Biomedical subjects
J F Collins
Publications and source records attributed to J F Collins.
The "constant intake rate" assumption in interim recruitment goal methodology for multicenter clinical trials.
A primary concern of any multihospital clinical trial is the recruitment of a predetermined number of patients during a prespecified interval of time. In several recent papers a Poisson based model was used to estimate the time needed to recruit a predetermined number of patients and the probabilities of recruiting specified fractions of the sample during subintervals. The Poisson model requires the assumption that patients be recruited at a constant rate over the entire length of the interval. In this paper we test the adequacy of this model and assumption using patient intake data from nine multihospital VA clinical trials and propose an alternative Bayesian model.
Reassortment of DNA recognition domains and the evolution of new specificities.
Type I restriction enzymes comprise three subunits only one of which, the S polypeptide, dictates the specificity of the DNA sequence recognized. Recombination between two different hsdS genes, SP and SB, led to the isolation of a system, SQ, which had a different specificity from that of either parent. The finding that the nucleotide sequence recognized by SQ is a hybrid containing components from both the SP and SB target sequences suggested that DNA recognition is carried out by two separable domains within each specificity polypeptide. To test this we have made the recombinant gene of reciprocal structure and demonstrate that it encodes a polypeptide whose recognition sequence, deduced in vivo, is as predicted by this model. We also report the sequence of the SB specificity gene, so that information is now available for the five known members of this family of enzymes. All show a similar organization of conserved and variable regions. Comparisons of the predicted amino acid sequences reveal large non-conserved areas which may not even be structurally similar. This is remarkable since these different S subunits are functionally identical, except for the specificity with respect to the DNA sequence with which they interact. We discuss the correlation of the variation in polypeptide sequence with recognition specificities.
Excitatory amino acid receptors and depolarization-induced Ca2+ influx into hippocampal slices.
Hippocampal brain slices were incubated with depolarizing agents or excitatory amino acids either alone or in the presence of excitatory amino acid antagonists [omega-phosphonic alpha-aminocarboxylic acids--2-amino-4-phosphonobutyric acid (AP4), 2-amino-5-phosphonovaleric acid (AP5), or 2-amino-7-phosphonoheptanoic acid (AP7)--or gamma-D-glutamylaminomethylsulphonic acid (GAMS)] or a calcium-channel blocker, (S)-1-(3-methoxyphenyl)-3-methylaza-7-cyano-7-(3,4-dimethoxyphenyl )-8-methyl- nonane hydrochloride [(-)-D888]. The uptake of 45Ca2+ and the efflux of glutamate or aspartate induced by veratrine or high K+ was blocked (54-76%) by AP7 (IC50 46-250 microM). AP5 and AP4 were less effective. (-)-D888 (10 microM) caused 100% block of evoked 45Ca2+ uptake. Uptake of 45Ca2+ induced by exogenous glutamate, aspartate, and N-methyl-D-aspartate (NMDA) was also inhibited by AP7, whereas GAMS completely blocked the action of kainate and partially blocked that of glutamate. The action of NMDA in stimulating 45Ca2+ uptake was Mg2+-sensitive, low Mg2+ levels in the incubation medium selectively enhancing the response. It is concluded that Ca2+ uptake evoked by excitatory amino acids is receptor-mediated, and that released excitatory amino acids are responsible for a large part of the action of veratrine and high K+ in stimulating 45Ca2+ uptake.
Results of a nationwide Veterans Administration Cooperative Study comparing the efficacy and toxicity of carbamazepine, phenobarbital, phenytoin, and primidone.
