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Biomedical subjects

S Kulkarni

Publications and source records attributed to S Kulkarni.

At least 91 records · Page 5Linked to original sources

Allograft reconstruction of the extensor mechanism for progressive extensor lag after total knee arthroplasty and previous patellectomy: a 3-year follow-up.

Major extensor lag after total knee arthroplasty may follow operative damage to the patellar tendon or its insertion. It may also occur in a late progressive form postoperatively. A successful allograft reconstruction of the extensor mechanism for progressive extensor lag after total knee arthroplasty is described. Patellectomy had been carried out earlier on the same knee for patellofemoral osteoarthritis.

Aged↗

Use of autologous growth factors in lumbar spinal fusion.

The results of spinal fusion, especially posteriorly above the lumbosacral junction, have been mixed. Autologous growth factor concentrate (AGF) prepared by ultraconcentration of platelets contains multiple growth factors having a chemotactic and mitogenic effect on mesenchymal stem cells and osteoblasts and may play a role in initiating bone healing. The purpose of this retrospective study is to review our results with AGF in lumbar spinal fusions. To date, AGF has been used in 39 patients having lumbar spinal fusion. The study group consisted of the first 19 consecutive cases to allow at least 6 months follow-up. The average follow-up was 13 months (range 6 to 18 months). Follow-up compliance was 91%. There were 7 men and 12 women. Average age was 52 years (range 30-72 years). Nine patients had prior back surgery. There were 8 smokers. AGF was used in posterior (n = 15) or anterior intradiscal (n = 4) fusions. AGF was used with autograft and coraline hydroxyapatite in all posterior fusions, and autograft, coral, and intradiscal spacer (carbon fiber spinal fusion cages or Synthes femoral ring) in intradiscal fusions. Posterior stabilization was used in all cases. Eight cases were single-level fusions, 6 were two-level, and 1 was a three-level fusion. Autologous iliac crest bone graft was taken in 14 cases and local autograft used in 5 cases. Posteriorly, a total of 23 levels were fused; of these, nine were at L5-S1, eight at L4-L5, five at L3-L4, and one at L2-L3. No impending pseudoarthroses were noted on plain radiographic examination at last follow-up visit. Solid fusion was confirmed in 3 patients having routine hardware removal, and in 2 patients who had surgery at an adjacent level. There was one posterior wound infection, which was managed without sequelae. When used as an adjunct to autograft, AGF offers theoretical advantages that need to be examined in controlled studies. Further study is necessary to determine whether coralline hydroxyapatite used as a bone graft extender in lumbar spinal fusion may help to obviate the need for secondary site graft harvesting.

Adult↗

Impact of previous high-dose therapy on outcome after allografting for multiple myeloma.

We describe a single centre experience of 33 patients allografted for multiple myeloma, of which 28 received matched sibling marrow, one haploidentical family donor marrow and four matched but unrelated donor marrow. Median follow-up after transplant is 27 months, and 13 patients are currently alive. One out of four patients with an unrelated donor survives and 12 out of 28 (42.8%) with matched sibling donors. Four patients were unevaluable because of early death (<day 21), and one patient experienced graft failure. The probability of overall survival is 35.7 % at 3 years. The probability of disease-free survival is 39% at 3 years, and the probability of treatment-related mortality is 54% at 1 year. Acute GVHD developed in 26 (78.8%) patients and was responsible for six deaths. Twenty-four patients (72.7%) developed renal dysfunction and 22 (66.7%) developed hepatic dysfunction. Seventeen patients (51.5%) died of transplant-related problems in the first 150 days, and one at 6 months. Among the 13 survivors, none has experienced disease progression at a median follow-up of 27 months (range 3-65 months). We conclude that since allogeneic bone marrow transplantation is the only potentially curative option in myeloma, it should be offered to younger patients early in the course of their disease, when procedure-related morbidity and mortality are likely to be at their lowest.

Adult↗

Recombinant tissue plasminogen activator (rtPA) for the treatment of hepatic veno-occlusive disease (VOD).

