Porphyria cutanea tarda and pregnancy.
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Biomedical subjects
Publications and source records attributed to B Katz.
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Many adverse reactions to quinine have been reported. A 65 year old woman taking quinine sulphate for nocturnal leg cramps presented for investigation of episodes of malaise, fever, nausea, vomiting, and polyarthralgia. Granulomatous hepatitis was diagnosed, for which no common cause was found. She was challenged with quinine sulphate; within hours her temperature had risen and her symptoms returned; transaminase activities rose within 48 hours, as did erythrocyte sedimentation rate. After withdrawal of the drug symptoms abated and transaminase activities returned to normal. The biochemical response to challenge with quinine implicates the drug as the cause of the liver disturbances. Quinine should be added to the list of drugs known to cause granulomatous hepatitis and should be considered in cases where symptoms are episodic or where no other cause is apparent.
To determine the utility of graded treadmill exercise test (ETT) in estimating severity of obstruction in postoperative patients with aortic stenosis, we compared results to a nonoperated aortic stenosis group. Cardiac catheterization was performed in all patients. The interval between surgery and ETT in the postoperative group was 7.5 years (range 1.1-12.9). Mean and range values for postoperative versus nonoperative aortic stenosis groups respectively were: age 14.5 (7.9-20.8) versus 12.5 years (5.9-19.7); peak left ventricular pressure 150 (101-190) versus 144 mmHg (100-183); peak systolic ejection gradient (PSEG) 41 (15-75) versus 38 mmHg (14-80); left ventricular end-diastolic pressure (LVEDP) 13.4 (7-20) versus 13.5 mmHg (8-20); and cardiac index 3.7 (2.4-5.6) versus 3.8 liters/min/m2 (2.6-4.9) (p for each = NS). ETT in the nonoperated patients correctly identified all those with PSEG greater than or equal to 50 mmHg (sensitivity 100%), but specificity was 56%, (i.e., the proportion correctly identified with PSEG less than 50 mmHg). By contrast, sensitivity and specificity for postoperative aortic stenosis patients were 67% and 63%, respectively. Furthermore, among nonoperated aortic stenosis patients ST depression on ETT identified those with increased left ventricular end-diastolic pressure. For LVEDP greater than or equal to 12 mmHg, sensitivity was 75% and specificity 100%, corresponding values for postoperative aortic stenosis patients were 45% and 33%, respectively. In the nonoperated aortic stenosis group with a PSEG greater than or equal to 50 mmHg, sensitivity and specificity for ETT-induced change in systolic blood pressure of less than or equal to 30 mmHg were 100% and 56%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Two patients developed traumatic orbital haemorrhage resulting in prolonged blindness. Orbital decompression successfully reversed the visual loss, though both eyes had no light perception for at least 3 1/2 hours. The clinical findings suggest damage to the posterior optic nerve as cause of the visual loss. The optic nerve tolerance time to ischaemic injury may be longer than previously thought.
A small endplate potential can be recorded in frog muscle fibres, after all acetylcholine-mediated transmission has been eliminated by pre- or postsynaptic blocking agents (botulinum toxin, calcium lack, manganese, curare, alpha-bungarotoxin). It is usually necessary to hyperpolarize the muscle membrane to detect this 'non-cholinergic' endplate potential. Below--100 mV little or no response is seen; a maximum is reached at about--140 mV, when the amplitude can be as large as 100 microV (endplate current up to about 1 nA). Other characteristic features are: the response shows no quantal fluctuations; its amplitude is not facilitated by repetitive impulses; its size and time course are not noticeably affected by prostigmine, curare or alpha-bungarotoxin; the half-time of decline of the endplate current is approximately 1.7 ms at 20 degrees C, and is lengthened by lowering the temperature with a Q10 of about 1.3; the response is abolished by barium. When iontophoretic pulses of potassium are applied to the endplate, local depolarization is recorded whose amplitude varies with membrane potential similarly to that of the nerve-evoked response. These observations strongly indicate that this 'non-cholinergic', 'non-quantal' endplate potential arises from a rapid synaptic transfer of potassium ions, released by the active nerve terminal into the synaptic cleft and entering the muscle fibre through 'anomalous rectifier' channels in the endplate membrane.
The effects of tetraethylammonium and manganese, which modify calcium entry into motor nerve terminals, have been studied during advanced stages of botulinum paralysis. Evidence has been obtained that the voltage-activated calcium current in the nerve endings is not significantly reduced by botulinum toxin. The depression of transmitter release that the toxin produces must arise at a later stage, at an intracellular site of the release mechanism.
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Endplate responses were recorded in frog muscle fibres during an advanced stage of botulinum (BoTX) paralysis, when transmitter release had fallen to a very low level. By simultaneous recording from two points, it was found that, even when the quantal responses had been reduced to less than 0.01 per impulse (that is, four to five orders of magnitude below normal), the release continued to be spatially dispersed along the terminal arborization. These observations make it very unlikely that whole "active zones' could be eliminated, as has been suggested, in all-or-none fashion by local action of BoTX molecules, and they suggest a more graded, indirect mechanism by which the toxin molecules interfere with the sites of transmitter release.
