Improved graft survival after renal transplantation in the United States, 1988 to 1996.

BACKGROUND: The introduction of cyclosporine has resulted in improvement in the short-term outcome of renal transplantation, but its effect on the long-term survival of kidney transplants is not known. METHODS: We analyzed the influence of demographic characteristics (age, sex, and race), transplant-related variables (living or cadaveric donor, panel-reactive antibody titer, extent of HLA matching, and cold-ischemia time), and post-transplantation variables (presence or absence of acute rejection, delayed graft function, and therapy with mycophenolate mofetil and tacrolimus) on graft survival for all 93,934 renal transplantations performed in the United States between 1988 and 1996. A regression analysis adjusted for these variables was used to estimate the risk of graft failure within the first year and more than one year after transplantation. RESULTS: From 1988 to 1996, the one-year survival rate for grafts from living donors increased from 88.8 to 93.9 percent, and the rate for cadaveric grafts increased from 75.7 to 87.7 percent. The half-life for grafts from living donors increased steadily from 12.7 to 21.6 years, and that for cadaveric grafts increased from 7.9 to 13.8 years. After censoring of data for patients who died with functioning grafts, the half-life for grafts from living donors increased from 16.9 years to 35.9 years, and that for cadaveric grafts increased from 11.0 years to 19.5 years. The average yearly reduction in the relative hazard of graft failure after one year was 4.2 percent for all recipients (P<0.001), 0.4 percent for those who had acute rejection (P=0.57), and 6.3 percent for those who did not have acute rejection (P<0.001). CONCLUSIONS: Since 1988, there has been a substantial increase in short-term and long-term survival of kidney grafts from both living and cadaveric donors.

Pharmacokinetics and tolerability of a novel 5-HT1D agonist, PNU-142633F.

OBJECTIVES: The objectives of this study were to characterize the safety, tolerability and pharmacokinetics of a single, oral dose of PNU-142633F escalating over the range of 1.0 mg to 100 mg (free base equivalents). METHODS: This was a randomized, double-blind, single-dose, placebo-controlled, dose-escalation trial, with each dose group (1.0, 3.0, 10, 30, 50, 75 and 100 mg) having eight volunteers (six PNU-142633F and two placebo). Clinical laboratory tests, electrocardiogram, Holter monitoring, and assessment of adverse events were used to gauge the tolerability of PNU-142633. Serial blood samples and urine collections were obtained and plasma and urine PNU-142633 concentrations were determined by a validated HPLC fluorescence method. RESULTS: PNU-142633 was well tolerated after oral administration. There were no reports of serious or unexpected adverse events. The most common adverse event that was possibly medication-related was transient dizziness. There were no clinically significant or dose-related effects of PNU-142633 on any vital sign parameters (aural temperature, systolic and diastolic blood pressure, pulse rate or respiratory rate), at any study time or dose. There were no clinically significant ECG changes. Only sporadic abnormalities in clinical chemistry values and hematology were noted. After the 1.0 mg and 3.0 mg doses, plasma concentrations of PNU-142633 were either below or only slightly above the lower limit of quantitation (2 ng/ml). At higher doses (30-100 mg) the terminal half-life was relatively constant at approximately 11 hours. Neither Cmax nor AUC(0-infinity) increased proportionally with the administered dose. The mean percentage of the dose excreted in the urine as intact PNU-142633 increased from 14.3% after the 1 mg dose to 49.3% after the 100 mg dose. CONCLUSIONS: The clinical safety and pharmacokinetic data support the study of this agent as a potential treatment for migraine attacks.

A meta-analysis of fibromyalgia treatment interventions.

OBJECTIVE: To evaluate and compare the efficacy of pharmacological and nonpharmacological treatments of fibromyalgia syndrome (FMS). METHODS: This meta-analysis of 49 fibromyalgia treatment outcome studies assessed the efficacy of pharmacological and nonpharmacological treatment across four types of outcome measures-physical status, self-report of FMS symptoms, psychological status, and daily functioning. RESULTS: After controlling for study design, antidepressants resulted in improvements on physical status and self-report of FMS symptoms. All nonpharmacological treatments were associated with significant improvements in all four categories of outcome measures with the exception that physically-based treatment (primarily exercise) did not significantly improve daily functioning. When compared, nonpharmacological treatment appears to be more efficacious in improving self-report of FMS symptoms than pharmacological treatment alone. A similar trend was suggested for functional measures. CONCLUSION: The optimal intervention for FMS would include nonpharmacological treatments, specifically exercise and cognitive-behavioral therapy, in addition to appropriate medication management as needed for sleep and pain symptoms.

