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Cim: an MHC class II-linked allelism affecting the antigenicity of a classical class I molecule for T lymphocytes.

Two alleles at the major histocompatibility complex (MHC)-linked locus cim determine "gain and loss" changes in the rat RT1.Aa class I molecule which affect its structure both as an alloantigen and as a restriction element. Alleles at the cim locus also influence the post-translational modification of RT1.Aa. These effects may reflect the participation of the cim gene product in the processes of peptide loading or assembly of RT1.Aa. In this study we have used the discriminating RT1.Aa-specific monoclonal antibody JY3/84, as well as cytotoxic T cells raised in appropriate combinations, to determine the cim alleles of eight haplotypes in 15 independent inbred strains of rat. We have also employed the same techniques to analyse a panel of F1 hybrid animals derived from various MHC recombinant strains. These experiments map the cim locus to the class II region of RT1, probably between the DP-related genes (RT1.H) and the DQ-related RT1.B alpha.

Alleles

Afferent and efferent connections of the mesencephalic cardioinhibitory area (CIM) in the cat.

The afferent and efferent connections between the cardioinhibitory area in the midbrain tegmental field (CIM) and brain stem structures related to cardiovascular integration in cats were investigated by horseradish peroxidase (HRP) for both cell origins and axonal terminations and by chemical (kainic acid) lesion for topographic pathways. Retrogradely labeled neurons were observed in the gigantocellular reticular nucleus (GRN), the pontine reticular nucleus of the pons (PON), the ambiguus nucleus (AN) and the paramedian reticular nucleus (PRN). A few neurons were also labeled in the following structures i.e., ventrolateral medulla (VLM), dorsomedial medulla (DMM), dorsomotor nucleus of the vagus nerve (DMV) and nucleus of solitary tract (NTS). Anterograde HRP labeled terminals were found surrounding the cell bodies of the aforementioned structures. They were most abundant in VLM, DMM, DMV, NTS, moderate in GRN, PRN and AN, but only scanty in hypothalamus. The fiber pathway of CIM neurons was also traced by degenerating fibers consequent to kainic acid lesion and by means of silver stain. Degenerating fiber bundle was found primarily projecting through the medial portion of the mesencephalic pontine structures. As the bundle reached the medulla oblongata, it bifurcated into a dorsal and a ventral tracts on its course. The dorsal tract was primarily coursing through the dorsomedial area, including DMM, NTS and DMV, and the ventral tract was mainly passing VLM, AN and inferior olivary nucleus (ION) areas. The present findings suggest that neurons in the CIM may receive inputs from various cardiovascular-related structures and make output bilaterally to some of pontine and medullary structures to modulate cardiovascular functions. Based on the anatomical findings, the profound bradycardia produced by CIM stimulation may be mediated through the following mechanisms: A. Direct activation of vagal preganglionic neurons in DMV, AN and ION. B. Indirect activation of neurons in GRN for vagal activation and of neurons in PRN for sympathetic inhibition.

Afferent Pathways

The major histocompatibility complex class II-linked cim locus controls the kinetics of intracellular transport of a classical class I molecule.

The dominant trans-acting major histocompatibility complex (MHC)-linked class I modifier (cim) locus, previously recognized through its ability to determine altered alloantigenicity of a rat class I molecule, RT1.A3, is shown here to influence class I intracellular transport. The MHC recombinant laboratory rat strains PVG.R1 and PVG.R8 display unusually long retention of RT1.Aa within the endoplasmic reticulum or cis-Golgi. In appropriate F1 hybrid cells heterozygous for RT1.Aa and another class I MHC allele, RT1.Ac, only the RT1.Aa protein is subject to slow transport. The cim gene product therefore shows class I allele specificity in its action, cim appears to be a polymorphic locus whose product is directly involved in the processes of class I MHC assembly and/or intracellular transport.

Animals

A method for the determination of amitriptyline and its metabolites nortriptyline, 10-hydroxyamitriptyline, and 10-hydroxynortriptyline in human plasma using stable isotope dilution and gas chromatography-chemical ionization mass spectrometry (GC-CIMS).

