Is substance P a primary afferent neurotransmitter for nociceptive input? III. Valproic acid and chlordiazepoxide decrease behaviors elicited by intrathecal injection of substance P and excitatory compounds

Intrathecal (i.t.) injections of substance P (SP) and kainic acid in rats produced rostrally directed scratches with the hindlimbs and caudally directed bites or licks. These behaviors, together with myoclonic twitches and vocalization, were also produced by I.T. morphine and strychnine. Intrathecal valproic acid (VA) significantly reduced all behaviors when these occurred spontaneously, and VA and chlordiazepoxide both reduced these behaviors when they were evoked by a light cotton swab tap to the lumbosacral region, in rats treated with the excitatory compounds. Since neither anticonvulsant affected the thermal or mechanical pain threshold at these doses, these results suggest that (a) the behaviors elicited by i.t. injection of the excitatory compounds are not responses to perceived pain, but rather the expression of a spinal convulsive-like state, and (b), since scratching and biting were the only behaviors produced by SP, this peptide is neither necessary nor sufficient for the elicitation of pain at the spinal level. Although our experiments do not rule out other roles for SP in pain processes such as that of a neuromodulator, it is unlikely that this compound is a traditional primary afferent neurotransmitter of pain.     

Electrode recovery potential

In some instances the same electrodes are used for stimulation and then for recording a bioelectric event immediately after the stimulus. However, after the current pulse there remains an electrode potential that decays quasiexponentially. We have designated this falling potential the electrode-recovery potential. This study investigated the recovery potentials of single electrodes of rhodium, stainless steel, platinum and platinum-iridium in contact with 0.9% saline at room temperature (25°C) over a current density ranging from 0.1 to 100 mA/cm² using a constant-current pulse. In all cases, with increasing current density, there was a decrease in the time for the electrode potential to fall to one half of the immediate post-stimulus value. Above about 20 mA/cm² the decrease in recovery time was smooth with increasing current density. Below 20 mA/cm², the recovery time was slightly irregular. The shortest recovery times were for platinum and platinum-iridium. The largest decrease in recovery time with increasing current density was for stainless steel, which decreased 10 fold from 0.1 to 100 mA/cm². The recovery time for rhodium decreased about three-and-one half fold over the same current density range. It was found that the waveform of the recovery potential is not a simple exponential because the Warburg and Faradic components of the electrode-electrolyte interface are current-density dependent. In general, for all current densities studied (0.1–100 mA/cm²), there was a sudden initial fall in electrode potential with cessation of current flow, followed by a very gradual nonexponential decrease in potential.     

Reformulation and drop size of apraclonidine hydrochloride.

We performed a prospective, double-masked, placebo-controlled, six-period, cross-over study in which normal subjects were randomly assigned to treatment and compared three different formulations of apraclonidine hydrochloride (the present commercially available formulation, and formulations with hydroxypropylmethylcellulose or lysolecithin). We also evaluated the efficacy of a 16-microliters and 30-microliters drop size. The magnitude and duration of decrease in intraocular pressure was comparable for all formulations. Most subjects tolerated all formulations well with only a few reporting any side effects. The best-tolerated formulation was 0.5% apraclonidine hydrochloride delivered with a 16-microliters drop size. Dry mouth developed frequently with the commercially available 1% apraclonidine solution. Blurred vision complicated the use of the formulation containing hydroxypropylmethylcellulose. Both dry mouth (P less than .05) and blurred vision (P = .004) were statistically significant side effects.     

Valproic acid induced encephalopathy--19 new cases in Germany from 1994 to 2003--a side effect associated to VPA-therapy not only in young children.

Valproic acid (VPA) is a broad-spectrum antiepileptic drug and is usually well-tolerated. Rare serious complications may occur in some patients, including haemorrhagic pancreatitis, bone marrow suppression, VPA-induced hepatotoxicity and VPA-induced encephalopathy. The typical signs of VPA-induced encephalopathy are impaired consciousness, sometimes marked EEG background slowing, increased seizure frequency, with or without hyperammonemia. There is still no proof of causative effect of VPA in patients with encephalopathy, but only of an association with an assumed causal relation. We report 19 patients with VPA-associated encephalopathy in Germany from the years 1994 to 2003, none of whom had been published previously.     

Methodological issues associated with using different cut-off points to categorize outcome variables.

Knowledge of the factors that contribute to delay in seeking medical treatment for acute myocardial infarction (AMI) provides the basis for interventions that are intended to facilitate prompt care-seeking behaviour. However, operational definitions of delay time vary across research studies. The use of inconsistent cut-off times to distinguish between delayers and non-delayers is likely to compromise comparability and generalizability of the findings across studies. The purpose of this paper is to examine the impact of inconsistent operationalization of delay, in terms of cut-off times, on the validity of research findings pertaining to identifying its predictors. Secondary data analysis was performed using a sample of 73 patients who had recently experienced out-of-hospital AMI and concluded that their symptoms were related to the heart. Several regression models were built to examine the influence of using different cut-off times (1, 2, 3, 6, and 12 hours, median delay) on the number and nature of predictors ofAMI care-seeking delay.The impact of varying cut-off times on the explained variance, sensitivity, specificity, and predictive values associated with each regression model was examined. The use of different cut-off times produced different sets of independent predictors, which varied in number and nature.The variance explained by the different regression models as well as their classification indices varied. Use of different cut-off times for the definition of delay time led to inconsistent results. Thus, it is recommended that criteria be established among clinicians and researchers with regard to operationally defining care-seeking delay for AMI.     

