Apolipoprotein (a) concentrations and susceptibility to coronary artery disease in patients with peripheral vascular disease.

OBJECTIVE--To investigate the relation between apolipoprotein(a) concentrations and angiographically defined coronary artery disease in patients with atheromatous peripheral vascular disease. DESIGN--40 consecutive patients were recruited at the time of admission for peripheral vascular surgery. All underwent clinical assessment and coronary arteriography. Apolipoprotein(a) concentrations were measured by an immunoradiometric assay. SETTING--Tertiary referral centre. SUBJECTS--Patients requiring surgical intervention for large vessel peripheral vascular disease. MAIN OUTCOME MEASURES--Presence or absence and severity and distribution of angiographically defined coronary artery disease. Measurement of circulating contractions of apolipoprotein(a) and other lipid indices. RESULTS--Coronary artery disease was absent in 11 patients (group 1), mild to moderate in 12 (group 2), and severe in 17 (group 3). The distribution of peripheral vascular disease and of standard lipid indices was similar in these three groups of patients. There was a significant difference in apolipoprotein(a) concentrations between the three groups, with concentrations progressively increasing with the severity of coronary artery disease (mean (95% confidence interval): group 1, 112 U/1 (52 to 242); group 2, 214 U/1 (129 to 355); group 3, 537 U/1 (271 to 1064) (analysis of variance p < 0.005). The prevalence of coronary artery disease was increased 7.4 fold in patients with apolipoprotein(a) concentrations that were greater than the cohort median (206 U/1) (p < 0.01). CONCLUSIONS--The results show an association between apolipoprotein(a) concentrations and angiographically defined coronary artery disease in patients with large vessel peripheral vascular disease. The findings imply differences in the pathogenesis of coronary and peripheral atheroma and suggest that the measurement of apolipoprotein(a) may prove a useful additional tool in the risk factor assessment of patients undergoing peripheral vascular surgery.     

Familial arteriopathic leukoencephalopathy: imaging and neuropathologic findings.

We present the clinical, imaging, and neuropathologic data for a family with an autosomal dominant, nonhypertensive, progressive cerebral arteriopathy and leukoencephalopathy. Clinical presentation was characterized by progressive dementia, gait abnormalities, and, in some, Parkinson-like symptoms. MR abnormalities, consisting of white matter T2 hyperintensities and cystic-appearing T1 hypointensities, were present in seven family members. The basal ganglia also showed cystic abnormalities. Neuropathologic examination in two cases revealed numerous lacunar infarctlike lesions, extensive demyelination, and widespread hyalinization of arteriolar walls with karyolysis and granular deposits within the media. These findings appear to constitute further evidence of a genetically determined arteriopathic leukoencephalopathy.     

Effective Treatment for Acute Alkali Injury to the Esophagus Using Weak-acid Neutralization Therapy: An Ex-vivo Study

Objective: 1) To evaluate whether neutralization therapy with weak acid is effective in reducing observed histopathologic esophageal tissue injury secondary to liquid alkali. 2) to quantify the temperature change of the neutralizing agent. and 3) to determine the effect of interval to therapy on injury severity.
Methods: Harvested Sprague-Dawley rat esophagi were catheterized and placed in an oxygenated saline bath (37°C) for 60 minutes and then fixed in 10% formalin. Nine groups ( ti = 10) were perfused with 50% sodium hydroxide (NaOH). Six of the groups were treated hy neutralization with cooled orange juice (OJ) or cola that was maintained between 2°C and 4°C. This was performed at 0, 5. or 30 minutes after injury. In addition, two positive control groups were exposed to OJ or cola at time 0 and were not exposed to strong alkali. A third control group was exposed to strong alkali hut was not administered any subsequent treatment. The temperature of the neutralizing agent was recorded prior to instillation and after exiting the esophagus. Blinded pathologic scoring of 0 (no injury) to 3 (severe) was performed for six histopathologic categories: epithelial cell viability, cornified epithelial cell differentiation, granular cell differentiation. epithelial cell nuclei, muscle cells, and muscle cell nuclei. Comparisons were made among treatment times using the Kruskal-Wallis test and linear trend analysis.
Results: For each histopathologic category and each treatment mode, the Kruskal-Wallis test showed significant differences between the groups (p < 0.003) over time. Trend analyses showed more severe injury with delayed ncutralization therapy (p < 0.05) for each treatment mode and histopathologic category.
Conclusion: Early neutralization therapy with OJ or cola reduces acute esophageal alkali injury. Additional in-vivo study is needed before neutralization therapy is adopted for clinical use.     

