Heartbeat perception and panic disorder: possible explanations for discrepant findings.

Results on cardiac awareness in panic disorder are inconsistent. The present study attempted to clarify whether differences in instructions or the inclusion of patients taking antidepressant medication could account for these inconsistencies. 112 patients with panic disorder with agoraphobia were compared to 40 normal controls on the heartbeat perception task developed by Schandry (1981) [Schandry, R., Psychophysiology, 18, 483-488] using a standard instruction ("count all heartbeats you feel in your body") and a strict instruction ("count only those heartbeats about which you are sure"). Superior heartbeat perception for patients was only found with the standard instruction. Similarly, only with the standard instruction, patients taking medication affecting the cardiovascular system performed worse than patients without medication, as expected based on the relationship between stroke volume and heartbeat perception. The pattern of group differences indicates that agoraphobic patients have a better feeling for how fast their heart is beating than controls although these differences may be due to a tendency to interpret weak sensations as heartbeats. Furthermore, we tested in a subgroup of 40 patients whether cardiac awareness changes with exposure treatment. No changes in heartbeat perception were observed.

Metabolites of [3-13C]1,2-dibromo-3-chloropropane in male rats studied by 13C and 1H-13C correlated two-dimensional NMR spectroscopy.

Metabolism of 1,2-dibromo-3-chloropropane (DBCP) was examined by direct 13C and 1H-13C correlated two-dimensional NMR spectroscopy of bile and urine of male albino rats treated intraperitoneally with [3-13C]DBCP at 81 mg/kg. The 3-13C label was introduced at 99% enrichment by coupling [13C]paraformaldehyde with vinyllithium to give [1-13C]allyl alcohol which was converted to allyl chloride with carbon tetrachloride/triphenylphosphine and then brominated. Fifteen 13C NMR signals were observed for biliary metabolites and twelve for urinary metabolites. Nine of the biliary metabolite 13C NMR signals were very similar or identical to those for nine urinary metabolites. The DBCP-derived moieties of five metabolites were identified by comparison of their 13C NMR chemical shifts, 13C multiplicities [obtained via the distortionless enhancement by polarization transfer (DEPT) pulse sequence], and chemical shifts of the directly-attached protons (obtained via two-dimensional NMR) with those of authentic standards. They were E- and Z-RSCH2CH = 13CHCl, RSCH2CHOH13CH2Cl, RSCH2CHOH13CH2OH and RS13CH2CHOHCH2OH, where R is probably glutathionyl in bile and N-acetylcysteinyl in urine. The mechanism proposed for formation of both the E- and Z-isomers of RSCH2CH = 13CHCl involves radical-initiated dehydrobromination followed by reaction of the intermediate allylic bromides with glutathione (GSH). The RSCH2CHOHCH2Cl conjugate may arise from direct GSH conjugation and hydrolysis of the secondary bromine via a thiiranium ion intermediate. The proposed origin of the RSCH2CHOHCH2OH conjugate labeled at either carbon-1 or carbon-3 is oxidation of DBCP at the bromomethyl or chloromethyl substituent, respectively, followed by two spontaneous dehydrohalogenations to give the highly reactive 2-bromopropenal, and addition of GSH followed by reduction of the aldehyde functionality. An alternative mechanism for the formation of the RSCH2CHOHCH2Cl and RSCH2CHOHCH2OH derivatives involves carbon-2 oxidation to give 1-bromo-3-chloroacetone followed by reaction with GSH and reduction of the ketone functionality with or without hydrolysis of the chloro substituent. 2-Bromopropenal, 1-bromo-3-chloroacetone, or GSH conjugates derived from these intermediates may be involved in the male reproductive toxicity, nephrotoxicity and genotoxicity of DBCP.

Biosynthesis and biotransformation of glutathione S-conjugates to toxic metabolites.