Seventeen patients who developed hepatic veno-occlusive disease (VOD) following hematopoietic stem cell transplantation were treated with recombinant tissue plasminogen activator (rtPA) with or without heparin. rtPA was started a median of 13 days post transplant (range 4-35). All patients received rtPA at a dose of 10 mg/day as a starting dose, and 12 patients also received heparin (1500 U bolus; then 100 U/kg/day as a continuous i.v. infusion). The median number of days of rtPA therapy was 2.5 (1-12). The median total serum bilirubin level was 116 mmol/l (range 63-194) at the beginning of treatment. Six patients showed a response to rtPA treatment (29%). It was observed that by day 2 of rtPA therapy, bilirubin levels in responders showed a downwards trend as compared to those in nonresponders. In all except one patient this response was observed after two doses of rtPA. Seven out of the 11 non-responders had a past history of liver dysfunction, compared with none of the responders. There were no differences between the two groups in terms of day of onset of liver dysfunction, manifestations of disease, maximum bilirubin and creatinine levels, and day of commencing treatment. No patient experienced severe hemorrhagic complications during therapy. Four responders survived for more than 100 days compared to none of the non-responders. Probability of survival was 33% at day 100. It is difficult to unequivocally establish the role of rtPA in the treatment of VOD. The importance of bilirubin levels on days 2 or 3 of therapy in predicting outcome should be established, as should the optimum dose of rtPA and optimum duration of therapy.

Adult↗

Long-term outcome of adult acute leukemia patients who are alive and well 2 years after autologous blood or marrow transplantation.

We studied the long-term outcome of 87 adults with acute leukemia (age 15-59 years at transplant, median 27; 44 myeloid, 42 lymphoblastic, one biphenotypic) who were alive in continuous remission 2 years after a marrow (n = 74) or blood stem cell (n = 13) autograft. Nine relapsed 25-50 months (median 38) after transplantation. Five relapses were straightforward with no karyotypic or morphologic evolution of the original disease. Four recurrences were unusual, with development of myelodysplasia (n = 3) or myeloproliferative disease (n = 1). Five patients died of relapsed disease and four are still alive. Two patients died of complications related to the transplant, and one of ischemic heart disease. Seventy-nine patients (91%) are alive in remission 24-149 months (median 67) after transplantation (75 in continuous remission and four after further therapy) with Karnofsky scores of 80-100% (median 100%). The 8-year probabilities of survival, toxic death, and relapse (from the 2-year mark) are 89%, 3% and 12%. Eleven (12%) survivors had creatinine levels of >110 micromol/l (one more than double), and 14 (16%) had bilirubin levels of >17 mmol/l (one more than double) at the last follow-up. None of the following factors was found to be predictive for survival, non-relapse death, or relapse from the 2-year mark in multivariate analysis: age, sex, type of leukemia, disease stage, diagnosis, conditioning, origin of cells, and nucleated cell dose. We conclude that adult patients with acute leukemia who are alive and well 2 years following an autograft have a high probability of being cured, and the incidence of long-term liver and kidney dysfunction measured by serum bilirubin and creatinine is low.

Acute Disease↗

Complete remission rate and outcome after intensive treatment of 177 patients under 75 years of age with IgG myeloma defining a circumscribed disease entity with a new staging system.

Because the presence of IgG paraprotein in the blood is clear cut, it makes IgG myeloma a more circumscribed disease than myeloma as a whole in which to study treatment efficacy, particularly relating to complete remission (CR). Between May 1989 and December 1997, 177 consecutive patients with IgG myeloma who were <75 years old were seen, of whom 153 entered a sequential therapy (ST) programme of initial courses of C-VAMP infusional chemotherapy (IC), high-dose treatment (with or without stem cell rescue) (119 patients) and maintenance interferon (87 patients). 74/153 (48.4%) patients entered CR. Median overall survival (OS) and event-free survival (EFS) were 4.9 and 2.1 years, respectively. Multivariate analysis at presentation showed OS was significantly prolonged for beta2M <2.7 mg/l and age 8.5 g/dl predicted for longer EFS. For CR patients, age <median 51 years, absence of Bence-Jones proteinuria (BJP), male sex and white blood cells (WBC) <7 x 109/l predicted for a longer OS. Longer length of first CR was predicted by absence of BJP at presentation (P = 0.03) and fewer than five courses of IC (P = 0.02) to attain CR. We have therefore been able to refine the use of ST in IgG myeloma, redefine CR as a 'macro' endpoint, and propose a new staging system for IgG myelomas. Analysis of 41 comparable IgA patients showed IgG to be a distinct entity.

