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Biomedical subjects

B Kaplan

Publications and source records attributed to B Kaplan.

At least 19 recordsLinked to original sources

Low bioavailability of cyclosporine microemulsion and tacrolimus in a small bowel transplant recipient: possible relationship to intestinal P-glycoprotein activity.

With intestine transplants the allograft is dependent on itself for maintenance of adequate immunosuppression. We evaluated an intestinal transplant recipient who required very large doses of either tacrolimus or cyclosporine emulsion to achieve acceptable blood concentrations. Pharmacokinetic studies revealed bioavailabilities of 2% and 6% respectively, while D-xylose and B12 absorption were found to be within normal limits and fecal fat was only slightly increased, suggesting that there was a selective absorptive defect for these drugs. Biopsies of the allograft ileum revealed a high P-glycoprotein activity compared to the jejunum or to intestinal biopsies from other normal subjects. This may be a contributing factor to poor immunosuppressive drug absorption in this patient and others.

Biological Availability

Biochemical assay for amyloid beta deposits to distinguish Alzheimer's disease from other dementias.

Biochemical markers for Alzheimer's disease (AD) are of great value for precise diagnosis and in studies of the pathogenetic processes of this disease. A new biochemical assay allowing to differentiate AD from other forms of dementia is described. The assay is based on the extraction of amyloid beta (A beta) from milligram amounts of brain tissue by using 20% acetonitrile in 0.1% trifluoroacetic acid and its detection by Western blotting. The presence of the 4 kDa A beta was demonstrated in all cases of AD (n = 8) that were diagnosed by the independent histopathological examination of the postmortem tissues. No A beta was found in tissue extracts from seven out of eight cases of other forms of dementia. In contrast to other biochemical techniques of A beta detection in brain, the developed assay is simple; it does not require any special equipment and allows detection of A beta using milligram amounts of brain tissue.

Alzheimer Disease

Predictive value of history and physical examination in patients with suspected ectopic pregnancy.

STUDY OBJECTIVE: To identify historical and physical examination findings that are predictive of ectopic pregnancy (EP) in pregnant patients with abdominal pain or bleeding. METHODS: This study was conducted in an urban academic emergency department as a prospective observational study of consecutive patients from August 1, 1991, to August 31, 1992, who had abdominal pain or vaginal bleeding and a positive beta-human chorionic gonadotropin level. Patients were excluded if they had a diagnostic ultrasound during a previous visit, or if the uterine size was larger than 12 weeks by pelvic examination. Data were analyzed using chi2 with a P value less than. 05 identified as significant. Odds ratios were determined for significant variables. A classification and regression tree analysis was then performed using the predictive variables to derive a decision tree. RESULTS: Four hundred forty-one patients were enrolled, 57 of whom (13%) had an EP. Factors by history that increased the risk of EP included pain that was described as moderate to severe, lateral, or sharp. Pain located in the midline decreased the risk of EP. A history of previous intrauterine device use, infertility, prior pelvic surgery, or tubal ligation were each found to be predictive. On physical examination, the presence of peritoneal signs, cervical motion tenderness, or lateral or bilateral abdominal or pelvic tenderness increased the risk of EP. A uterine size larger than 8 weeks by pelvic examination decreased the risk of EP. Combinations of predictive variables identified subsets of patients with either an increased or decreased frequency of EP, but in no case was a combination identified that would confirm or exclude this diagnosis with a high degree of certainty. CONCLUSION: History and physical examination findings predictive of EP were identified. However, no constellation of findings could confirm or exclude this diagnosis with a high degree of reliability.

Abdominal Pain

Effects of vitamin C supplementation on plasma antioxidant status in unfed periods.

