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An inhibitor of complement-mediated prevention of immune precipitation in rheumatoid arthritis--relationship to disease activity and systemic manifestations.

In normal serum complement prevents precipitation of antigen-antibody complexes (PIP). However rheumatoid arthritis (RA) serum contains an inhibitor of this complement-mediated function. We have undertaken two prospective studies in order to look for any relationship between the presence and levels of inhibitory activity in sera and synovial fluids (SF) of patients with RA and disease activity (study A), and the presence of systemic manifestations (nodules and vasculitis) of RA (study B). In study A, levels of inhibitory activity were highest in the sera and synovial fluids of patients with seropositive RA. However there was no correlation between the inhibitory levels and indices of generalised disease activity (articular index, erythrocyte sedimentation rate (ESR), haemoglobin, white cell and platelet counts). Local joint tenderness score correlated weakly with the inhibitory level in SF (P less than 0.05). There was no correlation, however, with either the SF protein concentration or white cell count. In study B, PIP was shown to be lower in patients with the systemic manifestations of RA than in those with purely articular manifestations. PIP was particularly low in those patients with vasculitis compared to those with subcutaneous nodules. Serum levels of inhibitory activity were highest in patients with vasculitis and lowest in those with articular disease only, whereas patients with nodules had intermediate levels. Our conclusion is that inhibition of immune precipitation is not associated with disease activity, but is associated with the extra-articular manifestations of RA. The inhibitory factor may play a role in the pathogenesis of RA.

Antigen-Antibody Complex↗

A direct-colouring, metal precipitation method for the demonstration of arylsulphatases A and B.

A new, direct-colouring, metal precipitation method for the light microscopical demonstration of arylsulphatases A and B is described. It is based on the reducing capacity of nitrocatechol liberated by arylsulphatases from p-nitrocatechol sulphate. The reaction is carried out in Karnovsky-Roots' copper ferricyanide incubation mixture at pH 5.0 or 5.5; the nitrocatechol liberated reduces ferricyanide to ferrocyanide, which in turn forms a brown precipitate with copper that indicates enzyme activity. Enzyme activity was localized in cytoplasmic particles compatible with a lysosomal localization of the enzyme. The histochemical reaction was inhibited by phosphate, which has been shown to inhibit arylsulphatases A and B in biochemical determinations. The method described is technically simple, and sections can be mounted in synthetic resin after dehydration.

Adrenal Glands↗

Symptomatic gastroesophageal reflux: incidence and precipitating factors.

The incidence and precipitating factors associated with symptomatic gastroesophageal reflux were evaluated by a questionnaire in 446 hospitalized and 558 nonhospitalized subjects. Of 385 control subjects 7% experienced heartburn daily, 14% noted heartburn weekly, and 15% experienced it once a month, giving a total of 36% of subjects having heartburn at least monthly. Daily heartburn occurred at a significantly greater (P less than 0.05) rate for 246 medical inpatients (14%) and for 121 patients seen in outpatient gastroenterological clinic (15%). Pregnant women seen in uncomplicated obstetrical clinic had symptoms of significantly greater (P less than 0.01) incidence: daily (25%) and at least once monthly (52%). Age, sex, or hospitalization did not significantly affect incidence. Fried foods, "spicy" foods, and alcohol were the most common precipitating factors.

Adult↗

Precipitation reactions with Newcastle disease virus.

Acid precipitated and detergent treated Newcastle disease virus (NDV) antigen was prepared and characterised using the agar gel precipitation (AGP) test. The detergent treated NDV antigen was used to screen antibodies to NDV and the results compared with the conventional haemagglutination inhibition (HI) test titres. AGP test could detect NDV antibodies in serum samples when the corresponding HI titres were 1:8 and above. Detergent treatment of Newcastle disease virus greatly reduced its haemagglutinating ability. Simultaneous detection of antibodies to NDV and infectious bursal disease virus in AGP test was attempted and found successful.

Animals↗

Yohimbine co-treatment during chronic morphine administration attenuates naloxone-precipitated withdrawal without diminishing tail-flick analgesia in rats.