Primary skeletal non-Hodgkin's lymphoma in the pediatric age group

The authors discuss rare primary skeletal non-Hodgkin's lymphoma in 16 patients treated from 1973 to 1989. The symptoms of these patients related to bone lesions in 95% of the cases. These bone lesions were monostotic or polyostotic, with or without regional and distant metastases. The locations of these lesions were long bones in 13 patients, pelvic bones in seven patients, and skull and vertebral bodies in two patients. The anatomical locations of these lesions in the bones were diaphysis alone in one patient, epiphysis in two patients, metaphysis in three patients, and a combination of diaphyseal, epiphyseal, and metaphyseal lesions in seven patients. Extraskeletal involvement was present in nine patients; extraskeletal sites included regional or distant lymph node involvement in seven cases, the mediastinum in two, lung nodules in two patients, the skin and subcutaneous regions in four patients; bone marrow in three patients, and peripheral nervous system (PNS) in one patient. Two patients had stage I disease, three had stage II disease, eight had stage III disease, and three had stage IV disease. The majority of patients had large noncleaved cell diffuse lymphomas or DHL by Rappaport classification. All patients were treated with the LSA₂-L₂ protocol; six patients received radiation therapy to the affected bone, and ten patients received no radiation therapy. Three patients failed on treatment within the first 4 months of therapy. Two patients developed a second tumor, one in the radiation therapy field and the other in a patient who received no radiation therapy. Eleven patients are alive without evidence of disease, with a median observation time of 6.5 years. The event-free survival for the 16 patients receiving LSA₂-L₂ was 73%, and the lymphoma-free survival was 81%. Extension of disease to multiple sites or location of the primary site was not of prognostic significance, but the finding of central nervous system (CNS), PNS, or bone marrow disease at diagnosis was. Whether the skeletal lesions were uni- or multifocal, with regional or distant metastases, the prognosis for lymphoma-free survival was good. The role of radiation therapy for all patients and intensive treatment for earlystage disease is discussed. The authors conclude that chemotherapy is the most important modality of treatment for any stage, histology, or location of the tumor. This chemotherapy shou ld include drugs that have been shown to be effective in the treatment of pediatric lymphoma, such as cyclophosphamide, cytosine arabinoside, vincristine, methotrexate, and daunomycin, in dosages sufficient to produce marrow suppression and early recovery, allowing for continuous or intermittent therapy. Radiation therapy should be used if there is no response or progression of disease (demonstrated either clinically or by scans, confirmed by a biopsy) within the first few months of treatment. © 1992 Wiley-Liss, Inc.     

Treatment of experimental osteomyelitis with antibiotic-impregnated bone graft substitute

The model of Norden was used to induce osteomyelitis in the left tibia of New Zealand White rabbits. Twenty-one days following inoculation, the animals had primary debridement and then were randomized into one of three treatment groups. Group I received no additional treatment; in Group II, plain hydroxyapatite beads were packed into the defect; and in Group III, gentamicin crobefat-loaded hydroxyapatite beads were packed into the defect. The animals were observed for 40 days after the primary debridement and then were killed. The intensity of infection was determined by swab cultures and quantitative bacterial cultures of the debrided material. At primary debridement, all of the animals in each group were equally infected. At the time of secondary debridement, only the animals in Group III had a statistically significant reduction in infection (p < 0.001). In this study, we demonstrated that an antibiotic-loaded osteoinductive ceramic bead can effectively eliminate bacteria from an osteomyelitic cavity.     

ORAL CONTRACEPTIVES ENHANCE THE RISK OF CLINICAL MANIFESTATION OF VENOUS THROMBOSIS AT A YOUNG AGE IN FEMALES HOMOZYGOUS FOR FACTOR V LEIDEN

In 29 patients (17 females) homozygous Arg 506 Gln mutation (FV Leiden) was identified. 25 had been investigated because of venous thromboembolism (VTE); four asymptomatic patients were found during family studies.
The first VTE had occurred significantly earlier in females (median age [m] 26 years, range 17–49) than in males (m=38 years, range 21–82) ( P  = 0.01). 12 females (80%) had taken oral contraceptives (OC, oestrogen content 0.02–0.1 mg) for 6–150 months prior to thrombosis. Further triggering conditions in females were hormone replacement ( n  = 1) and pregnancy ( n  = 2). In 8/10 males the first VTE had occurred spontaneously — in two after surgery. The sites of VTE were deep vein thrombosis, pulmonary embolism, caval vein thrombosis and superficial thrombophlebitis.
From our data we conclude that OC medication is the most important precipitating factor for VTE in females with homozygous FV Leiden.     

Phase II clinical trial of intralesional administration of the oncolytic adenovirus ONYX-015 in patients with hepatobiliary tumors with correlative p53 studies.

PURPOSE: ONYX-015 is a genetically modified adenovirus with a deletion of the E1B early gene and is therefore designed to replicate preferentially in p53-mutated cells. A Phase II trial of intralesional ONYX-015 was conducted in patients with hepatobiliary tumors to determine the safety and efficacy of such a treatment. EXPERIMENTAL DESIGN: All patients had biopsy-proven, measurable tumors of the liver, gall bladder, or bile ducts that were beyond the scope of surgical resection. Patients received intralesional injections of ONYX-015 at either 6 x 10(9) or 1 x 10(10) plaque-forming units/lesion up to a total dose of 3 x 10(10) plaque-forming units, and i.p. injections were allowed in patients with malignant ascites. The status of p53 was assessed by immunohistochemistry or Affymetrix GeneChip microarray analysis. Studies were conducted for viral shedding and for the presence of antiadenoviral antibodies before and after the injection of ONYX-015. Patients were assessed for response and toxicity. RESULTS: Twenty patients were enrolled, and 19 patients were eligible. Half of the patients had primary bile duct carcinomas. Serious toxicities (> grade 2) were uncommon and included hepatic toxicity (three patients), anemia (one patient), infection (one patient), and cardiac toxicity (one patient, atrial fibrillation). Sixteen patients were evaluable for response. Among these evaluable patients, 1 of 16 (6.3%) had a partial response, 1 of 16 (6.3%) had prolonged disease stabilization (49 weeks), and 8 of 16 (50%) had a >50% reduction in tumor markers. Of the 19 eligible patients, 18 (94.7%) had specimens available for p53 analysis. Fifteen of these 18 patients (83.3%) had evidence of p53 mutation by one or both methods, although the methods correlated poorly. Viral shedding was confined to bile (two of two patients) and ascites (four of four patients). Pretreatment adenoviral antibodies were present in 14 of 14 patients and increased by 33.2% after ONYX-015 treatment. CONCLUSIONS: Intralesional treatment with ONYX-015 in patients with hepatobiliary tumors is safe and well tolerated, and some patients had evidence of an anticancer effect. The high incidence of p53 mutations in these tumors makes this a logical population in which to test this therapy but precludes definitive evaluation about the necessity of a p53 mutation for ONYX-015 clinical activity.