Neuropeptides in idiopathic chronic constipation (slow transit constipation)

Tissue specimens from the large bowel of 18 patients with long-standing slow transit constipation were investigated to determine the distribution and density of several neuropeptides and amines in the enteric nerve system, and also of endocrine cells in comparison to normal individuals. CGRP (calcitonin gene-related peptide), galanin, glucagon, GRP (gastrin-releasing peptide), metenkephalin, motilin, neuropeptide Y (NPY), PACAP, peptide YY (PYY), serotonin, somatostatin, substance P and VIP were studied by immunohistochemistry. Tissue concentrations of VIP, substance P and galanin were also measured by radioimmunoassay. Significantly increased VIP, SP and galanin contents were found in specimens from the ascending colon. Levels of VIP and galanin were also increased in the transverse colon. Immunohistochemistry revealed only marginal changes with an increased density of PACAP nerve fibres in the smooth muscle and of VIP and PACAP nerves in the myenteric plexus of the transverse colon. In the descending colon substance P and NPY immunoreactivity were also increased in the myenteric plexus while the density of VIP nerve fibres was reduced in the mucosa/submucosa. The frequency of PYY-containing cells and the 5-HT-containing cells in the ascending colon was significantly increased in the constipated patients.     

Effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin on the dopaminergic and cholinergic receptors as evaluated by positron emission tomography in the Rhesus monkey

Summary The effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (R-THBP) on the central cholinergic and dopaminergic systems in the Rhesus monkey brain were investigated by positron emission tomography (PET) with the muscarinic cholinergic receptor ligands (N-[¹¹C]methyl-benztropine) and dopaminergic receptor ligands selective for D₁ D₂, and D₃ subtypes ([¹¹C]SCH23390, N-[¹¹C]methyl-spiperone, and (+)[¹¹C]UH232, respectively). None of the doses (3, 10, and 30 mg/kg i.v.) of R-THBP used significantly affected the regional cerebral blood flow (rCBF as determined by Raichle's H₂ ¹⁵O method), and 10 mg/kg of R-THBP had little effect on the regional cerebral metabolic rate of glucose (rCMRglc) in the Rhesus monkey brain, as assessed by the graphical [¹⁸F]fluoro-deoxyglucose method. The effect of R-THBP on the muscarinic cholinergic system was dose dependent; while 3 mg/kg of R-THBP did not significantly alter the uptake ratio of N-[¹¹C]methyl-benztropine in several brain regions to that in the cerebellum, 10 and 30 mg/kg of R-THBP significantly reduced the uptake ratio in the thalamus, as well as in the frontal and temporal cortices. None of the doses (3, 10, and 30 mg/kg i.v.) of R-THBP tested affected [¹¹C]SCH23390 (dopamine D₁ receptor) binding. However, the k3 value for N-[¹¹C]methyl-spiperone (dopamine D₂ receptor) binding, which represents the association rate × B_max value, was significantly decreased in the striatum. The uptake ratio of (+)[¹¹C]UH232 (dopamine D₃ receptor) in the striatum to that in the cerebellum was also decreased by administration of R-THBP (3 and 30 mg/kg i.v.). These findings suggest that R-THBP acts on dopamine D₂ and D₃ receptors selectively without markedly affecting dopamine D₁ receptor binding. Furthermore, the changes in cholinergic and dopamine D₂ and D₃ receptors in vivo can not be attributed to a change in rCBF but may depend on the action of R-THBP.Abbreviations R-THBP 6R-L-erythro-5,6,7,8-tetrahydrobiopterin - PET positron emission tomography - rCBF regional cerebral blood flow - rCMRglc regional cerebral metabolic rate of glucose     

Manganese induced brain lesions inMacaca fascicularis as revealed by positron emission tomography and magnetic resonance imaging

A series of positron emission tomography scans was made on two monkeys during a 16-month period when they received manganese(IV)oxide by subcutaneous injection. The distribution of [¹¹C]-nomifensine uptake, indicating dopamine terminals, was followed in both monkey brains. The brain distributions of [¹¹C]-raclopride, demonstrating D₂ dopamine receptors, and [¹¹C]-l-dopa, as a marker of dopamine turnover, were followed in one monkey each. The monkeys developed signs of poisoning namely unsteady gait and hypoactivity. The [¹¹C]-nomifensine uptake in the striatum was reduced with time and reached a 60% reduction after 16 months exposure. This supports the suggestion that dopaminergic nerve endings degenerate during manganese intoxication. The [¹¹C]-l-dopa decarboxylation was not significantly altered indicating a sparing of [¹¹C]-l-dopa decarboxylation during manganese poisoning. A transient decrease of [¹¹C]-raclopride binding occurred but at the end of the study D₂-receptor binding had returned to starting values. The magnetic resonance imaging (MRI) revealed that the manganese accumulated in the globus pallidus, putamen and caudate nucleus. There were also suggestions of gliosis/edema in the posterior limb of the internal capsule. MRI might be useful to follow manganese intoxication in humans as long as the scan is made within a few months of exposure to manganese, i. e. before a reversal of the manganese accumulation.     

