Increased immunosuppressive vulnerability in elderly renal transplant recipients.
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Adolescent↗
Biomedical subjects
B Kaplan
Publications and source records attributed to B Kaplan.
[Spontaneous bilateral ectopic pregnancy--an rare and dangerous occurrence].
Bilateral, spontaneous ectopic pregnancy is rare (1 in 125-1580 ectopic pregnancies). We describe a 30-year-old, unmarried woman with no predisposing factors for ectopic pregnancy who presented in hypovolemic shock, in the 7th week of gestation, complaining of abdominal pain. On immediate laparoscopy there were found blood and clots in the abdominal cavity, a left ampullar pregnancy (5 cm in diameter), and there was active bleeding from the fimbria of the right tube. Bilateral salpingectomy was performed and she received 3 units of packed red cells. She was discharged in good condition 3 days later. The pathologic diagnosis was pregnancy in each tube. This case emphasizes the need for thorough sonographic and laparoscopic observation in order not to miss the presence of bilateral ectopic pregnancy.
Adult↗
Efficacy of Daclizumab in an African-American and Hispanic renal transplant population.
Current immunosuppressive regimens have decreased acute rejection rates during the 1st year after renal transplantation. However, this decrease has not been as marked in high-risk groups, such as African-American and Hispanic renal transplant recipients. We compared two simultaneous cohorts of altogether 36 African-American and Hispanic renal transplant recipients. Cohort one received a regimen of mycophenolate mofetil, prednisone, and a calcineurin inhibitor. The second cohort received the same protocol with the addition of Daclizumab (1 mg/kg for five doses given every 2 weeks). The median follow-up was 15.2 months (range 11.8-19.9 months). One patient in the Daclizumab-treated group and seven patients in the control group experienced an acute rejection episode. The rejection-free survival was significantly higher in the Daclizumab-treated group (94.4 %) as compared to the control group (66.7 %, Log-rank < 0.05) at 17 months after transplantation. A Cox Proportional Hazard model revealed lack of Daclizumab therapy as the only significant risk factor for acute rejection. (hazard ratio 7.0, 95 % CI = 1.1-48). The addition of the IL-2 receptor blocker Daclizumab to a triple therapy regimen may decrease early acute rejection in the high-risk groups of African-American and Hispanic patients.
Adult↗
Advances in therapeutic drug monitoring for immunosuppressants: a review of sirolimus. Introduction and overview.
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Adjuvants, Immunologic↗
Toxicity and efficacy of sirolimus: relationship to whole-blood concentrations.
BACKGROUND: Sirolimus is a novel macrolide immunosuppressive drug with a mechanism of action distinct from that of both cyclosporine and tacrolimus. Recent clinical studies have demonstrated a decrease in acute rejection episodes in renal transplant patients receiving sirolimus compared with controls. The major toxicities associated with sirolimus treatment are thrombocytopenia and hyperlipidemia. In addition, concern has been raised by the higher serum creatinine levels noted in patients receiving sirolimus and cyclosporine compared with controls receiving cyclosporine and azathioprine. OBJECTIVE: The objective of the present review is to summarize the efficacy and toxicity data for sirolimus. Special consideration is given to evidence that links these effects to dose or whole-blood concentrations of sirolimus. RESULTS: The literature indicates that trough concentrations of sirolimus >15 ng/mL appear to be associated with a greater risk of both thrombocytopenia and hyperlipidemia, whereas trough sirolimus concentrations <6 ng/mL have been associated with an increased incidence of acute rejection. CONCLUSION: The evidence to date supports target trough sirolimus concentrations of 6 to 15 ng/mL in most patients. In higher-risk groups and patients receiving cyclosporine-sparing regimens, higher concentrations may be necessary to achieve similar efficacy.
Humans↗
Long-term retention of transient news events.
Many retrospective analyses of remote memory have demonstrated recency effects in that memory for events proximal to the time of testing is superior to memory for events from remote time periods. However, the rate at which information decays over time and the specific pattern of forgetting may vary depending upon the distinct attributes of stimuli used as indices of memory. Studies examining long-term forgetting of well rehearsed, conceptually integrated information underscore preservation of remote events, some of which are thought to be permanently stored in memory. A different pattern of forgetting emerges in relation to recall of discrete facts whereby recall declines according to a negatively accelerated decay curve. In the current study long-term retention of transient news events was examined. Results were examined in relation to the effects of age and sex. All age groups demonstrated recency effects in that events from the recent past were recalled better than remote events. Age did not exert a negative influence on recall of remote or recent events with the exception of younger participants who did not recall items predating their dates of birth. Older female participants were less adept at recalling very old events than their male counterparts.
