Anti-factor VIII antibodies of hemophiliac patients are frequently directed towards nonfunctional determinants and do not exhibit isotypic restriction

A significant proportion of hemophilia A patients receiving transfusions of factor VIII (FVIII) develop a specific antibody response towards FVIII. These antibodies are usually detected by assays in which they inhibit the function of the molecule, such as the Bethesda clotting test. We have prepared anti-FVIII antibodies by specific immunoadsorption from the plasma of four hemophiliacs with stable inhibitor levels. The isotypic distribution of such antibodies was determined and their capacity to bind to insolubilized FVIII was compared with their inhibitory activity in two functional assays, namely, the Bethesda assay and a chromogenic assay. In addition, the FVIII epitope specificity was determined by competition with monoclonal antibodies for the binding to insolubilized FVIII. We show here that (1) anti-FVIII antibodies are not isotypically restricted; thus, a significant proportion of specific IgG2 was found; (2) antibodies are frequently directed towards epitopes of FVIII that are not directly involved in the function of the molecule and therefore escape detection in the Bethesda method or chromogenic assay; and (3) each patient shows a unique pattern of FVIII epitope recognition. We conclude that evaluation of anti-FVIII antibodies by a functional method does not provide an accurate evaluation of the specific antibody response. These findings have important implications for the comparison of the immunogenicity of FVIII molecules produced by different technologies and for the development of methods to control anti-FVIII antibody production.     

In vivo expression of the B7 costimulatory molecule by subsets of antigen-presenting cells and the malignant cells of Hodgkin's disease

The B-lymphocyte/accessory-cell activation antigen B7 (BB1) has been shown in vitro to stimulate T-lymphocyte proliferation and cytokine production via CD28 present on the latter cells. In this study, benign lymphoid tissues, lymphomas, and extralymphoid inflammatory sites were examined immunohistochemically using anti-B7 and other relevant monoclonal antibodies. B7 was expressed by benign transformed germinal center B cells, as it was by B cells of follicular lymphomas. B7 was also expressed by a subpopulation (a mean of 31% to 65%) of macrophages and dendritic cells in a variety of lymphoid tissues. It was present in abundance on all macrophages constituting sarcoid granulomas in lymph nodes. In extralymphoid inflammation, 17% to 35% of macrophages expressed B7 only weakly. Cases of Hodgkin's disease showed expression of B7 by the majority of Reed-Sternberg cells or malignant mononuclear variants, a phenomenon that potentially contributes to the lymphocytic accumulation that is a feature of this condition. CD28+ T cells were seen in all areas where T cells were present. B7+ and CD28+ cells colocalized in, for example, lymphoid follicles, lymph node paracortex, sarcoid granulomas, and Hodgkin's disease tissue, indicating a potential for cellular interaction via these molecules at these sites.     

Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia is characterized by moderate thrombocytopenia and thrombotic complications, whereas quinine/quinidine-induced thrombocytopenia usually presents with severe thrombocytopenia and bleeding. Using flow cytometry and assays of procoagulant activity, we investigated whether sera from patients with these immune drug reactions could stimulate normal platelets to generate platelet-derived microparticles with procoagulant activity. Sera or purified IgG from patients with heparin-induced thrombocytopenia stimulated the formation of platelet-derived microparticles in a heparin-dependent fashion. Further studies showed that heparin-induced thrombocytopenia sera also produced a marked increase in procoagulant activity. In contrast, sera from patients with quinine- or quinidine-induced thrombocytopenia did not generate platelet-derived microparticles nor generate increased procoagulant activity. However, quinine/quinidine-induced thrombocytopenia sera produced a significant increase in the binding of IgG to platelets in a drug-dependent fashion, whereas sera from patients with heparin-induced thrombocytopenia demonstrated no drug-dependent binding of IgG to platelets. We also observed increased levels of circulating microparticles in patients with acute heparin-induced thrombocytopenia compared with control patients. Our observations indicate that the generation of procoagulant platelet-derived microparticles in vivo is a plausible explanation for the thrombotic complications observed in some patients with heparin-induced thrombocytopenia.     