In this study, the antioxidant protection of ascorbic acid (AA) supplementation during different unfed periods (24, 48, 120 h) was determined with blood lipid peroxidation level (thiobarbituric acid reactive substances, TBARS) and compared with plasma antioxidant sulfydryl group (RSH) content. Weight loss was induced by increasing the unfed period together with vitamin C supplementation. Blood AA levels decreased by starvation but increased by vitamin C supplementation. RSH content in plasma also decreased with the unfed period; these decreases became apparent by vitamin C supplementation. TBARS formation increased significantly by AA supplementation in the 120-h starvation period.

Animals

Prevention of age-related aneuploidies by polar body testing of oocytes.

PURPOSE: We previously demonstrated that aneuploidy-free oocytes may be preselected by testing the first and second polar bodies removed from oocytes following their maturation and fertilization. The present paper describes the results of the application of the method in 659 in vitro fertilization cycles from patients of advanced maternal age. METHODS: Using micromanipulation techniques, 3943 oocytes were tested by polar body sampling and fluorescent on situ hybridization analysis using specific probes for chromosomes 13, 18, and 21. RESULTS: Fluorescent in situ hybridization results were available for 3217 (81.6%) of 3943 oocytes studied, of which 1388 (43.1%) had aneuploidies; 35.7% of the aneuploidies were of first meiotic division origin, and 26.1% of second meiotic division origin. Most errors in the first meiotic division were represented by chromatid malsegregation. The transfer of embryos deriving from 1558 of 1829 aneuploidy-free oocytes in 614 treatment cycles resulted in 131 clinical pregnancies and 88 healthy children born after confirmation of the polar body diagnosis. CONCLUSIONS: Polar body testing of oocytes provides an accurate and reliable approach for prevention of age-related aneuploidies in in vitro fertilization patients of advanced maternal age.

Adult

Evaluation of urea kinetics utilizing stable isotope urea and pharmacokinetic modeling.

The determination of urea kinetics plays a central role in clinical dialysis prescription. There persist, however, significant limitations to current approaches, particularly as they pertain to rigorous explorations of urea metabolism, distribution, and removal. This report describes methodologies designed to address these limitations by coupling a stable nitrogen isotope method with strict compartmental pharmacokinetic modeling. The findings of the present study can be summarized as follows. First, the use of stable isotope labeled exogenous urea is a reliable clinically applicable method for determination of urea kinetics. Second, this method offers significant advantages in that it allows for an accurate measurement of urea distribution space, endogenous urea production, and non-renal clearance of urea. Third, this method is significantly more rigorous than urea kinetic models that utilize only endogenous urea and do not carefully fit data points. Finally, pharmacokinetic modeling suggests that a two-compartment model satisfies all aspects of urea distribution and removal, but these compartments should not be equated with specific physiologic spaces. The combination of stable isotope urea compartmental modeling is a rigorous methodology for the assessment and validation of urea kinetics.

Adult

Correlation between pretransplantation test dose cyclosporine pharmacokinetic profiles and posttransplantation sirolimus blood levels in renal transplant recipients.

We sought to determine whether pretransplantation test dose pharmacokinetic measurements of cyclosporine (CsA) concentrations would forecast the posttransplantation blood concentrations of sirolimus in renal transplant patients treated de novo with CsA, sirolimus, and prednisone. All 44 renal transplant recipients enrolled in Phase I/II studies of de novo posttransplantation therapy with sirolimus, CsA, and prednisone underwent pretransplantation pharmacokinetic profiling after having received paired intravenous (i.v.) and oral test doses of CsA. After transplantation, all patients were treated with CsA on a once- or twice-daily schedule (according to a concentration-controlled regimen), with tapering doses of prednisone, and with fixed doses of sirolimus on a once-daily schedule. Patients were divided into four cohorts based on the deviation of their pretransplantation CsA clearance or bioavailability values from the mean. Patients with high pretransplantation CsA clearance rates displayed a significantly lower mean posttransplantation value of sirolimus trough concentrations than patients with low pretransplantation CsA clearance rates. In contrast, values for pretransplantation absolute oral CsA bioavailability failed to correlate with the mean posttransplantation concentration of sirolimus but did predict posttransplantation CsA bioavailability. Therefore, pretransplantation CsA clearance rate estimates may forecast posttransplantation sirolimus concentrations, possibly guiding use of sirolimus therapy to achieve an optimal ratio of concentration-dependent immunosuppressive versus toxic effects.