The material presented in this review deals with the hypothesis that the nephrotoxicity of certain halogenated alkanes and alkenes is associated with hepatic biosynthesis of glutathione S-conjugates, which are further metabolized to the corresponding cysteine S-conjugates. Some glutathione or cysteine S-conjugates may be direct-acting nephrotoxins, but most cysteine S-conjugates require bioactivation by renal, pyridoxal phosphate-dependent enzymes, such as cysteine conjugate beta-lyase (beta-lyase). The biosynthesis of glutathione S-conjugates is catalyzed by both the cytosolic and the microsomal glutathione S-transferases, although the latter enzyme is a better catalyst for the reaction of haloalkenes with glutathione. When glutathione S-conjugate formation yields sulfur mustards, as occurs with vicinal-dihaloethanes, the S-conjugates are direct-acting toxins. In contrast, the S-conjugates formed from fluoro- and chloroalkenes yield S-alkyl- or S-vinyl glutathione conjugates, respectively, which are metabolized to the corresponding cysteine S-conjugates by gamma-glutamyltransferase and dipeptidases; inhibition of these enzymes blocks the toxicity of the glutathione S-conjugates. The cysteine S-conjugates must be metabolized by beta-lyase for the expression of toxicity; the beta-lyase inhibitor aminooxyacetic acid blocks the toxicity of cysteine S-conjugates, and the corresponding alpha-methyl cysteine S-conjugates, which cannot be metabolized by beta-lyase, are not toxic. Moreover, probenecid, an inhibitor of renal anion transport system, blocks the toxicity of cysteine S-conjugates, which cannot be metabolized by beta-lyase, are not toxic. Moreover, probenecid, an inhibitor of renal anion transport system, blocks the toxicity of cysteine S-conjugates. Homocysteine S-conjugates are also potent cyto- and nephrotoxins. The high renal content of gamma-glutamyltransferase and the renal anion transport system are probably determinants of kidney tissue as a target site. Biochemical studies indicate that renal mitochondrial dysfunction is produced by the cysteine S-conjugates. Finally, some of the glutathione and cysteine conjugates are mutagenic in the Ames test, and reactive intermediates formed by the action of beta-lyase may contribute to the nephrocarcinogenicity of certain chloroalkenes.

Spinal neurofibromas: a report of 66 cases and a comparison with meningiomas.

A series of 66 spinal cord neurofibromas was analyzed for history, signs, surgical approach, and outcome. The tumors presented primarily with sensory symptoms. Plain films were abnormal in 1/2 of cases and 1/2 had a complete block. They were primarily intradural, and primarily thoracic. A conservative exam system was used for follow-up and 85% with pain had complete relief; 50% with motor loss had normal motor function, and 88% had normal sensation who had prior sensory loss. In comparison to meningiomas, the principal differences were that neurofibromas had an even sex distribution, a lower incidence of cord signs and symptoms, more frequent findings on plain x-rays, and higher cerebrospinal fluid protein. Surgical outcome was similar. Sacrifice of the involved root during removal usually did not produce a deficit. The series is compared with a similar series of meningiomas from the same institution over the same time period.

Nephrotoxicity of S-(2-chloro-1,1,2-trifluoroethyl)glutathione and S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine, the glutathione and cysteine conjugates of chlorotrifluoroethene.

The glutathione and cysteine conjugates of the nephrotoxin chlorotrifluoroethene, S-(2-chloro-1,1,2-trifluoroethyl)glutathione (CTFG) and S-(2-chloro-1,1,2-trifluoroethyl)cysteine (CTFC), are potent nephrotoxins in male rats. Morphological changes in the kidneys were observed 1.5 hr after giving 100 mumol/kg of CTFG (i.v.), and severe damage to the proximal tubules was evident 24 hr after treatment; this dose of CTFG caused a 100-fold increase in urine glucose excretion, a 10-fold increase in urine protein excretion and a 4-fold increase in blood urea nitrogen concentrations 24 hr after administration. Administration of 50 mumol/kg of CTFG or 100 mumol/kg of CTFC produced similar lesions and increases in urine glucose excretion rates and blood urea nitrogen concentrations. Administration of 10 mumol/kg of CTFG produced no discernable effect on the kidneys. CTFG and CTFC did not alter plasma glucose concentrations or plasma glutamate-pyruvate transaminase activities. CTFG and CTFC produced time- and dose-dependent loses of cell viability in isolated rat renal tubular cells. The toxicity of CTFG to isolated renal tubular cells was prevented by the gamma-glutamyltransferase inhibitor AT-125, and the toxicity of CTFC and CTFG to isolated cells was prevented by aminooxyacetic acid, an inhibitor of pyridoxal phosphate-dependent enzymes. Moreover, S-(2-chloro-1,1,2-trifluoroethyl)-DL-alpha-methylcysteine, which cannot be metabolized by pyridoxal phosphate-dependent enzymes, was not toxic to isolated renal tubular cells. The data presented support the hypothesis that the nephrotoxicity of chlorotrifluoroethene is due to the enzymatic formation of a glutathione conjugate, which is metabolized to the ultimate nephrotoxin by the sequential action of renal gamma-glutamyltransferase, cysteinylglycine dipeptidase and cysteine conjugate beta-lyase.

