Fibromuscular dysplasia of the internal carotid arteries

Seven patients with fibromuscular dysplasia of the internal carotid arteries have been operated upon at Walter Reed Army Medical Center. One lesion was treated by graduated dilatation with Bake's dilators combined with resection, end-to-end anastomosis, and vein patching of a tortuous segment. All other lesions were treated by graduated dilatation with an arterial dilator-shunt. All of these patients are asymptomatic presently. One patient has been operated upon recently because of symptoms related to the previously unoperated side as well as mild symptoms related to the previous operation. Two other patients with arteriographic evidence of fibromuscular dysplasia are being followed clinically. One is asymptomatic and one has minimal symptoms. Both are being treated with acetylsalicylic acid in hopes of preventing microembolization from these lesions. Important technical considerations in treating this condition are meticulous dissection of the internal carotid artery as near to the base of the skull as possible, confining the arteriotomy to the region of the carotid bulb, and straightening the carotid artery while passing the dilator under direct vision. A technique for routine shunting in these patients now is available.     

Intracranial dural empyema

Intracranial dural empyema is a neurosurgical emergency with potentially devastating complications. The prognosis is adversely affected by delay in diagnosis. Modern imaging techniques, especially contrast enhanced CT and MRI, have improved the speed and accuracy of radiological diagnosis of this condition, with an associated reduction in mortality. Despite this, there may still be a delay in diagnosis, partly owing to the subtlety of early radiological signs, especially on unenhanced CT. We present cases that illustrate some of the radiological manifestations, complications and potential pitfalls in diagnosis.     

Synthesis of substrates and inhibitors of botulinum neurotoxin type A metalloprotease*

Abstract: Botulinum neurotoxin (BoNT) metalloproteases and related proteases are the most selective proteases known. X‐ray crystal structures suggest that the active sites of the native enzymes exist in catalytically incompetent forms that must be activated by substrate binding. In order to characterize the postulated substrate‐induced conformational changes for enzyme activation, we synthesized a series of transition‐state analog inhibitors in which the dipeptide cleavage site is replaced by tetrahedral intermediate analogs within the minimal substrate peptide sequence. In this paper, we report our efforts to design inhibitors of BoNT/A metalloprotease. We confirm that an effective substrate sequence for BoNT/A metalloprotease is a 17‐mer peptide corresponding to residues 187–203 of SNAP‐25. A more stable substrate, Nle²⁰²SNAP‐25 [187–203] was synthesized in order to develop an assay for proteolytic activity of BoNT/A metalloprotease that can be used to monitor time‐dependent inhibition. α‐Thiol amide analogs of Gln‐197 were incorporated via solid‐phase peptide synthesis into both 17‐mer minimal peptide substrate sequences. The synthesis, characterization and inhibition kinetics for the α‐thiol amide analogs of holotoxin A substrate are described. These substrate‐derived inhibitors were shown to be submicromolar inhibitors of BoNT/A catalytic activity.     

Phase II trial of gefitinib in recurrent glioblastoma.

PURPOSE: To evaluate the efficacy and tolerability of gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. PATIENTS AND METHODS: This was an open-label, single-center phase II trial. Fifty-seven patients with first recurrence of a glioblastoma who were previously treated with surgical resection, radiation, and usually chemotherapy underwent an open biopsy or resection at evaluation for confirmation of tumor recurrence. Each patient initially received 500 mg of gefitinib orally once daily; dose escalation to 750 mg then 1,000 mg, if a patient received enzyme-inducing antiepileptic drugs or dexamethasone, was allowed within each patient. RESULTS: Although no objective tumor responses were seen among the 53 assessable patients, only 21% of patients (11 of 53 patients) had measurable disease at treatment initiation. Seventeen percent of patients (nine of 53 patients) underwent at least six 4-week cycles, and the 6-month event-free survival (EFS) was 13% (seven of 53 patients). The median EFS time was 8.1 weeks, and the median overall survival (OS) time from treatment initiation was 39.4 weeks. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent at higher doses. Withdrawal caused by drug-related adverse events occurred in 6% of patients (three of 53 patients). Although the presence of diarrhea positively predicted favorable OS from treatment initiation, epidermal growth factor receptor expression did not correlate with either EFS or OS. CONCLUSION: Gefitinib is well tolerated and has activity in patients with recurrent glioblastoma. Further study of this agent at higher doses is warranted.     