Adult↗
A high-affinity calmodulin-binding site in a tobacco plasma-membrane channel protein coincides with a characteristic element of cyclic nucleotide-binding domains.
Recently we isolated a cDNA encoding a tobacco plasma membrane calmodulin-binding channel protein (designated NtCBP4) with a putative cyclic nucleotide-binding domain. Here we analyzed in detail the interaction of NtCBP4 with calmodulin. A full-length recombinant NtCBP4 (81 kDa) expressed in Sf9 insect cells, and the corresponding tobacco membrane protein were solubilized from their respective membrane fractions and partially purified by calmodulin affinity chromatography. NtCBP4 was detected in the eluted fractions using specific antibodies raised against the recombinant protein. By binding [35S]-calmodulin to recombinant NtCBP4 truncations fused to glutathione S-transferase, we identified a single region consisting of 66 amino acids capable of binding calmodulin. A 23 amino acid synthetic peptide from within this region formed a complex with calmodulin in the presence of calcium. We measured the fluorescence of dansyl-calmodulin interacting with this peptide, which revealed a dissociation constant of about 8 nM. The NtCBP4 calmodulin-binding domain was found to perfectly coincide with a phylogenetically conserved alphaC-helix motif of its putative cyclic nucleotide-binding domain. Furthermore, a 23 amino acid region in an equivalent site in the cAMP-binding domain of a mammalian protein kinase regulatory subunit was also found to bind calmodulin. Thus, coinciding calmodulin- and cyclic nucleotide-binding domains may serve as a point of communication between calcium and cyclic nucleotide signal transduction pathways in plants and animals.
Amino Acid Sequence↗
The effect of Daclizumab in a high-risk renal transplant population.
INTRODUCTION: African-American (AA) renal transplant recipients have a higher incidence of acute rejection when compared to Caucasian renal transplant recipients. This higher rejection rate holds true even with the addition of several of the newer immunosuppressive agents (e.g. mycophenolate mofetil (MMF) and Rapamycin). Acute rejection rates among Hispanic (H) renal transplant recipients are higher in some settings, while lower or the same as in Caucasians in other settings. IL-2 receptor antibodies have been shown to decrease rejection rates when added to a regimen of cyclosporine (CsA), azathioprine and prednisone. Limited data are available on these agents in conjunction with triple CsA, MMF and prednisone therapy, particularly in higher risk group patients. We studied the effect of the addition of the IL-2 receptor antibody Daclizumab to a CsA, MMF, prednisone regimen in a group of African American and high-risk Hispanic renal transplant recipients. METHODS: This was a non-randomized, prospective study. A total of 49 renal transplant recipients (29 African American and 20 Hispanic) were studied and followed. A simultaneous cohort of 56 (31 African-American and 25 Hispanic) renal transplant recipients receiving CsA, MMF and prednisone with no standard induction agent served as the control group. The study cohort received the same regimen with the addition of Daclizumab at 1 mg/kg for five doses over 10 wk. Multivariate analysis was performed to isolate independent factors influencing the study's results. RESULTS: A total of 56 patients in the control group and 49 patients in the Daclizumab group received an average follow-up of 17.1 +/- 6.9 and 12.7 +/- 5.1 months, respectively. Acute rejection rates were lower in the Daclizumab group as compared to the control group 26.4% versus 49.3% per patient years, respectively. A total of eight recurrent rejections in 6 patients occurred in the control group and none in the Daclizumab arm. Graft loss at this follow-up was no different between the groups. CONCLUSION: The addition of Daclizumab to a regimen of CsA, MMF and prednisone decreases acute rejection episodes in a high-risk group of African American and Hispanic renal transplant recipients.
Adult↗
Expression of a truncated tobacco NtCBP4 channel in transgenic plants and disruption of the homologous Arabidopsis CNGC1 gene confer Pb2+ tolerance.
