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Biomedical subjects

R Shapiro

Publications and source records attributed to R Shapiro.

At least 163 records · Page 9Linked to original sources
PubMed1997

Clinical features of acute reversible tacrolimus (FK 506) nephrotoxicity in kidney transplant recipients.

This study was designed to (a) estimate the contribution of tacrolimus nephrotoxicity to episodes of renal allograft dysfunction investigated by needle biopsy, (b) describe the temporal evolution of nephrotoxicity and its response to therapy, and (c) ascertain how often renal dysfunction is associated with concurrent extra-renal toxicity. Patients were selected based on a rising serum creatinine, normal ultrasound, and biopsy findings leading to a reduction in the dose of tacrolimus and a fall in serum creatinine. Twenty two (17%) cases of nephrotoxicity were identified amongst 128 consecutive kidney transplant biopsies with sufficient clinical data for analysis. There were 13 males and 9 females, 17-75 yr in age. Tacrolimus was administered initially as a 0.075-0.1 mg/kg/d IV continuous infusion followed by an oral dose of 0.15 mg/kg twice daily. The onset of nephrotoxicity in this study occurred 1-156 wk post-operatively. The mean baseline creatinine was 212.2 +/- 168.0 mumol/l (range 88.4-875.2) and rose 40.6% +/- 14.2% (range 11-66) during episodes of nephrotoxicity (p < 0.001). The highest recorded plasma and whole-blood tacrolimus levels during the toxic episodes were respectively 2.7 +/- 0.8 ng/ml (range 1.1-3.5) and 31.6 +/- 10.6 ng/ml (range 14.5-50.5). The drug levels were considered to be beyond the therapeutic range in 18/22 (82%) patients. The highest tacrolimus level preceeded the rise in serum creatinine in 20 cases by an interval of 1.6 +/- 1.8 d. A mean reduction in tacrolimus dosage of 41% +/- 21% (range 11-89) led to a 86% +/- 18% (range 45-100) fall in the serum creatinine within 1-14 d (p < 0.001). Interactions between tacrolimus and clarithromycin, diltiazem, or itraconazole modified the pharmakokinetic parameters in three cases. Serum potassium > 5.0 mequiv/l was recorded in 9/22 (41%) cases. Three or more elevations in blood glucose > 7.7 mmol/l (140 mg/dl) were recorded in 4/11 (36%) non-diabetic patients. Hand tremors were seen in two (9%) cases and elevated diastolic blood pressure > 90 mmHg in seven (32%) patients. In conclusion, tacrolimus nephrotoxicity accounted for 17% of graft dysfunction episodes investigated by biopsy. Concurrent hyperglycemia, hyperkalemia, or tremors were noted in several patients. Nephrotoxicity responded well to reduction in the drug dosage.

Acute Disease↗
PubMed1997

Surgical infections in immunocompromised patients--prevention and treatment.

The care of immunocompromised patients is a challenge to all physicians. The variety of opportunistic infections that can develop in these patients underscores the importance of the immune response. The key to success in the prevention and management of infections in these patients lies in knowing what kind of infections to expect and instituting empirical treatment even before a specific diagnosis is made. With the advent of better preventive strategies, the use of prophylactic and preemptive therapies, and the introduction of new immunomodulators, successful outcomes in these interesting and challenging patients may be more easy to achieve in the future.

AIDS-Related Opportunistic Infections↗
PubMed1997

Acute renal allograft rejection in patients with Epstein-Barr virus associated post-transplant lymphoproliferative disorder.

BACKGROUND: There is a reciprocal relationship between post-transplant lymphoproliferative disorder (PTLD) and rejection: aggressive treatment of rejection can result in PTLD, while treatment of PTLD by reducing immunosuppression can result in recrudescence of rejection. The literature on the relationship between PTLD and rejection episodes is limited. METHODS: The clinical course and outcome of rejection episodes occurring prior to and following a diagnosis of PTLD were studied in 20 renal transplant recipients. RESULTS: The diagnosis of PTLD was preceded by rejection in 12/20 (60%) patients. OKT3 treatment was associated with early onset PTLD, which involved the allograft in 6/7 patients (86%). The risk of rejection following reduced immunosuppression was 7/14 (50%). Post-PTLD rejection left untreated led to graft loss in 3 patients. The remaining 4 patients responded satisfactorily to anti-rejection therapy. CONCLUSIONS: Reduction of immunosuppression for PTLD is frequently, but not invariably, complicated by rejection. The clinical outcome of PTLD does not correlate with the occurrence or reversibility of rejection episodes.

