Bladder dysfunction in schizophrenia.

In schizophrenic patients with incontinence our previous urodynamic studies showed detrusor hyperreflexia in some cases. Many schizophrenic patients have brain abnormalities similar to those associated with urge incontinence and detrusor hyperreflexia in neurological patients. We therefore propose bladder dysfunction and incontinence as previously unrecognized neurobiological correlates of schizophrenia. To clarify this concept our first step, the present study, was a patient survey for urinary problems. Incontinence was more prevalent in schizophrenic patients than in a comparison group of mood disorder patients at the same hospitals. Urge incontinence and leakage of any type were related closely to psychiatric diagnosis. These data, like our pilot urodynamic studies, suggest that incontinence represents detrusor hyperreflexia in a significant subset of schizophrenic patients. Prospective urodynamic studies will be needed to test our proposal directly.

Aberrant right subclavian artery aneurysm: an analysis of surgical options.

During evaluation of a man for claudication, abnormal chest roentgenographic results were found. Computed tomography documented a 6.5-cm aneurysm of an aberrant retroesophageal right subclavian artery. Interruption of the right subclavian artery with an end-to-side subclavian-carotid anastomosis was performed via a right supraclavicular incision, followed immediately by left transthoracic interruption of the origin of the right subclavian artery using a heparin-bonded shunt. This approach avoids previously reported embolic complications while preserving brachial blood flow and providing safe access to the aorta.

Infratentorial cerebral cryptococcosis.

In a nonimmunocompromised patient with cerebral cryptococcosis, unique magnetic resonance findings included abnormalities limited to the posterior fossa and cerebellar hemispheric edema, gyriform enhancement of the vermis and cerebellar hemispheres, and infratentorial plaquelike enhancement. Magnetic resonance findings in central nervous system cryptococcosis are discussed.

Retrospective and prospective validity of aircraft accident risk indicators.

Data from a national survey of pilots were used to examine the validity of measures for the prediction of aviation accidents that had occurred prior to the survey (retrospective analysis) and accidents that occurred after the survey (prospective analysis). Separate retrospective and prospective analyses were conducted, and 45 measures from the survey were found to be associated significantly with accident involvement in the retrospective analysis. However, only 13 of those 45 measures achieved significance in the prospective analysis. Most of the measures found to be significantly related to accident involvement concerned aviation exposure; the remaining measures related to pilots' perceived and actual level of caution. The study is unique in its use of a cohort design for the examination of aircraft accident risk prospectively, and the results suggest the need for caution in the interpretation of retrospective analyses in this research domain. Actual or potential applications of this research include the design of aviation safety programs and the design or interpretation of studies that address indicators of aircraft accident risk.

Control of the mitochondrial permeability transition pore by high-affinity ADP binding at the ADP/ATP translocase in permeabilized mitochondria.

Low levels of ADP binding at the ADP/ATP translocase caused inhibition of the Ca2+-induced permeability transition of the mitochondrial inner membrane, when measured using the shrinkage assay on mitochondria, which have already undergone a transition. Inhibition was prevented by carboxyatractyloside, but potentiated by bongkrekic acid, which increased the affinity for inhibition by ADP. This suggests that inhibition was related to the conformation of the translocase. Ca2+ addition was calculated to remove most of the free ADP. Ca2+ added after ADP induced a slow decay of the inhibition, which probably reflected the dissociation of ADP from the translocator. We conclude that the probability of forming a permeability transition pore (PTP) is much greater when the translocase is in the CAT conformation than in the BKA conformation, and, in the absence of CAT and BKA, the translocator is shifted between the BKA and CAT conformations by ADP binding and removal, even in deenergized mitochondria with no nucleotide gradients.

Evidence for two distinct intracellular pools of inorganic sulfate in Penicillium notatum.

A strain of Penicillium notatum unable to metabolize inorganic sulfate can accumulate sulfate internally to an apparent equilibrium concentration 10(5) greater than that remaining in the medium. The apparent Keq is near constant at all initial external sulfate concentrations below that which would eventually exceed the internal capacity of the cells. Under equilibrium conditions of zero net flux, external 35SO42- exchanges with internal, unlabeled SO42- at a rate consistent with the kinetic constants with the sulfate transport system. Efflux experiments demonstrated that sulfate occupies two distinct intracellular pools. Pool 1 is characterized by the rapid release of 35SO42- when the suspension of preloaded cells is adjusted to 10 mM azide at pH 8.4 (t 1/2, 0.38 min). 35SO42- in pool 1 also rapidly exchanges with unlabeled medium sulfate. Pool 2 is characterized by the slow release of 35SO42- induced by azide at pH 8.4 or unlabeled sulfate (t 1/2, 32 to 49 min). Early in the 35SO42- accumulation process, up to 78% of the total transported substrate is found in pool 1. At equilibrium, pool 1 accounts for only about 2% of the total accumulated 35SO42-. The kinetics of 35SO42- accumulation is consistent with the following sequential process: medium----pool 1----pool 2. Monensin (33 microns) accelerates the transfer of 35SO42- from pool 1 to pool 2. Valinomycin (0.2 microM) and tetraphenylboron- (1 mM) retard the transfer of 35SO42- from pool 1 to pool 2. At the concentrations used, neither of the ionophores nor tetraphenylboron- affect total 35SO42- uptake. Pool 2 may reside in a vacuole or other intracellular organelle. A model for the transfer of sulfate from pool 1 to pool 2 is presented.

