Two mechanistic pathways for thienopyridine-associated thrombotic thrombocytopenic purpura: a report from the SERF-TTP Research Group and the RADAR Project.

OBJECTIVES: We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP). BACKGROUND: The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA). METHODS: Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals. RESULTS: Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without. CONCLUSIONS: Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival.     

Estimating genome conservation between crop and model legume species

Legumes are simultaneously one of the largest families of crop plants and a cornerstone in the biological nitrogen cycle. We combined molecular and phylogenetic analyses to evaluate genome conservation both within and between the two major clades of crop legumes. Genetic mapping of orthologous genes identifies broad conservation of genome macrostructure, especially within the galegoid legumes, while also highlighting inferred chromosomal rearrangements that may underlie the variation in chromosome number between these species. As a complement to comparative genetic mapping, we compared sequenced regions of the model legume Medicago truncatula with those of the diploid Lotus japonicus and the polyploid Glycine max. High conservation was observed between the genomes of M. truncatula and L. japonicus, whereas lower levels of conservation were evident between M. truncatula and G. max. In all cases, conserved genome microstructure was punctuated by significant structural divergence, including frequent insertion/deletion of individual genes or groups of genes and lineage-specific expansion/contraction of gene families. These results suggest that comparative mapping may have considerable utility for basic and applied research in the legumes, although its predictive value is likely to be tempered by phylogenetic distance and genome duplication.     

Effects of estrogen and medroxyprogesterone acetate on subpopulations of triglyceride-rich lipoproteins and high-density lipoproteins

Hormonal replacement therapy (HRT) in postmenopausal women has been shown to increase both triglyceride (TG) and high-density lipoprotein (HDL) cholesterol levels. To better understand the effects of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA), the 2 most commonly prescribed hormones in HRT, on the different subpopulations of TG-rich and HDL lipoproteins, we conducted a placebo-controlled, double-blind, randomized, crossover study consisting of 3 different phases in 14 postmenopausal women. The 3 phases, each 8-week long, included: (1) placebo, (2) CEE 0.625 mg/d, and (3) CEE 0.625 mg/d and MPA 2.5 mg/d. Slight and statistically nonsignificant elevations in TG levels were observed during the CEE treatment. While very-low-density lipoprotein (VLDL) cholesterol levels were not significantly affected by CEE and CEE + MPA, both HRT treatments lowered remnant lipoprotein (RLP) cholesterol (-14% and -37%, respectively). Compared with placebo, CEE caused a significant increase in HDL, HDL(2), apolipoprotein (apo) A-I, LpAI, alpha1, and prealpha1 levels (12%, 27%, 17%, 26%, 60%, and 102%, respectively). The combination therapy blunted the CEE effect on all HDL parameters, resulting in HDL, HDL(2), and LpAI levels being no longer significantly different from placebo. Apo A-I levels and alpha1, and prealpha1 levels were still significantly higher than placebo (+11%, +50%, and +112%, respectively). These results indicate that HRT has beneficial effects on RLP levels and that, while the estrogen component of HRT has a beneficial effect on the HDL subpopulations mostly associated with coronary heart disease (CHD) protection, MPA partially inhibits this effect.     

Is the treatment of Hodgkin's disease detrimental to the parathyroid gland?

The thyroid gland is often injured by supradiaphragmatic irradiation for Hodgkin's lymphoma. The aim of the present study was to examine whether the parathyroid gland gets injured by the treatment for Hodgkin's disease. Calcium, phosphorus and parathormone levels of 143 patients with primary treatment for Hodgkin's disease and in complete remission for 2 years were measured as well as the presence of antiparathyroid antibody in patients having antithyroid antibody. Out of the 143 patients studied, 104 received neck irradiation (with or without chemotherapy); among them laboratory alterations were observed in 7 cases. 39 patients received only chemotherapy; 3 of them had alterations. In contrast to the injury of the thyroid gland, no damage to the parathyroid glands associated with the treatment for Hodgkin's disease was noted. It has been concluded that the use of high-dose external radiotherapy does not mean a higher risk as regards the parathyroid gland but further follow-up studies of the patients may result in the revelation of the development of parathyroid lesions.     

Paramedic-Initiated Home Care Referrals and Use of Home Care and Emergency Medical Services

Objective: We examined the association between paramedic-initiated home care referrals and utilization of home care, 9-1-1, and Emergency Department (ED) services. Methods: This was a retrospective cohort study of individuals who received a paramedic-initiated home care referral after a 9-1-1 call between January 1, 2011 and December 31, 2012 in Toronto, Ontario, Canada. Home care, 9-1-1, and ED utilization were compared in the 6 months before and after home care referral. Nonparametric longitudinal regression was performed to assess changes in hours of home care service use and zero-inflated Poisson regression was performed to assess changes in the number of 9-1-1 calls and ambulance transports to ED. Results: During the 24-month study period, 2,382 individuals received a paramedic-initiated home care referral. After excluding individuals who died, were hospitalized, or were admitted to a nursing home, the final study cohort was 1,851. The proportion of the study population receiving home care services increased from 18.2% to 42.5% after referral, representing 450 additional people receiving services. In longitudinal regression analysis, there was an increase of 17.4 hours in total services per person in the six months after referral (95% CI: 1.7–33.1, p = 0.03). The mean number of 9-1-1 calls per person was 1.44 (SD 9.58) before home care referral and 1.20 (SD 7.04) after home care referral in the overall study cohort. This represented a 10% reduction in 9-1-1 calls (95% CI: 7–13%, p < 0.001) in Poisson regression analysis. The mean number of ambulance transports to ED per person was 0.91 (SD 8.90) before home care referral and 0.79 (SD 6.27) after home care referral, representing a 7% reduction (95% CI: 3–11%, p < 0.001) in Poisson regression analysis. When only the participants with complete paramedic and home care records were included in the analysis, the reductions in 9-1-1 calls and ambulance transports to ED were attenuated but remained statistically significant. Conclusions: Paramedic-initiated home care referrals in Toronto were associated with improved access to and use of home care services and may have been associated with reduced 9-1-1 calls and ambulance transports to ED.