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J McCauley

Publications and source records attributed to J McCauley.

At least 19 recordsLinked to original sources
PubMed2006

Living donor renal transplantation using alemtuzumab induction and tacrolimus monotherapy.

Alemtuzumab was used as an induction agent in 205 renal transplant recipients undergoing 207 living donor renal transplants. All donor kidneys were recovered laparoscopically. Postoperatively, patients were treated with tacrolimus monotherapy, and immunosuppression was weaned when possible. Forty-seven recipients of living donor renal transplants prior to the induction era who received conventional triple drug immunosuppression without antibody induction served as historic controls. The mean follow-up was 493 days in the alemtuzumab group and 2101 days in the historic control group. Actuarial 1-year patient and graft survival were 98.6% and 98.1% in the alemtuzumab group, compared to 93.6% and 91.5% in the control group, respectively. The incidence of acute cellular rejection (ACR) at 1 year was 6.8% in the alemtuzumab group and 17.0% (p < 0.05) in the historic control group. Most (81.3%) episodes of ACR in the alemtuzumab group were Banff 1 (a or b) and were sensitive to steroid pulses for the treatment of rejection. There was no cytomegalovirus disease or infection. The incidence of delayed graft function was 0%, and the incidence of posttransplant insulin-dependent diabetes mellitus was 0.5%. This study represents the largest series to date of live donor renal transplant recipients undergoing alemtuzumab induction, and confirms the short-term safety and efficacy of this approach.

Adult↗
PubMed2005

Variation in the ability of human influenza A viruses to induce and inhibit the IFN-beta pathway.

We investigated the ability of a selection of human influenza A viruses, including recent clinical isolates, to induce IFN-beta production in cultured cell lines. In contrast to the well-characterized laboratory strain A/PR/8/34, several, but not all, recent isolates of H3N2 viruses resulted in moderate IFN-beta stimulation. Through the generation of recombinant viruses, we were able to show that this is not due to a loss of the ability of the NS1 genes to suppress IFN-beta induction; indeed, the NS1 genes behaved similarly with respect to their abilities to block dsRNA signaling. Interestingly, replication of A/Sydney/5/97 virus was less susceptible to pre-treatment with IFN-alpha than the other viruses. In contrast to the universal effect on dsRNA signaling, we noted differences in the effect of NS1 proteins on expression of interferon stimulated genes and also genes induced by a distinct pathway. The majority of NS1 proteins blocked expression from both IFN-dependent and TNF-dependent promoters by an apparent post-transcriptional mechanism. The NS1 gene of A/PR/8/34 NS1 did not confer these blocks. We noted striking differences in the cellular localization of different influenza A virus NS1 proteins during infection, which might explain differences in biological activity.

Animals↗
PubMed2005

Reversal of acute cellular rejection after renal transplantation with Campath-1H.

Between September 2002 and February 2004, 40 kidney transplant (27 from deceased and 13 from living donors) recipients (25 male and 15 female, aged 50.3 +/- 15.1 years) were treated with Campath 1H (C 1H; 30 mg/dose IV) for biopsy-proven steroid-resistant rejection (SRR) or rejections equal to or worse than Banff 1B. All transplantations occurred between August 2001 and May 2003. All patients had received antibody preconditioning (RATG 5 mg/kg, n = 34; C 1H 60 mg, n = 4; C 1H 30 mg, n = 2) preoperatively and were treated with Tacrolimus monotherapy (target level 10 ng/ml) postoperatively and subsequent spaced weaning. Elevated creatinine levels at follow-up were evaluated by renal transplant biopsy. Rejection was treated with steroids, reversal of weaning, addition of sirolimus, and/or antibody treatment, depending on grade of rejection. The mean duration of follow-up was 453 +/- 163 days after C 1H administration. Twenty-nine patients received C 1H for SRR and 11 patients for Banff 1B or worse rejections; 26 patients received more than 1 dose of C 1H. Graft survival was 62.5% (25 patients); 6 of the 15 allografts (40%) that failed had presented with rejections because of noncompliance. Graft survival in compliant patients with SRR or rejections equal to or worse than Banff 1B was 73.5% (25 of 34). Fourteen patients (35%) had infectious complications, of whom 2 patients (5%) died. C 1H is an effective agent for SRR and Banff 1B or worse rejections, with 95% patient survival and 73.5% graft survival (in compliant patients). The number of doses of 30 mg C 1H should be restricted to two, as there is a high incidence of potentially fatal infectious complications.

