renal clearance of 26Al was approximately 0.75 ml.min-1.kg body wt-1 in both rats. The results clearly demonstrate the potential of this technique for isotope tracer studies in animals as well as in humans.

Aluminum↗
PubMed1991

Cerebral regional capillary perfusion and blood flow after carbon monoxide exposure.

Alterations in regional cerebral blood flow (rCBF) and percent perfused capillaries (indicative of functional intercapillary distance) were determined in conscious male Long-Evans rats after reducing their blood O2-carrying capacity by exposing them to 1% CO for 12 min. rCBF was determined by the iodoantipyrine method. rCBF increased from a mean of 106 +/- 8 (SE) ml.min-1.100 g-1 before CO exposure to 173 +/- 14 ml.min-1.100 g-1 after CO exposure. There was a greater flow increase (126%) in the cerebral cortex than in the lower brain stem [pons (45%), medulla (39%)]. Presence of fluorescein isothiocyanate-labeled dextran identified the perfused capillaries before and after CO exposure. The volume fraction (Vv) and number/mm2 (Na) of all capillaries (perfused and nonperfused) in a given area of brain were determined after staining for alkaline phosphatase. The percent Vv and percent Na of perfused capillaries increased uniformly (from approximately 50% to approximately 80%) in all parts of the brain after CO exposure. In the presence of tissue hypoxia with undiminished plasma PO2, the brain vasculature allowed greater flow of blood while the microvasculature adjusted to reduce the diffusion distance for O2.

Alkaline Phosphatase↗
PubMed1991

Dose-finding study of cilazapril (Inhibace) in patients with uncomplicated essential hypertension.

Cilazapril, an angiotensin converting enzyme (ACE) inhibitor with a long half-life, effectively reduced sitting diastolic blood pressure in patients with uncomplicated essential hypertension at dosages of 2.5, 5.0, and 10.0 mg/day, evaluated in a double-blind, placebo-controlled study. After a four-week placebo run-in period, 235 patients received either cilazapril or placebo for four weeks. At the end of the treatment period, significant decreases from baseline in sitting diastolic blood pressure were seen in all four groups (mean decreases of 3.3 mm Hg with placebo and 6.4, 9.2 and 8.3 mm Hg with 2.5, 5.0 and 10.0 mg cilazapril, respectively). The cilazapril groups had significantly greater blood pressure reductions than did the placebo group (p less than or equal to 0.02). The 5.0 mg cilazapril dose was significantly more effective than the 2.5 mg dose (p less than 0.03). The response rate was notably greater in the cilazapril treatment groups than in the placebo group (placebo, 27.5%; 2.5 mg cilazapril, 42.9%; 5.0 mg cilazapril 62.5%; 10.0 mg cilazapril, 50.0%). Cilazapril was well tolerated at all three dosages.

Adult↗
PubMed1991

Renal handling of cisplatin: interactions with organic anions and cations in the dog.

Cis-diamminedichloroplatinum (II) (cisplatin CDDP) is an extremely potent chemotherapeutic agent. Its efficacy, however, is hindered by the cumulative dose-dependent nephrotoxicity which can lead to permanent renal impairment. The mechanisms of the renal transport of cisplatin are not clear. As a first step towards understanding the renal handling of cisplatin we studied its renal clearance in dogs, as well as the effects of organic anion and cation administration on cisplatin. Our results document net tubular secretion of cisplatin. Both an organic anion (probenecid) and cations (quinidine, cimetidine, ranitidine) significantly decreased renal clearance of free CDDP without affecting GFR.

Animals↗
PubMed1991

Captopril pharmacokinetics, blood pressure response and plasma renin activity in normotensive children with renal scarring.

We studied blood pressure response, plasma renin activity (PRA) and captopril pharmacokinetics in 8 children receiving orally 0.7 mg/kg of the drug. The drug increased PRA in all patients, in 5 to abnormally high levels. Peak captopril concentrations were achieved between half an hour and 2 h, and ranged between 100 and 547 ng/ml. Mean elimination half-time (T1/2) was 1.5 h, ranging between 0.98 and 2.3 h. There was a significant positive correlation between the area under the curve (AUC) and elimination T1/2 of the drug. There was a significant inverse correlation between AUC or elimination T1/2 and percent change in diastolic blood pressure; the 2 children who had no change in diastolic blood pressure had the largest AUC and the lowest apparent clearance of captopril. The kidney is the major site of captopril's pharmacological action. It is possible that longer retention of captopril in the plasma, evidence by larger AUC, may reflect less captopril available to modulate renin activity in the kidney.

Administration, Oral↗
PubMed1991

A double-blind evaluation of the effect of amlodipine on ambulatory blood pressure.