A gas chromatography--mass spectrometry (GC-MS) method has been developed to measure amitriptyline and its metabolites nortriptyline, 10-hydroxyamitriptyline, and 10-hydroxynortriptyline in human plasma. Deuterated analogs of each compound were synthesized as internal standards. Isobutane was used as both gas chromatography (GC) carrier gas and chemical ionization (CI) reagent gas. In order to obtain compounds with satisfactory GC and mass spectrometry (MS) properties, the two alcohol metabolites were dehydrated without loss of label during sample preparation. Selective ion monitoring of the MH+ ions of the protio- and deuterio- compounds gave ion ratios which were converted to plasma concentrations using standard curves. For amitriptyline and nortriptyline, which are assayed using multiple deuterated analogs as internal standards, the curves are straight lines. For 10-hydroxyamitriptyline and 10-hydroxynortriptyline, which are assayed using monodeuterated analogs as internal standards, the curves are nonlinear and are analyzed using an iterative computer procedure. Assay sensitivity is 0.5 ng/ml for amitriptyline, nortriptyline, and 10-hydroxyamitriptyline and 1 ng/ml for 10-hydroxynortriptyline. Assay precision and accuracy in terms of percent error are both less than 5%. Following oral administration of a single 75-mg dose of amitriptyline to two subjects, the mean plasma levels of amitriptyline, nortriptyline, 10-hydroxyamitriptyline, conjugated 10-hydroxyamitriptyline, 10-hydroxynortriptyline, and conjugated 10-hydroxynortriptyline were 36, 8, 10, 66, 16, and 46 ng/ml, respectively, at 2 hr after dosing and 3, 4, 0.5, 1, 6, and 17 ng/ml, respectively, at 72 hr after dosing. Analyses of plasma samples from 12 subjects who had been receiving 50 mg amitriptyline therapy three times a day for an average +/- SD of 32 +/- 5 days gave a mean concentration of 81 +/- 40 ng/ml for amitriptyline, 71 +/- 57 ng/ml for nortriptyline, 12 +/- 5 ng/ml for 10-hydroxyamitriptyline, 91 +/- 30 ng/ml for conjugated 10-hydroxyamitriptyline, 82 +/- 27 ng/ml for 10-hydroxynortriptyline, and 176 +/- 64 ng/ml for conjugated 10-hydroxynortriptyline.

Amitriptyline

[Comparison between DSM III and CIM 9 in the data processing on computerized system. Study of 4000 records].

The authors expose the results of a confrontation between ICD 9 and the D.S.M. III's classification published by APA. This work is the issue of a collected data system'use (S.D.P.A.) which is a basic tool for epidemiological programm, applied in military psychiatrics department (actually 18 services have got computer sets). It is evident that military structure (centralized dans homogeneous), and the size of the samples, are good conditions for psychiatric epidemiology. The authors recall the different stages and the difficulties on the field, for such a wide scale application. The use of two principal world-known classifications raise up unanticiped remarks: indeed, we consider the logical structure of D.S.M. III's axis I as better than ICD 9 classification. Meanwhile, the axis III, IV and V caused a disappointment, for both clinicians and programm's responsibles. In fact, there were some statistical biases and a little gain of informations. The former system (applied for 1976) was more efficient. Some hypothesis about that insufficient acceptability and reliability are proposed as also an important project for system's modifications from 1989.

Electronic Data Processing

Evaluation of carbapenem inactivation method-based phenotypic assays for the detection of GES-type carbapenemases in Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii.

UNLABELLED: Detection of GES-type carbapenemases remains challenging because of their low prevalence and frequently weak hydrolytic activity against carbapenems. Carbapenem inactivation method (CIM)-based assays are widely used as phenotypic screening tools for carbapenemase detection; however, their performance in large collections of GES producers has not been systematically evaluated. We assessed the performance of CIM, modified CIM (mCIM), and CIM-Tris in a diverse collection of GES-producing clinical isolates, including 110 Enterobacterales and 108 Pseudomonas aeruginosa, recovered from Spanish hospitals (2010-2024), and 10 Acinetobacter baumannii isolates, mostly obtained from a hospital in Egypt. Whole-genome sequencing was carried out for species confirmation and resistome analysis. Meropenem MICs were determined by broth microdilution. Overall, 92.1% of isolates were GES-carbapenemase producers (CP), whereas 7.9% expressed GES-type extended-spectrum β-lactamases (ESBLs). In Enterobacterales (predominantly carrying blaGES-6), mCIM improved sensitivity compared with CIM (63.6% vs 40.0%), although many isolates remained undetected due to low meropenem MICs (MIC50, 0.5 µg/mL). In CP-P. aeruginosa (mainly blaGES-5), CIM, mCIM, and CIM-Tris showed sensitivities of 89.1%, 94.6%, and 100%, respectively; however, CIM-Tris yielded false-positive results in 50% of non-CP isolates (mostly blaGES-1 producers). Meropenem MICs in P. aeruginosa were higher (MIC50, >32 µg/mL). In A. baumannii, CIM-Tris improved sensitivity compared with CIM (100% vs 25.0%). These findings indicate that CIM-based methods can detect GES-type carbapenemases, but performance varies according to bacterial species and GES variant, and reduced specificity may occur in isolates producing GES-type ESBLs. Complementary molecular testing may therefore be necessary to ensure accurate detection of GES-type carbapenemases in routine clinical laboratories. IMPORTANCE: GES-type carbapenemases represent an important but underrecognized diagnostic challenge due to their low global prevalence, heterogeneous hydrolytic activity, and the limited performance data available for routine phenotypic detection methods. Although CIM-based assays are widely implemented in clinical microbiology laboratories for carbapenemase screening, their performance against GES-producing organisms has not been comprehensively evaluated across different bacterial genera and GES variants. In this study, we evaluated the performance of CIM, modified CIM (mCIM), and CIM-Tris in a large multicenter collection of well-characterized GES-producing clinical isolates, including Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii. Our findings demonstrate substantial variability in assay performance according to bacterial species and GES variant. Notably, mCIM improved sensitivity among Enterobacterales with low meropenem MICs, whereas CIM-Tris achieved excellent sensitivity in P. aeruginosa and A. baumannii but at the expense of reduced specificity in isolates producing GES-type ESBLs. To the best of our knowledge, this is the first study directly comparing multiple CIM-based approaches in such a large and taxonomically diverse collection of GES-producing isolates.