Acute Disease↗
PubMed2005

Steroid-free tacrolimus monotherapy after pretransplantation thymoglobulin or Campath and laparoscopy in living donor renal transplantation.

Living donor renal transplantation was performed under a regimen of recipient pretreatment and low-dose postoperative immunosuppression with subsequent weaning. From October 9, 2002, to December 31, 2004, 196 consecutive, unselected laparoscopic live donor nephrectomies resulting in 196 living donor renal transplantations were performed. Recipients were pretreated with rabbit antithymocyte globulin (thymoglobulin; 24 patients or [12%]) or Campath 1H (alemtuzumab; 166 patients [85%]), or were not in protocol (6 patients [3%]), and were given postoperative steroid-free low-dose tacrolimus immunosuppressive monotherapy with subsequent weaning. There was no donor mortality. Major and minor donor morbidities were 2.6% and 4.2%, respectively. Laparoscopic live donor nephrectomy recipient outcomes with a mean follow-up of 401 days included (1) recipient and graft survival of 99.0% and 97.4%, respectively; (2) no ureteral stenosis; (3) 0.5% delayed graft function, from recurrent focal segmental glomerulosclinosis; and (4) no vascular thrombosis. The incidence of acute rejection at 30, 90, and 401 days was 1.5%, 3.8%, and 11.2% (all 196 recipients), 0%, 25%, and 29.2% (thymoglobulin recipients), and 1.8%, 3.9%, and 8.4% (Campath 1H recipients), respectively. Sixty-six patients (33.7%) are receiving spaced-dose immunosuppressive monotherapy. The mean creatinine concentration in all recipients was 1.5 +/- 1.1 mg/dL. There were no instances of cytomegalovirus tissue invasive disease or posttransplantation lymphoproliferative disease. The incidence of new-onset posttransplantation insulin-dependent diabetes was 0.5%. At current follow-up, the use of Campath 1H rather than thymoglobulin for pretreatment seems to have significantly improved the efficacy of our regimen.

Adult↗
PubMed2001

An analysis of early renal transplant protocol biopsies--the high incidence of subclinical tubulitis.

To investigate the possibility that we have been underestimating the true incidence of acute rejection, we began to perform protocol biopsies after kidney transplantation. This analysis looks at the one-week biopsies. Between March 1 and October 1, 1999, 100 adult patients undergoing cadaveric kidney or kidney/pancreas transplantation, or living donor kidney transplantation, underwent 277 biopsies. We focused on the subset of biopsies in patients without delayed graft function (DGF) and with stable or improving renal function, who underwent a biopsy 8.2+/-2.6 d (range 3-18 d) after transplantation (n = 28). Six (21%) patients with no DGF and with stable or improving renal function had borderline histopathology, and 7 (25%) had acute tubulitis on the one-week biopsy. Of the 277 kidney biopsies, there was one (0.4%) serious hemorrhagic complication, in a patient receiving low molecular weight heparin; she ultimately recovered and has normal renal function. Her biopsy showed Banff 1B tubulitis. In patients with stable or improving renal allograft function early after transplantation, subclinical tubulitis may be present in a substantial number of patients. This suggests that the true incidence of rejection may be higher than is clinically appreciated.

Adult↗
PubMed2001

Interaction of the influenza virus nucleoprotein with the cellular CRM1-mediated nuclear export pathway.