The effects of amlodipine on ambulatory blood pressure were investigated in patients with mild-to-moderate hypertension. Ambulatory recordings showed that amlodipine maintained diastolic and systolic blood pressure below baseline levels for a full 24-h period without altering the normal circadian rhythm. No reflex tachycardia occurred and side effects were rare.

Adolescent↗
PubMed1991

["Anxiety glistens on our brows". Dream reports in literary works on the horrors of ghettos and concentration camps].

Dream reports occupy a special place in literature about confinement in concentration camps and ghettos (Robert Antelme, Charlotte Delbo, Anna Langfus, André Schwarz-Bart). They are central elements in the narrative that relate the anxiety of those threatened with destruction more faithfully than any realistic account could. They disrupt the chronological linearity and rationality and represent in images horror beyond memory or description.

Anxiety↗
PubMed1991

Borrelia burgdorferi as an etiologic agent in chronic heart failure?

Since 1980 cardiac manifestations of Lyme borreliosis have been described as selflimited conduction and transient left ventricular disorders or even cardiomegaly. An etiologic role of Borrelia burgdorferi in long-standing chronic heart disturbances is suggested by the cultivation of a strain of Borrelia burgdorferi which we were able to isolate from an endomyocardial biopsy of a patient with long-standing dilated cardiomyopathy. The aim of this study was to acquire information about the prevalence of serum antibodies to Borrelia burgdorferi in patients with dilated cardiomyopathy. By ELISA, we studied the sera of 72 consecutive patients with chronic heart failure due to dilated cardiomyopathy, of 55 patients with coronary heart disease, and of 61 healthy blood donors; positive ELISA values were determined in 26.4%, 12.7%, and 8.2% of serum samples, respectively. These findings further suggest an association or even an etiologic role for Borrelia burgdorferi in dilated cardiomyopathy.

Adult↗
PubMed1991

Pregnancy-induced changes in drug metabolism in epileptic women.

The pharmacokinetics of antiepileptic drugs may be altered during pregnancy, resulting in decline of serum concentrations and subsequent suboptimal control of seizures. We investigated changes which may occur during pregnancy in hepatic drug handling by comparing metabolic ratios of 15 pregnant epileptic women to 15 nonpregnant epileptic women, as well as 10 pregnant nonepileptic and 10 nonpregnant nonepileptic controls. We used the caffeine test to describe several enzyme activities: P450 1A2, xanthine oxidase, n-acetyltransferase and hydroxylation. For this end, ratios were calculated among a number of metabolites of the main demethylation pathway of caffeine. In addition, we measured D-glucaric acid excretion for specific characterization of antiepileptic drug metabolism. Paired comparison of epileptic women in late pregnancy and six to eight weeks post partum revealed statistically significant decreases in P450 1A2, xanthine oxidase and n-acetyltransferase activities, and a significantly increased hydroxylation activity during pregnancy. Twenty-one of the 30 epileptic women (70%) were found to be fast acetylators, whereas the normal distribution in the nonepileptic control groups was 50%. Excretion of D-glucaric acid was significantly increased in all epileptic patient groups as compared to the matched nonepileptic control groups. Importantly, it was also significantly increased in the pregnant nonepileptic control group as compared to the nonpregnant nonepileptic women. Overall, our results suggest that enzymatic pathways involved in antiepileptic drug metabolism tend to be increased during pregnancy as a potential cause for observed lower serum concentrations of these drugs.

Adult↗
PubMed1991

[Functional versus plaster cast treatment of acute rupture of the fibular ligament of the upper ankle joint. A randomized clinical study].

From November 1987 to December 1988, 60 patients with recent ruptures of the fibular ligament were enrolled in a randomized trial. After randomization patients were treated with a pneumatic leg brace (Aircast) or with cast immobilization for 6 weeks. Follow-up examination was carried out 15 months after cessation of therapy and was possible in 90% of the patients studied. Clinical criteria were evaluated according to a validated questionnaire including a 120-point scoring scale. In 42 patients stress tenography was carried out. The functionally treated group had significantly better score values than the immobilized group (functional treatment group 46.4 points; immobilization group 37.2 points). There was no significant difference between the treatment groups in radiological stability after the injury or at follow-up. On the basis of this study and the literature we recommend a primary functional treatment for recent ruptures of the fibular ligaments of the ankle in adults.

Adolescent↗
PubMed1990

Comparison of oral iron chelator L1 and desferrioxamine in iron-loaded patients.

