Mordechai Ravid

Spectral Analysis of Fluctuations in Heart Rate: An Objective Evaluation of Autonomic Nervous Control in Chronic Renal Failure

A quantitative, noninvasive method of assessing autonomic control, based on the spectral analysis of beat-to-beat fluctuations in heart rate (HR), was applied to patients with chronic renal failure (RF). Since the power spectrum of HR fluctuations measures the dynamic nervous control of HR, it can be used to quantitate a normal control system as opposed to a disturbed or depressed system. Indeed, in RF patients, a strong reduction in the HR power spectrum was observed in all frequency ranges, both sympathetically and parasympathetically mediated. A similar depression in autonomic control was demonstrated in patients on hemodialysis or peritoneal dialysis. RF patients not yet undergoing dialysis show a lesser degree of depression. Spectral analysis of HR fluctuations in RF patients makes it possible to quantitate autonomic dysfunction and to reliably measure its development as a function of time, and requires only a 10-min standard electrocardiogram recording.

Reduced cardiotoxicity of doxorubicin by a 6‐hour infusion regimen. A prospective randomized evaluation

In order to evaluate the possible cardiosparing effect of a prolonged infusion of doxorubicin as compared with the standard mode of administration 62 consecutive patients with metastatic carcinoma of the breast or carcinoma of the ovary Stage III or IV were prospectively randomized to receive doxorubicin either as a rapid infusion over 15 to 20 minutes at 8 AM or as a continuous infusion over 6 hours, 8 AM to 2 PM. The remaining protocol was identical for the two groups. The cardiotoxic effect of doxorubicin was evaluated by history and physical examination and by the decline in resting ventricular ejection fraction (LVEF) as determined by gated pool radionuclide angiography with technetium 99m (99mTc) and by the decline in the height of the QRS complexes in the standard leads of the echocardiogram (ECG). Initially there were 31 patients in each group. The cumulative dose of doxorubicin, was 410 mg/m2 ± 42 SD in the standard infusion group and 428 mg/m2 ± 48 SD in the 6‐hour infusion group. The mean decline in LVEF after a cumulative doxorubicin dose of 300 mg/m2 was 17% in the first group and only 4.1% in the second. After 400 mg/m2 the mean fall in LVEF was 21% in the first group and 6% in the second. The mean decline in QRS voltage after 300 mg/m2 was 29% and 1.5%, respectively. Four patients, all in the standard infusion group, developed congestive heart failure. These data suggest that slow infusion of doxorubicin is associated with reduced cardiotoxicity.

Usefulness of colchicine in preventing recurrences of pericarditis

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Incidence and origin of non-systemic microdeposits of amyloid

In a general hospital, 391 consecutive necropsies in which at least seven organs were available, were examined retrospectively by polarizing microscopy of Congo-red-stained sections for the presence of local amyloid deposits. Non-systemic microdeposits of amyloid were encountered in 72 cases, an overall incidence of 18·4%. They were usually small and frequently detectable only by virtue of polarizing microscopy. There is no indication that these microdeposits of amyloid are of pathogenetic significance. Although they sometimes occur in more than one organ, such deposits can be readily distinguished from those of systemic amyloidosis by their histological features.

Diabetic fibrillosis: A report of three cases

Three patients with diabetes are described. Two patients had a mild, well controlled, hyperglycemic syndrome; five years after its detection signs of nephropathy and retinopathy appeared. Both died of renal failure ten years after detection of diabetes. The third patient died at the age of forty-seven of recurrent myocardial infarction. During her terminal hospitalization uremia and hyperglycemia were first discovered. Histologic findings in postmortem material were identical in all three cases. Heavy deposits of pediodic acid-Schiff-positive, colloidal iron and Congo red negative material were found in the blood vessels of virtually all organs examined. The blood vessels involved ranged from capillaries, venules, arterioles to arteries of large size. In some areas the material was seen also in connective tissue outside of blood vessels. Electronmicroscopic examination revealed that the PAS-positive material was composed of fibrils, approximately 100A wide. These findings indicate the presence of a systemic disease of connective tissue in our cases, resembling systemic amyloidosis in extent, location and nature. We suggest the name, diabetic fibrillosis.