Adult↗

Functional and fibrinogen receptor studies in platelets in pre-eclamptic toxaemia of pregnancy.

It is believed that platelets play a key role in the production of pre-eclamptic toxaemia and toxaemia of pregnancy. Toxaemia of pregnancy is described as a condition of chronic DIC where there is thrombocytopenia as well as raised fibrin degradation products. Since fibrinogen receptors are involved in the final stage of the platelet aggregation reaction, we wanted to investigate the platelet receptors for fibrinogen in normal and abnormal pregnancy. Thirty-six normal pregnant women (12 in their 2nd trimester, 24 in their 3rd trimester), 24 pregnant pre-eclamptic toxaemia cases and 16 non-pregnant controls were included in the present study. All patients with pre-eclamptic toxaemia had oedema, proteinuria and hypertension. Flow cytometric study of platelets was undertaken utilizing fluorescein isothiocyanate (FITC)-labelled anti-human fibrinogen antibody in unstimulated and ADP-stimulated (final concentration 0.02 M) platelets. The intensity of platelet fluorescence was classified into three groups and expressed in arbitrary units. The results indicate that there are a higher number of stimulated platelets expressing fibrinogen receptors in the circulation of patients with pre-eclampsia. Thus, it is possible to hypothesize that platelets showing increased fibrinogen receptors aggregate and form microthrombi in smaller vessels in women with pre-eclamptic toxaemia.

Journal Article↗

Oral idarubicin as a single agent therapy in patients with relapsed or resistant multiple myeloma.

The established treatment for multiple myeloma (MM) comprises induction with infusional chemotherapy, high dose chemotherapy (HDC) and autologous transplantation followed by maintenance interferon. On relapse, patients (pts) are reconsidered for this however some are unsuitable and in this situation the therapeutic options are limited. Between June 1995 and May 1997, 14 pts with previously treated relapsed or refractory MM were recruited. Using a prospective database, the tolerability and efficacy of chronic low dose oral idarubicin was evaluated. The median age of pts was 63 years. All had received previous anthracycline in the form of infusional cVAMP chemotherapy. 11/14 had received previous HDC. Median time from diagnosis to commencing idarubicin was 77 months. 10 mg idarubicin was administered 3 times/week for 3 weeks of a 5 week cycle. The maximum number of courses was 6. Three pts completed 6 courses, 5 pts 3 courses, 2 pts 2 courses and 4 pts 1 course. The reasons for stopping treatment were death due to progressive disease (PD) in 7 pts, persistent thrombocytopenia in 2 pts, PD in 1 pt and 1 pt suffered a cerebral infarction not considered to be related to the idarubicin therapy. Two pts showed evidence of response, neither amounting to a partial response. One had stabilisation of paraprotein with a reduction in bone marrow infiltration (47% to 7% plasma cells), the other had a reduction in bone marrow infiltration after 3 course but an increase after 6 courses. In total forty-one courses of treatment were administered. Grade 3/4 haematological toxicities were noted in a minor fraction of cases and were as follows: anaemia 6/41, neutropenia 10/41 and thrombocytopenia 11/41. Our data therefore shows a minor response in 2/14 (14%) of heavily pretreated patients with MM, without evidence of severe toxicity. It provides the rationale for using oral idarubicin as either single agent or in combination therapy for patients earlier on in their disease course especially if they are unsuitable for standard therapy.

Adult↗

Immunochemotherapy for Leishmania donovani infection in golden hamsters: combinatorial action of poly ICLC plus L-arginine and sodium stibogluconate (Stibanate).

We demonstrate that golden hamsters infected with Leishmania donovani amastigotes develop the capacity to eliminate intracellular pathogens on treatment with low-dose standard antileishmanial sodium stibogluconate (Stibanate) in combination with polyinosinic-polycytidilic acid stabilized with polylysine and carboxymethycellulose (poly ICLC), a potent inducer of interferon (IFN) and immune enhancer, plus L-arginine. Data suggest that low doses of both Stibanate and poly ICLC plus L-arginine provide marginal inhibition against L. donovani infection in golden hamsters. When given in combination, however, a significant inhibition was achieved without toxicity, as all the animals survived up to 45 or 60 days. These results suggest that combination therapy using Stibanate and poly ICLC plus L-arginine may be very effective in reducing the dose of Stibanate and, hence, its dose-dependent toxicity in clinical situations.