Tacrine restores cholinergic nicotinic receptors and glucose metabolism in alzheimer patients as visualized by positron emission tomography

Three patients with Alzheimer's disease, a 68-year-old woman with mild dementia and 2 men (aged 64 and 72 years) with moderate dementia were treated orally with the cholinesterase inhibitor tacrine (tetrahydroaminoacridine), 80 mg daily, for several months. The patients were investigated using positron emission tomography (PET) prior to, and after 3 weeks and 3 months of treatment. The PET studies involved a multi-tracer system consisting of [¹⁸F]-fluoro-deoxy-glucose (¹⁸F-FDG) (tracer for glucose metabolism); ¹¹C-butanol (cerebral blood flow) and (S)(−)- and (R)(+)-[N-¹¹C-methyl]-nicotine (nicotinic receptors; cholinergic neural activity). Tacrine treatment increased the uptake of ¹¹C-nicotine to the brain. Significant reduced difference in uptake between the two enantiomers (S)(−)- and (R)(+)¹¹C-nicotine was observed in the frontal and temporal cortices after tacrine treatment in all three patients. The kinetic analysis indicated increased binding of (S)(−)¹¹C-nicotine in brain compatible with a restoration of nicotinic cholinergic receptors. The most pronounced effect was observed after 3 weeks and 3 months treatment in the patient with mild dementia. An increase in cerebral glucose utilization was found in the 68-year-old patient with mild dementia but also slightly in the 64-year-old man with moderate dementia when treated with tacrine for 3 months. Tacrine administration did not affect cerebral blood flow. The PET data obtained after 3 weeks of tacrine treatment was paralleled by improvement in neuropsychological performance. This study shows in vivo by PET neurochemical effects induced in brain by treatment with tacrine to Alzheimer patients. Intervention with tacrine in the early course of the disease might be necessary for clinical improvement.     

Antibody-dependent cell-mediated cytotoxicity against Tamm-Horsfall protein in acute pyelonephritis

The cytotoxic activity of leukocytes from humans and rats with pyelonephritis were examined in an antibody-dependent cell-mediated cytotoxicity assay (ADCC) with CrCl3-treated erythrocytes coated with Tamm-Horsfall (TH) as target cells. The specificity of the ADCC was confirmed by absorption with TH urinary glycoprotein and inhibition of the ADCC activity seen with polyclonal rabbit anti-TH antisera by monoclonal mouse antibodies. The ADCC activity detected in children with acute pyelonephritis was low in the initial phase of the disease, but increased significantly 9 days after the start of antibacterial treatment. In rats with experimental pyelonephritis, ADCC activity decreased significantly with increased duration of infection. Depletion of cells adhering to carbonyl iron led to higher ADCC activity. During the course of the infection the difference in ADCC activity between effector cell preparations depleted using carbonyl iron and those not depleted decreased. The decreased ADCC activity demonstrated during acute pyelonephritis may point to mechanisms operating to diminish the risk of tissue damage.     

The influence of the pelvic nerves on anorectal motility in the cat

The influence of the parasympathetic pelvic nerves on anorectal motility was studied in anaesthetized cats. Anal pressure and rectal motility were recorded by a manometric and a volumetric method, respectively. Severing of the pelvic nerves did not cause any pressure change in the anus, indicating that these nerves are not significantly tonically active. Efferent low intensity (0.05-0.5 ms, 8 V at 5 Hz) electrical stimulation of the pelvic nerves (PNS) elicited a contraction of the internal anal sphincter (IAS), while high intensity stimulation (greater than 1 ms, 8 V at 5 Hz) caused a sphincter relaxation. A rectal contraction was noted on both low and high intensity stimulation. After sectioning of the sympathetic nerves, PNS elicited a contraction in both the anus and the rectum irrespective of stimulation intensity. PNS inhibited the anal contraction elicited by simultaneous stimulation of the sympathetic nerves or noradrenaline infusion. The inhibitory anal responses to PNS were unaffected or augmented by atropine, unaffected by propranolol and abolished by hexamethonium. The excitatory anal effects of PNS were reduced or abolished by atropine and abolished by phentolamine. The rectal contraction induced by low intensity PNS was abolished by atropine or converted to a relaxation. In half of the experiments an atropine resistant rectal contraction was observed in response to high intensity PNS. The results are consistent with a pelvic nerve influence on IAS pressure through several mechanisms, including modulation of the activity in the sympathetic nerves and activation of inhibitory non-adrenergic, non-cholinergic neurons. The pelvic nerves convey both cholinergic and non-cholinergic excitatory, as well as non-adrenergic, non-cholinergic inhibitory fibres to the rectum.     

