The use of heat and chemical penetration enhancers to increase the follicular delivery of erythromycin to the skin.

The effect of heat on the follicular absorption of drugs into the skin has not previously been investigated. In comparison to drug delivery across the continuous stratum corneum (SC), follicular absorption is known to be relatively rapid and therefore the use of short durations of heat may be particularly useful for enhancing drug delivery to the hair follicles, as well as being practical for patients to use. In this study erythromycin has been used as a model drug and the combined use of heat and chemical penetration enhancers was found to be able to synergistically increase the penetration of erythromycin into human skin via the follicular route. Moreover durations of heat application as short as 10 min in combination with particular enhancer systems were found to be sufficient to significantly increase erythromycin delivery to the skin. Overall the data indicate that the use of heat with chemical penetration enhancers offers a potentially valuable strategy for delivering drugs via the follicular route.

Fat depot origin affects fatty acid handling in cultured rat and human preadipocytes.

Regional differences in free fatty acid (FFA) handling contribute to diseases associated with particular fat distributions. As cultured rat preadipocytes became differentiated, FFA transfer into preadipocytes increased and was more rapid in single perirenal than in epididymal cells matched for lipid content. Uptake by human omental preadipocytes was greater than uptake by abdominal subcutaneous preadipocytes. Adipose-specific fatty acid binding protein (aP2) and keratinocyte lipid binding protein abundance was higher in differentiated rat perirenal than in epididymal preadipocytes. This interdepot difference in preadipocyte aP2 expression was reflected in fat tissue in older animals. Carnitine palmitoyltransferase 1 activity increased during differentiation and was higher in perirenal than in epididymal preadipocytes, particularly the muscle isoform. Long-chain acyl-CoA levels were higher in perirenal than in epididymal preadipocytes and isolated fat cells. These data are consistent with interdepot differences in fatty acid flux ensuing from differences in fatty acid binding proteins and enzymes of fat metabolism. Heterogeneity among depots results, in part, from distinct intrinsic characteristics of adipose cells. Different depots are effectively separate miniorgans.

Blood viscosity and aging.

The objective of this study was to evaluate the relationship of whole blood viscosity and its major determinants (plasma fibrinogen level, hematocrit, hemoglobin and blood cell count) to advancing age. A total of 249 subjects (mean age 49.9+/-21.5; range 19-102 years) were included in the study. They were divided into three groups, (A) <30 years of age, n, 58; (B) 30-60 years, n, 107; (C) >60 years, n, 84. Whole blood viscosity at two different rates of shear (450 and 45 s(-1)) was evaluated using a cone-plate digital viscosimeter. The hematological parameters (hematocrit, hemoglobin and blood cell count) were evaluated using an automatic Coulter Counter. Plasma fibrinogen concentration was measured by a clotting method. When both sexes are considered together, whole blood viscosity shows no significant difference among age groups. Plasma fibrinogen concentration significantly increases with age (P<0.001); hemoglobin, red blood cell count and platelet count, on contrary, are significantly lower in aged group. In the male sex, blood viscosity at higher shear rate (450 s(-1)) negatively correlates with advancing age (P<0.005). The age-related decrease of hematocrit value in the male sex accounts for this occurrence.

Clinical effects of oral theophylline in elderly patients with sick sinus syndrome.

Theophylline increases the heart rate in patients with normal sinus rhythm and in patients with sick sinus syndrome. This effect is probably connected to the blockade of adenosine receptors by theophylline. This study evaluated the efficacy of theophylline in 34 elderly patients with symptomatic sinus bradycardia (age 68 +/- 11 years). A resting electrocardiogram, a 24-hour recording and treadmill test were performed both before and after administration of slow-release theophylline (700 mg/day). The drug increased resting heart rate (from 43 +/- 6 to 63 +/- 16 beats/min, p < 0.01), mean 24 hour heart rate (from 49 +/- 7 to 65 +/- 17 beats/min, p < 0.01), and minimal 24 hour heart rate (from 34 +/- 5 to 44 +/- 10 beats/min, p < 0.05 ). Cardiac pauses longer than 2.5 seconds were present in 8 patients during control recordings, and disappeared after theophylline. Twenty-six patients were followed for a period of 20 +/- 5 months. Suppression of symptoms was achieved in 24 of them. Asthenia and easy fatigue were reduced markedly by the drug. During long term therapy, the sinus rate was similar to that observed at the steady-state evaluation. In 6 of the 34 patients theophylline had to be discontinued because of gastric intolerance (in 4 cases at the end of the steady-state evaluation and in 2 during long-term therapy). These data suggest that oral theophylline can represent an effective therapy in some elderly patients with symptomatic sinus bradycardia and can avoid or delay the need of a permanent pacemaker.

