[Cluster headache and other trigeminal autonomic cephalalgias]. / Clusterhoofdpijn en andere trigeminale autonome cefalalgieën.

Trigeminal autonomic cephalalgias (TACs) are a group of 4 different primary headache syndromes that have a lot of pathophysiological and clinical features in common. The 4 different TACs are: cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks and hemicrania continua. TACs are characterized by frequent, strictly unilateral, (very) intense headache attacks with ipsilateral cranial autonomic symptoms or intrinsic restlessness or both. A distinction can be made between the 4 TACs on the basis of the duration and frequency of the headache attacks. The treatment of cluster headache consists of an acute treatment and a maintenance treatment. Headache attacks in the context of paroxysmal hemicrania and hemicrania continua (almost) always respond to treatment with indomethacin. More and more neuromodulation therapies are becoming available, such as vagus nerve stimulation, stimulation and blocking of the sphenopalatine ganglion, stimulation and blocking of the occipital nerve and deep brain stimulation.

Inhibition of transforming growth factor beta 1 induction by dietary vitamin E in unilateral ureteral obstruction in rats.

Free radical species associated with bilateral ureteral obstruction (BUO) are considered important in the pathogenesis of the glomerular and tubulointerstitial injury in BUO rats. We seek to test the hypothesis that the use of an easily administered antioxidant, vitamin E, at sufficient plasma concentrations, can decrease this release of free oxygen radicals in kidney tissue and ameliorate the increase of the fibrogenic cytokine, transforming growth factor beta-1 (TGF beta-1). We used the unilateral ureteral obstruction (UUO) rat model, because the presence of the uninjured contralateral kidney provides a nonuremic internal milieu, in contrast to the uremic, acidotic, and hypercholesterolemic BUO model. Compared to sham controls, the UUO animals showed a dramatic increase in renal cortical TGF beta-1 mRNA, as quantitated by Northern blot analysis with cyclophilin internal standards. This increase in TGF beta-1 mRNA was reversed in UUO rats treated with vitamin E. The plasma malondialdehyde (MDA) concentration, an index of lipid peroxidation and an indirect index of free radical release, was significantly elevated in UUO animals compared to sham animals. The vitamin E-treated UUO animals showed a significant decrease in both plasma and renal cortical tissue MDA content. Taken together, these findings provide evidence of the important biological role of reactive free radical species in the tubulointerstitial injury of UUO and the novel role of vitamin E in modulating the mRNA of the fibrogenic TGF beta-1 in obstructive uropathy.

The effects of running stress on plasma vitamin A levels in rats.

The plasma concentrations of vitamin A, zinc and proteins and the hepatic level of vitamin A were determined in rats subjected to running as a model for stress and which were receiving standard or vitamin-A free diets. All rats showed a decrease in plasma vitamin A with running compared with non-running control animals. Hepatic levels of vitamin A were higher in these two test groups than in their weight- and age-matched non-running controls. The data support that running, like other forms of stress, decreases plasma vitamin A, consistent with the retention of vitamin A in the liver.

Vitamin E ameliorates adverse effects of endothelial injury in brain arterioles.

Endothelium-dependent dilation, produced by applying acetylcholine (ACh) to pial arterioles, was unaffected after 6 mo of a diet with zero vitamin E or 8 mo of a vitamin E-enriched diet. The enriched diet did not affect constriction produced by topically applied NG-monomethyl-L-arginine, an inhibitor of the synthesis of endothelium-derived relaxing factor (EDRF). EDRF mediates the response to ACh and is a basally released dilator and antiplatelet paracrine substance. Endothelial injury produced by a helium-neon laser and Evans blue technique eliminates the response to ACh, but in vitamin E-enriched mice the response to ACh was unaffected by the injury. More prolonged exposure of the laser induces platelet adhesion/aggregation at the injured site. A significantly longer exposure to the laser was required to initiate adhesion/aggregation in vitamin E-enriched mice. Because effects of endothelial damage in this model are mediated at least in part by singlet oxygen produced by injured tissue (W.I. Rosenblum and G.H. Nelson, Am. J. Physiol. 270 (Heart Circ. Physiol. 39): H1258-H1263, 1996.), we conclude that the antioxidant, radical-scavenging actions of vitamin E explain the protective action of the vitamin E-enriched diet. However, raising vitamin E levels did not protect against putative adverse effects of normally occurring oxidants.

Murine red blood cell fragility is not affected by either vitamin E depletion or supplementation.