The sympathetic innervation of the internal anal sphincter and rectum in the cat

The distribution of the sympathetic innervation to the internal anal sphincter (IAS) and rectum and the occurrence of different types of adrenergic receptors in the two organs were investigated in anaesthetized cats. Anal pressure and rectal motility were recorded by a manometric and a volumetric method respectively. Division of both the hypogastric nerves (HGN) and the lumbar colonic nerves (LCN) reduced the anal pressure by 46 +/- 6% of the resting pressure (40.9 +/- 6.4 mmHg) and consistently increased rectal motility. Efferent electrical stimulation of the HGN as well as the LCN elicited a contraction in the anus and the rectum, which, at maximal stimulation, caused the anal pressure to reach a similar level to that recorded before division of these nerves. After injection of phentolamine the anal contraction was abolished, whereas the rectal contraction was either abolished or converted to a beta-adrenergic relaxation. Propranolol caused increased rectal contraction in response to stimulation of the HGN and the LCN, whereas the anal contraction was unaffected. The results imply that the sympathetic nerves exert a tonic excitatory effect on the IAS and a dual effect on the rectum in the cat. The results also indicate that sympathetic fibres to the IAS are conveyed in both the HGN and the LCN. Inhibitory beta-adrenergic receptors seem to be of minor importance in regulating anal pressure.     

CD28nullCD4+ T cells--characterization of an effector memory T-cell population in patients with rheumatoid arthritis

CD4+ T cells lacking the costimulatory molecule CD28 have been described both in elderly individuals and in chronic inflammatory disorders, one being rheumatoid arthritis (RA). We, in this study, provide a comprehensive characterization of cell surface markers on and function of such CD28nullCD4+ T cells, as well as correlations with clinical parameters. We conclude that of all surface markers associated with these cells, only CD57 and CD11b are expressed on the majority of them. This CD28null population occurred in one-third of patients with RA and was independent of clinical characteristics. The population was persistent and expanded in peripheral blood, but was excluded from the joint in most patients. Functionally, CD28nullCD4+ T cells were potent effector memory cells with regard to their proliferation and cytokine-secretion profiles. This capacity correlated with a hitherto unpublished surface phenotype, the cells being uniformly CCR7- and CD43high. Moreover, a new terminally differentiated CD45RA+CCR7- population of CD4+ T cells was identified. We would like to suggest that in the unbalanced immune system of patients with autoimmune disease and chronic infection an expanded CD28nullCD4+ T-cell population able to secrete high levels of cytokines is likely to contribute to disease manifestations.     

A critical analysis of commercially available latex particle reagents for C-reactive protein (CRP) slide agglutination tests

C-reactive protein (CRP) was assessed in pediatric serum samples using different commercial latex reagents, which were analyzed for species origin of the coating antibodies, homogeneity and density of the latex particles, and prozone agglutinating capacity. All reagents correctly agglutinated the positive and negative control sera. The antibodies coating the particles differed with regard to species origin: one was coated with rabbit, one with horse and goat, one with horse, goat, rabbit and swine, while the reference reagent had horse, goat and rabbit antibodies.Only the monospecies specific antibody-coated latex showed obvious prozoning; this reagent also had the smallest and most homogenous latex particles and showed the most clear-cut reactions. False agglutination was observed at 7–26% according to quantitation with the spot immunoprecipitate assay, which compared favorably with radial immunodiffusion measurements. The lowest percentage of false readings was noted for the rabbit antibody-coated particles; the highest for the reagent with particles coated using antibodies from 4 different species.No reagent had satisfactory precision for the low positive sera between 10 and 40 mg CRP/1.     

Impact of surgical aortic valve replacement on global and regional longitudinal strain across four flow gradient patterns of severe aortic stenosis

The International Journal of Cardiovascular Imaging - To evaluate the impact of surgical aortic valve replacement (SAVR) on global (GLS) and regional longitudinal strain (RLS) across four...