Protocol for verifying expertise in locating fibromyalgia tender points.

OBJECTIVE: To develop a protocol for determining when an individual is adequately trained to locate the tender points relative to fibromyalgia in an exam. METHODS: The error distance for each tender point was established by polling individuals with experience in conducting tender point exams. Bayesian statistical methods were employed to form a protocol for determining an individual's proficiency in locating the tender points. A predictive distribution was utilized to find the probability of remaining trained at locating tender points. Also, the probability of classifying at least 11 tender points as tender (mild) under different "locating" criteria and different number of points that are truly tender was computed. RESULTS: Critical values indicating the number of tender points needed in the qualification process for various standards of reliability--80%, 85%, and 90%--are presented. To be certified after 3 subjects have been examined in the 80%, 85%, and 90% criteria, one has to correctly identify 48, 50, and 52, respectively, out of the 54 possible tender points. CONCLUSION: We believe that at least 3 subjects should be examined before certification is granted using any of the 3 criteria--80%, 85%, and 90%. In our example, when using the 85% criterion, the qualification process required 7 subjects to certify an individual.

Biofeedback/relaxation training and exercise interventions for fibromyalgia: a prospective trial.

OBJECTIVE: To compare the effectiveness of biofeedback/relaxation, exercise, and a combined program for the treatment of fibromyalgia. METHODS: Subjects (n = 119) were randomly assigned to one of 4 groups: 1) biofeedback/relaxation training, 2) exercise training, 3) a combination treatment, or 4) an educational/attention control program. RESULTS: All 3 treatment groups produced improvements in self-efficacy for function relative to the control condition. In addition, all treatment groups were significantly different from the control group on tender point index scores, reflecting a modest deterioration by the attention control group rather than improvements by the treatment groups. The exercise and combination groups also resulted in modest improvements on a physical activity measure. The combination group best maintained benefits across the 2-year period. CONCLUSION: This study demonstrates that these 3 treatment interventions result in improved self-efficacy for physical function which was best maintained by the combination group.

Action of lead on neurotransmission in rats.

1. The neurotoxic effect of lead on the catecholaminergic and cholinergic nervous systems has been investigated using a rat model of lead exposure. 2. This model of lead exposure resulted in significant quantities of lead accumulating in the blood, brain and femur of the lead-exposed animals. 3. The biochemical effect of lead on brain neurochemistry was dependent on the degree and duration of lead exposure. However, the data points to a selective action of lead, with the midbrain and diencephalon being prime targets while very few lead-related alterations were observed in the cerebellum or the telencephalon. 4. Within the catecholaminergic nervous system, lead exposure resulted in alterations in the concentrations of the transmitters, noradrenaline and dopamine, in addition to changes in the activities of the enzymes tyrosine hydroxylase and phenylethanolamine-N-methyl transferase. The activity of the cholinergic biosynthetic enzyme, choline acetyltransferase was also noted to be altered by lead exposure.

Influence of lead exposure on catecholamine metabolism in discrete rat brain nuclei.

1. Using the rat exposed both acutely and chronically to lead as a model of lead neurotoxicity, various parameters of catecholamine metabolism were investigated. 2. The steady-state concentrations of noradrenaline, adrenaline and dopamine together with the activities of tyrosine hydroxylase and phenylethanolamine N-methyl transferase were measured in discrete brain nuclei--periventricular, paraventricular, median eminence, posterior and anterior hypothalamus, caudate putamen and globus pallidus. 3. Lead exposure resulted in significant fall in the activity of the rate-limiting enzyme of catecholamine synthesis, tyrosine hydroxylase which was associated with alterations in concentrations of catecholamines in the median eminence, periventricular nucleus and anterior hypothalamus. 4. No other brain nuclei investigated exhibited any effect of lead on the catecholaminergic nervous system and, therefore, the effect of lead on rat brain can be considered to be regionally specific.

