Citations

Abstract Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disease caused by platelet destruction resulting from autoantibodies against platelet surface proteins, particularly platelet glycoprotein IIb/IIIa (αIIbβ3). To localize the auto-epitopes on platelet αIIbβ3, the binding of autoantibodies to Chinese hamster ovary (CHO) cells expressing either αIIbβ3 or αvβ3was studied. Thirteen of 14 ITP autoantibodies bound only to CHO cells expressing αIIbβ3. Because these 2 integrins have the same beta chain (β3), these results show that most epitopes in chronic ITP are dependent on the presence of glycoprotein αIIb.

R115777 is a nonpeptidomimetic enzyme-specific inhibitor of farnesyl protein transferase (FT) that was developed as a potential inhibitor of Ras protein signaling, with antitumor activity in preclinical models. This study was a phase 1 trial of orally administered R115777 in 35 adults with poor-risk acute leukemias. Cohorts of patients received R115777 at doses ranging from 100 mg twice daily (bid) to 1200 mg bid for up to 21 days. Dose-limiting toxicity occurred at 1200 mg bid, with central neurotoxicity evidenced by ataxia, confusion, and dysarthria. Non–dose-limiting toxicities included reversible nausea, renal insufficiency, polydipsia, paresthesias, and myelosuppression. R115777 inhibited FT activity at 300 mg bid and farnesylation of FT substrates lamin A and HDJ-2 at 600 mg bid. Extracellular signal-regulated kinase (ERK), an effector enzyme of Ras-mediated signaling, was detected in its phosphorylated (activated) form in 8 (36.4%) of 22 pretreatment marrows and became undetectable in 4 of those 8 after one cycle of treatment. Pharmacokinetics revealed a linear relationship between dose and maximum plasma concentration or area under the curve over 12 hours at all dose levels. Weekly marrow samples demonstrated that R115777 accumulated in bone marrow in a dose-dependent fashion, with large increases in marrow drug levels beginning at 600 mg bid and with sustained levels throughout drug administration. Clinical responses occurred in 10 (29%) of the 34 evaluable patients, including 2 complete remissions. Genomic analyses failed to detect N-ras gene mutations in any of the 35 leukemias. The results of this first clinical trial of a signal transduction inhibitor in patients with acute leukemias suggest that inhibitors of FT may have important clinical antileukemic activity.

▪ Abstract The HACEK group of fastidious gram-negative organisms is a recognized but unusual cause of infective endocarditis, responsible for approximately 3% of cases. We report our experience with 45 cases of endocarditis caused by HACEK organisms. In Olmsted County, Minnesota, the incidence of HACEK endocarditis was 0.14 per 100,000 person-years. In patients with native valves, 33 cases occurred, and in patients with prosthetic valves, 12 cases occurred. The most common presenting symptoms were fever, splenomegaly, new or changing murmur, and microvascular phenomena. Symptoms were present in the majority of patients anywhere from two weeks to six months prior to diagnosis. Blood cultures became positive in a mean of 3.375 days, and therapy with a beta-lactam alone or as part of a combination was given for anywhere between three and six weeks. Within the first month of diagnosis, surgery was performed for 13 regurgitant valves in 11 patients (24%). Echocardiography was an insensitive predictor of subsequent major arterial embolization (odds ratio, 1.33; 95% confidence interval, 0.31–5.67). The overall survival in our cohort of patients was 87%. These results confirm previous reports that HACEK endocarditis portends a favorable prognosis.

▪ Abstract Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system (CNS). Diagnosis rests upon identifying typical clinical symptoms and interpreting supportive laboratory and radiological investigations. The etiology is unknown; however, strong evidence suggests that MS is an autoimmune disease directed against CNS myelin or oligodendrocytes. Genetic factors are important in the development of MS. Contributing environmental determinants (possibly including infectious agents) appear important but remain unidentified. Both cell-mediated and humorally mediated immune mechanisms contribute to pathological injury. Axonal damage occurs in addition to demyelination and may be the cause of later permanent disability. Distinct pathological subtypes may differentiate among patients with MS. Treatment is directed at acute attacks (with corticosteroids) and reduction of attack frequency (primarily with type-1 β interferons and glatiramer acetate). Research into the causes and treatments of MS has expanded our knowledge of this disease and promises improved care for MS patients in the future.

