Thiamine triphosphate deficiency in subacute necrotizing encephalomyelopathy.

Extracts of tissue fluids from a patient with subacute necrotizing encephalomyelopathy inhibit thiamine pyrophosphate-adenosine triphosphate phosphotransferase of rat brain. Brain tissue from the patient, in contrast to normal brain tissue, contained essentially no thiamine triphosphate, although thiamine and its other phosphate esters were present in normal concentrations. These findings suggest a relation between this disease and thiamine triphosphate.

Antibodies to pneumococcal polysaccharides: relation between binding and electrophoretic heterogeneity.

Antibodies to type III and type VIII pneumococcal polysaccharides were examined with respect to ligand binding and electrophoretic heterogeneity. Both antibodies showed apparent binding homogeneity, although multiple light chain and heavy chain electrophoretic species were demonstrated.

Transport characteristics of folates in cerebrospinal fluid; a study utilizing doubly labeled 5-methyltetrahydrofolate and 5-formyltetrahydrofolate.

Serum disappearance curves in dogs after the intravenous injection of radioactive methotrexate, 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, and folic acid followed first-order kinetics with half-disappearance times ranging from 1.3 to 9 hr respectively. Equilibration of spinal fluid tritium levels with those in serum was rapid (3.0 hr) for both of the reduced folates but was not observed at any time after folic acid and methotrexate. The only radioactive folate identified in the spinal fluid after intravenous injection of either 5-formyltetrahydrofolate or folic acid, as well as 5-methyltetrahydrofolate was 5-methyltetrahydrofolate. These findings indicated that 5-methyltetrahydrofolate was taken up preferentially into the spinal fluid and that the other folate congeners were converted to this compound before uptake. Diphenylhydantoin administration did not alter the uptake of 5-methyltetrahydrofolate into the spinal fluid but was associated with reduced renal excretion of this compound.

Characterization and use of neuraminidase-modified L1210 plasma membranes for protection against tumor growth.

Purified plasma membranes were prepared from L1210 ascites tumor cells and analyzed for their protein and carbohydrate composition. Conditions were developed for treating the isolated plasma membranes with Vibrio cholerae neuraminidase (VCN) so that 88% of the N-acetylneuraminic acid was removed without changing membrane proteins or other membrane carbohydrate constituents. The VCN-induced modifications were characterized by labeling VCN-treated and untreated L1210 cells by the galactose oxidase:sodium [3H]borohydride procedure. This showed that N-acetylneuraminic acid is the predominant saccharide at the nonreducing terminus of plasma membrane glycoproteins and that galactose and/or N-acetylgalactosamine residues are penultimate to these. VCN modification exposed the penultimate residues and was not limited to any single plasma membrane glycoprotein. DBA/2J mice were given i.p. injections of VCN-treated or untreated membranes and were challenged 3 weeks later with 10(4) viable L1210 cells. Mice pretreated with VCN-treated membranes resisted the tumor challenge; those receiving untreated membranes or no treatment succumbed to the tumor. Our results demonstrate that appropriately modified plasma membranes can be used to induce resistance to tumor growth. They also suggest that tumor cell membrane carbohydrate structures have an important role in this phenomenon.

Immunotherapy of L1210 leukemia using neuraminidase-modified plasma membranes combined with chemotherapy.

Purified L1210 plasma membranes treated with Vibrio cholerae neuraminidase (VCN) were used for active immunotherapy of L1210 tumors in DBA/2J mice. Immunotherapy with VCN-treated membranes was effective only when combined with 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU). Successful therapy was a function of the dose of MeCCNU, the dose of VCN-treated membranes, and the time after MeCCNU treatment when VCN-treated membranes were administered. Optimum conditions for treating animals with tumors initiated with 10(4) cells were MeCCNU (20/kg) given 3 days after tumor inoculation and 0.25 mg VCN-treated membranes given 1 day after chemotherapy. Control membranes, not treated with VCN, that were administered 1 day after MeCCNU were ineffective; when given 4 days after chemotherapy, the caused accelerated mortality, suggesting immunological enhancement of tumor growth. Our results indicate that VCN-treated plasma membranes can be used for active immunotherapy of established tumors and underscore the importance of carefully designing immunotherapy protocols to achieve optimum desirable effects.

Juvenile male sexual assaulters.

This study compares the psychiatric, neurological, and psychoeducational status of sexually assaultive male juveniles and other violent juveniles. The authors found that juvenile sexual assaulters suffered from neuropsychiatric problems similar to those of other violent juveniles, had committed violent acts other than sexual assault, and had had seriously aberrant behavior since early childhood. The findings contradict prevailing assumptions that sexual assaults by juveniles are rare occurrences and that juvenile sex offenders have low rates of recidivism. Theoretical and treatment implications are discussed.

Psychiatric, neurological, and psychoeducational characteristics of 15 death row inmates in the United States.

The authors present the results of clinical evaluations of 15 death row inmates, chosen for examination because of the imminence of their executions and not for evidence of neuropsychopathology. All had histories of severe head injury, five had major neurological impairment, and seven others had other, less serious neurological problems (e.g., blackouts, soft signs). Psychoeducational testing provided further evidence of CNS dysfunction. Six subjects had schizophreniform psychoses antedating incarceration and two others were manic-depressive. The authors conclude that many condemned individuals probably suffer unrecognized severe psychiatric, neurological, and cognitive disorders relevant to considerations of mitigation.

Objective documentation of child abuse and dissociation in 12 murderers with dissociative identity disorder.

