Eugene Sobel

Clinical Importance of Myeloid-Antigen Expression in Acute Lymphoblastic Leukemia of Childhood

BACKGROUND Leukemic cells in 15 to 25 percent of patients with acute lymphoblastic leukemia (ALL) express myeloid antigens as well as lymphoid antigens (the latter reflecting B-cell or T-cell lineage). The relations of myeloid-antigen expression to other features of ALL and to prognosis have been controversial. METHODS We analyzed clinical and laboratory features present at diagnosis in 236 consecutive cases of ALL in children. Immunophenotyping, including single- and dual-fluorescence analyses, was used to classify leukemic cells as B or T lymphoblasts and also to identify myeloid-antigen expression--the simultaneous expression of lymphoid-associated antigens and at least one of three myeloid-associated antigens (CD33, CD13, and CD14) on cells classified as L1 or L2 according to the French-American-British system. RESULTS Forty-five of 185 patients with B-lineage ALL had myeloid-antigen expression, as did 8 of 41 patients with T-lineage ALL. In 10 patients, the lineage could not be determined. Myeloid-antigen expression was associated with L2 morphology (P less than 0.05), but it did not correlate with other prognostic features recognized previously. Multivariate analysis showed that myeloid-antigen expression was an important predictor of relapse in childhood ALL and the most significant prognostic factor statistically (P less than 0.0001). A white-cell count greater than or equal to 50 x 10(9) per liter at diagnosis was also an important and highly significant prognostic feature (P less than 0.001). After 40 months, the estimated disease-free survival for patients with ALL was 84 percent for those without myeloid-antigen expression and with a low white-cell count, 57 percent for those without myeloid-antigen expression and with a high white-cell count, 47 percent for those with myeloid-antigen expression and a low white-cell count, and 26 percent for those with myeloid-antigen expression and a high white-cell count (P less than 0.00001). CONCLUSIONS Myeloid-antigen expression is an important independent predictor of a poor response to chemotherapy in childhood ALL.

Elevated risk of Alzheimer's disease among workers with likely electromagnetic field exposure.

We conducted a case-control study of the possible association of occupations with likely exposure to electromagnetic fields and Alzheimers disease (AD) with patients from the Alzheimer Disease Treatment and Diagnostic Center, Rancho Los Amigos Medical Center, Downey, CA. Patients with definite or probable AD were the case subjects (86 male, 240 female). Patients with cognitive impairment/dementia other than vascular dementia were control subjects (76 male, 76 female). The study was limited to patients who were at least age 65 at the time of their first examination at Rancho Los Amigos. The odds ratio for both sexes combined was adjusted for sex, education, and age at onset. The odds ratio for males was adjusted only for age at onset, and the odds ratio for females was adjusted for both education and age at onset. The adjusted odds ratio for both sexes was 3.93 (p = 0.006), 95% CI = (1.5 to 10.6). For males the adjusted odds ratio was 4.90 (p = 0.01), 95% CI = (1.3 to 7.9), and for females the adjusted odds ratio was 3.40 (p = 0.10), 95% CI = (0.8 to 16.0). These results are consistent with previous findings regarding the hypothesis that electromagnetic field exposure is etiologically associated with the occurrence of AD. NEUROLOGY 1996;47: 1477-1481

Creutzfeldt‐Jakob disease Possible medical risk factors

To explore possible risk factors in the past medical history of patients with Creutzfeldt-Jakob disease (CJD), we conducted a case-control study among 26 cases and 40 matched controls. Statistically significant odds ratios were obtained for intraocular pressure testing; injury to or surgery on the head, face, or neck; and trauma to other parts of the body. The odds ratios were nearly significant for head trauma and procedures requiring sutures. These data suggest that the CJD agent may be acquired by inoculation through injury or during surgery, and perhaps on certain absorbable sutures of animal origin. The tonometer used for glaucoma testing may also be a vehicle of transmission.

Stroke in the Lehigh Valley: seasonal variation in incidence rates.

