Cerebrovascular responses to capsaicin in vitro and in situ.

1. The cerebrovascular effects of capsaicin have been examined in vitro, in feline isolated cerebral arteries (circular segments, 2-3 mm long, 300-400 microns extended diameter) and, in situ, in pial arterioles (diameter 40-200 microns) on the cortical surface of chloralose-anaesthetized cats. 2. In isolated middle cerebral arteries, low concentrations of capsaicin (10(-14)-10(-10) M) effected a concentration-dependent relaxation of vessels precontracted with prostaglandin F2 alpha. This relaxant response was markedly attenuated by repeated administration of capsaicin but was minimally affected by the presence of atropine, propranolol, cimetidine or spantide in the tissue bath. 3. In isolated middle cerebral arteries, higher concentrations of capsaicin effected a marked concentration-dependent contraction. This contraction was not modified by 10(-6) M phentolamine or 10(-6) M ketanserin. A markedly reduced contraction by capsaicin was found upon the removal of calcium ions from the buffer solution. Also the calcium entry blocker nimodipine reversed the capsaicin-induced contraction. 4. Subarachnoid perivascular microapplication of capsaicin around individual pial arterioles in situ elicited a biphasic response (an immediate vasoconstriction followed by a sustained vasodilatation). The maximum vasoconstriction was a 60 +/- 6% reduction in diameter from base line and the maximum vasodilatation a 38 +/- 7% increase in diameter. Vasodilatation occurred at lower concentrations of capsaicin (EC50, approximately 5 x 10(-8) M) than those required for vasoconstriction (EC50 3 x 10(-7) M). 5. Trigeminal ganglionectomy 10-16 days before the microapplication abolished the in situ vasodilator effects of capsaicin (10(-6) M) applied perivascularly, but was without effect on the vasoconstrictor actions of this agent.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacologic studies on the antidegenerative effect of ademetionine in experimental arthritis in animals

A standardized pharmacological model of biochemically induced osteoarthritis in the knee joint of laboratory animals was used for the study of a possible antidegenerative effect of ademetionine (S-adenosyl-methionine, active substance of Gumbaral) in-vivo. Four days after the initial induction of osteoarthritis by 2 intraarticular injections of 0.6 mg sodium iodoacetate into the left knee joint of adult hens, the therapy started with once-weekly intraarticular doses of 0.5 mg, 1.0 mg and 2.0 mg ademetionine over a period of 14 weeks. Quantitative monitoring of the intensity and progression of osteoarthritis was performed every 2 weeks by joint space measurements, topographic-radiological evaluations, and by a macroscopic post-mortem assessment of the joint cartilage and bone. These objective analytical parameters clearly demonstrated that weekly intraarticular doses of 1.0 mg ademetionine significantly reduced the intensity of degenerative processes compared to the placebo (saline) treated joints. The antidegenerative effect of doses of 0.5 mg or 2.0 mg ademetionine were less pronounced and of no statistical significance. Our findings indicate an interesting therapeutic potency of ademetionine in experimental osteoarthritis and confirm the positive clinical observations as well as in-vitro results with this new drug by other researchers.     

Effects of polymerization heat and monomers from acrylic cement on canine bone

We investigated the effects of polymerization heat and toxicity of polymethyimetacrylate bone cement in the canine tibial diaphysis. Heat was studied by filling the tibias with either bone cement or bone wax contained in a monomer tight membrane pouch. Toxicity was studied by filling both tibias with cement, with the control side contained in the membrane pouch. Bone blood perfusion was measured by microsphere technic, and bone remodeling by ^99mTc-methylene diphosphonate uptake and by histologic technique. In bone exposed to the combination of polymerization heat and monomer, both perfusion and remodeling were impaired. We did not find any effects of polymerization heat alone.

We conclude that hot toxic chemicals from bone cement during polymerization may inhibit bone blood perfusion and remodeling, whereas heat alone seems to be of minor importance for the regenerative processes in cemented diaphyseal bone.     

Prognosis of fracture of the talus in children: 21 (7-34)-year follow-up of 14 cases

14 children suffering from a fracture of the talar neck or body were examined after 21 (7-34) years. The talar neck was fractured in 10 children and the talar body in 4. 3 fractures were displaced and primarily treated with reduction and immobilization. Nondisplaced fractures were treated conservatively. All fractures healed. All patients with displaced fractures had exercise-induced pain at follow-up. Of 11 patients with nondisplaced fractures only 1 had minor complaints.