Animals↗

Long-term outcome of adult acute leukemia patients who are alive and well two years after allogeneic bone marrow transplantation from an HLA-identical sibling.

We studied the long-term outcome of 136 adults with acute leukemia (age 15-48 years at transplant, median 28; 112 myeloid, 22 lymphoblastic, 2 undifferentiated) who were alive in continuous remission two years after allografting from HLA-identical sibling donors. Six relapsed 25-46 months (median 30) after BMT. Fourteen (10%) died of non-relapse causes (12 transplant-related and 2 unrelated) 24-140 months (median 73) after BMT; mainly due to complications of chronic GVHD (8 infections, 3 secondary malignancies). One hundred and seventeen (86%) patients are alive in remission 25-226 months (median 103) after BMT; 116 (85%) in continuous remission. Eight survivors have symptomatic chronic GVHD requiring therapy (Karnofsky scores 60-90%, median 80%). The majority of those without chronic GVHD have Karnofsky scores of 100%. The 10-year probabilities of survival, toxic death, and relapse (from the 2-year mark) are 81%, 13%, and 5%. Twenty-two (19%) survivors had creatinine levels of > 110 mumol/L (one more than double), and 11 (9%) had bilirubin levels of > 17 mmol/L (one more than double) at the last follow-up. The absence of chronic GVHD at the 2-year mark (RR 3.5, P = .004), and female sex (RR 2.9, P = .04) influenced overall survival favorably, and the absence of chronic GVHD at the 2-year mark (RR 8.1, P = .001) influenced toxic death favorably. We conclude that patients with acute leukemia who are alive and well without chronic GVHD two years following an allograft have a high probability of being cured, whereas patients with active chronic GVHD requiring immunosuppression continue to be at risk of non-relapse death. The incidence of long-term liver and kidney dysfunction measured by serum bilirubin and creatinine is low.

Acute Disease↗

Long-term follow-up of relapsed acute leukemia treated with immunotherapy after allogeneic transplantation: the inseparability of graft-versus-host disease and graft-versus-leukemia, and the problem of extramedullary relapse.

Long-term outcome of 23 acute myeloid (AML, n=16) or lymphoblastic (ALL, n=7) leukemia patients who had received immunotherapy for treatment of persistent or recurrent disease 1.5-26 (median 4) months after allogeneic transplantation was studied to determine eventual survival. Immune manipulation comprised donor leukocyte infusion (n=18), interferon-alpha2b and/or interleukin-2 (n=15), and cyclosporine withdrawal (n=11) in various combinations. Graft-versus-host disease (GVHD) developed in 12 patients. Thirteen of 20 evaluable patients responded; 6 relapsing again. Eight patients died of toxicity, and 10 of progressive disease at 3-206 weeks (median 11). Five patients (3 AML, 2 ALL) are alive in remission with GVHD 2-46 months (median 23) after immunotherapy with Karnofsky scores of 70-100% (median 80). The overall survival of the whole group is 1-206 weeks (median 12), with an actuarial survival of 22% at 2 years. The development of GVHD was associated with superior survival in multivariate analysis (P=.007). Seven patients received immunosuppression because of the severity of GVHD (grade III/IV acute or extensive chronic): 3 died of GVHD, 3 improved but relapsed concomitantly, and 1 is alive in remission with extensive chronic GVHD. Four episodes of extramedullary relapse (granulocytic sarcomas) were seen in 3 patients with AML whose marrow remained in remission. We conclude that GVHD appears to be inseparable from graft-versus-leukemia in relapsed acute leukemia patients undergoing immunotherapy with a high proportion of patients dying due to toxicity or progressive disease, and isolated extramedullary relapse seems to be unusually common.

Acute Disease↗

The impact of karyotype on remission rates in adult patients with de novo acute myeloid leukemia receiving high-dose cytarabine-based induction chemotherapy.