We investigated the seasonal pattern of stroke using the Lehigh Valley Stroke Register. This register includes all patients hospitalized with stroke or transient ischemic attack (TIA) from among the 600,000 Lehigh Valley residents. Meterological data were obtained from the National Oceanic and Atmospheric Administration. The study, which uses 18 months of data, included 1,944 cases. Using single harmonic regression analysis, the seasonal pattern of TIA and infarction, but not hemorrhage, fit a sine-cosine wavefunction with a 12-month period (R2 = 41% and 36%, respectively). For infarction, the strongest seasonal pattern was exhibited for women of all ages and for both sexes in the age groups 65-74 and 75-84, but only the sine component was significant. The peak months for TIA were June-August, while the peak months for infarcts were February-April. Correlations between ambient temperature and each type of stroke were computed. A significant positive correlation for TIA was found (r = 0.57, p = 0.01). After adjusting for a 2-month lag between the low for infarction and the peak for temperature, a significant negative correlation was found (r = -0.64, p = 0.01). No significant correlation was found for hemorrhage. Possible reasons for the opposite relations of TIA and infarct are discussed.

Stroke in the Lehigh Valley Racial/ethnic differences

We investigated black/white differences in stroke rate (standardized morbidity), severity, and subtype, and the relative frequencies of 5 primary risk factors (hypertension, diabetes, myocardial infarction, other heart diseases, and transient ischemic attack [TIA]) using the Lehigh Valley Stroke Register. Blacks had a statistically significant higher, age-adjusted rate of stroke than whites. We found no differences in stroke severity using our measures but blacks had a statistically higher proportion of lacunar stroke, while whites had a higher proportion of embolic stroke. There were no differences in proportions of thrombotic stroke or intracerebral hemorrhage. The relative frequencies of hypertension, myocardial infarction, other heart diseases, and diabetes were higher for blacks, while the relative frequency of TIA was higher for whites. These observations are consistent with other reports that blacks have a higher frequency of stroke and tend to have more small-vessel cerebrovascular pathology than whites.

Electromagnetic field exposure may cause increased production of amyloid beta and eventually lead to Alzheimer's disease

Based on earlier work by several groups, in 1989 Selkoe and colleagues [1,2] suggested that amyloid beta (A beta) found in cerebral blood vessels, skin tissue, and elsewhere might come from a peripheral source and might contribute to the Alzheimers disease (AD) pathogenesis. Independently, using four clinical series and four different types of controls, Sobel et al. [3,4] found that having a primary occupation likely to have resulted in medium-to-high extremely low frequency (ELF) electromagnetic field (EMF) exposure significantly increases the risk of AD. The means by which EMF (or any other) exposure might precipitate the Alzheimer pathogenesis are currently unknown. One possibility is that EMF exposure might affect the peripheral or neuronal processing of the amyloid precursor protein. We outlined a cascade of events as a hypothesis of how EMF exposure may be associated with AD onset. In two published papers, Sobel et al. [3,4] found elevated risk of AD associated with having a primary occupation likely to have resulted in medium-to-high EMF exposure. The four clinical series examined were widely separated by time or distance and the data were collected without any consideration of EMF exposure. (Table 1) provides information about patients and control subjects and the ascertainment period for each series. The total number of AD patients in the four series was 713 and the total number of control subjects was 627. Surrogate-derived data were used for all patients and for control subjects from Finnish Series 1 and the Rancho Los Amigos Medical Center (RLAMC), Los Angeles, series because these subjects were demented. Following standard practice, we defined high EMF exposure as averaging above 10 milligauss (mG) or often above 100 mG and medium EMF exposure as averaging between 2 and 10 mG or often above 10 mG. We classified all other EMF exposures as low. The …

A prospective study of platelets and plasma proteolytic systems during the early stages of Rocky Mountain spotted fever.

We prospectively examined early changes in platelets and plasma proteolytic systems in 12 vaccinated and 6 unvaccinated volunteers in whom Rocky Mountain spotted fever developed after challenge with Rickettsia rickettsii. The platelet counts declined while the plasma concentration of beta-thromboglobulin and the ratio of beta-thromboglobulin to platelet factor 4 increased, indicating in vivo activation of platelets. Plasma levels of antithrombin III decreased and levels of fibrinopeptide A increased, indicating in vivo activation of the coagulation system. Plasma fibrinogen levels peaked at 24 hours and gradually declined; this is consistent with the behavior of fibrinogen as an acute-phase reactant. Prolongation of the prothrombin time and a decrease in plasma levels of factor VII in the absence of evidence of liver injury suggested possible activation of the extrinsic pathway of coagulation. A decline in plasma prekallikrein levels with an increase in plasma C1-inhibitor-kallikrein complexes suggested activation of kallikrein, probably through the intrinsic coagulation system. Elevations in levels of plasma fibrin-degradation products and alpha 2-antiplasmin-plasmin complexes with declines in plasminogen and alpha 2-antiplasmin levels provided evidence of activation of the fibrinolytic system. Elevated plasma levels of tissue plasminogen activator and von Willebrand factor reflected endothelial stimulation. Thus, even early in the course of Rocky Mountain spotted fever that is treated promptly, there is activation of platelets, coagulation pathways, and the fibrinolytic system. These changes may be related to endothelial perturbation, a major pathogenetic mechanism in the disorder.