Noradrenergic neuronal hyperactivity following chronic morphine administration has been postulated to cause withdrawal signs and symptoms. Suppression of this hyperactivity, for example, by clonidine attenuates withdrawal. It might follow, therefore, that the prevention of suppression of noradrenergic systems during chronic morphine administration might diminish hyperactivity and prevent withdrawal. If the normalization of noradrenergic activity during opioid administration did not also suppress analgesia, it might be of medical and theoretical interest. To test this hypothesis, we gave the alpha-2-antagonist yohimbine to rats in order to increase noradrenergic activity during morphine treatment and then subsequently precipitated morphine withdrawal with naloxone. Six groups were examined: saline controls (N = 11), morphine (N = 11), morphine + 2.0 mg/kg/day yohimbine (N = 15), morphine + 3.0 mg/kg/day yohimbine (N = 5), 2.0 mg/kg/day yohimbine (N = 11) and 3.0 mg/kg/day yohimbine (N = 5). Subjects received 75 mg morphine pellets implanted on day 1,4 and 6 of the treatment or sham implantation. Yohimbine was delivered throughout the morphine treatment by subcutaneously implanted osmotic pumps. On day 7, all subjects were given 1.0 mg/kg naloxone and rated for behavioral signs of withdrawal. Analgesia was measured by observing tail flick latencies (TFL) before and after chronic drug treatments. Naloxone-precipitated withdrawal was characterized by irritability, ptosis, penile erection, diarrhea, rhinorrhea, abnormal posture, wet-dog shakes, jumping, and teeth chattering, none of which were observed in groups receiving only saline or yohimbine. Withdrawal behavior was attenuated in a dose-dependent manner when yohimbine was administered during morphine treatment but analgesia was not attenuated.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗

Clonidine but not nifedipine prevents the release of noradrenaline during naloxone-precipitated opiate withdrawal: an in vivo microdialysis study in the rat.

In this study we have examined whether the alpha 2-adrenoceptor agonist clonidine and the calcium channel antagonist nifedipine firstly inhibit the naloxone-precipitated withdrawal syndrome in morphine-dependent rats and secondly reduce central noradrenaline release during withdrawal. We demonstrate that both clonidine (0.1 mg/kg) and nifedipine (10 mg/kg) attenuate the naloxone-precipitated withdrawal syndrome. Using in vivo microdialysis, we demonstrate that following naloxone the release of noradrenaline, as measured by perfusates from hippocampus, increases 300% in morphine-dependent rats. However, whilst pretreatment with clonidine inhibited this increased noradrenaline release, nifedipine did not. These findings suggest that whilst the action of clonidine in attenuating the morphine withdrawal syndrome may be mediated by decreasing central noradrenaline release, this is not the mechanism by which nifedipine acts.

Animals↗

Ethopharmacological analysis of naloxone-precipitated morphine withdrawal syndrome in rats: a newly-developed "etho-score".

The intensity of opiate withdrawal syndrome in rats is usually quantified on the basis of selected physical signs or global scores. However, the selection criteria of signs and scores have not been subjected to an ethological discussion, hence they appear to be somewhat arbitrary. The objectives of this study were thus: i) to analyse the rat's behaviour during the naloxone-precipitated morphine withdrawal syndrome, ii) to evaluate the validity of classic methods, and iii) to design a new "etho-score". Ten rats were implanted with morphine pellets (75 mg x 2, SC), all receiving different naloxone doses following a within-subject design (0, 0.01, 0.05, 0.1, 0.5, 1 mg/kg SC). Twenty unexperienced rats and 20 with placebo pellets were injected with either saline or naloxone. Behaviour was videotaped and later analysed by computer-based ethological techniques. The ethogram encompassed 16 patterns displayed by rats during morphine withdrawal. Frequency, duration and latency of each pattern was measured, and a cluster analysis allowed discerning the structure of behaviour. Several physical signs and the Gellert-Holtzman score were also evaluated. The data revealed that writhing responses linearly changed in a dose-related fashion, and mastication was also enhanced after naloxone. Wet-dog shakes and jumping changed following an U-shaped curve. Significant changes in weight loss were found to be dose-dependent, and highly correlated to diarrhea. Learning effects were found to reliably affect exploration, writhing responses and some physical signs. The Gellert-Holtzman score was gradually enhanced after naloxone, being affected by learning as well. Naloxone affected lying and self-care responses in placebo rats. To sum up, the data indicated that: i) classic signs are useful, although most of them are disrupted by high naloxone or affected by learning effects, ii) the Gellert-Holtzman score was validated in this study, and iii) mastication and weight loss are good indicators of naloxone-precipitated morphine withdrawal, representing the basis of an "etho-score" which is herein proposed.