Effects of lead exposure on rat brain catecholaminergic neurochemistry.

1. The effects of lead on catecholaminergic neurotransmission have been investigated. 2. Using the rat as a model, animals were exposed both acutely and chronically to lead. The levels of catecholamines, noradrenaline, adrenaline, and dopamine along with the activities of tyrosine hydroxylase and phenylethanolamine-N-methyl transferase were measured in 5 brain regions--cerebral cortex, brainstem, hippocampus, anterior and posterior hypothalamus. 3. A lead related reduction in the activity of tyrosine hydroxylase was observed in association with alterations in steady-state levels of the catecholamines in the posterior and anterior hypothalamus. 4. Thus, lead exposure, known to result in behavioural changes, is associated with localised neurochemical effects on the hypothalamus.

An isolated upper airway preparation in conscious dogs.

The purpose of this study was to develop an isolated upper airway preparation in conscious dogs. Each of the four dogs was trained to wear an individually fitted respiratory mask and surgically prepared with two side-hole tracheostomies. After full recovery, one endotracheal tube was inserted caudally into the lower tracheostomy hole and another tube cranially into the upper tracheostomy. When the two endotracheal tubes were connected to a breathing circuit including a box-balloon system, the magnitude and pattern of the inspiratory flow through the upper airway were identical to that inhaled spontaneously into the lungs by the dogs, but the gas medium inhaled into the upper airway could be independently controlled. Thus it allowed test gas mixtures to be inhaled spontaneously through an isolated upper airway. One limitation was that the inspired gas remained in the upper airway during expiration, but this can be corrected by a simple modification of the breathing circuit. This preparation was tested in studying the respiratory effects of upper airway exposure to CO2 gas mixtures. Our results showed small but significant reduction in both rate and volume of respiration when the concentration of CO2 gas mixture inhaled through the upper airway exceeded 5%. Irregular breathing patterns were frequently elicited in these dogs by higher concentrations (greater than 12%) of CO2.

The neurotoxicology of lead.

In the past six years, our research group has investigated the relationship between lead exposure and mental and behavioural development. This has been carried out through studies in children and animals. Earlier studies in children have shown that associations might be expected between environmental exposure to lead and various aspects of cognitive and behavioural development. Our study has examined and continues to examine, a cohort of children sub-divided into three groups according to the level of lead exposure during early 'in utero' development. Data amassed to date includes measurement of psychometric function and post natal development, together with biochemical measures of lead exposure. Assessment will continue through to early scholastic performance and will include measurement of deciduous tooth lead concentration as an integrated measure of long term exposure. In addition to these studies in children, a series of neurochemical studies have been carried out using a rat model of lead exposure. Data obtained from both our own neurochemical experiments and those of other groups indicate an extremely complex plethora of neurotoxic actions of lead.

Neurotoxic action of lead: effect on tetrahydrobiopterin metabolism in the rat.

The effects of lead, a known neurotoxin on the metabolism of a vital tetrahydrobiopterin cofactor for the hydroxylation enzymes tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan hydroxylase, have been investigated. Reduced availability of this pteridine has the potential to reduce the level of the neurotransmitters noradrenaline, adrenaline and 5-hydroxytryptophan in the brain. Using the rat as a model, increases in tetrahydrobiopterin concentration and in the activity of dihydropteridine reductase, an enzyme involved in tetrahydrobiopterin metabolism, were observed after exposure to lead via the drinking water. Possible explanations for this increased level of tetrahydrobiopterin relate to alterations in the balance between synthesis and salvage of this co-factor.

Studies of lead and cadmium exposure in Glasgow, U.K.

Domestic water and whole blood samples were collected early in 1981 from two hundred volunteers living in the Glasgow area of Scotland, U.K. The concentration of lead in the water and blood samples, and of cadmium in the blood, was measured. The blood lead and cadmium concentrations were compared to those obtained in the Survey of 1979. There has been a fall in blood lead concentrations since the 1979 Survey. In contrast, the blood cadmium levels had remained similar. This diminution in blood lead concentration is attributed to a fall in water lead concentration caused by raising the pH of the water supply in the Glasgow area. The main determinant for cadmium in blood appears to be cigarette smoking habits, which had not changed.