Thyroid Hormone in the Treatment of Post-transplant Acute Tubular Necrosis (ATN)

Delayed graft function (DGF) in cadaver kidney transplants is a common problem and is often due to acute tubular necrosis (ATN). DGF in transplants may have a deleterious effect on long-term graft survival. Since thyroid hormone has been shown to hasten recovery from ATN in experimental models, we designed a trial to determine if a defined course of triiodothyronine (T3) would improve the short- or long-term outcome of patients with DGF in cadaveric transplants. A prospective, randomized, placebo controlled, double blind trial of T3 was carried out in patients with DGF in cadaveric renal transplants. End-points were percentage requiring dialysis, percentage recovering function, time to recovery and length of hospital stay. Long-term outcomes were percentage grafts functioning at 1 year and mean serum creatinine at 1 year. Forty-four patients were randomized to receive either T3 or placebo. Three patients were dropped from each group when early biopsies disclosed that DGF was due to rejection. The groups were well matched by age, cold ischemia time of the graft, and percentage reactivity to a random panel of antigens. Baseline thyroid function studies, including T3, reverse T3 (rT3), and thyroid stimulating hormone (TSH) levels, were similar between the two groups and typical of 'euthyroid-sick syndrome'. T3 had no effect on percentage requiring dialysis, time to recovery, percentage recovering function, or length of stay. At 1 year follow-up, graft function was similar in both groups and significantly lower than that seen in patients with good initial function. Thyroid hormone, given early in the course of DGF in cadaver kidney recipients, had no effect on the course of DGF. Long-term graft function is impaired in patients who experience post-transplant DGF compared to those who have good initial function.     

Classroom aeroallergen exposure in Arkansas head start centers.

BACKGROUND: The impact of preschool environmental conditions on classroom aeroallergen concentrations is not fully understood. OBJECTIVE: To examine the relationship between school environmental conditions and classroom aeroallergen concentrations in the Pulaski County Head Start (HS) Program. METHODS: Thirty-three HS centers in Pulaski County, Arkansas, underwent a detailed environmental evaluation. Classroom settled dust samples were analyzed for the presence of common indoor allergens. RESULTS: Classroom eating (70%), wall-to-wall carpeting (58%), and water damage (33%) were common. Median classroom allergen levels were as follows: dust mite (Der p 1 and Der f 1), 0.6 microg/g; Fel d 1, 0.4 microg/g; Can f 1, 1.7 microg/g; cockroach, below detection; Mus m 1, 0.18 microg/g; and mold spores, 17,800 CFU/g. Can f 1 and Mus m 1 allergens were detected in 100% of HS centers. Facilities with carpeting, increased humidity, and single-use facilities showed trends toward increased dust mite concentrations. Detectable cockroach allergen was more common in classrooms cleaned by teachers than by professional housekeepers. CONCLUSIONS: Aeroallergens were commonly detected in Pulaski County HS center classrooms, with dog and mouse allergens detected in 100% of centers. Median classroom allergen concentrations were low, and classroom characteristics were not strongly predictive of increased allergen exposure.     

A trial of thyroxine in acute renal failure

A trial of thyroxine in acute renal failure. BACKGROUND: Acute renal failure (ARF) remains a serious medical problem with a high mortality rate. Efforts to shorten the course of ARF might reduce this mortality. Since thyroxine has been shown in experimental models to shorten the course of ARF, we designed a trial to determine if a defined course of thyroxine would alter the course or change the mortality of clinical ARF. METHODS: A prospective, randomized, placebo-controlled, double-blind trial of thyroxine was carried out in patients with ARF. End points were the percentage requiring dialysis, the percentage recovering renal function, time to recovery, and mortality. RESULTS: Fifty-nine patients were randomized to receive either thyroxine or placebo. The groups were well matched in terms of basal and entry creatinines, age, sex, APACHE II scores at entry, and percentage oliguric. Baseline thyroid functions, including T3, T4, rT3, and thyroid stimulating hormone (TSH) levels, were equal between the two groups and typical of patients with euthyroid sick syndrome. Thyroxine resulted in a progressive and sustained suppression of TSH levels in the treated group, but had no effect on any measure of ARF severity. Mortality was higher in the thyroxine group than the control group (43 vs. 13%) and correlated with suppression of TSH. CONCLUSIONS: In contrast to the beneficial effects seen in experimental ARF, thyroxine has no effect on the course of clinical ARF and could have a negative effect on outcome through prolonged suppression of TSH. Critically ill euthyroid sick patients should not be replaced with thyroid hormone.     

Case report: isoimmune inhibition of erythropoiesis following ABO-incompatible bone marrow transplantation.