Animals↗

Systemic necrotizing angiitis with asthma: causes and precipitating factors in 43 cases.

Causes and precipitating factors for systemic necrotizing angiitis (NA) with asthma were sought in 43 patients, focusing on a history of vaccination and desensitization. Mean age of patients was 43.2 years. Diagnosis was based on histopathologic findings in 25 patients, arteriography in 2, and clinical criteria in 16. History of allergic manifestations (asthma, rhinitis, eczema, urticaria) was present in the family of 19 patients. Forty-two patients presented with asthma before development of NA and 23 of them were treated with steroids. Nineteen subjects gave a history of desensitization and 5 of vaccination in the 4 weeks preceding the disease. The main symptoms of NA were asthma in 43, fever in 25, weight loss in 31, peripheral neuropathy in 29, cutaneous signs in 25, digestive signs in 16 (abdominal pain, digestive bleeding, bowel perforation), noninfectious pneumopathy with pulmonary infiltrates in 33. Eosinophilia was 8,212 +/- 6,214/mm3. Antigen HBs was found in 2 of 30 patients. Prognosis of NA with asthma was good in 15 patients who recovered completely from the disease. Seven patients died and the other patients improved but remained under treatment. The survival curve showed that 75% of patients were alive after 60 months. Our findings suggest that different causes can be considered responsible for NA, and that, in cases of NA with asthma, there is reason to consider vaccination and desensitization as precipitating factors.

Adolescent↗

Atrial fibrillation precipitated by carotid sinus massage in a patient with unexplained syncope.

BACKGROUND: Carotid sinus massage (CSM) is a useful tool in the investigation of unexplained syncope, but is associated with risks. AIM: To describe the first reported case of atrial fibrillation precipitated by CSM during the investigation of a patient with recurrent unexplained syncope. RESULTS: A 58-year-old female underwent CSM as part of a tilt test protocol for the investigation of recurrent unexplained syncope. Left CSM revealed the diagnosis of mixed cardioinhibitory and vasodepressor carotid sinus syndrome but also precipitated atrial fibrillation, an arrhythmia previously unreported as a complication of the procedure. CONCLUSIONS: CSM is a useful tool in the investigation of patients with recurrent unexplained syncope, but may cause atrial fibrillation in addition to other previously described complications and should, therefore, be used with caution.

Atrial Fibrillation↗

Excitatory amino acid release in the locus coeruleus during naloxone-precipitated morphine withdrawal in adjuvant arthritic rats.

OBJECTIVE AND DESIGN: Excitatory amino acid levels in the locus coeruleus (LC) and the behavioral signs during naloxone-precipitated withdrawal in arthritic rats treated with chronic morphine were investigated by in vivo microdialysis. METHODS: Increases in glutamate (Glu) and aspartate (Asp) were noted after naloxone (48 nmol/5 microl, LC)-precipitated withdrawal from normal and adjuvant arthritic rats which had been intracerebroventricularly infused for 3 days with morphine (26 nmol/l microl/h). RESULTS: The increases in Glu and Asp levels on morphine withdrawal in normal rats were attenuated following naloxone challenge in the morphine-dependent arthritic rats. Moreover, behavioral signs during morphine withdrawal were detected following the naloxone challenge in both the morphine-dependent normal and adjuvant arthritic rats, but not in the saline-infused controls. CONCLUSIONS: These results show that the attenuation of Glu and Asp release from the LC in the adjuvant arthritic rats might explain the anti-inflammatory and analgesic effects of mu-opioids in adjuvant arthritic rats.

Animals↗

Conditioning processes contribute to severity of naloxone-precipitated withdrawal from acute opioid dependence.