Previous experiments have indicated that there is a continuous leakage of acetylcholine (ACh) from resting motor nerve terminals which can produce a small depolarization in anti-esterase treated endplates (Katz & Miledi 1977; Vyskocil & Illés 1978). This leakage might be expected to be intensified during the presynaptic action potential and also lead to a very small non-quantal endplate response. This hypothesis was examined, in frog and mammalian endplates, by stimulating the motor nerve in a calcium-deprived medium and recording the summated average response to several hundred stimuli. The result was completely negative; no trace of a non-quantal endplate potential was ever observed, with the limit of detection being always less than 10 microV, and sometimes as low as 2 microV. These experiments suggest that the leakage of ACh either does not originate predominantly from the synaptic region of the axon terminal, or that it occurs by a mechanism that is not directly influenced by the membrane potential.
The present study assesses client improvement from and satisfaction with CMHC services, and attempts to examine the presence of positive bias from responders. Results based on questionnaires mailed to 1,000 former clients indicated both high consumer satisfaction and reported improvement attributable to treatment. Responders and nonresponders did not differ on demographic or treatment variables related to post-treatment improvement. A multiple regression analysis was computed and yielded an estimated index of improvement for responders. No differences obtained on this measure between responders and nonresponders, thereby not supporting the presence of a positive bias in this sample. confidence in therapist, satisfaction with the therapeutic relationship, and number of individual sessions were the most positive improvement correlates, with lack of contact and increasing age most negatively related to improvement. Discussion focuses on the implications for generalization of results based on responders' data.
A short account is given of the author's work on the neuromuscular junction, starting with the intracellular recording of spontaneous miniature endplate potentials and its simulation with a local microinjection of acetylcholine. The nature of quantal transmitter delivery and the molecular components of miniature endplate potentials are described as well as the effects of physical and chemical agents on the kinetics and the opentime of the channels of the endplate. The study of a variety of drugs has led to important advances in the electrical exploration of drug receptors and promises to shed new light on their mechanism of action and on the behaviour of cell membranes.
The number of quantal transmitter packets (m), released from motor nerve terminals in response to a single stimulus, has been estimated from the ratio of the amplitudes of endplate currents (e.p.c.) to spontaneous miniature endplate currents (m.e.p.c.), in voltage-clamped endplates of the frog. At 6 degrees C, the average value of m at normal nerve-muscle junctions was about 300. If allowance is made for the temporal dispersion of quantal transmitter release during the e.p.c., this value is increased by about 30%. After treatment with diaminopyridine or tetraethylammonium, transmitter release in response to a nerve stimulus is greatly enhanced and values of m exceeding 10(4) are frequently found. Moreover, the duration of the e.p.c. becomes much longer than that of the m.e.p.cs. The number of packets then liberated during the e.p.c. is much larger than the number of 'active zones' of the endplate and may even exceed the total number of vesicles lined up in twin-files adjacent to the presynaptic membrane.
The analysis of chemical transmission at synapses, in particular at the neuromuscular junction, has proceeded from the cellular to the molecular level. Gradual refinements in electric recording technique have brought to light new features, first the quantal delivery of the transmitter substance, in multimolecular packets, from the nerve endings, and more recently the statistical elements of the postsynaptic potential change which arise from the molecular bombardment by acetylcholine and the transient opening of individual ion channels in the end-plate membrane.
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Recent evidence indicates that curare, in addition to its competitive' interference with endplate receptors, can block open ionic channels by a 'non-competitive' action on the activated acetylcholine-receptor complex. These findings called for further study of the kinetic behaviour of endplate channels and their modification by curare. Examining impulse-evoked endplate currents and acetylcholine-induced current fluctuations, it is found that the lifetime of the open channel is shortened by relatively high concentrations of curare (greater than 5 micrometer), an effect which shows up most strikingly at hyperpolarized levels of membrane potential (-130 mV and above). No shortening of this kind is observed when a neuromuscular block of equal or greater intensity is produced by a dose of alpha-bungarotoxin. Two other neuromuscular blocking agents, gallamine and pancuronium are shown to have an action on channel kinetics which cannot be explained by competitive receptor binding, but conforms to the hypothesis of rapidly repeated blocking and unblocking of individual ion channels, which had been proposed originally to account for the endplate action of local anaesthetics.
A group of patients with retroperitoneal liposarcoma is presented and general guidelines of management reviewed. It is suggested that aggressive, radical total surgical excision followed by adjuvant postoperative irradiation be used as the treatment of choice. Although the management of recurrent disease may be discouraging in terms of ultimate cure, reasonable palliation and prolonged survival may result from aggressive therapy.
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