3-Substituted 2-halopropenals: mutagenicity, detoxification and formation from 3-substituted 2,3-dihalopropanal promutagens.

The mutagenicity of halopropenals for Salmonella typhimurium strain TA100 is as follows (revertants/nmole): 2-halopropenals [H2C = C(X)CHO], F = less than 0.6, Cl = 135, Br = 1140 and I = less than 2.4; 3-substituted-2-halopropenals [CH3CH = C(X)CHO], Cl = 68 and Br = 108; [C6H5CH = C(X)CHO], Cl = less than 1 and Br = 5; [ClCH = C(Cl)CHO], 91; [CH3(CH2)2CH = C(Br)CHO], less than 1; [(CH3)2C = C(Br)CHO], less than 0.5. Each of the active compounds is detoxified by the liver S9 fraction. Glutathione also detoxifies the 2-halopropenals and 2-halobutenals, more rapidly for the bromo than the chloro analogs. The mutagenic potency on metabolic activation of the herbicide diallate by microsomes or the S9 fraction is attributable to approximately 50% conversion to 2-chloropropenal when corrected for detoxification in these systems or with GSH. There is no correlation between mutagenicity and reactivity with the model thiol, 4-nitrobenzenethiol. The mutagenicity of 2,3-dichloro- and 2,3-dibromo-propanals and the corresponding dihalobutanals is accounted for by their rapid dehydrohalogenation to the corresponding 2-haloalkenals under physiological conditions. Chemicals that are metabolized to 2,3-dichloropropanal, 2,3-dichlorobutanal, their dibromo analogs, or to the corresponding 2-halopropenals and 2-halobutenals should therefore be considered as candidate promutagens.

Enzymatic reaction of chlorotrifluoroethene with glutathione: 19F NMR evidence for stereochemical control of the reaction.

Chlorotrifluoroethene, a potent nephrotoxin, is a substrate for the glutathione S-transferases present in the cytosolic and microsomal fractions of rat liver. The glutathione conjugate formed by both subcellular fractions has been identified as S-(2-chloro-1,1,2-trifluoroethyl)glutathione by 1H and 19F NMR and by secondary ion mass spectrometry. The conjugate formed by the cytosolic fraction is an equimolar mixture of two diastereomers, whereas the conjugate formed by the microsomal fraction is predominantly one diastereomer, as judged by the 19F NMR spectra. No evidence for the formation of S-(trihalovinyl)glutathione derivatives by an addition/elimination reaction was found. High-performance liquid chromatography was employed to measure the rates of glutathione conjugate formation in vitro. The rates of S-(2-chloro-1,1,2-trifluoroethyl)glutathione formation were 75-107 nmol min-1 (mg of protein)-1 and 151-200 nmol min-1 (mg of protein)-1 catalyzed by the cytosolic and microsomal fractions, respectively (measured at pH 7.4, 37 degrees C, with 5 mM glutathione). These results suggest that glutathione conjugation occurs at high rates in vivo to produce the highly nephrotoxic S-(2-chloro-1,1,2-trifluoroethyl)glutathione.

N-demethylation of p-chloro-N-methylaniline catalyzed by subcellular fractions from the avocado pear (Persea americana).