Male ICR mice were Pair-fed semipurified diets containing 0, 55 (control), and 500 IU/kg of vitamin E. Plasma and hepatic concentrations of vitamin E were determined and found to parallel the vitamin E levels in the diet. Even though plasma vitamin E levels were virtually zero in mice fed the depleted vitamin E diet for up to 304 days, there was no statistical difference in the red blood cell fragility between these animals and controls, as determined by a hypoosmotic fragility test. The diet with enriched vitamin E concentrations also did not affect the fragility of the red blood cell (RBC). Even after 300 days of zero dietary vitamin E, mice appeared healthy, demonstrating neither neurologic dysfunction nor failure to thrive. The data indicates that mice, unlike several other species, are more resistant to vitamin E depletion and may have other mechanisms to compensate for loss of this important antioxidant.

Prediction of students' USMLE step 2 performances based on premedical credentials related to verbal skills.

PURPOSE: To examine the relationship between the objective premedical credentials and performances on Step 2 on the United States Medical Licensing Examination (USMLE) of 480 students in three classes at the Virginia Commonwealth University Medical College of Virginia School of Medicine. The purpose of the study was to seek those selection criteria that might best predict performance on an examination designed to assess problem-solving skills, the essence of clinical medicine. METHOD: Premedical data from two classes (1193, 1994) were analyzed, and a regression equation was used to calculate theoretical USMLE Step 2 scores for the students in the class of 1995, who had not yet taken this examination. The premedical variables were scores on the verbal and math section on the Scholastic Aptitude Test (SAT), scores on the six sections of the pre-1991 Medical College Admission Test (MCAT), grade-point average (GPA) in science courses required of premedical students, and undergraduate major. Once the class of 1995 had taken the USMLE Step 2, the equation was cross validated, and the theoretical and actual scores of the class of 1995 were correlated. RESULTS: The correlation between theoretical and actual scores was r = .443. In the analysis for the classes of 1993 and 1994, the single variables most highly predictive of USMLE Step 2 performance were scores on the verbal section of the SAT (r = .317) and the Skills Analysis: Reading section of the MCAT (r = .331). However, the MCAT scores were excluded from the final regression analysis because of the pre-1991 MCAT cannot be useful in predicting the performances of present medical school applicants. The resulting regression equation (using the SAT verbal section and premedical GPA) was able to account for 21.2% of the variance for the class of 1995. CONCLUSION: The use of the verbal section of the SAT as a predictive factor is unique. It is significant that this variable was strongly related to premedical GPA, suggesting that high verbal aptitude serves one well, even when coping with complex scientific concepts.

Evaluation of serum and tissue levels of alpha-tocopherol.

This study was designed to test the effect of supplementation of several antioxidants, including alpha-tocopherol, on the clinical reduction of premalignant oral lesions. Samples of oral mucosa and serum were taken from baseline to 9 months of supplementation from patients with premalignant oral lesions and analyzed for alpha-tocopherol by HPLC. Statistical increases in both serum and tissue alpha-tocopherol were found after supplementation. There was no statistical relationship between alpha-tocopherol and beta-carotene levels.

Use of antioxidant supplements in the treatment of human oral leukoplakia.

An increasing public awareness of antioxidants may prompt a patient's request to be treated without surgery if a leukoplakic lesion is discovered. However, surgical excision remains the treatment of choice for oral leukoplakia. The use of antioxidant supplements has shown some promise, but the predictability of success remains uncertain and long-term results are unavailable. Before the decision to use any antioxidant is made, it is critical to obtain a histopathologic diagnosis of the lesion. When dealing with a lesion diagnosed as hyperkeratosis, it may be appropriate to choose an antioxidant that may take some time for clinical improvement to occur. However, as the grade of epithelial dysplasia becomes more severe, consideration must be given to the possibility of malignant transformation during antioxidant treatment. We do not recommend the use of antioxidant supplements in the treatment of any carcinoma. The therapeutic use of antioxidant supplements outside of clinical trials conducted at academic medical centers should be done with considerable caution by practitioners in private practice. It should be emphasized that in these clinical trial patients were seen at frequent intervals to monitor their progress and to intervene if there was a noticeable deterioration in the clinical appearance of the lesion. In spite of the uncertainty with respect to antioxidant treatment, there are circumstances in which it should be considered. Recurrence after surgical excision when there is little reason to believe that a second surgical excision would be any more successful is an ideal candidate. Also, patients with widespread leukoplakia that involves a large area of the oral mucosa might be suitable for treatment with antioxidants, as well as patients who have extensive medical problems that make them surgical risks. The choice of which antioxidant(s) to use is complex because thus far there is no combination that is superior to the others. Beta-carotene with ascorbic acid or alpha-tocopherol is attractive because of a lack of side effects, but the range in reported values for lesion improvement has been broad and the clinical improvement typically takes several months. Clinical response with 13-cRA is faster but requires baseline and periodic serologic testing, as well as close monitoring for side effects. In those circumstances in which time is an important consideration, 13-cRA might be useful because clinical improvement can be evaluated within a matter of weeks as compared with beta-carotene. The group from M.D. Anderson Hospital has shown the value of an induction dose of 13-cRA that is followed by a lower maintenance dose. Unfortunately, the problem of recurrence after discontinuation of 13-cRA is quite common. One aspect that has not been evaluated is the combination of conventional surgical excision and the administration of postoperative antioxidants. This would have the obvious advantage of conventional treatment of surgery together with the possible protective effect of the antioxidants. Although this is an attractive hypothesis, we do not know of any studies that have proven this to be beneficial.