Adult↗
PubMed1996

Tacrolimus in pediatric renal transplantation.

Tacrolimus was used as the primary immunosuppressive agent in 69 pediatric renal transplantations between December 17, 1989, and June 30, 1995. Children undergoing concomitant or prior liver and/or intestinal transplantation were excluded from analysis. The mean recipient age was 10.3+/-5.0 years (range, 0.7-17.5 years). Seventeen (24.6%) children were undergoing retransplantation, and six (8.7%) had a panel reactive antibody level of 40% or higher. Thirty-nine (57%) cases were with cadaveric kidneys, and 30 (43%) were with living donors. The mean donor age was 28.0+/-14.7 years (range, 1.0-50.0 years), and the mean cold ischemia time for the cadaveric kidneys was 27.0+/-9.4 hr. The antigen match was 2.7+/-1.2, and the mismatch was 3.1+/-1.2. All patients received tacrolimus and steroids, without antibody induction, and 26% received azathioprine as well. The mean follow-up was 32+/-20 months. One- and 4-year actuarial patient survival rates were 100% and 95%. One- and 4-year actuarial graft survival rates were 99% and 85%. The mean serum creatinine level was 1.2+/-0.8 mg/dl, and the calculated creatinine clearance was 82+/-26 ml/min/1.73 m2. The mean tacrolimus dose was 0.22+/-0.14 mg/ kg/day, and the level was 9.5+/-4.8 ng/ml. The mean prednisone dose was 2.1+/-4.9 mg/day (0.07+/-0.17 mg/kg/day), and 73% of successfully transplanted children were off prednisone. Seventy-nine percent were not taking any antihypertensive medications. The mean serum cholesterol level was 158+/-54 mg/dl. The incidence of delayed graft function was 4.3%. The incidence of rejection was 49%, and the incidence of steroid-resistant rejection was 6%. The incidence of rejection decreased to 27% in the most recent 26 cases (January 1994 through June 1995). The incidence of new-onset diabetes was 10.1%; six of the seven affected children were able to be weaned off insulin. The incidence of cytomegalovirus disease was 13%, and that of posttransplant lymphoproliferative disorder was 10%; the incidence of posttransplant lymphoproliferative disorder in the last 40 transplants was 5% (two cases). All of the children who developed posttransplant lymphoproliferative disorder are alive and have functioning allografts. Based on this data, we believe that tacrolimus is a superior immunosuppressive agent in pediatric renal transplant patients, with excellent short- and medium-term patient and graft survival, an ability to withdraw steroids in the majority of patients, and, with more experience, a decreasing rate of rejection and viral complications.

Adolescent↗
PubMed1996

"Suboptimal" kidney donors: the experience with tacrolimus-based immunosuppression.

Female, pediatric, and older donors have been associated with inferior graft survival after renal transplantation. We analyzed these three subgroups in 397 patients receiving tacrolimus-based immunosuppression. There were no differences in recipient age, incidence of retransplantation, or percentage of sensitized patients. Female donors, compared with male donors, were associated with comparable 1- and 3-year patient survival rates (96% and 93% vs. 95% and 92%, respectively) and comparable 1- and 3-year graft survival rates (90% and 80% vs. 88% and 81%, respectively). Renal function was also similar. Recipients of pediatric en bloc kidneys, when compared with recipients of other cadaveric kidneys, also had comparable 1- and 3-year patient survival rates (94% and 94% vs. 95% and 91%, respectively) and comparable 1- and 3-year graft survival rates (84% and 84% vs. 89% and 79%, respectively). Renal function was better in recipients of en bloc kidneys, with a mean serum creatinine level of 1.4+/-1.8 mg/dl vs. 2.0+/-1.5 mg/dl (P=0.01). In contrast to the first two subgroups, donors over 60 years of age, when compared with donors under 60 years of age, were associated with worse 1- and 3-year patient survival rates (88% and 80% vs. 96% and 94%, respectively; P<0.03) and worse 1- and 3-year graft survival rates (74% and 62% vs. 91% and 83%, respectively; P<0.0001). Renal function was worse in the older donor group, with a serum creatinine level of 2.7+/-1.2 mg/ml vs. 1.9+/-1.5 mg/dl (P=0.01). We conclude that, under tacrolimus-based immunosuppression, kidneys from female or very young pediatric donors are not associated with adverse outcomes, whereas kidneys from donors over 60 years of age are associated with inferior outcomes.

