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Biomedical subjects

M M Mohiuddin

Publications and source records attributed to M M Mohiuddin.

10 recordsLinked to original sources

Severe acute enteritis in a multiple myeloma patient receiving bortezomib and spinal radiotherapy: case report.

Proteasome inhibitors have been reported to enhance radiosensitivity in vitro. A case of potential clinical interaction between bortezomib, a proteasome inhibitor, and spine radiation is reported. A woman undergoing palliative radiotherapy to the T12 -S2 spine with concurrent bortezomib developed unexpectedly severe, acute radiation enteritis requiring hospital admission. Clinicians are advised to consider the potential for interactions of bortezomib with radiotherapy when the two agents are used simultaneously in the clinic.

Acute Disease↗

Long-term survival of cardiac xenografts in fully xenogeneic (mouse --> rat) bone marrow chimeras.

BACKGROUND: The shortage of human hearts remains a major barrier to the efficacy of heart transplantation for the treatment of end-stage heart disease. One potential solution to the supply problem would be the use of hearts from nonhuman donors (xenografts). We have established a model of mouse to rat xenogeneic bone marrow chimerism, and in this study we have hypothesized that such chimeric rats will accept both donor and recipient specific heart grafts while rejecting third-party mouse and rat grafts. We also investigated humoral responses in naive and chimeric rats with and without donor murine cardiac grafts. METHODS: Recipient Lewis rats (n = 22) were given 1100 cGy lethal total body irradiation and the same day received 300 x 10(6) donor B10.BR mouse bone marrow cells intravenously. Peripheral blood of surviving rats (n = 18) was typed at 4 weeks and then monthly thereafter. Donor and recipient specific and third-party heterotopic heart transplantations were performed at 6 to 8 weeks after reconstitution with bone marrow. RESULTS: Multilineage bone marrow chimerism was produced in all experimental animals with complete replacement of recipient marrow by donor cells. Murine donor and rat recipient strain hearts transplanted in chimeric rats survived indefinitely. Third-party rat and mouse hearts were rejected, though at a slower rate than bone marrow matched naive controls. High levels of antimouse antibodies were detected in rats with rejected hearts. These antibodies were absent in chimeric animals with long-term surviving heart grafts. CONCLUSIONS: Long-term multilineage bone marrow chimerism can be produced in a mouse --> rat bone marrow transplant model. Long-term survival of donor specific and recipient specific vascularized cardiac grafts can be produced in these chimeric animals. These animals are clinically normal but show signs of subclinical immunosuppression regimen as they reject third-party hearts later than naive animals. Our results suggest that antibodies also play a significant role in concordant xenograft rejection, and induction of bone marrow chimerism can overcome this barrier.

Animals↗

Establishment of fully xenogeneic (mouse-->rat) bone marrow chimeras: evidence for normal development and clonal deletion of mouse T cells.

BACKGROUND: Xenotransplantation is a potential solution to the critical shortage of transplantable organs. However, conventional immunosuppressive agents do not control the vigorous cellular and humoral rejection across species disparities. The induction of donor specific tolerance via bone marrow chimerism may be a method to avoid xenograft rejection. In xenogeneic chimeras, T cell repertoire selection plays an important role in the induction of tolerance. Until now a model of mouse-->rat multilineage chimerism has not been reported. This study reports the establishment of fully xenogeneic mouse-->rat multilineage chimeras and evaluates the role of T cell development and repertoire selection in tolerance induction in a xenogeneic environment. METHODS: Recipient rats were irradiated at a dose of total body irradiation ranging between 800-1100 cGy and injected with 120-300x10(6) donor mouse bone marrow cells. Chimeras were typed for engraftment at 4 weeks and then monthly thereafter. T cell repertoire was evaluated in chimeras using two-color flow cytometry and monoclonal antibodies directed against the variable portion of the beta chain of the T cell receptor. RESULTS: Fully xenogeneic multilineage bone marrow chimerism was produced in a mouse-->rat model by using ablative radiation and a high dose of donor cells. Mouse T cells develop in a phenotypically normal fashion in chimeric rats and the host rat is capable of deleting T cells that are reactive to the donor mouse strain. CONCLUSION: Long-term multilineage bone marrow chimerism can be produced in a mouse-->rat bone marrow transplant model. Mouse T cells develop in a phenotypically normal fashion and negative selection of specific T cell receptor-Vbeta occurs in a xenogeneic environment in a predictable fashion paralleling that for syngeneic or allogeneic transplantation.

Animals↗

High-dose preoperative radiation and full-thickness local excision. A new option for patients with select cancers of the rectum.

Faced with the responsibility of treating patients with invasive distal rectal cancer who were medically unacceptable for the indicated radical surgery, a prospective study was initiated in which high dose preoperative radiation and full-thickness local excision were used. High dose preoperative radiation permitted full-thickness local excision of select cancers, which, by conventional standards, otherwise would have required radical surgery and permanent colostomy. Feasibility was measured on the basis of safety of the technique, control of the cancer, and the quality of anal sphincter function expected. Patients were selected initially because of their predicted inability to tolerate radical surgery, but indications were broadened to include those whose tumors had completely disappeared after irradiation. From 1984 to 1988, 20 patients underwent 21 operative procedures for cancers located between 0 and 7 cm from the anorectal ring. This report is concerned with the 14 patients of this group who were observed for a minimum of 24 months. High-dose preoperative radiation was administered for a total dose of 4500 cGy. Excision and repair were performed 4 to 6 weeks after completion of radiation therapy. Full-thickness disc or hemicircumferential excision was accomplished by transanal, transsphincteric, and transsacral techniques, which included, in several instances, excision of the sphincter mechanism and perineal body, and/or the vaginal wall. Full-thickness local excision after high-dose radiation therapy for rectal cancers has never been reported. Follow-up observation ranged from 24 to 48 months with a median of 31 months. Rectal reservoir function and sphincter control were good in 13 patients. Local recurrence developed in three patients (21 percent), two of whom had postradiation therapy B2 mucinous cancers. Three-year actuarial rate of local recurrence is 23 percent. One (7 percent) patient died of recurrent disease. Actuarial Kaplan-Meier survival at 3 years is 61 percent. Based on the results of this small, select patient group, high-dose radiation therapy followed by full-thickness local excision appears to be a reasonable option for patients who cannot tolerate radical surgery. This bimodal approach also may serve as an option for those who are good medical risks, but for whom sphincter preservation is at stake, and to whom radical surgery offers limited benefits.

Actuarial Analysis↗