A 26-year-old ABO-O positive patient with aplastic anemia received a bone marrow transplant from his genotypically HLA identical, but ABO-A positive, brother. Engraftment of myeloid and megakaryocytic lineages occurred within 4 weeks but pure red cell aplasia and transfusion dependent anemia persisted for 160 days. The authors postulated that the failure of erythropoiesis was due to a high titer of anti-A isohemagglutinins. They tested this hypothesis with clonal cell cultures and flow cytometric analysis of ABO antigen expression by colony forming cells in vitro. During the period of prolonged red cell aplasia, the patient had normal numbers (85 +/- 12 per 10(6) cells) of circulating donor derived, burst forming units-erythroid (BFU-E). Immunophenotypic analysis of erythroid burst colonies derived from culture of the patient's bone marrow cells showed that 91 +/- 5% of 274 nucleated red cells were A-antigen positive, confirming full donor engraftment. Autologous plasma and complement added on day 1 of culture did not affect the colony growth (82.5 +/- 15 per 10(6) cells). However, when the addition of complement was delayed until day 7 of culture, there was 90% inhibition of BFU-E (7.5 +/- 5 per 10(6) cells) compared to controls (p less than 0.0004). Based on this, the authors propose a model for expression of ABO antigens during erythropoiesis, in which BFU-E do not express ABO antigens but their progeny do. The data support the hypothesis that the mechanism of prolonged pure red cell aplasia after ABO-incompatible bone marrow transplantation is complement mediated immune destruction of erythroid progenitors past the stage of BFU-E in differentiation.     

Abrogating fibrinolysis does not improve bleeding or rFVIIa/rFVIII treatment in a non‐mucosal venous injury model in haemophilic rodents

Essentials

• The efficacy of systemic antifibrinolytics for hemophilic non‐mucosal bleeding is undetermined.
• The effect of systemically inhibiting fibrinolysis in hemophilic mice and rats was explored.
• Neither bleeding nor the response to factor treatment was improved after inhibiting fibrinolysis.
• The non‐mucosal bleeding phenotype in hemophilia A appears largely unaffected by fibrinolysis.

Summary

Background

Fibrinolysis may exacerbate bleeding in patients with hemophilia A (HA). Accordingly, antifibrinolytics have been used to help maintain hemostatic control. Although antifibrinolytic drugs have been proven to be effective in the treatment of mucosal bleeds in the oral cavity, their efficacy in non‐mucosal tissues remain an open question of significant clinical interest.

Objective

To determine whether inhibiting fibrinolysis improves the outcome in non‐mucosal hemophilic tail vein transection (TVT) bleeding models, and to determine whether a standard ex vivo clotting/fibrinolysis assay can be used as a predictive surrogate for in vivo efficacy.

Methods

A highly sensitive TVT model was employed in hemophilic rodents with a suppressed fibrinolytic system to examine the effect of inhibiting fibrinolysis on bleeding in non‐mucosal tissue. In mice, induced and congenital hemophilia models were combined with fibrinolytic attenuation achieved either genetically or pharmacologically (tranexamic acid [TXA]). In hemophilic rats, tail bleeding was followed by whole blood rotational thromboelastometry evaluation of the same animals to gauge the predictive value of such assays.

Results

The beneficial effect of systemic TXA therapy observed ex vivo could not be confirmed in vivo in hemophilic rats. Furthermore, neither intravenously administered TXA nor congenital knockout of the fibrinolytic genes encoding plasminogen or tissue‐type plasminogen activator markedly improved the TVT bleeding phenotype or response to factor therapy in hemophilic mice.

Conclusions

The findings here suggest that inhibition of fibrinolysis is not effective in limiting the TVT bleeding phenotype of HA rodents in non‐mucosal tissues.

     

Preceding standard therapy is the likely cause of MDS after autotransplants for multiple myeloma

Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) have been reported after autologous transplantation (AT) for lymphoma. It is not clear whether myeloablative therapy used in conjunction with autologous transplantation contributes to the development of MDS/AML or whether the conventional chemotherapy preceding the transplant, and administered over a prolonged period, causes these secondary malignancies. To address this issue, we examined 188 patients with multiple myeloma (MM) who had received AT. 71 patients with no more than one cycle of standard chemotherapy were enrolled in our Total Therapy program, designed to avoid exposure to alkylating agents prior to peripheral blood stem cell mobilization (group 1). The median duration of pre-transplant therapy in group 1 was 7.6 months and significantly shorter than the 24 months of 117 patients (group 2) with more prolonged conventional therapy ( P  = 0.0001). All seven patients developing MDS post-transplantation belonged to group 2 ( P  = 0.02); the median durations from initial therapy and first transplant were 66 months (range 38–86) and 24 months (range 9–39), respectively. Our findings provide evidence that prolonged standard-dose alkylating agent therapy prior to transplantation, rather than autotransplant-supported myeloablative treatment, is associated with development of MDS/AML. Stem cell damaging alkylator treatment should be avoided, not to compromise PBSC collection, but also to reduce the risk of treatment-related MDS/AML.     

Pregnancy Complications in Women with Weight Loss Surgery Compared to a Non-Surgical Population of Women with Obesity

Obesity Surgery - The objective of this study was to assess the effect of WLS on pregnancy and delivery complications in women who had WLS compared to women with obesity who did not undergo WLS. We...