Adult↗
PubMed1996

The effect of legislative requirements on the use of breast-conserving surgery.

BACKGROUND: We studied the effect of state legislation requiring the disclosure of options for the treatment of breast cancer on the use of breast-conserving surgery in clinical practice. METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results registry provided data on women from 30 through 79 years of age who underwent breast-conserving surgery or mastectomy for local or regional breast cancer from 1983 through 1990. We examined the trend over time in use of breast-conserving surgery among patients in four sites (Connecticut, Iowa, Seattle, and Utah) where there were no state laws specifically requiring the disclosure of options for the treatment of breast cancer by physicians. For four additional sites (Detroit, Atlanta, New Mexico, and Hawaii) that had such legislation, we determined whether the rate of breast-conserving surgery after the legislation was different from the expected rate. RESULTS: An attorney rated the legislation as giving most direction to physicians in Michigan, followed by Hawaii, Georgia, and New Mexico. The rate of breast-conserving surgery was up to 8.7 percent higher than expected in Detroit for six months after the passage of the Michigan law (P<0.01). The rate was up to 13.2 percent higher than expected in Hawaii for 12 months after that state's law was passed (P<0.05) and up to 6.0 percent higher than expected in Atlanta for 3 months after the passage of the Georgia law (P<0.01). After these transient increases, the surgery rates reverted to the expected levels. No significant effect was detected in New Mexico, where only a resolution without legal force was passed. CONCLUSION: Legislation requiring physicians to disclose options for the treatment of breast cancer appeared to have only a slight and transient effect on the rate of use of breast-conserving surgery.

Adult↗
PubMed1996

Characterization of mouse angiogenin-related protein: implications for functional studies on angiogenin.

Angiogenin-related protein (Angrp), the putative product of a recently discovered mouse gene, shares 78% sequence identity with mouse angiogenin (Ang). In the present study, the relationship of Angrp to Ang has been investigated by producing both proteins in bacteria and comparing their functional properties. We find that mouse Ang is potently angiogenic, but Angrp is not, even when assayed at relatively high doses. A deficiency in catalytic capacity, which is essential for the biological activity of Ang, does not appear to underlie Angrp's lack of angiogenicity. In fact, Angrp has somewhat greater ribonucleolytic activity toward tRNA and dinucleotide substrates than does Ang. Instead, an inability to bind cellular receptors is implicated since Angrp does not inhibit Ang-induced angiogenesis. Poor conservation of the Ang receptor recognition sequence 58-69 in Angrp most likely contributes to this defect. However, other substitutions must also influence receptor binding since an Angrp quadruple mutant that is identical to Ang in this segment still lacks both angiogenic activity and the capacity to inhibit Ang. The functional differences between Ang and Angrp, together with evidence presented herein that Angrp is regulated differently than Ang, suggest that the roles of the two proteins in vivo may be quite distinct.

Animals↗
PubMed1996

A combined kinetic and modeling study of the catalytic center subsites of human angiogenin.

Kinetic analysis and molecular modeling have been used to map the ribonucleolytic center of angiogenin (Ang). Pyrimidine nucleotides were found to interact very weakly with Ang, consistent with the inaccessible B1 pyrimidine binding site revealed by x-ray crystallography. Ang also lacks an effective phosphate binding site on the 5' side of B1. Although the B2 site that preferentially binds purines on the 3' side of B1 is also weak, its associated phosphate subsites make substantial contributions: both 3',5'-ADP and 5'-ADP have Ki values 6-fold lower than for 5'-AMP, and adding a 3'-phosphate to the substrate CpA increases Kcat/Km by 9-fold. Thus Ang has a functional P2 site on the 3' side of B2 and a site for a second phosphate on the 5' side of B2. Modeling of an Ang-d(ApTpApA) complex suggested that Arg-5 forms part of the P2 site and that a 2'-phosphate might bind more tightly than a 3'-phosphate. Both predictions were confirmed kinetically. The subsite map obtained by this combined approach indicated that 5'-diphosphoadenosine 2'-phosphate might be a more potent inhibitor than any of the nucleotides tested thus far. Indeed, its Ki value of 150 microM is 50-fold lower than that for the best nucleotide previously reported and 400-fold lower than the Km for the best dinucleotide substrate. This compound may serve as a suitable starting point for the eventual design of tight-binding inhibitors of Ang as antiangiogenic agents for human therapy.