Isoproterenol test and head-up tilt test for diagnosis of vasovagal syncope in elderly patients.

The elderly can be affected by vasovagal syncope, but they often do not have preceding symptoms. The head-up tilt test (HTT) is successfully used in half of the patients in which the diagnosis is difficult. In young people the association with the isoproterenol test improves the sensitivity of the HTT. In the elderly the effect of such an association is still debated, therefore, the present study was aimed at evaluating the usefulness of the association between the two tests in old subjects to unmask the vasovagal nature of some syncopes of unknown origin. Twenty-four patients with negative HTT (18 males and 6 females; mean age 65 years) 10 with and 14 without organic heart disease were studied. The test protocol consisted of a continuous intravenous infusion of isoproterenol in successive stages starting from a dosage of 1 gamma/min for 5 min in supine position and then for 10 min in passive upright position at 80 (1st stage) up to maximum of 5 gamma/min (5th stage). The results obtained were: 12 patients (50%) had a positive test (reproduction of syncope) with a vasodepressor response in 6 of them and a mixed response in 6 patients. The mean time to syncope was during the 4th min of the 4th stage of treatment. The heart rate increase was 36% between the initial and peak values achieved during the test in patients with a positive test, and 10.5% in patients with negative test (p < 0.05). These results indicate that the isoproterenol test seems to increase the sensitivity of HTT in elderly patients with syncope of unknown origin.

Determination of fractal dimension of physiologically characterized neurons in two and three dimensions.

Although there is a growing interest in the application of fractal analysis in neurobiology, questions about the methodology have restricted its wider application. In this report we discuss some of the underlying principles for fractal analysis, we propose the cumulative-mass method as a standard method and we extend the applicability of fractal analysis to both 2 and 3 dimensions. We have examined the relationship between the method of log-log Sholl analysis and fractal analysis and have found that they correlate well. Measurements of physiologically characterized retinal ganglion cells indicate that different cell types can have significantly different fractal dimensions. Such differences may allow the correlation of the physiological type of a neuron with its morphological fractal dimension.

Effect of viscosity on neurite outgrowth and fractal dimension.

The growth mechanism by which neurons achieve their characteristic ramified morphology has long been of interest, but determining whether physical parameters, such as viscosity, are important has been difficult due to a lack of useful hypotheses and standard reproducible techniques. We have recently shown that neurons exhibit fractal behavior and that their fractal dimension (df) is consistent with a physical process called diffusion-limited aggregation (DLA). We suggested that this DLA behavior might stem from viscosity differences, chemical gradients or electrical fields (Caserta et al., Phys. Rev. Lett., 64 (1990) 95-98). DLA is a model for a large family of growth processes. In order for a process to fit the DLA model, the growth rate must be proportional to the gradient of a field at a point on the growing structure (Feder, Plenum, New York, 1988, Ch. 4). Chemical, electrical, or fluid pressure fields can fit the model depending on the particular physical system under study. Here, we studied growth of retinal neurons from chick embryos in culture media of various fluid viscosities. Thus, we test whether DLA in this system was based on a fluid pressure field. As viscosity was increased from 1 to 4.3 cps, the number of neurite branches decreased 98%. However, there was no effect on df. Over this range of viscosities, total cellular protein synthesis decreased only 17%. The results indicate that, while differences in viscosity between the interior and exterior of the cell affect neurite outgrowth, they do not affect the fractal behavior of neurons. Thus, viscosity differences are not the basis for the DLA pattern of neuronal arborization.