Clinical and lymphocyte responses to beta-carotene supplementation in 11 HIV-positive patients with chronic oral candidiasis.

Eleven HIV-positive patients with chronic oral candidiasis were supplemented with 60 to 120 mg of beta-carotene daily for 3 to 7 months. Lymphocyte profiles were evaluated at intervals to help assess immune competence. Although there was a modest increase in some lymphocyte values at 2 months, there was a significant decrease in numbers of CD4 and CD8 cells and CD4 percentage of lymphocytes after 6 months of beta-carotene supplementation. Serum triglyceride and liver enzyme levels were not affected by the beta-carotene supplementation. No improvement was observed in the control of the oral candidiasis. Under the conditions of the study, there was no indication that daily beta-carotene supplements enhanced immune competence or was of benefit in managing oral candidiasis.

A clinical trial of antioxidant supplements in the treatment of oral leukoplakia.

Seventy-nine patients with oral leukoplakia that was histologically verified as either hyperkeratosis or epithelial dysplasia with hyperkeratosis were enrolled in an antioxidant supplementation program for the treatment of the oral lesions. The patients received 30 mg of beta-carotene, 1000 mg of ascorbic acid, and 800 IU of alpha-tocopherol per day for 9 months. Clinical improvement of the oral lesion was noted in 55.7% of the patients and was more likely to occur in patients who reduced their use of alcohol or tobacco (p = 0.0056). Although risk-factor reduction was important, approximately half of the patients who did not alter their exposure to either alcohol or tobacco showed clinical improvement. The antioxidant supplementation significantly increased serum and tissue levels of beta-carotene, ascorbic acid, and alpha-tocopherol, but these changes did not correlate strongly with clinical improvement.

A review of the use of antioxidant supplements in the treatment of human oral leukoplakia.

Over the past twenty years, research into the role of antioxidants in the prevention of cancer has increased dramatically. The use of antioxidant supplements to treat oral leukoplakia has gained acceptance due to the success demonstrated in several clinical trials. This review discusses the role of antioxidants in the development of cancer and their possible use in the treatment of oral leukoplakia.

The prevalence of oral lesions in smokeless tobacco users and an evaluation of risk factors.

BACKGROUND: The widespread use of smokeless tobacco (ST) has prompted concern in regard to the development of oral lesions in long-term users. METHODS: For inclusion in the current study, a subject must have used an ST product, either snuff or chewing tobacco, for at least 6 months. The subjects were recruited by advertising, and none was referred for the evaluation of an oral lesion. The following were performed on all subjects: assessment of exposure to ST, cigarettes, and alcohol; examination of the oral cavity; a biopsy, if an oral lesion was found; and analysis of a blood sample for beta-carotene. The dietary intake of most of the subjects was analyzed. RESULTS: Of the 347 ST users, all of whom were white male subjects, 45 (13.0%) had an oral lesion. Thirty-five of the lesions were hyperkeratosis and 10 were epithelial dysplasia. CONCLUSIONS: Snuff exposure was associated significantly with the presence of an oral lesion (P < 0.0001). A decreased vitamin C intake also was found among the ST users with oral lesions (P < 0.01). The ST users with epithelial dysplasia, as compared with those with hyperkeratotic lesions, were slightly older, had a lower intake of vitamin C (P < 0.05), and were more likely to have used chewing tobacco than snuff.

Effects of proteolytic and thermal action on the activity of lactate dehydrogenase isozymes LD-1 and LD-5.

L-Lactate dehydrogenase (LD) catalyzes the interconversion of pyruvate and lactate. Using a spectrophotometric assay to determine LD activity, incubation of rabbit, porcine, and bovine LD-1 and LD-5 isozymes with the protease subtilisin (Carlsberg) gave first-order degradation kinetics. Degradation half-lives were significantly lower for the LD-5 isozymes from the three species when incubated with subtilisin at temperatures from 4 degrees C to 25 degrees C. The energy involved in the degradation process, however, was not different. The activation energy for the conversion of pyruvate to lactate by LD-1 at pH 7.4 was significantly higher than that for LD-5 for all three species examined (P less than 0.005). Thermocalorimetry showed that the LD-1 isozymes have both a higher mean temperature of denaturation and a higher heat uptake during the denaturation process than corresponding LD-5 forms. The results suggest that the LD-5 isozymes in the species studied are more metabolically efficient, whereas the LD-1 forms have greater structural stability.