Influenza virus transcription occurs in the nuclei of infected cells, where the viral genomic RNAs are complexed with a nucleoprotein (NP) to form ribonucleoprotein (RNP) structures. Prior to assembly into progeny virions, these RNPs exit the nucleus and accumulate in the cytoplasm. The mechanisms responsible for RNP export are only partially understood but have been proposed to involve the viral M1 and NS2 polypeptides. We found that the drug leptomycin B (LMB), which specifically inactivates the cellular CRM1 polypeptide, caused nuclear retention of NP in virus-infected cells, indicating a role for the CRM1 nuclear export pathway in RNP egress. However, no alteration was seen in the cellular distribution of M1 or NS2, even in the case of a mutant virus which synthesizes greatly reduced amounts of NS2. Furthermore, NP was distributed throughout the nuclei of infected cells at early times postinfection but, when retained in the nucleus at late times by LMB treatment, was redistributed to the periphery of the nucleoplasm. No such change was seen in the nuclear distribution of M1 or NS2 after drug treatment. Similar to the behavior of NP, M1 and NS2 in infected cells, LMB treatment of cells expressing each polypeptide in isolation caused nuclear retention of NP but not M1 or NS2. Conversely, overexpression of CRM1 caused increased cytoplasmic accumulation of NP but had little effect on M1 or NS2 distribution. Consistent with this, NP bound CRM1 in vitro. Overall, these data raise the possibility that RNP export is mediated by a direct interaction between NP and the cellular CRM1 export pathway.

Animals↗
PubMed2000

Renal allograft rejection with normal renal function in simultaneous kidney/pancreas recipients: does dissynchronous rejection really exist?

BACKGROUND: Between July 1, 1994 and December 1, 1998, 147 simultaneous kidney/pancreas transplantations were performed at our center. Of 95 patients who experienced at least one acute renal allograft rejection episode after transplantation, 7 (7.4%) developed rejection in the presence of stable and normal or near-normal renal function. METHODS: The indication for renal allograft biopsy was a rising serum lipase, i.e., suspected pancreatic rejection. All seven patients were treated with steroids and augmentation of the tacrolimus dose, with a fall in the serum lipase and no change in the serum creatinine. RESULTS: The serum creatinine levels just before, at the time of, 1 week after the biopsy, and at most recent follow-up were 1.4+/-0.4, 1.3+/-0.3, 1.2+/-0.2, and 1.2+/-0.2 mg/dl. The serum lipase levels just before, at the time of, 1 week after the biopsy, and at most recent follow-up were 1022+/-1157 mg/dl, 874+/-996 mg/dl, 243+/-260 mg/dl, and 94+/-75 mg/dl. The tacrolimus dosages and levels at the time of the biopsy and 1 week later were 14.9+/-5.0 mg/day and 15.0+/-4.0 ng/ml, and 16.4+/-6.3 mg/day and 15.1+/-6.8 ng/ml. CONCLUSIONS: These findings suggest that, in patients undergoing simultaneous kidney/pancreas transplantation, the entity of dissynchronous pancreatic allograft rejection without renal allograft rejection may not really exist. These data also make an additional fundamental point that acute rejection may occur in patients with normal and stable renal function.

Graft Rejection↗
PubMed1999

Posttransplant lymphoproliferative disorders in adult and pediatric renal transplant patients receiving tacrolimus-based immunosuppression.

