Biomedical subjects
Publications and source records attributed to J Abrams.
We describe the third known case of a traumatic left anterior descending artery to left ventricular fistula. Emergency operative repair was required on day 7 for delayed pericardial tamponade. The significant incidence of late serious sequelae with traumatic coronary artery fistulas suggests that early surgery is warranted.
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Accumulating data indicate that cytokines, peptides involved in regulation of both physiological and pathological immune responses, are produced predominantly at the site of local antigen stimulation. Cytokine-producing cells were detected at the protein level in human tonsil tissue obtained from children with recurrent tonsillitis or infectious mononucleosis (IM). Concomitant production of 19 different human cytokines, interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-1 receptor antagonist (ra), IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, tumour necrosis factor-alpha (TNF-alpha), TNF-beta, interferon-gamma (IFN-gamma) and transforming growth factor-beta 1-3 (TGF-beta 1-3), was identified at a single-cell level by indirect immunohistochemical staining procedures and use of carefully selected cytokine-specific antibodies (Ab). Fresh frozen sections were fixed with 4% paraformaldehyde and permeabilized by 0.1% saponin treatment, eluting cholesterol from the cell-surface membrane and the Golgi complex. The intracellular localization of all cytokines, except IL-1 and IL-1ra, was demonstrated by a characteristic local cytoplasmic perinuclear configuration in producer cells. In addition, the immunoreactivity for certain cytokines (IL-2, IL-4, IL-5, G-CSF and GM-CSF) was expressed on the cell membranes and extended over a large extracellular area encompassing the producer cell. Localization of the cytokine to the Golgi organelle was established by co-staining with a monoclonal antibody (mAb) specific to the Golgi complex. Both the extra- and intracellular cytokine staining reactions could be blocked by preincubation of the cytokine-specific Ab with the corresponding purified natural or recombinant cytokine. A complex cytokine pattern was established in both groups studied, where most T-helper type 1 (Th1) and Th2 lymphokines were expressed in the tonsils but at different frequencies and localizations. Cells expressing IL-4, IL-5, IL-10 and IL-13, (Th2 response) were evident at higher frequencies in recurrent tonsillitis compared to sections from IM, which were associated with a more pronounced IL-2, IFN-gamma and TNF-beta expression.
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Survival after irradiation with LD100/30 (radiation dose lethal to 100% of mice in 30 days) is based on recovery of impaired hematopoietic function. Our previous studies using antibodies to interleukin-1 receptor (IL-1R), tumor necrosis factor (TNF), and IL-6 demonstrated that endogenous production of these three cytokines is required for untreated mice as well as mice protected with lipopolysaccharide (LPS), IL-1, or TNF to survive lethal irradiation. In this report we show that anti-c-kit ligand/steel factor (SIF) antibody similarly abrogates LPS- and IL-1-induced radioprotection. Furthermore, administration of this antibody to unmanipulated mice increased LD50/30 radiation lethality from 50% to 100%. Such an effect was not obtained using anti-IL-3, anti-IL-4, or anti-granulocyte-macrophage colony-stimulating factor antibody. Thus, like IL-1, TNF, and IL-6, SIF is required for survival from lethal irradiation.
Trauma, disease, developmental deformities, and tumor resection frequently cause bone defects that seriously challenge the skills of orthopedic and maxillofacial surgeons. Currently, repairing osseous deficiencies involves various medical surgical techniques, including autogenous grafts, allografts, internal and external fixation devices, electrical stimulation, and alloplastic implants. The existing technology, though effective in many cases, still is beset with numerous difficulties and disadvantages. A critical need for improved treatment methods exists today. Biotechnology now provides access to new bone repair concepts via administration of protein growth and morphogenic factors. Implantable device and drug delivery system technologies also have advanced. The converging biopharmaceutical, device, and delivery technologies represent an opportunity to improve the quality of health care for individuals with orthopedic and maxillofacial deficiencies. This report reviews current concepts in fracture healing and bone repair and examines existing treatment modalities. It also addresses novel protein drugs that stimulate osseous regeneration and delivery systems for these drugs.