Plasma vitamin B-12 concentrations relate to intake source in the Framingham Offspring study

BACKGROUND: Low vitamin B-12 status is prevalent among the elderly, but few studies have examined the association between vitamin B-12 status and intake. OBJECTIVE: We hypothesized that vitamin B-12 concentrations vary according to intake source. DESIGN: Plasma concentrations and dietary intakes were assessed cross-sectionally for 2999 subjects in the Framingham Offspring Study. The prevalence of vitamin B-12 concentrations <148, 185, and 258 pmol/L was examined by age group (26-49, 50-64, and 65-83 y), supplement use, and the following food intake sources: fortified breakfast cereal, dairy products, and meat. RESULTS: Thirty-nine percent of subjects had plasma vitamin B-12 concentrations <258 pmol/L, 17% had concentrations <185 pmol/L, and 9% had concentrations <148 pmol/L, with little difference between age groups. Supplement users were significantly less likely than non-supplement-users to have concentrations <185 pmol/L (8% compared with 20%, respectively). Among non-supplement-users, there were significant differences between those who consumed fortified cereal >4 times/wk (12%) and those who consumed no fortified cereal (23%) and between those in the highest and those in the lowest tertile of dairy intake (13% compared with 24%, respectively), but no significant differences by meat tertile. Regression of plasma vitamin B-12 on log of intake, by source, yielded significant slopes for each contributor adjusted for the others. For the total group, b = 40.6 for vitamin B-12 from vitamin supplements. Among non-supplement-users, b = 56.4 for dairy products, 35.2 for cereal, and 16.7 for meat. Only the meat slope differed significantly from the others. CONCLUSIONS: In contrast with previous reports, plasma vitamin B-12 concentrations were associated with vitamin B-12 intake. Use of supplements, fortified cereal, and milk appears to protect against lower concentrations. Further research is needed to investigate possible differences in bioavailability.     

Prevalence, clinical characteristics, and mortality among patients with myocardial infarction presenting without chest pain

CONTEXT: Although chest pain is widely considered a key symptom in the diagnosis of myocardial infarction (MI), not all patients with MI present with chest pain. The extent to which this phenomenon occurs is largely unknown. OBJECTIVES: To determine the frequency with which patients with MI present without chest pain and to examine their subsequent management and outcome. DESIGN: Prospective observational study. SETTING AND PATIENTS: A total of 434,877 patients with confirmed MI enrolled June 1994 to March 1998 in the National Registry of Myocardial Infarction 2, which includes 1674 hospitals in the United States. MAIN OUTCOME MEASURES: Prevalence of presentation without chest pain; clinical characteristics, treatment, and mortality among MI patients without chest pain vs those with chest pain. RESULTS: Of all patients diagnosed as having MI, 142,445 (33%) did not have chest pain on presentation to the hospital. This group of MI patients was, on average, 7 years older than those with chest pain (74.2 vs 66.9 years), with a higher proportion of women (49.0% vs 38.0%) and patients with diabetes mellitus (32.6% vs 25. 4%) or prior heart failure (26.4% vs 12.3%). Also, MI patients without chest pain had a longer delay before hospital presentation (mean, 7.9 vs 5.3 hours), were less likely to be diagnosed as having confirmed MI at the time of admission (22.2% vs 50.3%), and were less likely to receive thrombolysis or primary angioplasty (25.3% vs 74.0%), aspirin (60.4% vs 84.5%), beta-blockers (28.0% vs 48.0%), or heparin (53.4% vs 83.2%). Myocardial infarction patients without chest pain had a 23.3% in-hospital mortality rate compared with 9.3% among patients with chest pain (adjusted odds ratio for mortality, 2. 21 [95% confidence interval, 2.17-2.26]). CONCLUSIONS: Our results suggest that patients without chest pain on presentation represent a large segment of the MI population and are at increased risk for delays in seeking medical attention, less aggressive treatments, and in-hospital mortality. JAMA. 2000;283:3223-3229     

Further evidence for a susceptibility locus for type 2 diabetes on chromosome 20q13.1-q13.2

We previously reported suggestive linkage between type 2 diabetes and markers in a region on chromosome 20q using data from a collection of 29 Caucasian families in which type 2 diabetes with middle-age-onset was segregated as an autosomal-dominant disorder. To map more precisely the susceptibility locus (or loci) within this broad region, we increased the family collection and genotyped all families for additional markers, both within the critical region and spaced over the rest of chromosome 20. Altogether 526 individuals (including 241 with diabetes) from the total collection of 43 families were included in the study. All individuals were genotyped for 23 highly polymorphic markers. Positive evidence for linkage was found for a 10-cM region on the long arm of chromosome 20q13.1-q13.2 between markers D20S119 and D20S428. The strongest evidence in two-point as well as multipoint linkage analysis (P = 1.8 x 10(-5)) occurred at the position corresponding to marker D20S196. The individuals with diabetes in the seven most strongly linked families had high serum insulin levels during fasting and 2-h post-glucose load periods. We did not find any evidence for linkage between type 2 diabetes and any other region on chromosome 20. In conclusion, our larger and more comprehensive study showed very strong evidence for a susceptibility gene for insulin-resistant type 2 diabetes located on the long arm of chromosome 20 around marker D20S196.