Between March 27, 1989 and December 31, 1997, 1316 kidney transplantations alone were performed under tacrolimus-based immunosuppression at our center. Posttransplant lymphoproliferative disorders (PTLD) developed in 25 (1.9%) cases; the incidence in adults was 1.2% (15/1217), whereas in pediatric patients it was 10.1% (10/99; P<.0001). PTLD was diagnosed 21.0+/-22.5 months after transplantation, 25.0+/-24.7 months in adults and 14.4+/-18.2 months in pediatric patients. Of the 4 adult cases in whom both the donor and recipient Epstein Barr virus (EBV) serologies were known, 2 (50%) were seropositive donor --> seronegative recipient. Of 7 pediatric cases in whom both the donor and recipient EBV serologies were known, 6 (86%) were EBV seropositive donor --> seronegative recipient. Acute rejection was observed before the diagnosis of PTLD in 8 (53%) of 15 adults and 3 (30%) of 10 pediatric patients. Initial treatment of PTLD included a marked decrease or cessation of immunosuppression with concomitant ganciclovir therapy; two adults and two pediatric patients required chemotherapy. With a mean follow-up of 24.9+/-30.1 months after transplantation, the 1- and 5-year actuarial patient and graft survival rates in adults were 93% and 86%, and 80% and 60%, respectively. Two adults died, 3.7 and 46.2 months after transplantation, of complications related to PTLD, and 10 (including the 2 deaths) lost their allograft 3.7-84.7 months after transplantation. In children, the 1- and 5-year actuarial patient and graft survival rates were 100% and 100%, and 100% and 89%, respectively. No child died; one child lost his allograft 41.3 months after transplantation. One child had presumed recurrent PTLD that responded to discontinuation of tacrolimus and reinitiation of antiviral therapy. The mean serum creatinine level in adults was 2.5+/-1.2 mg/dl, and in children, it was 1.3+/-0.6 mg/ dl. Under tacrolimus-based immunosuppression, PTLD is less common after renal transplantation in adults than in children, but PTLD in children is associated with more favorable outcomes than in adults.

Adolescent↗
PubMed1999

Relenza.

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Antiviral Agents↗
PubMed1999

Imino sugars inhibit the formation and secretion of bovine viral diarrhea virus, a pestivirus model of hepatitis C virus: implications for the development of broad spectrum anti-hepatitis virus agents.

One function of N-linked glycans is to assist in the folding of glycoproteins by mediating interactions of the lectin-like chaperone proteins calnexin and calreticulin with nascent glycoproteins. These interactions can be prevented by inhibitors of the alpha-glucosidases, such as N-butyl-deoxynojirimycin (NB-DNJ) and N-nonyl-DNJ (NN-DNJ), and this causes some proteins to be misfolded and retained within the endoplasmic reticulum (ER). We have shown previously that the NN-DNJ-induced misfolding of one of the hepatitis B virus (HBV) envelope glycoproteins prevents the formation and secretion of virus in vitro and that this inhibitor alters glycosylation and reduces the viral levels in an animal model of chronic HBV infection. This led us to investigate the effect of glucosidase inhibitors on another ER-budding virus, bovine viral diarrhea virus, a tissue culture surrogate of human hepatitis C virus (HCV). Here we show that in MDBK cells alpha-glucosidase inhibitors prevented the formation and secretion of infectious bovine viral diarrhea virus. Data also are presented showing that NN-DNJ, compared with NB-DNJ, exhibits a prolonged retention in liver in vivo. Because viral secretion is selectively hypersensitive to glucosidase inhibition relative to the secretion of cellular proteins, the possibility that glucosidase inhibitors could be used as broad-based antiviral hepatitis agents is discussed. A single drug against HBV, HCV, and, possibly, HDV, which together chronically infect more than 400 million people worldwide, would be of great therapeutic value.

1-Deoxynojirimycin↗
PubMed1999

Renal transplantation in recipients over the age of 60: the impact of donor age.