Adenosine Diphosphate↗
PubMed1996

The use of tacrolimus in renal transplantation.

Tacrolimus (FK 506) is a novel immunosuppressive agent that has been in clinical use for solid organ transplantation since 1989. Early clinical trials of tacrolimus in liver, heart, kidney, lung, and intestinal transplantation at the University of Pittsburgh have demonstrated it to be a safe and effective agent with several potential advantages over existing immunosuppressive drugs. More recently, phase I and II multicenter trials of tacrolimus for renal transplantation have been performed; however, data are not yet available from these trials. Our experience with this drug has demonstrated excellent 1- and 2-year actuarial graft survival rates of 89% and 83%, respectively, in adult renal transplantation and 1- and 3-year graft survival rates of 98% and 85%, respectively in pediatric renal transplantation. A major advantage of tacrolimus noted in these trials was the ability to discontinue steroid therapy in approximately 50% of the patients. Tacrolimus has also shown efficacy as a rescue agent for renal allograft rejection failing conventional therapy in 74% of cases. This paper expands on these observations and focuses on the experience we have gained with the use of tacrolimus at our institution over the last 6 years.

Graft Survival↗
PubMed1996

Cryoablation of unresectable malignant liver tumors.

BACKGROUND: Unresectable malignant liver tumors, particularly metastases of gastrointestinal origin, are rapidly lethal in a vast majority of patients, regardless of treatment. PATIENTS AND METHODS: We evaluated 58 patients by laparoscopy and/or laparotomy. Thirty-nine were treated with cryoablation of liver tumors using a liquid-nitrogen cryoprobe delivering a tumoricidal temperature of -196 degrees C with intraoperative ultrasound monitoring. Histologic evaluation showed that 25 patients had colorectal metastases, 3 had gastric tumors, 4 hepatocellular carcinomas, 6 carcinoids, and 1 gastrinoma. RESULTS: All patients who received complete cryoablation are alive with a mean follow-up of 14 months. Five whose treatment could not be completed died between 3 and 9 months postoperatively. Thirteen patients (28%) have recurrent disease and 20 (51%) have no evidence of disease. There were no operative mortalities. Postoperative transient elevation of liver function tests and thrombocytopenia were noted. All patients received postoperative chemotherapy. CONCLUSION: Cryoablation is an active and safe treatment for advanced liver malignancies.

Adult↗
PubMed1996

Delayed expansion of V delta 2+ and V delta 1+ gamma delta T cells after acute Plasmodium falciparum and Plasmodium vivax malaria.

T lymphocytes that express T-cell receptors encoded by the gamma and delta T-cell receptor genes (gamma delta T cells), and preferentially those expressing the V gamma 9 and V delta 2 gene segments, are activated by microbial and parasitic organisms in vitro and have been implicated in the pathogenesis of the fever and rigors during acute malaria. We have found, in a cohort of nine nonimmune patients who contracted malaria during travel to endemic areas (five with Plasmodium falciparum and four with P. vivax infections) that gamma delta T lymphocytes expanded to comprise 17.92% +/- 11% of the peripheral blood mononuclear cells (vs 3.08% +/- 2.4% gamma delta cells in normal control subjects). Although V delta 2+ cells predominated among the gamma delta subset, gamma delta lymphocytes expressing the V delta 1 gene segment also expanded significantly in some patients. Importantly, the gamma delta cells continued to expand for 2 months after the infection, and the mean level of gamma delta cells peaked during the second month after the acute clinical syndrome, when patients were free of symptoms. Thus although gamma delta T cells may contribute to the pathogenesis of the acute clinical syndrome, our findings suggest that gamma delta lymphocytes could also play a role in generating an immune response to plasmodia.