Clinical implications of immunologic phenotyping in cutaneous T cell lymphoma

The composition of cutaneous lesions from 158 patients with confirmed cutaneous T cell lymphoma, 91 patients with suspected cutaneous T cell lymphoma, and 145 patients with lymphoid disorders other than cutaneous T cell lymphoma was quantitated in situ with the use of commercially available murine monoclonal antibodies that identify the Pan T, T-helper/inducer (Th), T cytotoxic/suppressor (Ts), and Pan B lymphocyte subsets. On average, cutaneous infiltrates of confirmed cutaneous T cell lymphoma were found to contain significantly more Th and less Ts or Pan B cells compared to benign lymphoid disorders. Moreover, when analyzed in terms of the type of lesion examined by biopsy, the absolute amount of Th cells progressively expands with increasing magnitudes of infiltrate in the dermis while the amount of Ts and Pan B cells remains relatively constant among lesions. A useful diagnostic criterion (anti-Leu 1/4 greater than or equal to 70% and anti-Leu 3a/anti-Leu 2a ratio greater than or equal to 6) correctly discriminated between cutaneous T cell lymphoma and non-cutaneous T cell lymphoma in 87.5% of cases. A positive immunodiagnostic result also may be useful for the prediction of subsequent histopathologic confirmation of cutaneous T cell lymphoma in patients who have suspect lymphoid infiltrates, such as alopecia mucinosis or idiopathic generalized erythroderma, when first seen. With the use of multivariate analysis, stage and possibly the percentage of Th cells within the T cell component in cutaneous infiltrates were covariates with significant relationships to survival in patients with confirmed cutaneous T cell lymphoma. In addition, Ts cells in infiltrates did not correlate significantly with observed responses to topical treatment and subsequent course in pretumorous mycosis fungoides. These results indicate that Ts cells play little biologic role in modifying the natural history of cutaneous T cell lymphoma.

Stroke in the Lehigh Valley Risk factors for recurrent stroke

Age-specific risk of recurrent stroke for various risk factors, calculated independently, was estimated using the first year of data from the Lehigh Valley Stroke Register. The register is based on a population of more than one-half million. Among the risk factors examined, the highest overall risk of recurrent stroke, 41.4, occurred with a history of at least one transient ischemic attack (TIA). After myocardial infarction (MI), the relative risk of a recurrent stroke was 8.0, while with all other heart diseases combined it was 8.4. With diabetes, the relative risk of a recurrent stroke was 5.6; with hypertension, it was 4.5. The relative risk increased with age after TIA and MI, but not for other heart disease, diabetes, and hypertension, except in the 85 + year-old age group.

The agraphia of Alzheimer's disease

Hypothesizing that agraphia in Alzheimers disease (AD) reflects disturbances in multiple cognitive domains, we evaluated writing samples from 33 patients meeting strict criteria for probable AD. We found agraphia to be common on a standard narrative writing task. When compared with 41 education- and age-matched normal control subjects, AD patients had significantly lower writing scores, wrote significantly fewer words, mentioned significantly fewer categories of information, and were significantly more likely to make writing errors. On stepwise regression procedures, neuropsychological measures of visuoperceptual impairment and disease severity were the strongest predictors of agraphia, but other analyses indicated that measures of language, praxis, and attention could also contribute significantly to agraphia. On two writing tasks, we failed to confirm the previous contention that agraphia is a marker for familial AD. However, there was a highly significant interaction between family history, oral naming, and writing: patients with non familial AD, but not those with a family history of dementia, showed a strong correlation between naming and writing performance. We conclude that agraphia in AD can be variously determined and that agraphia is not a reliable marker for familial disease.