beta-Lactamases

Differential effects of clomipramine given locally or systemically on extracellular 5-hydroxytryptamine in raphe nuclei and frontal cortex. An in vivo brain microdialysis study.

The antidepressant drug clomipramine (CIM) blocks 5-hydroxytryptamine (5-HT) uptake in vitro. Electrophysiological studies have shown that CIM also reduces the firing of serotonergic neurons in the dorsal raphe nucleus. In order to assess the effects of CIM on serotonergic transmission in vivo, the technique of intracerebral microdialysis was used. CIM was administered either through the dialysis probe or i.p., and dialysate 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were determined in frontal cortex and/or raphe nuclei. In addition, the action of extracellular 5-HT in raphe nuclei on the release of 5-HT in frontal cortex was studied. The administration of CIM through the dialysis probe increased dialysate 5-HT in frontal cortex in a dose-dependent fashion. An actual ED50 of 3.15 microM CIM for the in vivo inhibition of 5-HT uptake can be calculated in this brain area. When given systemically (10 or 20 mg/kg i.p.), CIM did not increase dialysate 5-HT in the frontal cortex. The occurrence of extracellular 5-HT in the the raphe area was demonstrated. This pool of 5-HT increased markedly after local (10 or 40 microM) or systemic (20 mg/kg i.p.) administration of CIM. We also examined the effect of CIM applied locally in the raphe nuclei on extracellular 5-HT in the frontal cortex. The increased dialysate 5-HT in raphe after 10 or 40 microM CIM paralleled a decrease of dialysate 5-HT in the two areas correlated negatively. The administration of CIM through the dialysis probe slightly decreased dialysate 5-HIAA in the frontal cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals

The effect of cimetidine on adaptive cytoprotection by mild irritant dose of HCl in the rat gastric mucosa.

While cimetidine (CIM) is strikingly effective in inhibiting gastric acid secretion, its effect on the defensive mechanisms of the gastric mucosa has been controversial. The aims of the present study were to test if administration of CIM at an antisecretory dose is protective against acid-induced injury and to assess its effect on adaptive cytoprotection induced by non-necrotizing concentrations of HCl in rats. A dose of 100 mg/kg of CIM was administered once, or twice a day for 5 days intraperitoneally. To study the effect of CIM on HCl-induced damage, 0.6 N HCl was given orally one hour after the last administration of CIM. To study the effect of CIM on adaptive cytoprotection, 0.35 N HCl was given orally one hour after the last administration of CIM. Fifteen minutes later, 0.6 N HCl was given orally. Thirty minutes after the administration of 0.6 N HCl, the stomach was removed and ulcer indices were calculated. Pretreatment with CIM did not prevent 0.6 N HCl induced gastric damage. Prior administration of 0.35 N HCl significantly reduced ulcer indices caused by 0.6 N HCl. Short or long term treatment with CIM did not have significant effects on the reduction of ulcer indices. These results suggest that CIM at an antisecretory dose neither acts as a protective agent nor modulates the protective process of the gastric mucosa.

Adaptation, Physiological

The effect of cimaterol and its withdrawal on carcass composition and meat tenderness of broiler chickens.