BACKGROUND: Kidneys from older donors exhibit a series of changes characterized by glomerular, vascular, and tubular senescence. These changes may be aggravated by atherosclerosis, hypertension, or diabetes, which are highly prevalent in older individuals. METHODS: We analyzed the outcome after transplantation in 230 recipients over the age of 60, who received transplants between February 1990 and December 1996. We assessed the 1- and 5-year patient and graft survival, the quality of renal function, tacrolimus levels, the incidence of rejection, and the incidence of delayed graft function, and compared the outcomes in recipients of kidneys from donors over the age of 60 (group 1, n = 40) with those in recipients of kidneys from donors under the age of 60 (group 2, n = 190). There were no differences between the two groups in terms of recipient sex, race, age, and cold ischemia time. Immunosuppression was with tacrolimus and steroids in 61% of cases; in the remainder of the patients, a third agent, either azathioprine, cyclophosphamide (for 1 week), or mycophenolate mofetil was administered as well. The median follow-up was 31.5 months (range: 1-86). RESULTS: In recipients over the age of 60 receiving tacrolimus-based immunosuppression, overall patient survival at 1 and 5 years was 90% and 76%, and was not significantly compromised in recipients receiving a kidney from a donor over the age of 60. The overall 1-and 5-year actuarial graft survival was 84% and 64%; in recipients from donors over the age of 60, it was 73% and 52%, whereas in recipients of kidneys from donors under the age of 60, it was 87% and 66% (P<0.05). Most of the effect on graft survival was seen by 1 year. The mean serum creatinine was 2.6+/-2.7 mg/dl, without any difference between the two groups. Although the incidence of delayed graft function was higher in recipients of kidneys from donors over the age of 60, this difference did not reach statistical significance. CONCLUSIONS: Although the overall outcomes of transplantation in older recipients remain reasonable, the inferior outcomes with older donor kidneys call into question proposals to utilize older donor kidneys preferentially in older recipients.

Adult↗
PubMed1999

A prospective, randomized trial of tacrolimus/prednisone versus tacrolimus/prednisone/mycophenolate mofetil in renal transplant recipients.

BACKGROUND: Between September 20, 1995 and September 20, 1997, 208 adult patients undergoing renal transplantation were randomized to receive tacrolimus/prednisone (n=106) or tacrolimus/prednisone/mycophenolate mofetil (n=102), with the goal of reducing the incidence of rejection. METHODS: The mean recipient age was 50.7+/-13.7 years. Sixty-three (30.3%) patients were 60 years of age or older at the time of transplantation. The mean donor age was 34.5+/-21.7 years. The mean cold ischemia time was 30.5+/-9.2 hr. The mean follow-up is 15+/-7 months. RESULTS: The overall 1-year actuarial patient survival was 94%; the overall 1-year actuarial graft survival was 87%. When the patient and graft survival data were stratified to recipients under the age of 60 who did not have delayed graft function, the overall 1-year actuarial patient survival was 97%, and the corresponding 1-year actuarial graft survival was 93%. There were no differences between the two groups. The overall incidence of rejection was 36%; in the double-therapy group, it was 44%, whereas in the triple therapy group, it was 27% (P=0.014). The mean serum creatinine was 1.6+/-0.8 mg/dl. A total of 36% of the successfully transplanted patients were taken off prednisone; 32% of the patients were taken off antihypertensive medications. The incidence of delayed graft function was 21%, the incidence of cytomegalovirus was 12.5%, and the initial and final incidences of posttransplant insulin-dependent diabetes mellitus were 7.0% and 2.9%; again, there was no difference between the two groups. CONCLUSIONS: This trial suggests that the combination of tacrolimus, steroids, and mycophenolate mofetil is associated with excellent patient and graft survival and a lower incidence of rejection than the combination of tacrolimus and steroids.

Adolescent↗
PubMed1999

Pediatric renal transplantation under tacrolimus-based immunosuppression.