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PURPOSE: The impact of the side effects of megestrol acetate on the quality of life of noncachectic women with advanced breast cancer was studied in a dose-response clinical trial of the Cancer and Leukemia Group B (CALGB 8741). Side effects of appetite increase and weight gain at higher doses were predicted to have a negative effect on quality of life. PATIENTS AND METHODS: Stage IV breast cancer patients were randomized to receive either 160, 800, or 1,600 mg/d of megestrol acetate. Quality of life was assessed in 131 patients at trial entry and at 1 and 3 months while on treatment, by telephone interview, using the following measures: the Functional Living Index-Cancer (FLIC), Rand Functional Limitations Scale, Rand Mental Health Inventory (MHI), the Body Image Subscale, and linear analog scales of drug side effects. RESULTS: At 3 months, women treated with 160 mg/d reported less severe side effects (P < .0005), better physical functioning (FLS, P < .0005), less psychologic distress (MHI, P = .008), and an improvement in overall quality of life (FLIC, P = .003) from the time of study entry as compared with those treated with 1,600 mg/d. Patients who received the 800-mg/d dose fell between the low- and high-dose arms in reported intensity of drug side effects, but responded similarly to those in the 160-mg/d group in terms of physical functioning, psychologic distress, and overall quality of life. CONCLUSION: Unless additional follow-up data demonstrate a survival advantage at higher doses, the 160-mg/d dose is optimal, achieving maximal treatment effect with the fewest side effects and better quality of life.
The efficacy of three hypertonic saline solutions for treating dialysis-induced hypotension in a randomized, blinded, crossover clinical trial of 10 patients (a minimum of three cycles per solution) was compared. Dialysis-induced hypotension, defined as a decrease in systolic blood pressure of at least 10 mm Hg or systolic blood pressure less than 100 mm Hg, was treated with an iv bolus of either 10 mL of 23% saturated hypertonic saline, 30 mL of 7.5% hypertonic saline, or 30 mL of 7.5% saline with 6% dextran 70, each containing similar osmolar loads of 80, 80, and 100 mosM, respectively. All three solutions raised systolic blood pressure within 5 min (mean pretreatment systolic blood pressure, 87 mm Hg; mean posttreatment systolic blood pressure, 101 mm Hg; P < 0.05). The magnitude of the increase was greater with saturated hypertonic saline (15 mm Hg) and dextran 70 (17 mm Hg) compared with that with hypertonic saline (9 mm Hg; P < 0.05). At 10 min, dialysis-induced hypotension was less frequent with saturated hypertonic saline (incidence, 9%) compared with hypertonic saline (45%). Beyond 10 min, however, there was a trend toward a lower incidence of further dialysis-induced hypotension with dextran 70. There were no side effects. Given equal osmole loads, the more concentrated solution produced a greater increase in systolic blood pressure. The addition of an oncotic agent such as dextran may prolong the blood pressure response beyond 10 min. It was concluded that hypertonic saline solutions safely and effectively treat dialysis-induced hypotension.
Perioperative cardiac morbidity is the leading cause of death following the administration of general anesthesia. With the aging of the population, the number of patients at significant cardiac risk for noncardiac surgical procedures is expected approximately to double over the next 30 years. Assessing cardiac risk will assume increasing importance in surgical decisions. Historical predictors, diagnostic testing predictors, and recent data concerning preoperative cardiac physiology assessment and optimization are discussed.
Combined team effort in liver procurement and transplantation has proven to be very advantageous as compared to same team effort in our experience. The incidence of primary nonfunction was almost identical between the two groups. We recommend that a combined team effort be used in liver transplantation to conserve the resources and ensure the safety of the transplant team. The practice of only a single local recovery team for all abdominal organ procurement should be encouraged.
A statistically significant difference was discovered when comparing the 1-year graft survival of CAUC and AA. The difference was due in part to nine AA failures that occurred within the first week posttransplant (Fig 3). Using a multivariant analysis both the AA and CAUC were found to be normally distributed in regard to CIT, HLA mismatch, transplant number, and PRA. If these traditional variables thought to have relevance on graft survival in cadaveric renal transplantation are ruled out as contributing factors other avenues must be explored. If credence is given to the theory that the difference in function between AA and CAUC is due to the difference in the number of transplants that failed within the first week then factors such as immunosuppressive therapy and noncompliance can also be ruled out. One possible area of explanation may lie in the area of specificity to HLA antibody. It is possible that these recipients received transplants from a donor to which they were sensitized. A closer analysis of donor and recipient HLA typing as well as the recipient's transfusion and transplant history is recommended. Despite the fact that all transplants occurred in the presence of negative preliminary and final XM's using American Society for Histocompatibility and Immunogenetics (ASHI) certified techniques (Table 2), transplant centers may wish to consider using a more sensitive XM technique such as flow cytometry for these patients. We hope that these recommendations will enable transplant centers to continue their commitment to transplanting the highly sensitized recipient.