RATIONALE: Single injections with morphine can induce a state of acute opioid dependence in humans and animals, typically measured as precipitated withdrawal when an antagonist such as naloxone is administered 4-24 h after morphine. Repeated treatment with morphine results in further increases in naloxone potency, and prior work has shown that this progressive shift in naloxone potency requires repeated naloxone experience under some but not all experimental conditions. OBJECTIVE: The current study sought to further characterize the experimental conditions that support naloxone experience-dependent and experience-independent potentiation of precipitated suppression of operant responding in morphine pretreated rats, and to assess more directly whether conditioning mechanisms may contribute to the former process. METHODS: Rats trained on an FR15 schedule for food received a total of five vehicle or morphine injections (5.6 mg/kg SC) at 4, 8, or 22 h prior to an operant session in which a cumulative dose-effect function for naloxone-induced suppression of responding was determined. Separate groups of animals at each interval between morphine and naloxone received cumulative naloxone dosing after all morphine pretreatments (NAL ALL DAYS) or after just the first and last morphine pretreatment (NAL FIRST/LAST). Additional groups of rats at the 4 h MOR-NAL interval received most of their naloxone cumulative dose-effect experience in either the home cage or in the operant context with levers retracted. RESULTS: Vehicle-pretreated (Morphine-Naive) rats showed little change in the naloxone dose-effect function even after five cumulative dose-effect determinations. With a single morphine pretreatment, naloxone potency was increased at 4 or 8 h post-morphine, but not at 22 h. With repeated morphine treatment, all MOR-NAL intervals resulted in significant shifts in naloxone potency across treatment days even when naloxone was administered only after the first and last morphine pretreatment. However, much greater shifts in naloxone potency were observed at 4-h and 8-h intervals when naloxone was administered on all treatment days. At the 22 h MOR-NAL interval, there was no further potentiation in naloxone potency with additional naloxone experience provided on the intermediate days. Finally, when the repeated naloxone experience occurred in the home cage at the 4-h interval, naloxone potency was identical to that seen after limited naloxone experience (NAL FIRST/LAST), and significantly less than naloxone potency in groups receiving repeated naloxone experience in the operant context. CONCLUSIONS: The results suggest that conditioned withdrawal mechanisms may play a significant role in the initial development of opioid dependence.

Animals↗

Flumazenil-precipitated withdrawal in healthy volunteers following repeated diazepam exposure.

RATIONALE: Parametric preclinical studies of the benzodiazepine antagonist flumazenil have contributed to the understanding of the physical dependence associated with chronic benzodiazepine use. However, few parametric studies have been conducted in human participants. OBJECTIVE: This study was designed to assess the effect of duration of benzodiazepine exposure on the intensity of flumazenil-precipitated withdrawal in healthy volunteers. METHOD: Participants were randomly assigned to receive either oral diazepam (15 mg/70 kg; n=10) or placebo (n=8) capsules nightly for 28 days. Effects of flumazenil (1 mg/70 kg, intravenously administered) were assessed in challenge sessions conducted before capsule ingestion, and after 1, 7, 14, and 28 days of capsule ingestion. RESULTS: Flumazenil produced a profile of participant-rated effects consistent with benzodiazepine withdrawal that peaked immediately after completion of the 5-min flumazenil injection and rapidly dissipated thereafter. The magnitude of these effects was comparable after 7, 14, and 28 days of diazepam. Flumazenil also produced modest elevations in blood pressure and decreases in skin temperature in the diazepam group, both of which were sustained throughout the approximate 60-min session. CONCLUSIONS: These findings support previous human research studies indicating that flumazenil precipitates withdrawal after short chronic exposure to benzodiazepines and suggests that duration of exposure does not influence the intensity of withdrawal beyond the first week of exposure.

Administration, Oral↗

Spontaneous and precipitated withdrawal after chronic intragastric administration of gamma-hydroxybutyrate (GHB) in baboons.