CT and conventional radiographs showed arthrosis in the talocrural joint and normal subtalar joints in those with displaced fractures. The radio- graphic findings were normal after nondisplaced fractures.     

Neuromuscular hyperexcitability features in patients suffering from musculoskeletal pain: a neuroepidemiologic survey.

We studied the reported frequencies of clinical complaints of neuromuscular hyperexcitability (muscle cramps and fasciculations) in random samples of 527 Dutch adults, who were and 253 Dutch adults, who were not suffering from musculoskeletal pain and tenderness. Data were collected by telephone-interview and by self-administered questionnaire. Muscle cramps and fasciculations were recorded more frequently in the category that suffered from musculoskeletal pain (p less than 0.001). This association warrants further investigation into the possible intrinsic role of neuromuscular hyperexcitability in musculoskeletal pain and primary fibromyalgia.     

AT base pairs are the main target for mutations at the hprt locus of rat skin fibroblasts exposed in vitro to the monofunctional alkylating agent N-ethyl-N-nitrosourea

Spectra of N-ethyl-N-nitrosourea (ENU)-induced mutations differwidely among various in vitro and in vivo mutational systems.To investigate possible reasons for these differences, a mutationalsystem is needed in which the same target gene is used for comparisonin the same type of cells in vitro and in vivo. In the presentstudy, this was achieved by analysing at the molecular level35 hprt mutant rat fibroblast clones obtained from cell populationsexposed in vitro to ENU and comparing the mutational spectrumwith the previously determined spectrum of ENU-induced hprtmutants in the same target cells exposed in vivo. Twenty-eightmutants contained a single base pair alteration in the hprtcoding sequence. Most of these changes were found at AT basepairs (19/28), the AT to TA transversion being the most frequentkind of mutation (12/19), which is probably caused by O²-ethylthymine.Transversions at AT base pairs showed all mutated T's to belocated in the nontranscribed strand of the hprt gene, suggestinga strand specific fixation of mutations induced by O²-ethylthymine,which appears to be a general feature of ENU- and ENNG-inducedhprt mutations in mammalian cells. GC to AT transitions, probablycaused by O⁶-ethylguanine, were detected at a lower frequency(7/28). This in vitro mutational spectrum was very similar tothat of the same target cells exposed in vivo to ENU. A comparisonof the mutational spectra in AGT-proficient and AGT-deficientrodent cells exposed to ethylating agents showed that in contrastto the situation in AGT-proficient rat fibroblasts, GC to ATbase pair changes (and not AT to TA) are the predominant mutationsin AGT-deficient hamster cells. ⁴To whom correspondence should be addressed     

CARD15 in inflammatory bowel disease and Crohn''s disease phenotypes: An association study and pooled analysis

BACKGROUND: Three major polymorphisms of the Caspase-Activation Recruitment Domain containing protein 15 gene have been described to be associated with Crohn's disease. Genotype-phenotype studies reported in literature provide conflicting data on disease localisation and behaviour. We investigated the relation of Caspase-Activation Recruitment Domain containing protein 15 with inflammatory bowel disease and Crohn's disease phenotypic characteristics in a large Dutch cohort and performed a pooled analysis on inflammatory bowel disease patients and Crohn's disease phenotypic characteristics reported in association studies. METHODS: We genotyped 781 cases and 315 controls for the R702W, G908R and 1007fsinsC variants and for six microsatellite markers in and close to Caspase-Activation Recruitment Domain containing protein 15. In the pooled analysis data of 7201 inflammatory bowel disease patients and 3720 controls from 20 studies were included. RESULTS: Association was found for Crohn's disease with R702W and 1007fsinsC, including several disease characteristics, and not for ulcerative colitis. In the pooled analysis all three common Caspase-Activation Recruitment Domain containing protein 15 variants showed strong association with Crohn's disease (p<0.00001; odds ratio varying from 3.0 for single heterozygotes to 14.7 for compound heterozygotes) and not with ulcerative colitis. Phenotype analysis showed association with small bowel involvement, stricturing and penetrating disease. CONCLUSION: Caspase-Activation Recruitment Domain containing protein 15 is associated with Crohn's disease and not with ulcerative colitis. All three common Crohn's disease-associated variants are associated with small bowel involvement, the G908R and 1007fsinsC alleles also being associated with a complicated disease course.