Allosteric inhibition of the Ca2+-activated hydrophilic channel of the mitochondrial inner membrane by nucleotides.

The control by nucleotides of the Ca2+ -activated channel which regulates the nonspecific permeability of the mitochondrial inner membrane has been investigated quantitatively. The cooperative binding of two molecules of ADP to the internal (matrix) side of the channel causes a mixed-type inhibition of channel activity. ATP, AMP, cAMP and GDP are all ineffective. NADH shows a pattern of inhibition similar to that of ADP, though the apparent KI is higher by a factor of 200. NADPH relieves the inhibition by NADH. NAD+ also inhibits, b,t its affinity is a factor of 10 less than that of NADH. When ADP and NADH are added together, they act synergistically to inhibit the Ca2+-activated channel. It is concluded that the concept of the modification of enzyme activity by the allosteric binding of nucleotides, which is well established for soluble enzyme systems, also has application to the regulation of channels that control membrane permeability.

Effect of weak acids on amino acid transport by Penicillium chrysogenum: evidence for a proton or charge gradient as the driving force.

A variety of weak acids at and below their pK(a) are potent inhibitors of transport in Penicillium chrysogenum. The effective compounds include sorbate, benzoate, and propionate (common antifungal agents), indoleacetate (a plant hormone), acetylsalicylate (aspirin), hexachlorophene, and a yellow pigment produced by the mycelia under nutrient-deficient conditions, as well as the classical uncouplers 2,4-dinitrophenol, p-nitrophenol, and azide. The results suggest that a proton gradient or charge gradient is involved in energizing membrane transport in P. chrysogenum. The unionized form of the weak acids could discharge the gradient by diffusing through the membrane and ionizing when they reach an interior compartment of higher pH. Experiments with 2,4-dinitrophenol and p-nitrophenol established that the ionized species are not absorbed by the mycelium to any great extent. The transport inhibitors also caused a decrease in cellular adenosine 5'-triphosphate (ATP) levels, but there was no constant correlation between inhibition of transport and suppression of cellular ATP. A decrease in aeration of the mycelial suspension had the same effect on transport and ATP levels as the addition of a weak organic acid. The effects on transport rates and ATP levels were reversible. The instantaneous inhibition of [(14)C]l-leucine transport by NH(4) (-) (and vice-versa) in nitrogen-starved mycelia at pH values of 7 or below can be explained by competition for a common energy-coupling system. The inhibition is not observed in carbon-starved mycelia in which the NH(4) (+) transport system is absent or inactive (but the general amino acid transport is fully active), or in iodoacetate-treated mycelia in which the NH(4) (+) transport system has been differentially inactivated. At pH values greater than 7.0, NH(3) and HPO(4) (2-) inhibit transport, presumably by discharging the membrane proton or charge gradient. Aniline counteracts the inhibitory effect of NH(3) and HPO(4) (2-) possibly by acting as a proton reservoir or buffer within the membrane.

Temporal bone radiography: a screening survey approach.

For preliminary evaluation of the temporal bone, a combination of conventional radiographs and hypocycloidal tomography in the frontal projection is advocated. If significant abnormalities are detected in this screening survey, a more in-depth study can then be pursued.

Control of the Na-Ca exchanger in isolated heart cells. I. Induction of Na-Na exchange in sodium-loaded cells by intracellular calcium.

Isolated adult rat heart cells in suspension were loaded with sodium by incubation with ouabain in the absence of calcium for 30 minutes. Addition of low levels of calcium induced accelerated rates of sodium influx and efflux, as measured with 22Na. The magnitude of calcium-induced 22Na efflux was 50-fold greater than the net rate of calcium uptake and required extracellular sodium, but not extracellular calcium, once some calcium was taken up. Calcium did not induce 86Rb efflux. The accelerated rate of 22Na efflux was prevented by verapamil, but verapamil was ineffective when added after calcium. Addition of EGTA after calcium reversed the effect of calcium, but only after incubation. Dichlorobenzamil, unlike verapamil, both prevented and reversed the induction of sodium fluxes by calcium. We conclude 1) that intracellular calcium induces Na-Na exchange through the Na-Ca exchanger in sodium-loaded cells exposed to calcium; and 2) that Na-Na exchange can be activated by calcium that enters the cell through calcium channels. We propose that this Na-Na exchange reflects the intrinsic activity of the Na-Ca exchanger.

Cellular calcium turnover in the perfused rat heart: modulation by caffeine and procaine.