RATIONALE: gamma-Hydroxybuyrate (GHB) is a current drug of abuse that may produce physical dependence. OBJECTIVES: The present study characterized the behavioral effects of chronic GHB in baboons (n = 4), and evaluated whether signs of withdrawal occurred (1) after administration of the GABA-B antagonist CGP36742 during chronic GHB administration (precipitated withdrawal) and (2) following discontinuation of chronic GHB administration (spontaneous withdrawal). METHODS: Water (vehicle) and then GHB was continuously infused via intragastric (IG) catheters. GHB administration was initiated at 350 mg/kg per day, and the dose was increased by 100 mg/kg over 4 days to 750 mg/kg per day. Food pellets were available 20 h/day under a fixed ratio (FR5 or 10) schedule of reinforcement. Observation sessions and a 2-min fine motor task were conducted during vehicle and GHB administration. CGP36742 (32 and 56 mg/kg, IM) was administered during vehicle and chronic GHB administration. After a total of 32-36 days GHB administration was abruptly discontinued. Blood samples were collected during all interventions and analyzed for GHB content. RESULTS: Chronic GHB decreased food-maintained behavior, disrupted performance of the fine motor task, and produced ataxia, muscle relaxation, tremors and jerks. At the end of GHB administration, plasma levels of GHB ranged from 486 to 2080 micromol/L. Administration of CGP36742 during chronic GHB administration produced increases in aggression, self-directed behaviors, vomit/retch, tremors and/or jerks, which is consistent with a precipitated withdrawal syndrome. Similar signs were observed when GHB administration was discontinued. Seizures were not observed. CONCLUSIONS: These data indicate that chronic GHB administration produced physical dependence and that activation of the GABA-B receptor may be important for GHB physical dependence.

Animals↗

Precipitating factors in spontaneous recurrence of methamphetamine psychosis.

This paper examines noradrenergic hyperactivity in response to stress in the development of spontaneous recurrences of methamphetamine (MAP) psychosis, a phenomenon known as flashbacks, in studies of psychedelic drug use. We studied predictors of flashbacks in 36 subjects with flashbacks, along with 80 subjects with a history of MAP psychosis who did not experience flashbacks. Plasma monoamine metabolite levels were assayed in 26 of the 36 subjects with flashbacks, 16 of the 80 subjects without flashbacks, nine subjects with persistent MAP psychosis, and 28 normal controls. None of the 28 controls became psychotic. A square root transformation was applied to all monoaminergic values, resulting in data nearly normally distributed. The subjects with flashbacks had been exposed to stressful events or threatening paranoid-hallucinatory states or both during previous MAP use. Most flashbacks occurred under conditions that provoked a mild fear of other people. Plasma norepinephrine levels were markedly increased during flashbacks. Thus, stressful experiences together with MAP use may have induced noradrenergic hyperreactivity to a mild stress, which in turn may elicit memories of MAP psychosis associated with stressful experiences. A mild fear of other people precipitated the flashbacks, including markedly increased noradrenergic activity. The results of this study suggest that noradrenergic hyperreactivity to a mild stress is a precipitating factor in spontaneous recurrences of MAP psychosis.

Adult↗

A controlled study of flumazenil-precipitated withdrawal in chronic low-dose benzodiazepine users.

RATIONALE: Preclinical studies of the benzodiazepine antagonist flumazenil (Romazicon) have contributed to the understanding of the physical dependence associated with chronic benzodiazepine use; when administered to animals chronically pretreated with benzodiazepines, flumazenil precipitates a withdrawal syndrome. However, few controlled clinical studies have been conducted. OBJECTIVES: The objective was to characterize the effects of flumazenil in long-term users of therapeutic doses of benzodiazepines. METHODS: The acute physiological, participant-rated, and observer-rated effects of intravenously administered flumazenil (1 mg/70 kg) and caffeine (300 mg/70 kg; active drug control) were evaluated in an experimental group of 13 long-term users (mean 4.6 years) of low therapeutic doses (mean 11.2 mg/day diazepam equivalent) relative to a matched group of 13 volunteers without prior exposure to benzodiazepines in a double-blind, placebo-controlled, mixed design. RESULTS: Whereas the experimental group did not differ from the control group with respect to the effects of placebo, and both groups showed some changes in response to caffeine (e.g., increased blood pressure and anxiety scores), only the experimental group showed considerable changes in physiological measures, participant ratings (e.g., increased ratings of dizziness, blurred vision, heart pounding, feelings of unreality, pins and needles, nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch), and observer ratings in response to flumazenil; in addition, four participants developed panic attacks. CONCLUSIONS: This study clearly demonstrates that flumazenil can precipitate symptoms commonly associated with benzodiazepine withdrawal in chronic low-dose benzodiazepine users.

Adult↗

Sulfate-reducing bacteria-dominated biofilms that precipitate ZnS in a subsurface circumneutral-pH mine drainage system.

