Effects of baclofen and phaclofen on receptive field properties of rat whisker barrel neurons

Extracellular single-unit recordings were made in somatosensory cortical barrels of fentanyl-sedated rats. Whiskers were deflected singly or in paired combinations. lontophoretically-applied (−)-baclofen disproportionately reduced weak responses, and phaclofen disproportionately increased them, resulting in more tightly focused or more broadly focused receptive fields, respectively. Both drugs had only minor effects on surround inhibition. In light of previous findings, we conclude that GABA_A and GABA_B mechanisms both act to enhance spatial contrast, but that the former plays a much greater role in enhancing temporal resolution.     

Proliferative activity of mast cells in allergic nasal mucosa

The proliferative activity of mast cells in the nasal mucosae of allergic (n= 14) and non-allergic (n= 18) rhinopathic patients was studied by a sequential double immuno-histochemistry using anti-proliferating cell nuclear antigen (PCNA) and anti-tryptase antibodies. Two hundred to 300 tryptase-positive cells (mast cells) were studied in each allergic nasal epithelium. In case of non-allergic nasal mucosa, only a few mast cells existed in the epithelial layer. The total number of mast cells which we could detect in all patients was 168 cells. One of these cells contained PCNA. Three hundred to 500 mast cells were studied in each subepithelial layer and deep layer of lamina propria of both diseases. PCNA-positive mast cells were observed in the nasal epithelia of 10 allergic patients. In the subepithelial layer, PCNA-positive mast cells were observed eight allergic patients and four non-allergic patients, respectively, In the deep lamina propria, PCNA-positive mast cells were observed in a few patients with both diseases. The percentage of PCNA-positive mast cells of all mast cells each area ranged from 0 to 1.7%. The incidence of PCNA-positive mast cells was statistically higher in the allergic epithelium and subepithelial layer than in the deep layer of lamina propria. Moreover, that of PCNA-positive mast cells in the subepithelial layer was higher in allergic than in non-allergic nasal mucosa. Our results suggest that mast cell proliferation may contribute to the number of mast cells in the nasal epithelium and subepithelial layer of allergic patients.     

Raf-1 kinase,epidermal growth factor receptors,and mutant ras proteins in colonic carcinomas

Epidermal growth factor receptors (EGFR) andras mutations are known to play a significant role in controlling cell growth and tumor promotion. Both of them transmit mitogenic signals to the nucleus by activation of Raf-1 kinase. In this study, the expression of EGFR and mutant Ras proteins, and, for the first time, the expression, phosphorylation and kinase activity of Raf-1 kinase have been determined in paired samples of colorectal cancer and mucosa. The tumor and mucosa samples did not differ significantly with regard to Raf-1 kinase content and activity. A major difference between tumors and mucosa was found, however, in the phosphorylation of Raf-1. Most of the mucosa samples (13/20), but only 1/20 of the cancer samples, contained hyperphosphorylated Raf-1. EGFR were significantly (p=0.0025) decreased in the tumors. The decreased phosphorylation of Raf-1 in colonic carcinomas could be the result of activation of Raf-1 phosphatases or inactivation of kinases phosphorylating Raf-1. New forms of treatment based on EGFR overexpression do not seem to be suitable for the majority of colonic cancers.This work was supported by the state of Baden-Württemberg (Verbundforschungsprojekt: Aufklärung von Mechanismen der Tumorentstehung und Tumorabwehr).     

High-dose intravenous immunoglobulin therapy improved muscle strength in a patient with multifocal motor neuropathy and antibodies against the glycolipid LK1

We report improvement in muscle strength in a patient with multifocal motor neuropathy (MMN) when given high-dose intravenous immunoglobin (i.v.-Ig) treatment. The patient had asymmetrical limb weakness, atrophy and absent or weak reflexes, but no sensory disturbances. Neurography showed multiple conduction blocks in peripheral motor nerves but no sensory nerve abnormalities. Serum and anti-GM1 antibodies were not found, however, the patient had serum antibodies against the glycolipid LK1, an epitope found both in glycolipid and also in some glycoproteins in peripheral nerve myelin. Muscle strength improved 5 days after i.v.-Ig therapy, and lasted about 10 weeks. Repeated courses of treatment resulted in similar improvement. This is, to our knowledge, the first patient reported with MMN found to have antibodies against the glycolipid LK1.     

Fluctuating PEEP (F–PEEP) versus conventional PEEP in dogs with asymmetrical lung injury

Fluctuating PEEP (F-PEEP) is a newly developed PEEP in which end-expiratory pressure (EEP) is periodically changed within a certain range. In a dog model with unilateral lung injury induced by the introduction of hydrochloric acid, F-PEEP in which the EEP was periodically changed from 0.5 to 1.5 kPa at periods of 6 min, and conventional PEEP (C-PEEP) with an optimized EEP of 1.0 kPa, were each applied for 30 min. F-PEEP produced a significantly greater improvement of PaO2 and intrapulmonary shunt (QS/QT) than C-PEEP, and at the low EEP phase, the greatest improvement accompanied by an increased dynamic compliance and a large cardiac output was obtained. These results suggest that F-PEEP provides a useful mode of artificial ventilation for the treatment of unilateral lung injury.     