Recently we reported on a plasma membrane tobacco protein (designated NtCBP4) that binds calmodulin. When overexpressed in transgenic plants, NtCBP4 confers Pb2+ hypersensitivity associated with enhanced accumulation of this toxic metal. To further investigate possible modulation of Pb2+ tolerance in plants, we prepared transgenic plants that express a truncated version of this protein (designated NtCBP4DeltaC) from which its C-terminal, with the calmodulin-binding domain and part of the putative cyclic nucleotide-binding domain, was removed. In contrast to the phenotype of transgenic plants expressing the full-length gene, transgenic plants expressing the truncated gene showed improved tolerance to Pb2+, in addition to attenuated accumulation of this metal. Furthermore, disruption by T-DNA insertion mutagenesis of the Arabidopsis CNGC1 gene, which encodes a homologous protein, also conferred Pb2+ tolerance. We suggest that NtCBP4 and AtCNGC1 are components of a transport pathway responsible for Pb2+ entry into plant cells.
Adaptation, Physiological↗
Treatment of scalp seborrheic dermatitis and psoriasis with an ointment of 40% urea and 1% bifonazole.
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Antifungal Agents↗
Effect of waiting time on renal transplant outcome.
BACKGROUND: Numerous factors are known to impact on patient survival after renal transplantation. Recent studies have confirmed a survival advantage for renal transplant patients over those waiting on dialysis. We aimed to investigate the hypothesis that longer waiting times are more deleterious than shorter waiting times, that is, to detect a "dose effect" for waiting time. METHODS: We analyzed 73,103 primary adult renal transplants registered at the United States Renal Data System Registry from 1988 to 1997 for the primary endpoints of death with functioning graft and death-censored graft failure by Cox proportional hazard models. All models were corrected for donor and recipient demographics and other factors known to affect outcome after kidney transplantation. RESULTS: A longer waiting time on dialysis is a significant risk factor for death-censored graft survival and patient death with functioning graft after renal transplantation (P < 0.001 each). Relative to preemptive transplants, waiting times of 6 to 12 months, 12 to 24 months, 24 to 36, 36 to 48, and over 48 months confer a 21, 28, 41, 53, and 72% increase in mortality risk after transplantation, respectively. Relative to preemptive transplants, waiting times of 0 to 6 months, 6 to 12 months, 12 to 24 months, and over 24 months confer a 17, 37, 55, and 68% increase in risk for death-censored graft loss after transplantation, respectively. CONCLUSIONS: Longer waiting times on dialysis negatively impact on post-transplant graft and patient survival. These data strongly support the hypothesis that patients who reach end-stage renal disease should receive a renal transplant as early as possible in order to enhance their chances of long-term survival.
Adult↗
Effect of perilesional injections of PEG-interleukin-2 on basal cell carcinoma.
BACKGROUND: Multiple modalities are available for the treatment of basal cell carcinoma (BCC). The most commonly used modalities include simple excision, Mohs micrographic surgery, curettage and electrodessication, cryosurgery, and irradiation therapy. Interleukin-2 (IL-2) is a cytokine produced chiefly by activated T lymphocytes and has effects on various components of the immune system. Until now the primary clinical use of IL-2 has been in advanced stages of metastatic melanoma and renal cell carcinoma. Systemic administration of IL-2 is known to cause significant toxicity. OBJECTIVE: The objective of this study was to evaluate the therapeutic efficacy and safety of perilesional PEG-IL-2 injections in patients with BCC in an open label, uncontrolled pilot study. METHODS: Patients with histologically confirmed primary BCC over 18 years of age were included in the study. Lesions were treated by injecting a total volume of 0.5 cc of IL-2 in a radial fashion in the subcutaneous tissue. Injection dosages ranged from 3000 to 1,200, 000 IU in one to four weekly dosages. A total of 12 tumors were treated in eight patients. RESULTS: Overall response rates were as follows: complete response in 8 of 12 treated tumors (66.6% cure rate), partial response in 3 of 12 injected tumors (25% partial response rate), stable disease with no improvement in 1 treatment site (8.4%). Side effects included local pain, swelling, and erythema, and in one patient flulike symptoms. There were no significant changes of blood tests as compared to baseline levels. CONCLUSIONS: The therapeutic response induced by perilesional PEG-IL-2 injections was found to be an encouraging, safe, and well-tolerated treatment of BCC. Further studies including a larger patient population and long-term follow-up are necessary in order to substantiate these findings.
Aged↗
Pharmacokinetics and concentration-control investigations of mycophenolic acid in adults after transplantation.