Solid organ referrals for AA have been growing since 1989. One third of AA referrals are in the 16 to 30 year age group with the majority of these males suffering traumatic injury. AA donors have increased from 11 in 1989 to 32 in 1992. This is in spite of AA and minority consent rates that are 20% to 30% below that of the CAUC group. This gap represents a vital opportunity for improvement. Increased education to minority groups with a message that considers the ethnic and cultural diversity of the minority community coupled with an increase in the number of minority transplant coordinators should help to increase the number of AA referrals and donors.
Nitroglycerin and the long-acting nitrates are widely used in all of the anginal syndromes and have proven effectiveness in relieving or preventing myocardial ischemia. Recent developments into nitrate mechanisms of action provide new insights as to the many anti-ischemic effects of these agents. Important concepts relating to coronary arterial endothelial function are germane to nitrate therapy. Endothelial-derived relaxing factor (EDRF) is presently believed to be nitric oxide (NO), which exerts vasodilatory and/or antiplatelet actions by increasing intracellular cyclic guanosine monophosphate as a result of activation of the enzyme guanylate cyclase. In the setting of coronary atherosclerosis, or even hyperlipidemia without histologic vascular disease, endothelial dysfunction may be present, promoting a vasoconstrictor/proplatelet aggregatory milieu. Nitroglycerin and the organic nitrates are NO donors; NO is the final product of nitrate metabolism, and in the vascular smooth muscle NO induces relaxation, resulting in vasodilation of arteries and veins. In the presence of inadequate EDRF production and/or release, it appears that nitroglycerin may partially replenish EDRF-like activity. Nitrates have long been known to have major peripheral circulatory actions resulting in a marked decrease in cardiac work. Venodilation and arterial relaxation result in a decrease in intracardiac chamber size and pressures, with a resultant decrease in myocardial oxygen consumption. In addition, a variety of direct coronary circulatory actions of the nitrates have been documented. These include not only epicardial coronary artery dilation, but the prevention of coronary vasoconstriction, enhanced collateral flow, and coronary stenosis enlargement. Recent work suggests that the nitrates may also act by preventing distal coronary artery or collateral vasoconstriction, which can reduce blood flow downstream from a total coronary obstruction. Thus, there are many anti-ischemic mechanisms of action by which nitroglycerin and the organic nitrates may be beneficial in both acute and chronic ischemic heart disease syndromes. The unique salutory effects of the nitrates in subjects with left ventricular dysfunction or congestive heart failure make these drugs particularly attractive for patients with abnormal systolic function and intermittent myocardial ischemia. Finally, the emergent role of intravenous nitroglycerin in acute myocardial infarction offers new prospects that nitrate therapy may prove to be beneficial in acute myocardial infarction as well as postmyocardial infarction for the reduction of left ventricular remodeling.
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Primary responsibility for the induction of various acute phase reactions has been ascribed to interleukin 1 (IL-1), tumor necrosis factor (TNF), or IL-6, suggesting that these cytokines may have many overlapping activities. Thus, it is difficult to identify the cytokine primarily responsible for a particular biologic effect, since IL-1 and TNF stimulate one another, and both IL-1 and TNF stimulate IL-6. In this work, the contribution of IL-6 in radioprotection, induction of adrenocorticotropic hormone (ACTH), and induction of hypoglycemia was assessed by blocking IL-6 activity. Administration of anti-IL-6 antibody to otherwise untreated mice greatly enhanced the incidence of radiation-induced mortality, indicating that like IL-1 and TNF, IL-6 also contributes to innate resistance to radiation. Anti-IL-6 antibody given to IL-1-treated or TNF-treated mice reduced survival from lethal irradiation, demonstrating that IL-6 is also an important mediator of both IL-1- and TNF-induced hemopoietic recovery. A similar IL-1/IL-6 interaction was observed in the case of ACTH induction. Anti-IL-6 antibody blocked the IL-1-induced increase in plasma ACTH, whereas recombinant IL-6 by itself did not induce such an increase. Anti-IL-6 antibody also mitigated TNF-induced hypoglycemia, but did not reverse IL-1-induced hypoglycemia. It is, therefore, likely that TNF and IL-1 differ in their mode of induction of hypoglycemia. Our results suggest that an interaction of IL-6 with IL-1 and TNF is a prerequisite for protection from radiation lethality, and its interaction with IL-1 for induction of ACTH.