Pool A is a rapidly exchangeable cellular pool of Ca++ whose release is triggered by a mechanism involving extracellular Ca++ (Hunter et al., 1981). We have now found that pool A is rapidly released from the perfused rat heart when 10 mm caffeine is added to the perfusate. Pool A release by caffeine was demonstrated during a Ca++ free perfusion. When the perfusate contained 2.5 mm Ca++, caffeine induced an immediate contractile failure. The steady state level of pool A (normally 69 +/- 10 nmol Ca++/g wet wt heart) was also decreased by 60%. Pool A was similarly depleted in hearts perfused with medium containing 0.2 mm Ca++. Procaine (5 mm) inhibited by 50% the release of pool A triggered by caffeine and inhibited by 86% the release triggered by extracellular Ca++. The inhibition of Ca++-induced release of pool A by procaine was partially relieved by externally stimulating the hearts. External stimulation also decreased the inhibition by procaine of Ca++ uptake by pool A from 83% to 28%. These results are further evidence that pool A is located in the sarcoplasmic reticulum and that release of pool A to the myofibriles is triggered by excitation-dependent Ca++ influx.

Cellular lithium uptake as a probe of sodium channels in the rat heart: modulation of lithium uptake by tetrodotoxin, verapamil, anthopleurin-A, isoproterenol and external stimulation.

Since the initial rate of sodium influx by the perfused rat heart is too rapid to measure accurately, lithium was used as an analogue for sodium. 10 mM lithium was added to the perfusate, and the rate of cellular lithium uptake was found to be linear for 5 min and was equal to 1.29 +/- 0.26 mumol/5 min/g wet wt heart. The cell took up lithium ions 36% as fast as sodium ions, but after 30 min the cellular/perfusate ratio of lithium reached nine times the cellular/perfusate ratio of sodium. Lithium uptake was inhibited 43% by 1 microM tetrodotoxin (TTX) (P greater than 0.05) and 47% by 1.4 microM verapamil (P less than 0.05). External stimulation abolished the inhibition by TTX. Anthopleurin-A (60 nM) stimulated TTX-sensitive lithium uptake by 118% (P less than 0.01) and stimulated verapamil-sensitive lithium uptake by 213% (P less than 0.01) but did not stimulate verapamil-sensitive manganese uptake. Anthopleurin-A also increased dP/dt by 164% (P less than 0.01). Isoproterenol (150 nM) stimulated both verapamil-sensitive lithium uptake (72%, P less than 0.01) and verapamil-sensitive manganese uptake (128%, P less than 0.01). This suggests that there are both TTX-sensitive and verapamil-sensitive sodium channels in the rat heart.

Measurement of rapidly exchangeable cellular calcium in the perfused beating rat heart.

Although Ca2+ has long been known to play a vital role in excitation--contraction coupling in the heart, investigation of the details of this role has been hampered by the experimental difficulty of measuring Ca2+ movements through the different compartments of the cell. A major problem has been to distinguish the relatively small amount of rapidly exchangeable cellular Ca2+ from the large amount of vascular and interstitial Ca2+. We report here a method that overcomes this problem. Rat hearts were labeled by perfusion at 37 degrees C with medium containing 45Ca2+. They were then cooled, and extracellular 45Ca2+ was removed by perfusion at 6 degrees C with Ca2+-free medium. Cellular 45Ca2+ that had been trapped in the hearts by cooling was then released by reperfusion at 37 degrees C with medium containing unlabeled Ca2+. The cellular origin of this 45Ca2+ was confirmed by using [3H]sucrose: When hearts were also labeled with [3H]sucrose, very little [3H]-sucrose was released with the 45Ca2+ peak. The amount of exchangeable cellular Ca2+ in hearts labeled for 5 min was 125 +/- 13 nmol/g of wet weight. The half-time for its release was less than 1 min. This cellular Ca2+ contained at least two pools: a rapidly exchanging pool that required extracellular Ca2+ for release (pool A, 38% of total), and a more slowly exchanging pool that did not (pool B, 62% of total). Hearts stimulated with isoproterenol during the 5-min labeling period showed an increase of 46% for the total amount of exchangeable cellular Ca2+; this increase was entirely located in pool A.

Contracture in isolated adult rat heart cells. Role of Ca2+, ATP, and compartmentation.

Isolated intact quiescent myocytes from the adult rat were used as a model system for investigating the determinants of contracture induced by metabolic deprivation. The model simulated the pattern of contracture and ATP decline seen in the intact heart during ischemia. Three new insights into the contracture process were gained: (1) in the quiescent cell system, the rate of onset of contracture was independent of external Ca2+, supporting the view that the Ca2+ dependence of the rate of onset in the whole heart is related to beat-dependent substrate utilization; (2) the second phase of ATP decline was paralleled by a decline in the percentage of cells which had not undergone contracture, suggesting that-in any cell-contracture is immediately preceded by a total loss of ATP; and (3) oligomycin delayed the onset of contracture by 55 +/- 12%, suggesting that mitochondrial ATPase activity is a significant drain on energy resources in the quiescent ischemic heart.