Effect of two preventive programs on oral health knowledge and habits among Brazilian schoolchildren

Abstract – The effect upon dental health knowledge and dental health behavior of a comprehensive and a less comprehensive preventive program was compared in a 3-yr follow up study. The comprehensive program included active participation of the students and parental involvement. The study group consisted of 186 Brazilian schoolchildren 13 yr of age at the start of the program. A reference group from another school of similar socioeconomic level was included in the analyses. The data were collected from questionnaires filled in by the children under surveillance after the completion of the program. Significant differences in knowledge as well as in reported behavior were observed. The children enrolled in the comprehensive program in general scored higher in dental health knowledge than did those in the less comprehensive program. However, the latter group of children seemed to have acquired more correct knowledge during the period than had the control and reference children. Similar results were obtained concerning reported dental health behavior.     

Primary Radiotherapy of Stage IIA/B–IIIB Cervical Carcinoma

BACKGROUND: Comprehensive literature on cervical cancer demonstrates, even today, the need for optimization of the timing of external-beam radiotherapy (EBRT) and high-dose-rate brachytherapy (HDR-BT) in the treatment of stage IIA/B-IIIB cervical carcinoma. PATIENTS AND METHODS: 210 patients with carcinoma of the cervix were treated in the Municipal Center of Oncoradiology between January 1991 and December 1996 (FIGO IIA: n = 10, FIGO IIB: n = 113, and FIGO IIIB: n = 87). Two regimens were compared: sequential radiation therapy (SRT) with 4 x 8 Gy HDR-BT to point A followed by EBRT, and continuous radiation therapy (CRT) in which 5 x 6 Gy HDR-BT to point A, one session per week, was integrated into the EBRT. A total dose of 68-70 Gy to point A and 52-54 Gy to point B was given in EBRT with SRT, five fractions per week were applied. Four fractions per week were applied in CRT, i. e., no EBRT was performed on the day of HDR-BT. Total doses to points A and B were identical in both regimens. Overall treatment time (OTT) amounted to 56 days for SRT and 35 days for CRT. Median follow-up time was 3.4 (2.5-4.2) years. RESULTS: Progression-free 5-year-survival (PFS) was 71% in the CRT and 56% in the SRT group. Nevertheless, this difference was not statistically significant (p = 1.00), and the same was found in a subgroup analysis of the different tumor stages, showing, however, an unequivocal trend. Late bladder and rectal injuries occurred in 13% and 25%, respectively. Late rectal injuries were significantly more frequent with SRT than CRT (35 patients in the SRT and 18 patients in the CRT group; p = 0.037). This was due to the higher doses per fraction of HDR-BT in the SRT group. No difference was found regarding late bladder injuries (p = 0.837). CONCLUSION: For the patients included in this study, no advantage has been found so far in using CRT, i. e., shortening the OTT by weekly integration of HDR-BT into EBRT. Nevertheless, an obvious trend exists. The dose of 8 Gy per fraction of HDR-BT in the SRT regimen was obviously too high. To achieve a significant improvement in local control and disease-free survival (DFS) as well as overall survival (OS), the combination with modern chemotherapy regimens and regional deep hyperthermia may rather be the treatment option.     

Time course of vascular prostanoid production in the fructose‐hypertensive rat

1 There is a relationship between hypertension, insulin resistance and an altered plasmatic lipid profile known as ‘metabolic syndrome’. Fructose (F) overload induces in the rat a mild hypertension associated with metabolic alterations such as hyperglycemia, hypertriglyceridemia and insulin resistance, resembling such syndrome. 2 Prostanoids (PR), metabolites of arachidonic acid, include vasoactive substances synthesized and released by the vessel wall. An altered pattern of PR release has been previously found in mesenteric vessels of experimental diabetic rats. 3 This study analyzed the effects of F‐overload during different periods (4, 9, 15 and 22 weeks) on PR release in aorta (A) and mesenteric vascular beds (MVB). Animals received tap water (control) or F solution (10% w/v) to drink. 4 Rats with F overload showed significantly higher systolic blood pressure, glycemia and triglyceridemia than controls; but no differences in this parameters were found among periods of treatment either in controls or experimental animals. 5 In A, prostacyclin was decreased at 9, 15 and 22 weeks of treatment when compared to 4 weeks and controls. In MVB, prostacyclin showed different patterns of release in the studied periods of F overload. Prostaglandin (PG) E₂ diminish in MVB at the same extent in all periods. No changes were observed in A. The vasoconstrictor thromboxane was elevated in the MVB at 9 weeks. PGF₂α, also a vasoconstrictor, remains unchanged. 6 In conclusion, F overload provokes in the rat a decrease in the vascular production of vasodilator PR and, in one of the studied periods, an increase in the release of the vasoconstrictor thromboxane, leading to a negative imbalance in the prostacylin/thromboxane ratio. This could be involved in the blood pressure alterations found in this experimental model of metabolic syndrome.