In 1985 a 5-year multicenter Veterans Administration Cooperative Study was completed that compared the efficacy and toxicity of phenobarbital, carbamazepine, phenytoin, and primidone in a double-blind prospective study design. A total of 622 patients, either previously untreated or undertreated, were entered into the study. Strict exclusion criteria limited confounding factors such as drug or alcohol abuse. Results showed that each of the four drugs used as monotherapy were similarly effective in the treatment of generalized tonic clonic seizures, but carbamazepine was significantly more effective in the treatment of complex partial seizures as measured by 100% control. When the results for all four drugs were combined, the data showed that approximately 80% of the patients were adequately managed on monotherapy. Differences in toxicity were the most significant factor that discriminated between these four drugs. Both carbamazepine and phenytoin were associated with significantly lower incidences of intolerable side effects than were primidone or phenobarbital. A behavioral toxicity battery was performed whenever possible prior to administration of any antiepileptic drug and at 1, 3, 6, and 12 months after initiation of monotherapy. Significant differences in performance on all subtests of the battery were found between patients with epilepsy and a control group matched by age, sex, and education. When the differential effects of all four drugs on behavioral toxicity were compared, few statistically significant differences emerged. However, carbamazepine consistently produced fewer adverse effects on tests of attention/concentration and motor performance than did the other three antiepileptic drugs.
One hundred percent oxygen lung injury in adult baboons.
Healthy adult baboons exposed to 100% oxygen for 5 to 7 days maintained on continuous mechanical ventilation develop severe bilateral noncardiogenic pulmonary edema that resembles in many aspects the human adult respiratory distress syndrome (ARDS). In the present study, we evaluated the effects of hyperoxia for 5 to 6 days in 8 baboons to compare changes in abnormalities in bronchoalveolar lavage fluid (BALF) biochemical markers, hemodynamic measurements, and pulmonary function tests in order to find early predictors of lung injury. All animals had bilateral alveolar infiltrates, severe hypoxemia, and progressive deterioration of pulmonary function tests. Diffuse alveolar damage and mild-moderate pneumonias were found and were associated with low-grade bacterial infection. Total lung capacity, diffusing capacity for carbon monoxide, pulmonary static compliance, and oxygenation were significantly impaired after Day 5; BALF proteins, elastase, and total polymorphonuclear leukocytes increased significantly at least 24 h before (Day 4) any abnormalities in chest radiographs, pulmonary function tests, and hemodynamic measurements were detected. We conclude that exposure to 100% oxygen in this model causes marked gas exchange, hemodynamic, biochemical, cytologic, radiographic, and pathologic changes similar to those noted in patients with ARDS. Bronchoalveolar lavage abnormalities precede hemodynamic and gas exchange abnormalities.
Induction of acute pulmonary inflammation. A differential effect of C5 and the 200,000 molecular weight form of trypsin-activated C5 (C5').
A series of studies was performed in which Syrian golden hamsters were injected intratracheally with 25 to 200 micrograms of highly purified human C5 or the 200,000 molecular weight form of trypsin-activated C5 (C5'). Bronchoalveolar lavage (BAL) was performed 4 h after intratracheal injection, the recovered white cells were counted and differentiated, and the BAL fluid was assayed for in vitro neutrophil chemotactic activity. A significant increase in BAL neutrophils and total BAL cell numbers was evident at 4 h after C5' instillation. In contrast, highly purified native C5 induced no evidence of pulmonary inflammation, even at the highest injection doses studied. Kinetic experiments indicated that hamsters receiving an intratracheal injection of 60 micrograms of C5' per animal demonstrated rapid pulmonary neutrophil infiltration that persisted for 120 to 168 h. Control hamsters receiving intratracheal injections of phosphate-buffered saline (PBS) or 60 micrograms of highly purified C5 did not demonstrate significant neutrophil infiltration. Lung pathology studies revealed neutrophilic alveolitis with intraalveolar and intracapillary neutrophil infiltration in the C5'-treated animals. The BAL fluid obtained from C5'-treated, but not from C5-treated or control hamsters, contained chemotactic factors for neutrophils, which appeared to be unrelated to C5. From these studies we conclude that C5', the 200,000 molecular weight form of protease-activated C5, is capable of mediating an acute inflammatory response in the hamster lung in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
Distribution of [3H]kainic acid and binding sites in the rat brain: in vivo and in vitro receptor autoradiography.