The bioavailability of griseofulvin from microsized and ultramicrosized tablets in nonfasting volunteers

Tablets of either microsized or ultramicrosized griseofulvin (2 x 125 mg), were administered to 6 healthy volunteers of either sex just before a breakfast containing 4o g. of butter. The plasma concentration of griseofulvin were determined 1, 3, 5, 7, 9, 24, and 32 h. after dosing using a spectrofluorometric method, and pharmacokinetic parameters (Cp max, t max, AUC 0 - greater than 32) were calculated. These parameters were found to be; Cp max = 0.0.681 +/- 0.1 mu/ml, t max. = 2.51 +/- 0.33 h. and AUC = 14.14 +/- 2.33 micrograms h/ml for microsized tablets and Cp max = 0.80 +/- 0.08 +/- g/ml, t max = 2.44 +/- 0.54 and AUC = 16.25 +/- 1.16 microgram h/ml for ultramicrosized tablets. Our results show that mean peak plasma level and AUC (0 - greater than 32) are only slightly higher for the ultramicrosized preparation and the time to peak plasma level is similar in two preparations. Therefore, it is concluded that coadministration of griseofulvin with food will tend to reduce the difference between the bioavailability of the two type of preparations.     

Vasodilator effects of sarafotoxins and endothelin-1 in spontaneously hypertensive rats and rat isolated perfused mesentery

Sarafotoxins (SRTa, SRTb and SRTc) and ET-1 produced a potent vasodilator effect in spontaneously hypertensive rats in vivo and in rat isolated perfused mesenteries in vitro. Among these peptides SRTc demonstrated the most potent vasodilator activity, and was three times more active than SRTa in both preparations. These peptides induced endothelium-dependent vasodilatation in vitro and pretreatment with methylene blue inhibited this effect, while exposure to the antagonists of other vasodilators did not. In contrast, [nitrophenylsulfenylated Trp21]SRTc, SRTc(1-18) and reduced and S-carboxymethylated SRTc caused no vasodilatation in either animal model; the vasodilator effect of acetylated SRTc was less potent than that of SRTc. These results suggest that (i) the vasodilatations of these peptides may be exerted through the release of endothelium derived relaxing factor; (ii) the C-terminal Trp21 and disulfide bonds are essential; and (iii) the N-terminal amino group plays an important role in vasodilator activity.     

Evaluation of drugs for treatment of urinary bladder dysfunction in conscious rats with intact pelvic nerve and after resection of the left pelvic nerve

We studied the effects of drugs used for treatment of bladder dysfunction in conscious rats with intact pelvic nerves and also in rats at one or two weeks after nerve decentralization on the left side. Bladder contraction accompanying micturition was continuously induced by infusion of solution at a constant rate. When the effects of oxybutynin (3 mg/kg, i.p.) and terodiline (3 and 10 mg/kg, i.p.) on the cystometrogram were studied for about 2 hr, these drugs shortened and then prolonged the micturition interval (MI), but atropine (1 and 5 mg/kg, i.p.), butylscopolamine (20 mg/kg, i.p.) and nifedipine (3 mg/kg, i.p.) exhibited only a shortening effect on the MI. After injection of oxybutynin (10 mg/kg, i.p.), solution dribbled from the urethra for about 30 min. Terodiline (3 mg/kg) caused ischuria in the rats one week after resection of the left pelvic nerve, but not in the rats two weeks after surgery. Physostigmine (0.3 mg/kg, i.p.) improved micturition in the rats one week after surgery, but the effect was not evident in the rats with intact pelvic nerves. It was found that the drugs used for treating failure to store or expel urine exhibited a beneficial effect on micturition in rats with intact pelvic nerves and also in rats one week after nerve decentralization, respectively.     

DNA-directed alkylating agents. 3. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the length of the linker chain

Four series of acridine-linked aniline mustards have been prepared and evaluated for in vitro cytotoxicity, in vivo antitumor activity, and DNA cross-linking ability. The anilines were attached to the DNA-intercalating acridine chromophores by link groups (-O-, -CH2-, -S-, and -SO2-) of widely varying electronic properties, providing four series of widely differing mustard reactivity where the alkyl chain linking the acridine and mustard moieties was varied from two to five carbons. Relationships were sought between chain length and biological properties. Within each series, increasing the chain length did not alter the reactivity of the alkylating moiety but did appear to position it differently on the DNA, since cross-linking ability (measured by agarose gel assay) altered with chain length, being maximal with the C4 analogue. The in vivo antitumor activities of the compounds depended to some extent on the reactivity of the mustard, with the least reactive SO2 compounds being inactive. However, DNA-targeting did appear to allow the use of less reactive mustards, since the S-linked acridine mustards showed significant activity whereas the parent S-mustard did not. Within each active series, the most active compound was the C4 homologue, suggesting some relationship between activity and extent of DNA alkylation.