Age effect in recall performance according to the levels of processing, elaboration, and retrieval cues

The present study was conducted to investigate the incidence of several factors contributing to age-related memory decrement. Variables manipulated include quality (level of processing encoding conditions), the degree of effort and encoding quantitative elaboration (active/passive encoding conditions), and the influence of retrieval support (free-/cued recall conditions). In support of the environmental support hypothesis, middle-old and old subjects benefited more than young ones from cued recall in all the memory tests. Moreover, the results showed a differential (qualitative vs. quantitative) impairment of conceptual processing between the middle-old and the old-age groups. In the middle-olds, age differences were abolished by deep processing in old adults, age differences were attentuated only with deep and active processing associated with retrieval support. These gradual memory impairments are evaluated according to Mandler's model of memory (1979, In L. G. Nilsson [Ed.], Perspective in memory research. Hillsdale: Lawrence-Erlbaum), and the environmental support hypothesis is discussed in terms of the involvement of encoding and retrieval operations required by the memory task.     

Attenuated Familial Adenomatous Polyposis

PURPOSE: Familial adenomatous polyposis is a well-described, autosomal dominant, inherited syndrome characterized by diffuse polyposis of the colon and rectum as well as various upper gastrointestinal and extraintestinal manifestations. A subset of patients present with fewer colorectal polyps, later age of onset of polyps and cancer, and a predilection toward involvement of the proximal colon. This variant of familial adenomatous polyposis is known as attenuated familial adenomatous polyposis. The purpose of this review is to summarize current knowledge regarding this poorly understood entity and propose guidelines for diagnosis, surveillance, and surgical management. METHODS: The MEDLINE database was searched from 1985 onward using the keywords, attenuated familial adenomatous polyposis, AFAP, adenomatous polyposis coli gene, and APC gene. Additional articles were identified through the reference sections of retrieved papers. All papers that pertained to attenuated familial adenomatous polyposis or mutations in the APC gene producing an attenuated phenotype were included. RESULTS: Attenuated familial adenomatous polyposis is transmitted in an autosomal dominant fashion. Several distinct mutations within the APC gene have been associated with an attenuated phenotype, but variability of disease expression within kindreds possessing identical mutations makes classification difficult. Polyps are diagnosed at a mean age of 44 years, with cancer diagnosed at a mean of 56 years of age. Frequent involvement of the proximal colon necessitates the use of colonoscopy for surveillance, and infrequent involvement of the rectum supports the role of a total abdominal colectomy and ileorectal anastomosis. CONCLUSIONS: Although currently recognized as a distinct clinical entity, attenuated familial adenomatous polyposis may be part of a spectrum of disease that includes familial adenomatous polyposis and is caused by different mutations within the APC gene. Because of its unique characteristics, yet apparent overlap with familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, increased awareness of attenuated familial adenomatous polyposis should improve diagnosis, surveillance, and treatment strategies in this unique subset of familial polyposis syndromes.     

Electrophysiologic effects of intravenous flecainide in intranodal junctional tachycardia in 30 patients

The electrophysiological effects of flecainide acetate were studied in 30 patients (10 men, 20 women, mean age 48.3 +/- 18 years) suffering from sustained re-entrant intranodal tachycardia. A 2 mg/kg dose of flecainide administered over 10 minutes was given after the onset of sustained tachycardia within 3.8 +/- 2.3 min in 25 of the 30 patients; this was effected by a block in the retrograde leg of the circuit in 22 patients and by a block in the anterograde leg in 3 patients. In the remaining 5 patients the tachycardia was slowed down (367 +/- 27 ms vs 431 +/- 48 ms) chiefly by prolongation of the atrioventricular anterograde conduction. No significant side-effect was observed while the drug was being injected. Following treatment with flecainide, tachycardia was no longer inducible in 24 out of 30 patients (A) and it remained inducible in 6 patients (B, non-responders). The initial electrophysiological exploration revealed differences between these two groups in retrograde conduction: prolongation of the ventriculoatrial time during incremental ventricular stimulation (A: 41 +/- 32 ms vs B: 81 +/- 142 ms, p less than 0.05) and prolongation of the atrioventricular time above 100 ms (A: 2/24 patients, B: 3/6 patients, p less than 0.01). The following electrophysiological parameters were significantly (p less than 0.01) ,modified after intravenous flecainide: AH and HV conduction intervals, atrial refractory periods, anterograde and retrograde atrioventricular conduction. Complete retrograde block was observed in 12 patients of group A. Thus, in this study flecainide arrested a reciprocal intranodal rhythm in 25 out of 30 patients and prevented the reinduction of tachycardia in 24 of these.(ABSTRACT TRUNCATED AT 250 WORDS)     