Acute Disease↗
PubMed1996

Adjuncts to mechanical ventilation.

Adjunctive ventilatory strategies have been developed to improve oxygenation and carbon dioxide (CO2) removal during mechanical ventilation of critically ill patients. These techniques allow clinicians to attain their clinical goals at lower levels of ventilatory support. In this article, the authors discuss extracorporeal CO2 removal, venovenous intravena caval oxygenator, and tracheal gas insufflation as adjuncts to CO2 removal and nitric oxide, surfactant replacement therapy, perfluorocarbon-associated gas exchange, and prone positioning as adjuncts to oxygenation.

Animals↗
PubMed1996

Solution properties and computational analysis of an oligodeoxynucleotide containing N-(deoxyguanosin-8-yl)-1-aminopyrene.

An oligodeoxyribonucleotide 5'-d(CTCATGAPATTCC), in which G(AP) denotes N-(guanin-8-yl)-1-aminopyrene, the C8-guanine adduct of reductively activated 1-nitropyrene, was synthesized and characterized by polyacrylamide gel electrophoresis, absorption and fluorescence spectroscopy, circular dichroism, and thermal melting studies. Polyacrylamide gel electrophoresis showed slower mobility of the adducted oligonucleotide in single-stranded form compared to its unmodified counterpart, as expected. In duplex form, however (with a deoxycytidine opposite the adduct), the adducted 11mer migrated faster than the parent duplex. Absorption and fluorescence studies indicated significant interaction of the aminopyrene residue with the DNA bases in the modified 11mer. The spectroscopic data also suggested the presence of one or more conformers in which the aminopyrene residue is quasi-intercalative, as well as one(s) in which the aminopyrene is externally bound. Thermodynamic parameters for the helix-to-coil transitions for the 11mer duplex were determined. The difference in free energy (delta delta G degree) between the unmodified and modified sequences was relatively small (approximately 1.2 kcal/mol). Circular dichroism spectra indicated the presence of essentially B-form DNA. The energy minimizations suggested that the most stable conformers shared a common feature: displacement of the modified guanine from the double helix. In the global minimum, the aminopyrene residue was inserted in the helix in the site of displaced guanine. In other low energy structures, the aminopyrene was also displaced towards the minor groove (in addition to guanine), or partly inserted and partly in the groove. More conventional structures were also encountered, with anti-guanine within the helix and aminopyrene in the major groove, or syn-guanine within the helix, and aminopyrene in the minor groove. Such structures were 12-20 kcal/mol less stable than the global minimum, however. The C8-guanine adduct of aminopyrene thus appears to perturb the B-DNA structure to a greater extent than do the adducts of less bulky amines such as aminofluorene and 4-aminobiphenyl.

Base Sequence↗
PubMed1996

Microvascular changes in renal allografts associated with FK506 (Tacrolimus) therapy.

FK506 (Tacrolimus) recently has been shown to be an effective immunosuppressant after renal transplantation. It is associated with less hypertension, hypercholesterolemia and steroid use compared with cyclosporine. We report 10 patients on FK506 who showed fibrin thrombi within the glomerular capillaries and/or arterioles at renal allograft biopsy. These biopsies were generally performed to assess increasing serum creatinine levels; laboratory evidence of hemolytic uremic syndrome was present in one instance. Plasma or whole blood FK506 levels were elevated in eight of 10 cases. Reduction of immunosuppression led to clinical improvement or biopsy-proven resolution of thrombi in all cases. These observations suggest that FK506 may occasionally produce microvascular changes in the renal allograft. The estimated incidence of this occurrence (1%) is comparable with that reported with cyclosporine (3%).

Adult↗
PubMed1996

Renal allograft involvement by Epstein-Barr virus associated post-transplant lymphoproliferative disease.