Evaluation of risk factors in smokeless tobacco-associated oral lesions.

Smokeless tobacco (ST) users and nonusers were recruited to evaluate the contribution of various risk factors (ST use, cigarettes, alcohol, and diet) in the development of oral mucosal lesions. Ninety-eight ST users with no lesion, 29 ST users with an oral lesion, and 33 nonusers were enrolled in the study. ST users with lesions, when compared with users with no lesion, were more likely to have used snuff than chewing tobacco (p = 0.01) and to have used more ST (p less than 0.01). Alcohol consumption, dietary intake of beta-carotene, and serum levels of beta-carotene were not related to an increased risk of lesion development. Our findings showed that the only significant risk factor for ST-associated oral lesions was the extent of ST exposure. Of 127 ST users, 29 (22.8%) had an oral lesion at the time of examination. Of these lesions, 23 (79.3%) were hyperkeratotic and 6 (20.7%) were epithelial dysplasia.

Lactate dehydrogenase in rat mitochondria.

Small but persistent amounts of L-lactate dehydrogenase (LDH) activity were found in mitochondrial preparations isolated from rat heart, kidney, liver, and lymphocytes. Brain mitochondrial preparations were also isolated, but the results were inconclusive. A variety of cytosolic markers were used and it was found that essentially no cytosolic contamination was present except in brain preparations. A bacterial protease was used along with digitonin fractionation to determine localization of the mitochondrial LDH. Approximately 80% of the LDH activity associated with heart and kidney mitochondrial preparations was on the inside compared to about 40% for liver. Lymphocyte mitochondrial LDH activity was about 70% on the inside. Cytosolic LDH-5 preferentially adheres to outer mitochondrial membrane of liver, kidney, and heart. Agarose gel electrophoresis showed LDH isozymes in mitochondria qualitatively similar to that of the corresponding cytosol except in kidney mitochondrial preparations, where a specific electrophoretic band was found which did not correspond to any of the common LDH isozymes.

Calculation of inhibitor Ki and inhibitor type from the concentration of inhibitor for 50% inhibition for Michaelis-Menten enzymes.

The use of I50 (concentration of inhibitor required for 50% inhibition) for enzyme or drug studies has the disadvantage of not allowing easy comparison among data from different laboratories or under different substrate conditions. Modifications of the Michaelis-Menten equation for treatment of inhibitors can allow both the determination of the type of inhibition (competitive, noncompetitive, and uncompetitive) and the Ki for the inhibitor. For competitive and uncompetitive inhibitors when the assay conditions are [S] = Km, then Ki = I50/2. For different conditions of [S] there is a divergence between competitive and uncompetitive inhibitors that may be used to identify the type of inhibitor. The equation for Ki also differs. For noncompetitive inhibitors the Ki = I50 and this relationship is valid with changing [S]. The equations developed require a single substrate, reversible-type inhibitors, and kinetics of the Michaelis-Menten type. Examples of the use of the equations are illustrated with experimental data from scientific publications.

Nicotinic acid or N-methyl nicotinamide prolongs elevated brain dopa and dopamine in L-dopa treatment.

A peripheral dopa decarboxylase inhibitor, benserazide, was given ip, followed by intubation with L-dopa. Brain dopa and DA levels were elevated maximally between 0.5-2.5 hr and 1.0-2.5 hr, respectively. Dopa in serum, liver, and brain were at control values after 4 hr. Supplementation of dopa with NAM or NAC, as possible methyl group acceptors to lower catabolism of DA, showed that NAM had no effect on DA levels or on SAM. However, with both NAC and N-methyl NAM (a methylated compound intended as a control) at time periods where dopa and DA were normally decreasing, the brain levels were increased over control values with benserazide and dopa alone. NAC or N-methyl NAM appeared to extend the period of elevated brain DA levels with L-dopa treatment. The mechanism responsible for these results is uncertain.

Decrease of available vitamin A in parenteral nutrition solutions.

The efficiency of vitamin A delivery in total parenteral nutrition solutions was determined using spectrofluorometric and radioisotope assays. Experiments incubating total parenteral nutrition solutions in intravenous tubing demonstrated that an 88% decrease in vitamin A content from solution occurred over a 5-hr period. This decrease was independent of the method of assay and was not due to photodecomposition. Recovery of vitamin A from hexane rinses of the intravenous tubing demonstrated that the vitamin decrease was due to uptake by the tubing. Experiments simulating clinical practice situations showed saturation of these binding sites, with mean decrease of 26 to 67% of the vitamin, which were partially dependent on flow-rate. Clinical samples analyzed for comparison showed a greater loss of vitamin (77-98%) from the intravenous solutions. A decrease of vitamin A from solution should be a consideration when using parenteral nutrition.