Trisomies 9 and 8 detected by fluorescence in situ hybridization in patients with systemic mastocytosis

BACKGROUND Systemic mastocytosis is a rare disease characterized by proliferation of mast cells in one or more organs. The origin of the mast cells is still debated, although it has been recently shown that they derive from CD34+ hematopoietic progenitors. Some clinical and in vitro studies have suggested a possible link between myeloproliferative disorders and systemic mast cell disease. OBJECTIVE This study was designed to further evaluate the association between systemic mast cell disease and other hematologic disorders by means of conventional cytogenetic analysis and fluorescent in situ hybridization. METHODS We used cytogenetic analysis and fluorescent in situ hybridization with probes to chromosomes 8 and 9 in six patients with systemic mast cell disease. RESULTS Fluorescent in situ hybridization helped to identify five patients with trisomy 9 and one with trisomy 8. In contrast, chromosomal analysis demonstrated an abnormal karyotype (45,XO/46,XY) in only one patient. CONCLUSION The association between myeloproliferation disorders and systemic mast cell disease may be explained by the finding that trisomy 9 and trisomy 8 are common in both disorders. A trisomy was detected in all of the patients in our small group compared with nearly 40% of previously reported patients with myeloproliferative disorders. FISH is more sensitive than conventional cytogenetics in detecting these aberrations.

Fluorescence in situ hybridization for the detection of trisomies 8 and 9 in polycythemia vera.

Trisomies 8 and 9 are the most common numerical chromosome abnormalities in polycythemia vera (PCV). Their role in the pathogenesis of the disease is unclear, however, as is their diagnostic or prognostic value. We evaluated fluorescent in situ hybridization as compared to chromosome analysis for the detection of trisomies 8 or 9 in peripheral blood cells of PCV patients. We demonstrated that FISH is a more sensitive method for the detection of the abnormalities. A positive correlation between the duration of the disease and trisomy 9 was found. FISH is a sensitive, convenient, and rapid method for the diagnosis and follow-up of chromosome aberrations in patients with PCV. The application of FISH to a larger cohort of patients may provide valuable information regarding the role of the chromosomal aberrations in the initiation and progression of this disease.

Quantitative Electron Microscopic Study of Capillaries in Diabetes mellitus

A systematic microscopic examination of all elements of the capillary wall was performed on quadriceps muscle biopsies from 9 diabetic patients and 8 controls. The capillary basement membrane (CBM) was markedly thicker in diabetics; it consisted of several lamellae and contained large vacuoles which were never observed in non-diabetic subjects. Large magnifications revealed fibrils in greater number and markedly larger in diameter in diabetics, these accounting for a considerable volume of the CBM and the adventitia and increased diameter and thickness of the capillary wall, without encroaching on the lumen. The intracellular fibrils in pericytes and endothelial cells were also larger and thicker in diabetic subjects. The prevalence of fibrillar material in the vascular disease of diabetes mellitus suggests the importance of research into possible measures to arrest fibril formation.

Fluorescence in situ hybridization (FISH) for retrospective detection of trisomies 3 and 7 in multiple myeloma

The malignant plasma cells of multiple myeloma (MM) have a low proliferative activity and therefore cytogenetic studies of the disease have been severely limited. We evaluated the role of fluorescence in situ hybridization (FISH) in the detection of numerical chromosomal abnormalities in early stages of myeloma and the applicability of the method to stored archival slides. Old air-dried bone marrow smears from 15 myeloma patients obtained at presentation were probed with alpha satellite DNA sequences to chromosomes 3 and 7. Numerical chromosome aberrations were found in eight (53%) of the patients, including six (of 12) with trisomy 7, and two (of eight) with trisomy 3. This study demonstrates that FISH is a sensitive method for the detection of numerical aberrations in myeloma and for the study of old slides for retrospective analysis.

Characterization of the interference of T cell activation by reserpine

It has been suggested that reserpine blocks expression of delayed hypersensitivity (DH) reactions by depleting tissue mast cells of serotonin, thereby preventing a T cell-dependent release of mast cell serotonin necessary to localize and to amplify the DH response. However, reserpine blocks expression of DH in mast cell-deficient mice. Recently, we showed that the ability of reserpine to interfere with the expression of contact sensitivity was independent of an effect on mast cells, but reflected an effort of the drug on effector T cell function. In the present study we evaluated the mechanisms by which reserpine abrogates the expression of T cell functions. By using human peripheral blood mononuclear cells or enriched T cell populations we found that the drug inhibited, in a dose-dependent fashion, the proliferation of T cells after mitogen stimulation. Reserpine also interfered with the mitogen-induced IL-2 production by these cells, but the IL-2 receptor expression, as measured by immunofluorescence, was unaffected. Despite this, in the continuous presence of reserpine, exogenous IL-2 did not bypass reserpine inhibition of PHA-induced proliferation. By using the fluorescent indicator quin-2 we have demonstrated that preincubation with reserpine prevented the increase of cytosolic free calcium, which accompanies PHA-induced proliferative responses of human T lymphocytes. These results identify the sites of action of reserpine in human T lymphocytes and are sufficient to explain its ability to block cell-mediated immune responses in vitro and in vivo.