BACKGROUND: Tacrolimus has been used as a primary immunosuppressive agent in adult and pediatric renal transplant recipients, with reasonable outcomes. Methods. Between December 14, 1989 and December 31, 1996, 82 pediatric renal transplantations alone were performed under tacrolimus-based immunosuppression without induction anti-lymphocyte antibody therapy. Patients undergoing concomitant or prior liver and/or intestinal transplantation were not included in the analysis. The mean recipient age was 10.6+/-5.2 years (range: 0.7-17.9). Eighteen (22%) cases were repeat transplantations, and 6 (7%) were in patients with panel-reactive antibody levels over 40%. Thirty-four (41%) cases were with living donors, and 48 (59%) were with cadaveric donors. The mean donor age was 27.3+/-14.6 years (range: 0.7-50), and the mean cold ischemia time in the cadaveric cases was 26.5+/-8.8 hr. The mean number of HLA matches and mismatches was 2.8+/-1.2 and 2.9+/-1.3; there were five (6%) O-Ag mismatches. The mean follow-up was 4.0+/-0.2 years. RESULTS: The 1- and 4-year actuarial patient survival was 99% and 94%. The 1- and 4-year actuarial graft survival was 98% and 84%. The mean serum creatinine was 1.1+/-0.5 mg/dl, and the corresponding calculated creatinine clearance was 88+/-25 ml/min/1.73 m2. A total of 66% of successfully transplanted patients were withdrawn from prednisone. In children who were withdrawn from steroids, the mean standard deviation height scores (Z-score) at the time of transplantation and at 1 and 4 years were -2.3+/-2.0, -1.7+/-1.0, and +0.36+/-1.5. Eighty-six percent of successfully transplanted patients were not taking anti-hypertensive medications. The incidence of acute rejection was 44%; between December 1989 and December 1993, it was 63%, and between January 1994 and December 1996, it was 23% (P=0.0003). The incidence of steroid-resistant rejection was 5%. The incidence of delayed graft function was 5%, and 2% of patients required dialysis within 1 week of transplantation. The incidence of cytomegalovirus was 13%; between December 1989 and December 1992, it was 17%, and between January 1993 and December 1996, it was 12%. The incidence of early Epstein-Barr virus-related posttransplant lymphoproliferative disorder (PTLD) was 9%; between December 1989 and December 1992, it was 17%, and between January 1993 and December 1996, it was 4%. All of the early PTLD cases were treated successfully with temporary cessation of immunosuppression and institution of antiviral therapy, without patient or graft loss. CONCLUSIONS: These data demonstrate the short- and medium-term efficacy of tacrolimus-based immunosuppression in pediatric renal transplant recipients, with reasonable patient and graft survival, routine achievement of steroid and anti-hypertensive medication withdrawal, gratifying increases in growth, and, with further experience, a decreasing incidence of both rejection and PTLD.

Actuarial Analysis↗
PubMed1999

Vitamin K deficiency with hemorrhage after kidney and combined kidney-pancreas transplantation.

Vitamin K deficiency is a common occurrence in the surgical and intensive care unit population, but its incidence in kidney and combined kidney-pancreas allograft recipients has not been described. We report four patients who received cadaveric kidney or combined kidney-pancreas allografts and subsequently developed significant bleeding associated with deficiency of vitamin K. Their coagulopathy promptly resolved with the parenteral administration of vitamin K. Treatment with vitamin K should be considered in kidney or combined kidney-pancreas allograft recipients with a prolonged prothrombin or partial thromboplastin time during the first postoperative week to avoid hemorrhagic complications.

Adult↗
PubMed1999

Centrosome proteins: a major class of autoantigens in scleroderma.

Autoantibodies to intracellular antigens are a hallmark of autoimmune diseases, although their role in disease pathogenesis is unclear. Centrosomes are organelles involved in the organization of the mitotic spindle and they are targets of autoantibodies in systemic sclerosis (SSc). We used recombinant centrosome autoantigens, centrosome-specific antibodies, and immunoassays to demonstrate that a significant proportion of SSc patients exhibited centrosome reactivity. Two centrosome proteins cloned in our laboratory were used to screen 129 SSc sera by Western blotting. The same sera were screened by immunofluorescence using centrosome-specific antibodies to distinguish centrosomes from nuclear speckles commonly stained by SSc sera. Using these criteria, 42.6% of SSc patients were autoreactive to centrosomes, a larger percentage than reacted with all other known SSc autoantigens. Most centrosome-positive sera reacted with both centrosome proteins and half were negative for other routinely assayed SSc autoantibodies. By these criteria, we have identified a novel class of SSc autoreactivity. Only a small percentage of normal individuals and patients with other connective tissue diseases had centrosome reactivity. These results demonstrate that centrosome autoantibodies are a major component of autoreactivity in SSc and thus have potential in disease diagnosis. Centrosome autoantigens may be useful in studying the development of autoantibodies and chronic inflammation in SSc and perhaps other autoimmune diseases.

Antigens↗