Antiidiotypic IgG crossreactive with Rh alloantibodies in red cell autoimmunity

IgG autoantibodies eluted from RBCs of antiglobulin positive normal blood donors contained at least two antibody populations, an IgG autoantibody (Ab 1), and an IgG population (Ab 2) that agglutinated RBCs coated with some Rh(D) alloantibodies. Eight of 24 autoantibody eluates tested agglutinated 3 of 10 anti-Rh(D) sensitized RBCs. The agglutinating activity was inhibited specifically by preincubation of the autoantibody eluate with the reactive anti-D. The reaction did not require the Fc domain of the anti-Rh(D), since autoantibody eluates agglutinated RBCs coated with F(ab')2 prepared from the reactive anti-D sera. These findings indicate that the RBCs of some antiglobulin- positive blood donors contain an immunoglobulin auto-antiidiotype (Ab 2) against the RBC autoantibody (Ab 1) which is demonstrable through its cross-reactivity with selected Rh(D) alloantibodies. Identification of auto-antiidiotypes in RBC autoimmunity lends support to the idiotype- antiidiotype network hypothesis of immune regulation and is consistent with the bizarre and complex serology of autoimmune hemolytic anemia. The absence of clinical hemolysis in antiglobulin-positive normal blood donors suggests that immunoglobulin idiotype-antiidiotype interactions may play a role in modulating the effects of RBC autoimmunity.     

Mexiletine: double-blind comparison with procainamide in PVC suppression and open-label sequential comparison with amiodarone in life-threatening ventricular arrhythmias

The antiarrhythmic effects of mexiletine (n = 14) were compared to procainamide (n = 16) by a double-blind parallel protocol in 30 patients (group I) with frequent premature ventricular contractions (PVCs) (greater than 20/hr), and to amiodarone by an open-label sequential approach in 25 patients (mean left ventricular ejection fraction of 32.6 +/- 13.4%) with life-threatening ventricular arrhythmias (group II) resistant to two or more conventional agents. The predetermined end point of therapy in group I patients was met in 6 of 14 (43%) given mexiletine, with 7 (50%) requiring drug discontinuation for severe gastrointestinal or central nervous system side effects and only 3 of 16 patients (19%) given procainamide, with 5 (31%) developing limiting side effects. Increases in dose led to a higher efficacy rate for PVC suppression with a corresponding increase in side effects with mexiletine; with procainamide, the higher dose was not associated with greater PVC suppression. In group II patients, mexiletine was effective in 4 (16%), with one patient discontinuing the drug during long-term therapy; mexiletine was ineffective in 16 (64%) and early side effects developed in 5 (20%). Patients not responding to or not tolerating mexiletine were given amiodarone; 20 of 21 (95%) responded with arrhythmia control after the loading dose. During a mean follow-up period of 2 years, sudden death occurred in two patients, death from heart failure in two, and death from subarachnoid hemorrhage in one patient; 15 (75%) patients are alive and free of arrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Progression of coronary atherosclerosis. Clues to pathogenesis from serial coronary arteriography.

Fifty two patients with coronary artery disease underwent repeat coronary arteriographic studies separated by 2-108 (mean 51) months of medical treatment. The results were compared and correlated with symptoms to determine the nature of the progression of coronary atherosclerosis. The condition appeared to progress episodically in the proximal segments of the coronary arteries and in relation to the abrupt development of new symptoms or acute coronary events such as unstable angina or myocardial infarction. Thirty four of 105 (33%) of the pre-existing stenoses showed evidence of progression. Progression to total occlusion was uncommon (13) except for stenoses greater than 90% (six out of 18). New lesions frequently occurred (37) in previously normal segments of the arteries; most of these were stenoses greater than 90% (13) or total occlusions (12). Rapid progression of a mild lesion and new lesions occurred in the form of smooth intimal protrusions into the arterial lumen. Intimal haemorrhages are the likely explanation for these intimal encroachments and also for the episodic nature of the progression of coronary artery disease. Coronary atherosclerosis does not progress gradually in a linear fashion, and local anatomical factors appear to play a dominant role in the natural history.     

Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma

Our recent study demonstrated that a novel proteasome inhibitor NPI-0052 triggers apoptosis in multiple myeloma (MM) cells, and importantly, that is distinct from bortezomib (Velcade) in its chemical structure, effects on proteasome activities, and mechanisms of action. Here, we demonstrate that combining NPI-0052 and bortezomb induces synergistic anti-MM activity both in vitro using MM cell lines or patient CD138(+) MM cells and in vivo in a human plasmacytoma xenograft mouse model. NPI-0052 plus bortezomib-induced synergistic apoptosis is associated with: (1) activation of caspase-8, caspase-9, caspase-3, and PARP; (2) induction of endoplasmic reticulum (ER) stress response and JNK; (3) inhibition of migration of MM cells and angiogenesis; (4) suppression of chymotrypsin-like (CT-L), caspase-like (C-L), and trypsin-like (T-L) proteolytic activities; and (5) blockade of NF-kappaB signaling. Studies in a xenograft model show that low dose combination of NPI-0052 and bortezomib is well tolerated and triggers synergistic inhibition of tumor growth and CT-L, C-L, and T-L proteasome activities in tumor cells. Immununostaining of MM tumors from NPI-0052 plus bortezomib-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Taken together, our study provides the preclinical rationale for clinical protocols evaluating bortezomib together with NPI-0052 to improve patient outcome in MM.     

Newly diagnosed arrhythmogenic right ventricular dysplasia in an octogenarian

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is thought to be a disease of the young, with the majority of newly diagnosed patients under 40 years of age. Establishing this diagnosis in elderly patients may be challenging, and a few reports exist of patients older than 70 years diagnosed with ARVD/C at autopsy. We report the case of an octogenarian with antemortem newly diagnosed ARVD/C. This case report represents the oldest patient to date to have a newly established diagnosis of ARVD/C and highlights the difficulty in making the diagnosis in the elderly.     

Tuberculous anal sepsis

INTRODUCTION: Tuberculosis is a neglected cause of anal sepsis, often is not recognized, and therefore is not treated properly. METHOD: All patients were reviewed who had tuberculous anal sepsis diagnosed by histology reports of fistulectomy specimens or abscess scrapings from January 1990 to April 1999. RESULTS: Twenty patients (median age, 53 years; 18 males) with anal tuberculous sepsis were identified. They presented with abscesses (n=2), abscesses and fistulas (n=6), or fistulas (n=12). All patients had a long history of anal complaints (3 months to 20 years), for which 15 patients were operated on previously. Nearly all fistulas (17/18) were complex, and secondary tracks or additional complicating features were common, even at first presentation. Eight patients had active concurrent pulmonary tuberculosis, and six showed evidence of previous pulmonary tuberculosis. Six patients had no signs of concurrent or previous tuberculosis elsewhere. Recurrence was observed only in cases where tuberculosis was initially not recognized, and antitubercular treatment therefore was not started. CONCLUSION: Contrary to views held previously, anal tubercular sepsis seems to have characteristic clinical features. It should be considered in cases of known pulmonary or extrapulmonary tuberculosis or if anal sepsis is persistent, recurrent, or complex in nature.