Brain sections incubated in vitro with alpha-[3H]kainic acid (KA; spec. act. 62.5 Ci/mmol), reveal a heterogeneous distribution of low and high affinity KA binding sites in the brain. The highest density of KA binding sites was localised to the hippocampus CA3 region and to superficial layers of the entorhinal cortex (3.8-6.0 mu Ci/g tissue). Intravenous injection of [3H]KA (1 mu Ci/g) reveals limited overall penetration of [3H]KA across the blood-brain barrier. However, a dense labelling of the hippocampus, entorhinal cortex and lateral septal regions (2.5-3.8 mu Ci/g tissue) was observed. Behaviourally, these rats exhibited mild limbic seizure activity possibly as a result of a direct action of KA in the hippocampus or entorhinal cortex.
The distribution and function of DL-[3H]2-amino-4-phosphonobutyrate binding sites in the rat striatum.
The binding of the glutamate-like radioligand, DL-[3H]2-amino-4-phosphonobutyrate (DL-[3H]APB), to L-glutamate-sensitive sites in the rat striatum was investigated. A single, saturable population of binding sites, indistinguishable from that characterized previously on rat whole brain synaptic membranes, was identified. The effects of specific lesions of the striatum: decortication; striatal injection of kainic acid; and 6-hydroxydopamine injections into the substantia nigra, were also examined. Specific DL-[3H]APB binding in the striatum was elevated significantly following decortication. An increase in the number of binding sites was found to be responsible for this enhancement in binding. Lesions of the postsynaptic targets of corticostriatal fibres reduced the number of DL-[3H]APB binding sites in the striatum without affecting binding site affinity. This finding suggests that L-APB sensitive excitatory amino acid receptors are located predominantly on membranes derived from structures postsynaptic with regard to the glutamatergic innervation. The possible physiological role of these receptors was examined using an in vitro release technique. Both L-glutamate and L-APB were found to facilitate potassium evoked [3H]dopamine release from striatal slices. This finding supports the proposed existence of functional acidic amino acid receptors on dopaminergic terminals in the striatum. These receptors may play an important role in the control of motor function.
Purine nucleotides inhibit the binding of DL-[3H] 2-amino-4-phosphonobutyrate (DL-[3H] APB) to L-glutamate-sensitive sites on rat brain membranes.
The effects of purine nucleotides on the binding of DL-[3H] 2-amino-4-phosphonobutyrate (DL-[3H] APB) to rat brain membranes were investigated. Certain guanine nucleotides, especially cyclic GMP and GTP, were found to be potent inhibitors of binding. Kinetic studies revealed that both cyclic GMP and GTP acted to decrease receptor affinity without affecting significantly binding site density. These endogenous substances may therefore play an important role in the regulation of excitatory amino acid receptor function.
Effects of kainic acid analogues on the high affinity uptake of D-[3H] aspartate into rat cerebellar homogenates.
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Novel kainic acid analogues. Effects on cyclic GMP content of adult rat cerebellar slices.
On the basis of previous electrophysiological studies, it has been proposed that there are three main classes of excitatory amino acid receptor in the mammalian central nervous system, which are activated preferentially by kainic acid, quisqualic acid and N-methyl-D-aspartate respectively. Although the pharmacology of the N-methyl-D-aspartate receptor has been investigated extensively, potent and selective ligands which act at the kainate or quisqualate sites are lacking. In this study, we report that a number of novel kainate analogues possess either agonist or antagonist activity in a system which permits investigation of receptor-mediated coupled responses, viz. the ability of excitatory amino acids to elevate cyclic GMP concentrations in incubated cerebellar slices prepared from the adult rat. The data reported here provide some clues as to the likely structural requirements for developing effective kainate antagonists.
Acute effects of oleic acid-induced lung injury in baboons.
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Activity of beta-kainic acid on neocortical neurons in vivo and hippocampal neurons in vitro.
The beta-isomer of kainic acid has been reported to have anticonvulsant activity with a profile suggesting amino acid antagonism. The present study, on neurons in the cerebral cortex of anaesthetised rats or in hippocampal slices, shows that beta-kainate does not antagonise any of the major agonists at amino acid receptors: N-methylaspartate, quisqualic acid or alpha-kainic acid. beta-Kainate does have an excitant action of its own which can be partially reduced by 2-amino-5-phosphonovaleric acid but is unaffected by gamma-D-glutamylglycine. It is blocked completely by kynurenic acid.
