Rheumatoid arthritis and its animal models: the role of TNF-α and the possible absence of specific immune reactions

Rheumatoid arthritis is an organ-specific inflammatory disease of humans. Recent studies have focused on associations with non-MHC genes, new autoantigens and the role of innate immune responses. The success of anti-TNF-α in the majority (but, interestingly, not all) of patients has implications for disease mechanisms but the dangers of long-term therapy are becoming clearer. A number of new models of arthritis have been defined and emphasize the importance of the genetic make-up of the host. Attention has also focused on why the joint is a particularly vulnerable site for inflammatory responses.     

Acupuncture at the Huatuojiaji point affects nerve root regional interleukin-1 level in a rat model of lumbar nerve root compression

BACKGROUND:It has been shown that interleukin-1 (IL-1) may cause inflammatory reactions, which stimulate the nerve root of patients with lumbar intervertebral disc protrusion and leads to pain. Whether the clinical curative effects of acupuncture in the treatment of lumbar and leg pain are linked to an inhibition of local IL-1 secretion is unknown. OBJECTIVE: To assess the influence of acupuncture on IL-1, this study was designed to verify the effects of acupuncture at the Huatuojiaji (Extra) point on the n...     

Budget Impact Analysis of Thrombolysis for Stroke in Spain: A Discrete Event Simulation Model

Objective:  Thrombolysis within the first 3 hours after the onset of symptoms of a stroke has been shown to be a cost-effective treatment because treated patients are 30% more likely than nontreated patients to have no residual disability. The objective of this study was to calculate by means of a discrete event simulation model the budget impact of thrombolysis in Spain.
Methods:  The budget impact analysis was based on stroke incidence rates and the estimation of the prevalence of stroke-related disability in Spain and its translation to hospital and social costs. A discrete event simulation model was constructed to represent the flow of patients with stroke in Spain.
Results:  If 10% of patients with stroke from 2000 to 2015 would receive thrombolytic treatment, the prevalence of dependent patients in 2015 would decrease from 149,953 to 145,922. For the first 6 years, the cost of intervention would surpass the savings. Nevertheless, the number of cases in which patient dependency was avoided would steadily increase, and after 2006 the cost savings would be greater, with a widening difference between the cost of intervention and the cost of nonintervention, until 2015.
Conclusion:  The impact of thrombolysis on society's health and social budget indicates a net benefit after 6 years, and the improvement in health grows continuously. The validation of the model demonstrates the adequacy of the discrete event simulation approach in representing the epidemiology of stroke to calculate the budget impact.     

The effect of experimentally-induced renal failure on accumulation of bupropion and its major basic metabolites in plasma and brain of guinea pigs

Dosage regimen adjustments because of poor renal function are often assumed to be unnecessary for extensively metabolized antidepressants. This assumption is being increasingly questioned in recognition of the role of active drug metabolites. The purpose of this study was to assess the steady-state accumulation of the new antidepressant bupropion and its three major basic metabolites in guinea pigs, with and without experimentally-induced renal guinea pigs, with and without experimentally-induced renal failure. Two groups of guinea pigs were treated by intraperitoneal (IP) implantation of mini-osmotic pumps containing bupropion hydrochloride. Immediately after surgery, one group of animals received an injection of uranyl nitrate. After 4 days, all animals were sacrificed by decapitation following blood removal by cardiac puncture. Analysis of plasma and brain samples by high performance liquid chromatography (HPLC) for concentrations of bupropion (BUP) and its major basic metabolites, the erythro-amino alcohol (EB), the threo-amino alocohol (TB) and the hydroxy metabolite (HB) revealed greater accumulation of BUP, TB, and HB in plasma and brain of the animals with renal failure compared to controls. No difference was found between groups in the concentrations of the EB metabolite. As the guinea pig shows a BUP and metabolite plasma concentration profile similar to that seen in human studies, these results suggest that further studies of bupropion and its major metabolites are warranted in patients with impaired renal function to assess possible excessive drug and metabolite accumulation.     

A variance components/major locus likelihood approximation on quantitative data

The variance components/major locus model encompasses a major locus, a polygenic component, and shared environmental effects. The model attributes familial correlations to polygenic and shared environmental effects when testing for major locus inheritance or accounts for the major locus when estimating variance components. Because exact computation of the likelihood of the variance components/major locus model on quantitative data requires excessive computer time, I developed an approximation. The approximation retained the general shape of the likelihood surface. Accuracy of the approximation did not vary consistently with allele frequency or the size of the major locus effect.     

Acute dystonia induced by neuroleptic drugs

About 2.5% of patients treated with neuroleptic drugs develop acute dystonia within 48 h of commencing therapy. The symptoms remit on drug withdrawal or following anticholinergic therapy. Acute dystonia can also be reliably induced in many primate species by neuroleptic treatment with comparable time course, symptomatology and pharmacological characteristics to those observed in man. In general, New World monkeys appear more susceptible to acute dystonia than Old World primates. It is at present not clear whether all primates, including man, would exhibit dystonia if a sufficiently high dose of neuroleptic was administered. Alternatively, some unknown, possibly species-specific or even genetic, factors may determine an individual's susceptibility to develop dystonia. Use of a rodent model of dystonia might enable more detailed analysis of biochemical correlates of dystonic behaviour. Whilst rodents do not exhibit overt dystonic behaviour after neuroleptic treatment, they may develop oral dyskinesias which bear a close pharmacological similarity to dystonia in man and primates. However, it is not known whether chewing induced by neuroleptic drugs in rats resembles acute dystonia in primates or whether this is another movement disorder possibly unique to rodent species. The pathophysiology of acute dystonia remains unknown, but may involve striatal dopaminergic and cholinergic function. In view of the close similarity between dystonia in man and other primates, studies on the mechanisms whereby neuroleptic drugs cause acute dystonic reactions in monkeys may give some clues to the pathogenesis of spontaneous dystonia in man.     