Surgical management of isolated retroperitoneal recurrences of colorectal carcinoma

PURPOSE: Isolated locoregional disease accounts for approximately 20 percent of recurrences after treatment for colorectal cancer. It has been suggested that complete resection of these recurrences can result in increased survival. The value of surgery for isolated retroperitoneal recurrences has not been well defined. We have sought to characterize outcome and survival in patients undergoing resection for isolated retroperitoneal recurrences of colorectal cancer. METHODS: From a prospective database, 25 patients were identified as having undergone surgical exploration with curative intent for isolated retroperitoneal recurrences of colorectal cancer between 1988 and 1999. Variables studied included age, gender, location and size of the tumor, extent of resection, disease-free interval, and morbidity and mortality. Statistical analyses were performed using the log-rank test and Kaplan-Meier estimates, with overall survival as the primary end point. RESULTS: The study population consisted of 25 patients (13 males), with a median age of 55 years and a median follow-up of 29 (range, 1–151) months. The median time to first retroperitoneal recurrence was 23 (range, 3–72) months. Twenty patients underwent resection, whereas five patients were deemed unresectable at the time of operation. The median survival in patients who underwent resection patients was 31 months compared with 3 months in those patients who did not undergo resection (P = 0.0001). Analysis of the entire group demonstrated a disease-free interval of greater than 24 months to be a positive predictor of outcome (median survival, 30 vs. 48 months; P = 0.02). For patients undergoing resection, the presence of positive margins (P = 0.01) and tumor size 5 cm (P = 0.008) predicted a worse prognosis. In patients who underwent resection, the two-year and five-year overall survival rates were 60 and 15 percent, respectively. CONCLUSIONS: Patients with isolated retroperitoneal recurrences of colorectal cancer generally have a poor prognosis. However, a longer disease-free interval, complete negative-margin resection, and smaller tumor size are associated with long-term survival in selected patients.     

Identification of Patients with High-Risk Stage II Colon Cancer for Adjuvant Therapy

Purpose Adjuvant therapy for Stage II colon cancer remains controversial but may be considered for patients with high-risk features. The purpose of this study was to assess the prognostic significance of commonly reported clinicopathologic features of Stage II colon cancer to identify high-risk patients. Methods We analyzed a prospectively maintained database of patients with colon cancer who underwent surgical treatment from 1990 to 2001 at a single specialty center. We identified 448 patients with Stage II colon cancer who had been treated by curative resection alone, without postoperative chemotherapy. Results With median follow-up of 53 months, 5-year disease-specific survival for this cohort was 91 percent. Univariate and multivariate analyses identified three independent features that significantly affected disease-specific survival: tumor Stage T4 (hazard ratio (HR), 2.7; 95 percent confidence interval (CI), 1.1–6.2; P = 0.02), preoperative carcinoembryonic antigen >5 ng/ml (HR, 2.1; 95 percent CI, 1.1–4.1; P = 0.02), and presence of lymphovascular or perineural invasion (HR, 2.1; 95 percent CI, 1–4.4; P = 0.04). Five-year disease-specific survival for patients without any of the above poor prognostic features was 95 percent; five-year disease-specific survival for patients with one of these poor prognostic features was 85 percent; and five-year disease-specific survival for patients with ≥2 poor prognostic features was 57 percent. Conclusions Patients with Stage II colon cancer generally have an excellent prognosis. However, the presence of multiple adverse prognostic factors identifies a high-risk subgroup. Use of commonly reported clinicopathologic features accurately stratifies Stage II colon cancer by disease-specific survival. Those identified as high-risk patients can be considered for adjuvant chemotherapy and/or enrollment in investigational trials. Read at the meeting of The American Society of Colon and Rectal Surgeons, St. Louis, Missouri, June 2 to 6, 2007. Reprints are not avaliable.