Relapsing peritonitis in a patient undergoing continuous ambulatory peritoneal dialysis due to Corynebacterium aquaticum.
Corynebacterium aquaticum was the cause of peritonitis in a 33-year-old diabetic woman on continuous ambulatory peritoneal dialysis (CAPD). This case represents the first reported instance of CAPD peritonitis due to this organism. Moreover, the organism was recovered from fibrin clots removed from dialysate bags when the patient was on antibiotic therapy. Routine cultural methods failed to reveal the organism at that time. The organism is described and key points differentiating it from similar organisms are emphasised. The world literature on C. aquaticum infections is reviewed.
Effects of bacterial endotoxin on protecting copper-deficient rats from hyperoxia.
The administration of very low doses of bacterial endotoxin protects rats during exposure to hyperoxia and is associated with the induction of lung antioxidant enzyme activities. Copper-deficient rats have increased susceptibility to O2 toxicity, which may be related to their decreased lung superoxide dismutase activity (SOD) or decreased plasma ceruloplasmin concentrations. To determine whether endotoxin can protect against hyperoxia in this susceptible model, we exposed copper-deficient and control rats to a fractional inspiratory concentration of O2 greater than 0.95 for 96 h after pretreatment with 500 micrograms/kg of bacterial endotoxin or phosphate-buffered saline (PBS). Mortality in the copper-deficient and control rats given PBS and exposed to O2 for 96 h was 100%. Copper-deficient rats died significantly earlier during the exposure than controls. No mortality occurred in either group treated with endotoxin and hyperoxia despite the decreased activity of copper-dependent enzymes in the copper-deficient rats. Copper-deficient rats treated with endotoxin and exposed to hyperoxia did increase lung Cu-Zn-SOD activity, but activity remained below levels found in air-exposed controls. Mn-SOD activity was found to be induced above air-exposed controls in the copper-deficient rats treated with endotoxin and exposed to hyperoxia. Hyperoxic exposure resulted in a marked increase in plasma ceruloplasmin concentrations in the control rats, but no increases in ceruloplasmin occurred in the copper-deficient animals. Endotoxin protects copper-deficient rats from hyperoxia despite their decreased lung Cu-Zn-SOD activity, and decreased plasma ceruloplasmin.
The subcellular distribution of DL-[3H]2-amino-4-phosphonobutyrate binding sites in the rat brain.
The subcellular distribution of DL-[3H]2-amino-4-phosphonobutyrate binding sites in rat brain was examined. Binding sites for this radioligand, which selectively labels a chloride/calcium-dependent subpopulation of glutamate binding sites, were highly concentrated in synaptic membrane fractions. This is wholly consistent with the proposed involvement of this site in physiological responses.
Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures.
We conducted a 10-center, double-blind trial to compare the efficacy and toxicity of four antiepileptic drugs in the treatment of partial and secondarily generalized tonic-clonic seizures in 622 adults. Patients were randomly assigned to treatment with carbamazepine, phenobarbital, phenytoin, or primidone and were followed for two years or until the drug failed to control seizures or caused unacceptable side effects. Overall treatment success was highest with carbamazepine or phenytoin, intermediate with phenobarbital, and lowest with primidone (P less than 0.002). Differences in failure rates of the drugs were explained primarily by the fact that primidone caused more intolerable acute toxic effects, such as nausea, vomiting, dizziness, and sedation. Decreased libido and impotence were more common in patients given primidone. Phenytoin caused more dysmorphic effects and hypersensitivity. Control of tonic-clonic seizures did not differ significantly with the various drugs. Carbamazepine provided complete control of partial seizures more often than primidone or phenobarbital (P less than 0.03). Overall, carbamazepine and phenytoin are recommended drugs of first choice for single-drug therapy of adults with partial or generalized tonic-clonic seizures or with both.