Reciprocal inhibition between seizures induced by intermittent light stimulation and premotor cortical stimulation in Senegalese baboons, Papio papio

The temporal relationship between the degree of photosensitivity and the intensity of kindling stimulus response was examined in four Senegalese baboons, Papio papio, kindled at the premotor cortical area. When fully kindled, the intensity of photosensitivity diminished significantly in all the animals. With successive daily intermittent light stimulation, two animals showed partial recovery and the other two showed complete recovery to the prekindling level of photosensitivity. When premotor cortical kindling stimulation was subsequently reapplied, three-quarters of the animals failed to respond with kindled seizures and additional stimulations were necessary to reestablish kindled seizure. Two of these three animals also required increased stimulus intensity before the previously established generalized seizure threshold could be reinstated. The frontorolandic cortex is known as the most epileptogenic area in photosensitive Papio papio. In this species, spontaneous generalized convulsive seizures, intermittent light stimulation-induced seizures, and kindled generalized convulsive seizures are all known to share a common electroclinical phenomenology. The reciprocal inhibition observed in this study between generalized seizures induced by either intermittent light stimulation or by premotor cortical kindling stimulation further strengthens the possibility that they also share a common neuronal mechanism.     

Cognition and life events in major depression: A test of the mediation and interaction hypotheses

This study tested two hypotheses derived from Beck's cognitive model of depression. The mediation hypothesis states that the relations of depression to dysfunctional attitudes and negative life events are mediated by the individual's perceptions of those events. The interaction hypothesis states that the relation of depression to negative events is greater in the context of disfunctional attitudes and/or event perceptions, and, analogously, the relations of depression to dysfunctional attitudes and event perceptions are greater in the context of negative events. We compared 65 unipolar major depression patients with 28 nondepressed schizophrenic patients on measures of dysfunctional attitudes, negative event frequency, and event perceptions. We found that (1) depressed patients reported more dysfunctional attitudes and a greater number of recent negative events, and differed from nondepressed schizophrenic patients on a number of event perceptions; (2) the data supported the mediation hypothesis but not the interaction hypothesis.We would like to thank the staff and patients at the Manhattan Veterans Administration Hospital, Beth Israel Medical Center, and the Foundation for Depression and Manic Depression for their cooperation in facilitating the study, and Deborah Long for secretarial assistance. The first author gratefully acknowledges support from National Institute of Mental Health Research Grant MH-40917 during the period in which this paper was written. The data were collected while the first two authors were at New York University.     

A New Experimental Model for Drug Studies: Effects of Phenobarbital and Phenytoin on Photosensitivity in the Lateral Geniculate-Kindled Cat

Photosensitivity was acquired as a result of kindling in the lateral geniculate body (GL), and the GL-kindled cat pretreated with DL-allylglycine showed a stable level of photosensitivity. To test the usefulness as a model for the evaluation of anticonvulsant drugs, the effects of phenobarbital (PB) and phenytoin (PHT) on photosensitivity were studied in the GL-kindled cat under DL-allylglycine. PB (5 and 10 mg/kg intravenously, i.v.) completely suppressed photically induced seizures in most subjects at plasma concentrations of 7-16 micrograms/ml, and this anticonvulsant action persisted for at least 4 h after the injection. PHT (15 mg/kg, i.v.) at plasma concentrations of 9-15 micrograms/ml produced toxic signs, e.g., pupil dilatation, hypersalivation, and tachypnea. At this dose, PHT was inactive against photically induced myoclonus but prevented the elicitation of a generalized tonic-clonic convulsion. From these results showing that the effects of anticonvulsant drugs on photically induced seizures can be assessed in relation to plasma concentration and acute neurologic toxicity, we suggest that the GL-kindled cat is a potentially useful animal model of epilepsy for testing the efficacy of anticonvulsant drugs.     

A circulation model for teaching fluid dynamics in laboratory courses in physiology

Medical students in Germany do not usually have a strong enough basis in physics to understand the mechanical and fluid dynamic problems involved in the physiology of the circulation. To alleviate this situation we developed a circulation model for use in laboratory courses in physiology. The following parameters can be varied: stroke volume, heart rate, systemic filling pressure, compliance of the arterial system (Windkessel), and total peripheral resistance. Arterial and venous pressure are recorded as a function of time. The following points are worked out by the students by adjusting the parameters of the model and by calculation: static equilibrium, transient and steady state in flow, compliance of the arterial and venous system, arteriovenous pressure difference, cardiac output, total peripheral resistance, regulation of cardiac output, pulse pressure amplitude, volume stored periodically in the arterial Windkessel, diastolic pressure decay of arterial pressure, diagnosis of arterial hypertension at different Windkessel compliances.