To examine the effects of cimaterol (CIM) and its withdrawal on meat tenderness and carcass composition, 21-d-old broiler chickens (n = 288) were randomly assigned to one of nine treatments. For Treatments 1 through 6, birds were fed a control diet or a diet containing 1 ppm CIM until slaughter at 35, 42, or 49 d of age. Treatments 7 and 8 consisted of birds fed the CIM diet for 14 d and then withdrawn from CIM for either 7 or 14 d before slaughter (42 or 49 d of age). In Treatment 9, birds were fed the CIM diet to 42 d of age, then withdrawn from CIM for 7 d. Breast muscle (BM) weight, leg muscle (LM) weight, whole body weight, and BM and LM cathepsin B and L activities were obtained on 12 birds/treatment. Body, LM and BM composition and BM shear values were obtained on 12 additional birds/treatment. Eight birds/treatment were used to balance the number of birds per pen. Leg muscle weight, as a percentage of whole body weight, was elevated in CIM-fed birds at all ages, and BM percentage was greater at 35 d of age (P less than .05). Leg muscle fat percentage was reduced at 35 and 42 d of age (P less than .05), and LM protein was elevated at 42 and 49 d of age (P less than .05) in CIM-fed birds. Percentage of protein in the BM of CIM-fed birds was elevated at 35 and 42 d of age. Protein content of the whole body was also increased at 35 d of age. Shear values were higher in 42- and 49-d-old CIM-fed birds.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue

Muscle protein turnover and tenderness in broiler chickens fed cimaterol.

To investigate the impact of cimaterol (CIM) on muscle protein turnover, carcass and muscle composition, muscle cathepsin B + L activity and meat tenderness, 21-d-old broiler chickens (n = 88) were assigned to dietary treatments of either 0 or 1 ppm CIM. Fractional synthesis rates (FSR), fractional accretion rates (FAR), proximate composition and collagen content were determined in the breast muscle (BM); pectoralis major) and a group of leg muscles (LM; gastrocnemius and peroneous longus) from groups of six birds per treatment within each of two time periods (age = 38 or 56 d). Whole body composition, serum hydroxyproline content and BM cathepsin B + L activity also were measured. Fractional degradation rates (FDR) were calculated as the difference between FSR and FAR. Feeding CIM increased (P less than .01) whole body protein content. Weights of LM and percentage of body weight as BM and LM were increased (P less than .05) when CIM was included in the diet. Although FSR was not significantly reduced by CIM feeding it decreased (P less than .05) with increasing age. Due to decreases in FAR, FDR thereby was reduced by CIM 31.5% and 11.9% in BM and 38.2% and 37.4% in LM at 38 d and 56 d of age, respectively. Cathepsin B + L activities also were reduced 33.6% (P less than .01) and shear forces were increased by 41% (P less than .05) by CIM feeding. For chickens fed CIM, the correlation between cathepsin B + L activity and shear force was -.63 (P less than .01). Feeding CIM improved carcass leanness and muscling due to reductions in FDR and proteolytic enzyme activity. Feeding CIM also reduced meat tenderness.

Administration, Oral

Analyses of oviposition times and intervals in a wide range of layer flocks under normal and continuous lighting regimes.

Distributions of oviposition times and intra-clutch oviposition intervals in continuous light (CL) and normal light (NL) environments were studied in 39 populations of 27 different genotypes. The populations showed a range of mean intervals from 23.1 to 27.6 h in CL, arising from the history of selection directly on interval in some populations. The data were analysed to infer empirical relations of descriptive statistics of the distribution to each other and to rate of lay to 301 d of age (PRL). In NL, as the mean intra-clutch interval decreased, more intervals tended to accumulate against the barrier of 24 h imposed by the light-dark cycle and the variability of intervals declined rapidly. Similar, but less striking, relations were found in CL above a mean interval of about 24 h. Under CL, the mean intra-clutch interval (CIM) decreased beneath 24 h and the variability of intervals tended to show a steep increase. The rate of lay to 301 d of age increased linearly at a rate of 6.3% for each hour by which CIM decreased to about 24 h, but no further below that level. Oviposition time in NL was advanced with a decrease in CIM, apparently in two linear phases of differing slopes, perhaps reflecting different physiological bases of the change. The degree of entrainment in NL, measured by the proportion of eggs laid in the model 8 h, increased with reduction of CIM. The distribution of oviposition times in CL showed a great deal of variation among the populations and departed significantly (P less than 0.05) from the uniform rectangular distribution, in all but three populations. The proportion of eggs laid in the modal 8 h of the day, suggested as an indicator of sensitivity to uncontrolled timing cues in CL, was positively correlated with CIM. Free-running periods were estimated for individual pullets from sequences of oviposition times in CL. The mean period for a population declined linearly with CIM, but only when CIM had decreased below about 25.75 h, suggesting that the period of endogenous circadian rhythm might have been altered in some populations with low CIM's. The proportion of eggs laid in the modal 8 h of the free-running period, perhaps an indicator for regularity of the circadian rhythm, was negatively correlated with CIM.

Animals