This study describes nine cases of post-transplant lymphoproliferative disease (PTLD) presenting as renal allograft dysfunction. Onset of symptoms was 34 to 265 days post-transplant, typically (in six of nine cases) after refractory rejection treated with OKT3. Diagnosis was made by histopathologic examination of needle biopsy (three of nine cases) or allograft nephrectomy (six of nine cases) specimens. Disease was confined to the allograft in three patients. The morphology was polymorphic in eight cases and monomorphic in one case. Five cases showed monotypic kappa or lambda light chain expression. Expansile lymphoid infiltrates, serpiginous necrosis, nuclear atypia, and presence of Epstein-Barr virus RNA helped to distinguish PTLD from severe rejection. Tubular damage and venulitis was common in PTLD lesions, but arterial involvement was not prominent. Infiltration of the ureter, hilar adipose tissue, and nerve twigs was frequent in nephrectomy specimens. Reduction of immunosuppression led to resolution of PTLD in two of three cases diagnosed by needle biopsy, but severe acute rejection led to graft loss in one case; the third case progressed to fatal multisystem disease. Among cases diagnosed at nephrectomy, two of six patients died of disseminated PTLD and one of six died of sepsis. The five surviving patients are alive 41 to 99 months after initial diagnosis without evidence of recurrent PTLD.

Adult↗
PubMed1996

Characteristic immune abnormalities in hemophagocytic lymphohistiocytosis.

PURPOSE: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by fever, hepatosplenomegaly, pancytopenia, and infiltration of vital organs by non-Langerhans histiocytes and is rapidly fatal without early diagnosis and institution of therapy. Immune dysregulation is thought to be responsible for the disease. PATIENTS AND METHODS: Extensive immune evaluation was performed on 13 consecutive patients diagnosed with HLH over a 4-year period to characterize existing immunologic abnormalities in order to improve early diagnosis. Evaluation included quantitative immunoglobulins, immunophenotyping, mitogen-induced lymphoproliferation, natural killer (NK) cell function, and cytotoxic T cell lymphocytolysis (CTL). RESULTS: Immunoglobulin levels showed no consistent abnormality. Immunophenotyping showed an absolute decrease in number of B cells but normal numbers and proportional distribution of T cell subsets and NK cells. Most patients demonstrated decreased proliferative responses to mitogens (10/13) and severely decreased to absent T cell cytotoxicity (11/12) and NK cytotoxic function (13/13). CONCLUSIONS: Our results show that while humoral immunity is essentially intact, cellular immune function is significantly impaired in the vast majority of patients with HLH. The coincident finding of profoundly decreased T cell cytotoxicity along with absent NK cytotoxicity suggests that patients with active HLH may have global cytotoxic dysfunction. Since the majority of our patients were studied prior to starting therapy, we feel that these findings reflect the pathophysiologic process and are not therapy related. Unclear from the present work is whether these findings represent primary or secondary dysfunction. We conclude from these studies that profoundly decreased CTL function and absence of NK cell function are characteristic immunologic features of HLH and may serve as additional laboratory data, in conjunction with currently proposed diagnostic guidelines, to support a diagnosis of HLH.

Antigens, Surface↗
PubMed1996

Promoter elements that mediate the pH response of PCK mRNA in LLC-PK1-F+ cells.

The onset of metabolic acidosis causes an increased transcription of the renal phosphoenolpyruvate carboxykinase (PCK) gene. When transgenic mice carrying a bovine growth hormone (bGH) gene driven by the -460 to +73 segment of the PCK promoter were made chronically acidotic, the bGH mRNA was increased twofold after 4 days. Confluent and well-differentiated cultures of LLC-PK1-F+ cells exhibit a 2.5-fold increase in PCK mRNA when transferred to acidic media (pH 6.9, 10 mM HCO3-) for 16 h. Confluent cultures transfected with PCK-490 CAT exhibit an increase (3.5-fold) in chloramphenicol acetyltransferase (CAT) activity when shifted to acidic medium for 48 h. Mutation or deletion of the P2 element causes a four- to fivefold decrease in basal CAT activity but does not affect the pH response. In contrast, mutations of the P3(II) element or the CRE-1 cAMP-response element have little effect on basal activity but cause a 50% decrease in the pH response. Other deletions or mutations have little effect on either activity. Thus changes in the activity or levels of the protein(s) in the renal proximal tubule that binds to the P3(II) and CRE-1 elements may mediate increased transcription of the PCK gene during metabolic acidosis.

Animals↗