The efficacy of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) was compared with that of subcutaneous desferrioxamine in 26 patients with transfusional iron overload. Immediately after red-cell transfusion, 20 patients were randomised to receive either desferrioxamine (50 mg/kg daily as a 12 h subcutaneous infusion), or L1 (50 mg/kg daily by mouth). Patients were evaluated during treatment with the other drug after transfusion the next month. Mean (SD) daily urinary iron excretion was lower during L1 than during desferrioxamine (12.3 [6.7] vs 18.2 [15.3] mg/day). In 5 patients the dose of L1 was raised from 50 to 75 mg/kg daily; mean urinary iron excretion rose from 13.8 (7.0) mg/day to 26.7 (17.8) mg/day, comparable with that during desferrioxamine (24.9 [24.3] mg/day). Faecal iron excretion rose slightly over baseline in 6 patients studied during L1 administration (from 8.5 [0.9] mg/day to 12.2 [0.9] mg/day). Pharmacokinetic studies showed an elimination half-life for L1 of 117-237 min. Studies in dogs and in volunteers showed no absorption of the L1-iron complex, excluding a contribution of absorption of intraluminal complexes of L1 and food iron to urinary iron excretion. Further animal toxicity testing is needed before L1 can be studied in a broader group of patients.

Adolescent↗
PubMed1990

Systemic exposure to mercaptopurine as a prognostic factor in acute lymphocytic leukemia in children.

BACKGROUND: Despite a success rate of more than 90 percent in inducing remission in children with acute lymphocytic leukemia, 30 to 40 percent of such children relapse. Maintenance therapy during remission usually includes oral mercaptopurine and methotrexate. Recently, wide variability in the bioavailability of oral mercaptopurine has been demonstrated, and there is concern that this may affect the risk of relapse. METHODS: To investigate whether lower systemic exposure to mercaptopurine may increase the risk of relapse in acute lymphocytic leukemia, we prospectively studied 23 children receiving maintenance therapy. On the basis of disease features, 11 were classified as being at low risk of relapse, and 12 at standard risk. Those who relapsed (n = 10) did not differ from those who did not in their mean age, hemoglobin level, mean daily dose of mercaptopurine and weekly dose of methotrexate, or the total number of days during which mercaptopurine and methotrexate therapy was interrupted. RESULTS: There was a significant difference in the mean (+/- SEM) area under the mercaptopurine concentration-time curve achieved by a dose of 1 mg of mercaptopurine per square meter of body-surface area: 1636 +/- 197 nmol per liter x minutes in those who relapsed, as compared with 2424 +/- 177 nmol per liter x minutes in those who did not (P less than 0.005). This caused a significantly lower total daily systemic exposure to mercaptopurine in those who relapsed (104,043 +/- 12,812 nmol per liter x minutes) than in those who did not (168,862 +/- 18,830 nmol per liter x minutes) (P less than 0.005). An identical tendency prevailed when patients at low risk and patients at standard risk were analyzed separately. Kaplan-Meier analysis revealed that children in whom an area under the curve of less than 1971 nmol per liter x minutes was achieved by a dose of 1 mg of mercaptopurine per square meter had a significantly poorer prognosis than those with larger areas under the curve (P less than 0.01). Similarly, those with a total daily systemic exposure of more than 137,970 nmol per liter x minutes had a significantly better prognosis than those with a lower exposure (P less than 0.005). CONCLUSIONS: Low systemic exposure to oral mercaptopurine during maintenance therapy for acute lymphocytic leukemia in childhood adversely affects prognosis. Children should be studied at the beginning of maintenance therapy to establish the pharmacokinetics of mercaptopurine, and the dose should be tailored to achieve an appropriate systemic exposure.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Lead exposure among mothers and their newborns in Toronto.

Recent studies have suggested that a fetal blood lead level of 0.48 mumol/L (much lower than 1.21 mumol/L, which is the level previously believed to be toxic to the developing brain) may impair brain development permanently. We measured the maternal and umbilical cord blood levels of lead and free erythrocyte protoporphyrin (FEP) among 95 consecutive mother-infant pairs to determine whether neonates in Toronto are in the high-risk group. There was a significant correlation between the maternal and the cord blood lead levels (r = 0.59, p less than 0.0001). Most (99%) of the infants had cord blood lead levels below 0.34 mumol/L; in 11 cases the levels were below the detection limit of 0.01 mumol/L. The cord blood FEP levels were higher than the maternal levels. The US Centers for Disease Control, Atlanta, currently finds acceptable a blood FEP level of 0.62 mumol/L among children up to 10 years of age; however, this is not applicable to newborns since their higher FEP levels apparently reflect immature heme synthesis and increased erythrocyte volume rather than lead poisoning. Our data suggest that living in Toronto does not impose increased teratogenic risk from intrauterine exposure to lead; however, residents in high-risk areas should be followed up.

Adult↗