Biological Availability

Quality of cryopreserved testicular sperm in patients with obstructive and nonobstructive azoospermia.

PURPOSE: Sperm retrieved by testicular sperm extraction is routinely used to attempt pregnancy by in vitro fertilization-intracytoplasmic sperm injection. We evaluated the efficacy of cryopreserving testicular sperm collected by testicular sperm extraction at diagnostic biopsy. MATERIALS AND METHODS: A total of 73 men with obstructive and 42 with nonobstructive azoospermia underwent testicular sperm extraction at diagnostic biopsy. Sperm was retrieved and cryopreserved in all cases of obstruction and in 15 of nonobstructive azoospermia cases. Before freezing we determined sperm count, motility, morphology and viability, and after thawing we assessed sperm motility and viability. In 17 couples a total of 20 cycles of in vitro fertilization-intracytoplasmic sperm injection were performed and fertilization, cleavage and pregnancy rates were determined in cases of obstruction and nonobstruction. RESULTS: Sperm count and morphology were lower in the testicular biopsies of men with nonobstructive versus obstructive azoospermia. Motility was low or absent in all testicular sperm extraction specimens. Importantly, pre-freeze (63%) and post-thaw (31%) viability was the same in both patient groups. After in vitro fertilization-intracytoplasmic sperm injection using frozen and thawed testicular sperm the fertilization, cleavage, implantation and clinical pregnancy rates were 60, 86, 16 and 50%, respectively. Using cryopreserved sperm we observed no differences in outcome of any in vitro fertilization-intracytoplasmic sperm injection procedure in patients with obstructive versus nonobstructive azoospermia. CONCLUSIONS: Cryopreservation of testicular sperm provides enough good quality sperm after thawing to result in excellent in vitro fertilization-intracytoplasmic sperm injection outcomes. Cryopreservation does not adversely affect intracytoplasmic sperm injection outcomes, including pregnancy rate. Therefore, we recommend routine testicular sperm extraction and cryopreservation of sperm at testicular biopsy.

Cryopreservation

Apoptotic proteins Reaper and Grim induce stable inactivation in voltage-gated K+ channels.

Drosophila genes reaper, grim, and head-involution-defective (hid) induce apoptosis in several cellular contexts. N-terminal sequences of these proteins are highly conserved and are similar to N-terminal inactivation domains of voltage-gated potassium (K+) channels. Synthetic Reaper and Grim N terminus peptides induced fast inactivation of Shaker-type K+ channels when applied to the cytoplasmic side of the channel that was qualitatively similar to the inactivation produced by other K+ channel inactivation particles. Mutations that reduce the apoptotic activity of Reaper also reduced the synthetic peptide's ability to induce channel inactivation, indicating that K+ channel inactivation correlated with apoptotic activity. Coexpression of Reaper RNA or direct injection of full length Reaper protein caused near irreversible block of the K+ channels. These results suggest that Reaper and Grim may participate in initiating apoptosis by stably blocking K+ channels.

Amino Acid Sequence

Potential interaction of troglitazone and cyclosporine.

BACKGROUND: Troglitazone (Rezulin) is a promising new oral hypoglycemic agent recently approved by the Federal Drug Administration for use in type II diabetes mellitus. Although troglitazone is not metabolized by the cytochrome p450 3A isozyme family, it is a potential inducer of this system. Other medications, e.g., rifampin and phenobarbital, which also induce p450 3A activity, have been reported to significantly decrease cyclosporine (CsA) concentrations. METHODS: We report a case of a stable renal transplant patient who had a decrease in CsA concentration after beginning troglitazone and who subsequently developed an acute rejection episode. We then reviewed all stable renal patients begun on troglitazone over the previous 6 months. RESULTS: The seven transplant patients who had been started on troglitazone therapy experienced a statistically and clinically significant decrease in CsA 12-hr trough levels immediately after the institution of troglitazone therapy. CONCLUSION: A potential interaction exists between troglitazone and CsA. Transplant patients on CsA who receive troglitazone therapy should be monitored closely.