One hundred and twenty-eight patients aged 15 years or over (median 34) with de novo acute myeloid leukemia (AML) received 2- or 3-drug induction chemotherapy comprising 5 days of daily high-dose cytarabine (2 g/m2 q12h) and etoposide (100 mg/m2), without (n=62, 1985-90, protocol BF11) or with (n=66, 1990-97, protocol BF12) daily 5 mg/m2 anthracycline (61 idarubicin, 5 mitoxantrone). Twelve patients with t(15;17) were not included. Evaluable karyotypes were obtained in 110 (86%): 30 (27%) favorable, 60 (55%) intermediate, and 20 (18%) adverse. Three patients dying during chemotherapy were inevaluable. Eighty-four (67%) patients remitted with one cycle, and the overall complete remission (CR) rate was 72%. CR rates were comparable for patients with and without evaluable karyotypes. CR rates with BF11 (64% after one cycle; 72% overall) and BF12 (70% after one cycle; 72% overall) were comparable (P=.4 and 1.0 respectively). CR rates after one cycle (86%, 61% and 55%; P=.03) as well as overall CR rates (90%, 69% and 55%; P=.02) were significantly different for patients with favorable, intermediate and adverse karyotypes respectively. In Cox analysis, the karyotype was the only factor found to influence CR independently. We conclude that the karyotype of the leukemic clone is the most important determinant of response to high-dose cytarabine-based induction chemotherapy in AML. The addition of idarubicin to high-dose cytarabine and etoposide does not appear to improve CR rates. A different treatment strategy may be needed to improve CR rates for patients with non-favorable karyotypes.

Acute Disease↗

Two patients with novel BCR/ABL fusion transcripts (e8/a2 and e13/a2) resulting from translocation breakpoints within BCR exons.

We have identified novel BCR-ABL mRNA fusions by RT-PCR in two patients with Philadelphia (Ph) chromosome positive leukaemia. Sequencing revealed in-frame fusions consisting of part of BCR exon e8 spliced to ABL exon a2 in one patient and part of BCR exon e13 spliced to ABL exon a2 in the other. The breaks within BCR exons e8 and e13 did not conform to consensus splice sites, suggesting that the aberrant fusion mRNAs may have arisen as a result of translocation breakpoints at these sites. This was confirmed by genomic DNA bubble PCR for the second patient. These data show that BCR-ABL translocation breakpoints can occasionally occur within coding exons.

Adult↗

Mammalian Grb2 regulates multiple steps in embryonic development and malignant transformation.

Proteins with SH2 and SH3 domains link tyrosine kinases to intracellular pathways. To investigate the biological functions of a mammalian SH2/SH3 adaptor, we have introduced a null mutation into the mouse gene for Grb2. Analysis of mutant embryonic stem cells, embryos, and chimeras reveals that Grb2 is required during embyrogenesis for the differentiation of endodermal cells and formation of the epiblast. Grb2 acts physiologically as an adaptor, since replacing the C terminus of the Ras activator Sos1 with the Grb2 SH2 domain yields a fusion protein that largely rescues the defects caused by the Grb2 mutation. Furthermore, Grb2 is rate limiting for mammary carcinomas induced by polyomavirus middle T antigen. These data provide genetic evidence for a mammalian Grb2-Ras signaling pathway, mediated by SH2/SH3 domain interactions, that has multiple functions in embryogenesis and cancer.

Adaptor Proteins, Signal Transducing↗

Programmed cell death.

Programmed cell death (PCD) is currently one of the most intensively studied areas in cell biology. Substantial evidence now exists demonstrating the integral role of PCD in many fundamental immunologic processes; therefore, understanding the mechanisms of PCD may provide advances with broad implications in immunobiology. This Overview provides a definition of PCD, a description of known PCD biochemical pathways, and finally a discussion of the implications of PCD in transplantation.

Animals↗

Histopathology of cultured shrimp showing gross signs of yellow head syndrome and white spot syndrome during 1994 Indian epizootics.

Two epizootics of cultured shrimp occurred in India in 1994. The first case of mass mortalities of tiger shrimp Penaeus monodon in July 1994 was very similar to that caused by yellowhead virus (YHV) infection with regard to gross clinical signs, host species and size of shrimp affected, but it was histologically atypical. Very interestingly, intranuclear inclusions typical of a white spot syndrome virus (WSSV) infection were present in shrimp showing gross signs of yellow head syndrome, suggesting a dual infection. The second case of mass mortalities of P. monodon and P. indicus of all age groups and sizes in November 1994 was typical of a WSSV infection, clinically and histopathologically. Densely stained, round intracytoplasmic inclusions typical for YHV infection found in the lymphoid organ and haematopoietic tissue of WSSV-infected shrimp indicated a possible dual infection.