The microbial diversity of ZnS-forming biofilms in 8 degrees C, circumneutral-pH groundwater in tunnels within the abandoned Piquette Zn, Pb mine (Tennyson, Wisconsin, USA) has been investigated by molecular methods, fluorescence in situ hybridization (FISH), and cultivation techniques. These biofilms are growing on old mine timbers that generate locally anaerobic zones within the mine drainage system. Sulfate-reducing bacteria (SRB) exclusively of the family Desulfobacteriaceae comprise a significant fraction of the active microbiota. Desulfosporosinus strains were isolated, but could not be detected by molecular methods. Other important microbial clusters belonged to the beta-, gamma-, and epsilon-Proteobacteria, the Cytophaga/Flexibacter/Bacteroides-group (CFB), Planctomycetales, Spirochaetales, Clostridia, and green nonsulfur bacteria. Our investigations indicated a growth dependence of SRB on fermentative, cellulolytic, and organic acid-producing Clostridia. A few clones related to sulfur-oxidizing bacteria were detected, suggesting a sulfur cycle related to redox gradients within the biofilm. Sulfur oxidation prevents sulfide accumulation that would lead to precipitation of other sulfide phases. FISH analyses indicated that Desulfobacteriaceae populations were not early colonizers in freshly grown and ZnS-poor biofilms, whereas they were abundant in older, naturally established, and ZnS-rich biofilms. Gram-negative SRB have been detected in situ over a period of 6 months, supporting the important role of these organisms in selective ZnS precipitation in Tennyson mine. Results demonstrate the complex nature of biofilms responsible for in situ bioremediation of toxic metals in a subsurface mine drainage system.

Bacteria↗

Radioactive contamination in the upper part of the Techa river: stirring-up of bottom sediments and precipitation of suspended particles. Analysis of the data obtained in 1949-1951.

A hydrodynamic model of the upper part of the Techa river was developed on the basis of the river valley geometry as well as data of hydrological conditions and of the granulometric composition of bottom sediments. The model describes the transport of radioactivity by suspended sediments with different granulometric compositions (clay, silt) in the early 1950s. It includes the stirring-up of bottom sediments and the precipitation of suspended sediments as a function of water discharge rate and water level in the investigated part of the river. The results allow to specify the development of the river system contamination as a result of inflow of suspended sediments contaminated with radionuclides. In the period of liquid radioactive waste (LRW) discharges, the water of the Techa river contained a large fraction of finely dispersed particles of less than 5 micro m diameter. At the site of LRW discharge 80% of the discharged activity was adsorbed to these particles. Depending on the water flow, 40-80% of the suspensions precipitated at the bottom of subsequent sedimentation reservoirs. A total of about 1.6 MCi adsorbed to the suspended particles entered the open hydrographic system of the Techa river. The conclusion that the largest part of the activity was adsorbed on the suspended particles contradicts the assumption in the Techa river dosimetry system, TRDS-2000, that most of the released activity entered the Techa river in soluble form. For a correct reconstruction of the doses received by the Techa river population it is, therefore, essential to consider hydrodynamic models that take into account the transport of radionuclides adsorbed on the suspended particles.

Geologic Sediments↗

Water conservation in Artemisia tridentata through redistribution of precipitation.

Water conservation is important for plants that maintain physiologically active foliage during prolonged periods of drought. A variety of mechanisms for water conservation exist including stomatal regulation, foliage loss, above- and below-ground allocation patterns, size of xylem vessels and leaf pubescence. Using the results of a field and simulation study with Artemisia tridentata in the Great Basin, USA, we propose an additional mechanism of water conservation that can be used by plants in arid and semi-arid environments following pulses of water availability. Precipitation redistributed more uniformly in the soil column by roots (hydraulic redistribution of water downward) slows the rate at which this water can subsequently be taken up by plants, thus prolonging water availability during periods of drought. By spreading out water more uniformly in the soil column at lower water potentials following precipitation events, water use is reduced due to lower soil conductivity. The greater remaining soil water and more uniform distribution result in higher plant predawn water potentials and transpiration rates later in the drought period. Simulation results indicate that plants can benefit during drought periods from water storage following both summer rain events (small summer pulses) and overwinter recharge (large spring pulse). This mechanism of water conservation may aid in sustaining active foliage, maintaining root-soil hydraulic connectivity, and increasing survival probability of plants which remain physiologically active during periods of drought.

Artemisia↗