Acute Disease

Decreased protein binding of mycophenolic acid associated with leukopenia in a pancreas transplant recipient with renal failure.

BACKGROUND: Mycophenolate mofetil (MMF) is rapidly hydrolyzed to its active metabolite mycophenolic acid (MPA), which is excreted by the kidney after undergoing glucuronidation to MPAG. MPAG has been shown to accumulate in patients with renal failure. MPA is extensively and avidly bound to human serum albumin. In vitro inhibition of the pharmacologic target, inosine monophosphate dehydrogenase, is dependent on free MPA. It has been demonstrated that high MPAG concentrations decrease MPA protein binding in vitro. In addition, the uremic state is associated with altered protein binding of many drugs. METHODS: We assessed free MPA, total MPA, and MPAG kinetics in a patient with renal failure receiving MMF for a pancreas transplant, who presented with signs of MMF toxicity. MPA, MPAG, and free MPA were measured by high performance liquid chromatography and a validated 14C-MPA ultrafiltration methodology. RESULTS: The MPAG area under the concentration curve (AUC) in this patient was extremely high (5899 microg x hr/ml). The total MPA AUC of 36.8 microg x hr/ml was within the range usually obtained in stable renal patients. The free fraction of MPA and the free MPA AUC were markedly elevated (13.8% and 5.07 microg x hr/ml, respectively). CONCLUSIONS: Patients with severe renal insufficiency may have markedly increased free MPA levels that may not be reflected in total MPA concentrations. These patients may be at increased risk for MMF-related toxicity.

Adult

Genetic association between reduced P300 amplitude and the DRD2 dopamine receptor A1 allele in children at high risk for alcoholism.

BACKGROUND: There is evidence that both reduction in P300 amplitude and the presence of the A1 allele are risk markers for alcoholism. We hypothesized that demonstration of a relationship between the marker and the trait in young children who had not begun to drink regularly would provide evidence for dopaminergic mediation of the reduction in P300 often seen among high-risk children. A previous association between the A1 and the P300 amplitude in screened controls supports the hypothesis that this association occurs in the general population. METHODS: Children were assessed using both visual and auditory paradigms to elicit event-related potentials (ERPs). The P300 component of the ERP was investigated with respect to the genetic variation of the Taq1A D2 receptor in these children. RESULTS: Genetic association between a marker locus (Taq1 A RFLP near the D2 receptor locus) and the amplitude of P300 was found to be present in 58 high-risk children and their relatives (a total of 100 high-risk individuals). CONCLUSIONS: A higher proportion of children from alcoholic families may exhibit lower P300 because more of these children carry the A1 allele than is seen in the normal population.

Acoustic Stimulation

Three births after preimplantation genetic diagnosis for cystic fibrosis with sequential first and second polar body analysis.

OBJECTIVE: The purpose of this study was to determine the accuracy and feasibility of sequential polar body removal and analysis for preimplantation genetic diagnosis of mendelian disorders. STUDY DESIGN: Three couples with risk factors for cystic fibrosis had preimplantation genetic diagnosis with the use of sequential polar body analysis. After stimulation, oocytes were harvested and the first polar bodies were removed and analyzed on the day of aspiration. The following day, after fertilization, the second polar bodies were aspirated. Only embryos known to have inherited the normal maternal allele were transferred. RESULTS: All three couples had successful pregnancies resulting in the births of unaffected infants. CONCLUSIONS: Preimplantation diagnosis with the use of sequential polar body removal is feasible and can prevent the establishment of genetically abnormal pregnancies for couples at risk.

Alleles