An ex vivo rabbit tibia perfusion model was developed to investigate the vascular reactivity and vascular endothelial function of bone tissue. The tibiae of 36 adult New Zealand rabbits were isolated and perfused through the cannulated nutrient artery at a constant flow rate in an organ chamber. The increase in perfusion pressure caused by graded doses of norepinephrine produced a dose response curve, which was first recorded under control condition, and then during perfusion with acetylcholine (ACh), N G -monomethyl-L-arginine acetate (L-NMMA), and/or L-arginine (nitric oxide precursor) infusion. The optimal flow rate for rabbit tibia was 0.3 to 0.4 ml/min, depending on the weight of the tibia. The perfusion baseline and the norepinephrine dose-response curve (NEDRC) remained stable for at least eight hours. Acetylcholine (1 × 10-5 M ) infusion attenuated the NEDRC (33 ± 5%) for 1.5 hours. Thereafter, the vasorelaxant effect of ACh diminished due to depletion of nitric oxide, and ultimately caused an increase in the NEDRC due to a vasoconstrictive action. The rebound vasoconstriction did not occur in the presence of constant L-arginine infusion, which maintained nitric oxide production, and ACh continued to attenuate the NEDRC (36 ± 4.5%) for at least eight hours. L-NMMA, which inhibits the synthesis of nitric oxide, increased the vasoconstrictive effect of norepinephrine significantly (155 ± 16%). The rabbit tibia ex vivo model seems ideal for the study of bone vascular bed activity, due to its stable baseline, reliable NEDRC and cost efficiency. We have further demonstrated that the intraosseous vascular endothelium of rabbit tibia produces nitric oxide as one method of regulating bone perfusion.

AIM To examine in vitro the effects of brief contact with various infusion solutions on red blood cells from newborn infants, as occurs in the “waste” syringe during routine blood sampling from umbilical artery catheters. The mixture of blood and solution in the “waste” syringe is usually reinfused into the baby. Reinfused red blood cells may be damaged by the infusion solution. It is hypothesised that an isotonic amino acid solution would cause no red blood cell agglutination and no more haemolysis than many commonly used solutions. METHODS Blood was obtained from the placentas of 15 normal term babies. Haemolysis was estimated by measuring plasma (free) haemoglobin after mock blood sampling. Agglutination was measured semiquantitatively by direct observation. RESULTS A 0.25% normal saline solution caused 5.4% haemolysis, significantly more than all the other fluids tested. There was less haemolysis with 0.25% normal saline when there was complete mixing of blood and solution within the “waste” syringe. Normal saline and isotonic sodium acetate solutions caused < 0.1% haemolysis, significantly less than all the other fluids tested. The isotonic amino acid solution caused 0.8% haemolysis, which is similar to that caused by the remaining solutions tested. Agglutination was seen with isotonic dextrose and with the two isotonic amino acid solutions containing cysteine. CONCLUSIONS Isotonic amino acid solution (without added cysteine) caused no agglutination and the same or less haemolysis than many commonly used solutions and may offer advantages in nutrition and fluid balance.

OBJECTIVES To examine the impact of time to thrombolytic treatment on multiple acute outcome variables in a single trial of thrombolysis in acute myocardial infarction. DESIGN AND PATIENTS Mortality and reinfarction rate were measured in 2770 patients with acute myocardial infarction who received thrombolysis within 12 hours in CORE, an international, dose ranging trial of poloxamer 188. Tc-99m sestamibi infarct size and radionuclide angiographic ejection fraction substudies included 1099 and 1074 patients, respectively. RESULTS Time to thrombolysis, subgrouped by intervals (< 2, 2–4, ⩾ 4–6, and ⩾ 6 hours), was significantly associated with infarct size (median 15.0%, 18.5%, 22.0%, 18.5% of left ventricle; p = 0.033), mean (SD) ejection fraction (51.5 (12.0)%, 48.3 (13.9)%, 48.2 (13.3)%, 48.2 (15.0)%; p = 0.006), 35 day mortality (5.7%, 7.1%, 7.9%, 12.5%; p = 0.0004), six month mortality (7.3%, 8.6%, 10.4%, 15.5%; p < 0.0001), and 35 day reinfarction rate (6.1%, 3.2%, 4.0%, 0.9%; p = 0.0001). CONCLUSIONS In this single large trial, the beneficial effect of time to thrombolysis on infarct size and ejection fraction was restricted to treatment given within two hours of symptom onset, while the effect on mortality was evident over all time intervals. Reinfarction rate was higher in patients treated with earlier thrombolysis.

BACKGROUND Chronic ulcerative conditions in the gastrointestinal tract result in the appearance of the ulcer associated cell lineage (UACL). The glands of this new cell lineage secrete epidermal growth factor, transforming growth factor α, and the trefoil factor family (TFF) peptides, which are known to participate in repair processes. Pouchitis is the most frequent complication of ileal pouch-anal anastomosis. AIM Our aim was to determine whether the mucosal ulceration present in pouchitis can induce the development of UACL glands. METHODS Biopsies from ileal pouches with pouchitis (n=10), healthy pouches (n=5), and normal terminal ileum (n=5) were studied. Expression of TFF mRNA was assessed by in situ hybridisation. TFF1 and TFF2 proteins were localised by immunochemistry. RESULTS UACL glands containing TFF1 and TFF2 were observed in six patients with pouchitis. In some glands, there was TFF3 mRNA as has been reported for Crohn's UACL. None of the biopsies from ileal reservoirs without pouchitis showed UACL glands (p<0.05). Neither TFF1 nor TFF2 expression was detected in ileal reservoirs without pouchitis. CONCLUSION UACL glands arise de novo in ileal pouch mucosa of patients with pouchitis and express all three TFF peptide genes. Chronic inflammation alone, present in healthy pouches, is not enough to stimulate the growth of the UACL, and additional stimuli consequent on ulceration may be needed.