Single-unit activity of cerebellar nuclear cells in the awake genetically dystonic rat.

The purpose of this study was to characterize neuronal activity in the deep cerebellar nuclei of the unanesthetized genetically dystonic rat during the neonatal period when the clinical signs of the dystonic syndrome first appear. Previous lesion studies have established cerebellar output as critical to the expression of the dystonic rat's motor syndrome, a disorder that closely resembles generalized dystonia in humans. In the dystonic rat, both cerebellectomy and selective lesions of the deep cerebellar nuclei decrease the frequency of abnormal motor signs and improve performance on tests of motor function. Single-unit activity was recorded from the medial, interpositus and lateral cerebellar nuclei in awake normal (N=49) and dystonic (N=54) rats at postnatal days 12-26. One hundred and eighty-three cells were isolated, 91 from normal and 92 from dystonic rats. Interspike interval histograms, autocorrelations and ratemeter histograms were generated for each cell's spike train. Interspike interval histograms were modeled with single and double gamma distributions. Cells from dystonic rats as young as 12 days of age showed bursting firing patterns, positively skewed or bimodal interspike interval histograms, and sinusoidal autocorrelations. Bursting activity increased linearly with postnatal age in dystonic rats. Cells from normal rats demonstrated non-sinusoidal autocorrelations and unimodal interspike interval histograms. Spike frequency increased linearly with postnatal age in both normal and dystonic rats. There were no statistically significant group differences in spike frequency between normal and dystonic rats. These findings show that functional neuropathology can be detected at the level of single neurons in the deep cerebellar nuclei at the earliest behavioral stages of the dystonic rat's movement disorder. The degree of abnormality in spike train parameters correlates with the severity of the movement disorder. Independent of neuronal firing rates, abnormal neuronal firing patterns can serve as a guide to the localization of pathological cell populations within the central nervous system. These results provide additional evidence that abnormal cerebellar output plays a critical role in the pathophysiology of the dystonic rat's motor syndrome.

Birth defects surveillance: Jefferson County, Alabama, and Uppsala County, Sweden.

Birth defects in live-born infants were documented for 2 years in Jefferson County, Alabama (USA)--1986 and 1987--and in Uppsala County, Sweden--1985 and 1986. A total of 27,561 live births (9,179 white male, 8,728 white female, 4,883 black male, and 4,771 black female infants) occurred in Jefferson County; 6,896 live births (3,535 male and 3,361 female) were recorded in Uppsala County. These newborns were studied to establish a database of birth defects for the two small geographic areas and to study similarities and differences. Rates of hip dislocation, heart malformations, and clubfoot were high in Swedish infants. Similar frequencies of spina bifida and polydactyly were noted in Alabama whites and Swedish infants. Regional registries offer a systematic approach to detection of clustering of specific birth defects, identification of families for further study, location of patients with unique needs, and enhanced coordination of health services, including genetic counseling.

Ictal EEG wave forms from epidural electrodes predictive of seizure control after temporal lobectomy.

Ictal wave form characteristics--frequency, spatial distribution, and duration--were analyzed for 140 complex partial seizures recorded from epidural strip electrodes implanted in 28 patients. None had abnormalities on imaging studies. All had bilateral electrode placements, unilateral seizure onsets, temporal lobectomies, and were followed for a mean of 33 months postoperatively. Sixteen patients (57%) became free of complex partial seizures: 12 had reductions in seizure frequency of at least 50% but were not seizure-free. The only predictor of the seizure-free state was the presence of low voltage fast activity (LVF), in the alpha or beta ranges, localized to one gyrus. This phenomenon occurred in 14/16 seizure-free patients, 2/12 of others (P < 0.001). As seizures progressed, LVF typically increased in amplitude, propagated, and slowed into the theta range. Wave forms were classified into 8 categories based upon their frequency and morphology. Stepwise discriminant analysis of these wave forms, with consideration of whether they were localized or regional, revealed that both frequency and localization were critical for the post-surgical prognosis. The mere presence of a localized seizure onset was unreliable unless the wave form was taken into account. Well-localized rhythmic activity over 8 Hz at seizure onset from epidural subtemporal electrodes predicts surgical success. Slower rhythms imply greater separation in space and time from seizure onset.

Niacin revisited: clinical observations on an important but underutilized drug.