Animals↗

Consistent fusion of ZNF198 to the fibroblast growth factor receptor-1 in the t(8;13)(p11;q12) myeloproliferative syndrome.

The 8p11 myeloproliferative syndrome is a rare, aggressive condition associated with reciprocal translocations of chromosome band 8p11, most commonly the t(8;13)(p11;q12). To identify the genes involved in this translocation, we used fluorescence in situ hybridization (FISH) analysis to show that the chromosome 8 breakpoints fell within YAC 899e2 and that the chromosome 13 breakpoints are clustered in a region flanked by YACs 929f11 and 911h8. FISH using chromosome 13 PAC clones indicated that the t(8;13) is not simply a reciprocal translocation but also involves an inversion of 13q11-12. Exon trapping of a PAC that spanned the chromosome 13 translocation breakpoints led to the identification of a gene, ZNF198, that detected rearranged bands when used as a probe against Southern blots of patient DNA. Conceptual translation of the full-length ZNF198 cDNA sequence predicts a protein of 1377 amino acids that shows significant homology to the DXS6673E/KIAA0385 and KIAA0425 proteins. Alignment of these three proteins revealed a novel, conserved Zn-finger-related motif (MYM domain) of the general form CX2C19-22CX3CX13-19CX2CX19-25FCX3CX3F/Y that is repeated five times in each protein. To identify the translocation partner gene on chromosome 8, 5' and 3' RACE polymerase chain reactions (PCRs) were performed on patient RNA with several combinations of ZNF198 primers. Clones were identified in which the ZNF198 was fused to exon 9 of the fibroblast growth factor receptor-1 (FGFR1), a gene known to map to 8p11. An identical ZNF198-FGFR1 fusion was detected in the three patients with a t(8;13) for whom RNA was available; reciprocal FGFR1-ZNF198 transcripts were not detected. Rearrangements of both ZNF198 and FGFR1 were found in two further patients by Southern blotting. ZNF198-FGFR1 includes the five MYM domains of ZNF198 and the intracellular tyrosine kinase domain of FGFR1. We hypothesize that this fusion leads to constitutive activation of the FGFR1 tyrosine kinase in a manner analogous to the activation of ABL by BCR in chronic myeloid leukemia.

Amino Acid Sequence↗

Identification of patients who may benefit from prophylactic immunotherapy after bone marrow transplantation for acute myeloid leukemia on the basis of lymphocyte recovery early after transplantation.

Two hundred and one patients (median age, 29 years) with acute myeloid leukemia (AML) underwent bone marrow transplantation (BMT) from HLA-identical sibling donors after conditioning with melphalan-total-body irradiation (TBI) (57%), cyclophosphamide-TBI (35%), or chemotherapy alone (8%). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine alone (68%), cyclosporine-methotrexate (26%), or T-cell depletion (6%). The probability of relapse was calculated as a function of the absolute lymphocyte count (10(9)/L) on days 27 to 30 posttransplant (<0.1 v >/=0.1, <0.2 v >/=0.2, and <0.3 v >/=0.3). In each of these 12 comparisons, the probability of relapse was higher for the group with the lower lymphocyte count. Because the difference was most significant (P = .004) for an absolute lymphocyte count of <0.2 on day 29 (3-year relapse probability, 42%) versus >/= 0.2 (16%), this variable was included in a Cox model to determine factors independently affecting relapse. Multivariate analysis showed that conditioning regimens other than melphalan-TBI, a low lymphocyte count on day 29, French-American-British (FAB) subtypes M4-7, and a nucleated cell dose of > 2.42 x 10(8)/kg was associated with a higher risk of relapse. We conclude that slow lymphocyte recovery after allogeneic BMT, to < 0.2 x 10(9)/L 29 days in this analysis, appears to be associated with a higher risk of relapse in patients with AML. This group of patients may benefit from posttransplant immune manipulations such as abbreviated GVHD prophylaxis, or donor cell or cytokine administration to enhance graft-versus-leukemia reactions to reduce relapse.

Acute Disease↗