Subcellular fractions from the avocado pear ( Persea americana) catalyzed formation of p-chloroaniline from p-chloro-N-methylaniline. Fractions prepared by centrifugation of avocado homogenates at 20, 000g for 20 min formed p-chloroaniline (2900 +/- 500 pmol min-1 mg protein-1) with an NADPH-generating system. p-Chloroaniline formation required reduced pyridine nucleotide (NADPH was 6-7 times more effective than NADH) and O2. N-Demethylation was inhibited by CO (55% inhibition at CO:O2 = 1) and was not inhibited by CN. Cytochrome P-450 was detected in the 20, 000g pellet at levels of 300-380 pmol/mg protein. This particulate preparation was also active in catalyzing the NADPH-dependent epoxidation of the chlorinated cyclodiene aldrin. Improvements to a colorimetric procedure for measuring p-chloroaniline increased the sensitivity of the procedure fourfold, and allowed use of samples containing high amounts of lipid. Avocado pear is suitable tissue for further studies on the oxidation of foreign compounds by higher plants.

Spinal cord meningioma.

The authors present a retrospective analysis of 97 cases of spinal meningioma. Age, sex, tumor location, and clinical presentation are similar to that reported by others. Importantly, even among paraplegic patients, one-third eventually walked. Other findings of note were poor results among those with calcified or recurrent tumors, and a high incidence of invasiveness among the rare epidural lesions. Males do not show the preference for a thoracic location that is found among females, and cervical tumors are almost all anterior to the cord. This last point suggests a different surgical approach in some cases. A large percentage of cases carried other diagnoses before tumor was recognized.

Central cord syndrome as a delayed postoperative complication of decompressive laminectomy.

We report five cases of a central cord syndrome that appeared as a delayed surgical complication several days after decompressive laminectomy with the patient in the sitting position. Some episode of abnormal positioning of the neck or hypotension seems to have triggered the central cord syndrome. The patients improved slowly, but did not return to their immediate postoperative status. This complication probably can be avoided with careful mobilization after operation, with the avoidance of hypotension, and with the use of a firm collar during the first few postoperative days.

Recurrence of lumbar canal stenosis a decade after decompressive laminectomy.

Lumbar canal stenosis is treated by decompressive laminectomy with a high rate of success, but patients may experience late recurrence of pain. We report on 3 patients with return of symptoms years after their original decompression. CT scanning showed reformation by bone; their symptoms were relieved by decompression. While scarring is probably a more common cause of the return of pain, this reformation of bone can be more easily treated than scar formation and its presence should be sought by CT scanning.

Giant fusiform aneurysm of the cerebral arteries.

Giant fusiform aneurysm of the cerebral arteries was found in 11 patients during a 20-year period. The 7 males and 4 females ranged in age from 9 to 68 years (mean: 49 years). The supraclinoid segment of the internal carotid artery (ICA) and the M-1 segment of the middle cerebral artery (MCA) were the most frequently involved arteries. Multiple aneurysms were identified in 3 patients. Compression of adjacent intracranial structures was the usual cause of symptoms, and only 2 patients experienced subarachnoid hemorrhage. One patient presented with transient ischemic attacks. Computed tomography, with and without Hypaque infusion, clearly demonstrated the aneurysms in the 6 of 7 patients studied. Thrombus was invariably seen in the lumen of the aneurysm. Cerebral angiography in 11 patients displayed marked dilatation and elongation of the involved artery. The dilatation frequently extended into connecting arteries. Surgical treatment was carried out in 6 patients, including 2 with aneurysm entrapment and decompression, 2 with proximal ICA ligation, 1 with wrapping and 1 with wrapping and superficial temporal artery (STA) to MCA anastomosis. Death occurred in 2 patients not treated surgically.

Neuroendocrinological aspects of histiocytosis X of the central nervous system.

Detailed neuroendocrine studies were carried out in a patient with histiocytosis X involving the hypothalamus. She presented with amenorrhea, galactorrhea, and diabetes insipidus. The diagnosis was established through needle biopsy with the aid of a computerized tomography (CT) scanner. The basic pathology and clinical features of the disease are outlined, with particular emphasis on the endocrine abnormalities seen in isolated hypothalamic histiocytosis X.

Effect of hyaluronidase on acute spinal cord injury.

Three control and five experimental dogs were subjected to 500 gm-cm injury of the midthoracic spinal cord by the weight dropping technique. Five hundred units per kilogram of hyaluronidase injected intravenously 20 minutes after injury in the experimental animals did not alter the loss of dorsal column evoked potentials (nonaveraged) or improve the pathological results up to three hours. These results imply that hyaluronidase will not significantly alter the functional outcome of trauma of the spinal cord in dogs.