STUDY OBJECTIVE: To evaluate the efficacy and side effects of niacin therapy in dyslipidemic individuals. DESIGN: A retrospective analysis of patients' charts. SETTING: An outpatient referral-based clinic specializing in the treatment of lipid disorders. PATIENTS: All patients with dyslipidemia treated by niacin (n = 82) at the Atherosclerosis Detection and Prevention Clinic during 1987 to 1990, including a subgroup of 17 dyslipidemic heart transplant recipients. RESULTS: Niacin was well tolerated in 83% of the nontransplant group (n = 65) at an average dose of 2.5 +/- 0.9 g/day. Similar beneficial lipoprotein effects were found in the transplant and nontransplant patients. The high-density lipoprotein cholesterol (HDL-C) response to niacin therapy was independent of the baseline (HDL-C level. In the transplant group, 11 patients (65%) discontinued treatment, primarily because of hyperglycemia; this was especially prominent in those patients with pretreatment diabetes mellitus. Of the 15 patients using sustained-release niacin, eight cases of hepatitis were recorded, some during therapy with relatively low niacin doses. Several different sustained-release preparations were responsible for this phenomenon, suggesting that the cause was not a contaminant in the preparation. No cases of hepatitis were documented in the 67 patients using regular niacin. One case of hepatitis was recently observed in a patient who switched from one type to regular niacin to another; however, we have data to suggest that the substituted preparation was not an immediate-release niacin. A familial predisposition to hepatitis is suggested by the occurrence of this side effect in identical twin brothers and two sisters. A pharmacy survey disclosed that most pharmacists are unaware of the relationship of sustained-release niacin to hepatitis, have a negative impression of regular niacin, and do not stock this formulation. Finally, we found that in this small sample of patients, niacin used with lovastatin is a particularly effective drug combination and appears to have few side effects beyond those seen with niacin alone. CONCLUSIONS: Our experience supports the fact that regular niacin is a useful lipid-modifying drug. When used appropriately, patients can usually tolerate adequate doses for prolonged periods and achieve meaningful results. However, this requires a certain amount of physician skill and patient motivation. The use of sustained-release preparations to overcome this problem can lead to harmful consequences and should only be done under strict medical supervision. In our opinion, the availability of sustained-release niacin as a nonprescription drug is unjustified and should be reexamined. Finally, we have observed that reduction of very-low-density lipoprotein cholesterol (VLDL-C) with niacin alone leads to an elevation in low-density lipoprotein cholesterol in many patients; this indicates to us that the mechanism whereby niacin lowers VLDL-C and total cholesterol is not solely the result of a decreased synthesis of VLDL-C.

Analysis of neuronal soma size distributions.

Neuronal soma size distributions are often very skewed, leading to difficulty in their characterization and in the application of statistics commonly used to describe normally distributed variables. A particular family of curves, called Weibull functions, can be shown to fit cell size data extremely well. These functions not only characterize these skewed distributions, but do so in a way which permits powerful, sensitive comparisons of differences between distributions. Because of the flexibility of the Weibull functions, they may be used to describe a variety of morphological attributes. Several applications of these functions to neuroanatomical data are described using methods which require only graph paper and hand calculator for curve fitting. An extension of the basic curve fitting method permits mixtures of Weibull functions to be used in describing multimodal size histograms.

Density, soma size, and regional distribution of rabbit retinal ganglion cells.

Cell soma area or diameter distributions are generally very skewed and present some unusual problems in characterization and description. In this study of ganglion cell soma size in rabbit retina, our conclusions are based on a statistical method which not only characterizes this particular neuronal population but which also may be of considerable value in other species and other parts of the nervous system. To facilitate comparisons between retinas, we used ganglion cell density as the measure of retinal location. The rabbit retina has a horizontally extended area centralis, the visual streak, which we show to have a uniformly high peak cell density along most of its length. Cell density maps were used to estimate the total number of ganglion cells in the retina; the mean for three retinas was about 406,000 cells, which corresponds well to an earlier count of optic nerve axons (394,000 +/- 20,000; Vaney, D.I., and A. Hughes (1976) J. Comp. Neurol. 170: 241-252). Contrary to other reports, we could not find any large differences in ganglion cell size distributions between the inferior peripheral retina and the visual streak nor could we confirm the report of a large cell area temporalis (Provis, J. M. (1979) J. Comp. Neurol. 185: 121-138). Cell size distributions in the superior and inferior retina were very different, however, and, within the inferior retina, there was a small but systematic change in cell size between the periphery and the visual streak. In general, small and medium size cells were present in nearly constant proportions throughout the inferior retina, while the large ganglion cells showed a small decrease in proportion from the periphery to the visual streak; the decline in large cells was a linear function of cell density. In terms of ganglion cell soma size, there was no sharp distinction between the visual streak and the peripheral retina.

Sequential appearance of auto-erythrocyte antibody immunoglobulin classes with age.

The autoimmune, short-lived, NZB/BINJ mice were followed for the changes taking place in the number of thymic and splenic nucleated cells from day 1 up to 12 mo of age. The long-lived C57BL/6J mice were monitored in parallel with the NZB mice to see whether similar changes were reflected. Both strains of mice were investigated for the sequential appearance of anti-erythrocyte autoantibody classes by the direct Coombs' agglutination test. IgG1 was the first class of antibody detected on the erythrocytes and was followed by IgG3, IgG2 and IgA, simultaneously. IgM was the last antibody to react with erythrocytes. The C57BL strain had a very small number of mice with low levels of IgG1 antibody on erythrocytes throughout the study.

An experimental approach to relate a tumor-associated enzyme marker to tumor cell numbers.

Alkaline phosphatase was monitored in 17 mice with s.c.-implanted tumors to relate the total circulating alkaline phosphatase to the total number of tumor cells in each mouse. There was a semilogarithmic relationship between the alkaline phosphatase units and the number of tumor cells. A time-independent standard plot of alkaline phosphatase and the number of tumor cells was used to estimate the size of disseminated and localized tumors. In animals treated with cyclophosphamide, the alkaline phosphatase marker was used to monitor the regression and recurrence of the neoplasm in vivo.