Data have emerged that provide the scientific basis for therapeutic drug monitoring of mycophenolic acid (MPA) in transplant patients receiving mycophenolate mofetil (MMF), the parent drug, in combination with other immunosuppressive agents. There is a significant relationship between the dose-interval MPA AUC and risk for acute rejection based on retrospective investigations in renal and heart transplant patients and on prospective investigations in renal transplant patients. The MPA dose-interval AUC varies naturally by more than 10-fold in renal and heart transplant patients. Other significant sources of pharmacokinetic variability for MPA include the effects of concomitant medications, and the effects of disease states such as renal dysfunction and liver disease on the steady state MPA AUC. Individualized MMF dose evaluation, guided by MPA plasma concentrations, is becoming the standard of practice at a growing number of transplant centers worldwide because of these factors and because of the need to closely evaluate the immunosuppression afforded by MPA when a change in the immunosuppression regimen in stable transplant patients is planned. Investigations of therapeutic drug monitoring strategies with an emphasis on identifying an optimal abbreviated sampling strategy for MPA AUC estimation are ongoing. Based on the concentration-outcome studies and experience at the authors' institutions and other centers, the authors propose a set of therapeutic drug monitoring guidelines for MPA in stable renal and heart transplant patients for the immediate (first 3 months posttransplant) and maintenance (>3 months) periods. When MPA binding to human serum albumin is altered, as occurs in patients with significant renal dysfunction, liver disease, or a substantial reduction in human serum albumin concentration, the possibility of increased MPA free fraction and free concentration will need to be taken into account in the interpretation of MPA total concentrations.
Area Under Curve↗
Pharmacokinetics of mycophenolic acid in renal insufficiency.
Mycophenolate mofetil (MMF) is now widely used in solid organ transplantation. MMF is rapidly converted to its active form, mycophenolic acid (MPA), upon reaching the systemic circulation. MPA is metabolized to its glucuronide metabolite, mycophenolic acid glucuronide (MPAG), by glucoronyl transferases in the liver and possibly elsewhere. MPAG is then excreted by the kidney. MPA is extensively and avidly bound to serum albumin. Previous studies have demonstrated that it is only the free (non-protein-bound) fraction of MPA that is available to exert its action. In vivo and in vitro studies demonstrate that renal insufficiency decreases the protein binding of MPA and increases free MPA concentrations. This decrease in protein binding seems to be caused both by the uremic state itself and by competition with the retained metabolite MPAG. The disposition of MPA in patients with severe renal impairment may be significantly affected by this change in protein binding.
Biotransformation↗
Concurrent genital and rectal prolapse: two pathologies--one joint operation.
This study is a prospective assessment of a joint operation to repair concomitant genital and rectal prolapse, including 10 women treated for concomitant genital and rectal prolapse from 1991 to 1995. Joel-Cohen vaginal hysterectomy was used to correct the genital prolapse, followed by the Altemeier procedure (transperineal rectosigmoidectomy) to correct the rectal prolapse. The post-operative course was uneventful in all cases and there were no recurrences of prolapse in the three year follow up period. Improvement of sphincteric tone was shown in all cases by transrectal manometry, and bladder and rectal continence was maintained. The combined surgical procedure for concurrent genital and rectal prolapse is easy to perform and safe and efficient in terms of recurrence and continence. It is hoped this report will increase multidisciplinary awareness of an effective solution for a potentially debilitating problem.
Aged↗
Hyperemesis gravidarum during Ramadan.
During Ramadan, adult Muslims fast from dawn to dusk. We frequently encounter young pregnant Muslim women with hyperemesis gravidarum who fast during this holy month. We have investigated whether there is an association between the prolonged fasting during Ramadan and excessive vomiting during pregnancy. Possible psychologic and physiologic explanations are presented and discussed.
Fasting↗
Cyclic-nucleotide- and Ca2+/calmodulin-regulated channels in plants: targets for manipulating heavy-metal tolerance, and possible physiological roles.
Recently we discovered a tobacco protein (designated NtCBP4) that modulates heavy-metal tolerance in transgenic plants. Structurally, NtCBP4 is similar to mammalian cyclic-nucleotide-gated non-selective cation channels containing six putative transmembrane domains, a predicted pore region, a conserved cyclic-nucleotide-binding domain, and a high-affinity calmodulin-binding site that coincides with its cyclic-nucleotide-binding domain. Transgenic tobacco expressing the plasma-membrane-localized NtCBP4 exhibit improved tolerance to Ni(2+) and hypersensitivity to Pb(2+), which are associated with a decreased accumulation of Ni(2+) and an enhanced accumulation of Pb(2+) respectively. Transgenic plants expressing a truncated version of NtCBP4, from which regulatory domains had been removed, have a different phenotype. Here we describe our approach to studying the involvement of NtCBP4 in heavy-metal tolerance and to elucidate its physiological role.
Amino Acid Sequence↗