OBJECTIVE: The skepticism regarding the existence of dissociative identity disorder as well as the abuse that engenders it persists for lack of objective documentation. This is doubly so for the disorder in murderers because of issues of suspected malingering. This article presents objective verification of both dissociative symptoms and severe abuse during childhood in a series of adult murderers with dissociative identity disorder. METHOD: This study consisted of a review of the clinical records of 11 men and one woman with DSM-IV-defined dissociative identity disorder who had committed murder. Data were gathered from medical, psychiatric, social service, school, military, and prison records and from records of interviews with subjects' family members and others. Handwriting samples were also examined. Data were analyzed qualitatively. RESULTS: Signs and symptoms of dissociative identity disorder in childhood and adulthood were corroborated independently and from several sources in all 12 cases; objective evidence of severe abuse was obtained in 11 cases. The subjects had amnesia for most of the abuse and underreported it. Marked changes in writing style and/or signatures were documented in 10 cases. CONCLUSIONS: This study establishes, once and for all, the linkage between early severe abuse and dissociative identity disorder. Further, the data demonstrate that the disorder can be distinguished from malingering and from other disorders. The study shows that it is possible, with great effort, to obtain objective evidence of both the symptoms of dissociative identity disorder and the abuse that engenders it.

Psychomotor epilepsy and violence in a group of incarcerated adolescent boys.

The authors report the finding of psychomotor epilepsy in 18 of 97 incarcerated delinquent boys. Number of psychomotor symptoms was correlated with degree of violence in the members of this group. In addition, psychomotor symptoms were correlated more strongly with certain psychotic symptoms than with soft neurological signs or intellectual deficits. The relationship of violence to ictal and interictal states is explored.

Neuropsychiatric, psychoeducational, and family characteristics of 14 juveniles condemned to death in the United States.

Of the 37 juveniles currently condemned to death in the United States, all of the 14 incarcerated in four states received comprehensive psychiatric, neurological, neuropsychological, and educational evaluations. Nine had major neurological impairment, seven suffered psychotic disorders antedating incarceration, seven evidenced significant organic dysfunction on neuropsychological testing, and only two had full-scale IQ scores above 90. Twelve had been brutally physically abused, and five had been sodomized by relatives. For a variety of reasons the subjects' vulnerabilities were not recognized at the time of trial or sentencing, when they could have been used for purposes of mitigation.

Plasma levels of amino acids correlate with motor fluctuations in parkinsonism.

Seven patients with Parkinson's disease who experienced severe motor fluctuations in response to levodopa were studied in detail with relation to the effect of dietary protein on their motor function. The levodopa dose for each patient was not changed during the period of study, and no other antiparkinsonian drugs were used. Regular and high-protein diets resulted in a marked elevation in the plasma concentrations of large neutral amino acids (LNAAs) that are known to compete with levodopa for transport across the blood-brain barrier. Despite elevated plasma levodopa levels, all patients with elevated LNAA levels experienced parkinsonian symptoms. When the amino acid level dropped while plasma levodopa levels were elevated, patients experienced relief of these symptoms. On a low-protein diet, LNAA levels remained low and all patients were consistently dyskinetic throughout the day, even though the mean plasma levodopa levels were somewhat lower than when the patients consumed a high-protein diet. A redistribution diet that is virtually protein free until supper and then unrestricted until bedtime is tolerated by patients because this simple manipulation permits near-normal daytime motor function.

Influence of dietary protein on motor fluctuations in Parkinson's disease.

On a nearly zero protein diet, 11 patients with Parkinson's disease with the "on-off" effect demonstrated great sensitivity to levodopa (L-dopa)-carbidopa and reduced fluctuations. Eight patients required a 41% reduction in total L-dopa dosage and discontinuation of all adjuvant therapy to reduce the preponderance of chorea. On a high-protein diet, all patients were immobilized by bradykinesia for most of the day. A low-protein dietary regimen during the daytime offers an important technique for the control of fluctuations in patients with Parkinson's disease who are receiving L-dopa-carbidopa.

Cryptococcal meningitis. False-negative antigen test results and cultures in nonimmunosuppressed patients.

All cases of cryptococcal meningitis at Yale-New Haven (Conn) Hospital seen during a 4 1/2-year period were reviewed to calculate the rate of false-negative antigen test results and cultures preceding diagnosis. Of 13 patients, 9 were immunosuppressed and were diagnosed following the initial lumbar puncture, with both antigen test results and cultures positive in all cases. Among 4 nonimmunosuppressed patients, the rate of false-negative antigen test results was 77%, and of cultures, 89%. The diagnosis was consequently delayed in 3, 2 of whom died despite treatment. Cryptococcal meningitis may be underdiagnosed and undertreated to a significant degree in nonimmunosuppressed patients.

Protein redistribution diet remains effective in patients with fluctuating parkinsonism.

Forty-three carbidopa-levodopa (Sinemet)-treated parkinsonian patients with protein-sensitive motor fluctuations were started on the protein redistribution diet within the past 48 months. Thirty patients (70%) are still using the diet successfully after more than 12 months (mean duration, 33.6 months; range, 12 to 48 months). The diet was discontinued in the other 13 cases. In 10 of these 13 patients, the protein redistribution diet was discontinued for a variety of reasons, despite continued sensitivity to dietary protein; in only three patients (7%), those with the most severe and complicated disease, was the protein redistribution diet stopped because of its limited therapeutic benefit. The protein redistribution diet is a simple adjunct to the treatment of Parkinson's disease that can significantly prolong the efficacy of levodopa therapy in many fluctuating "end-stage" patients.

Standard and controlled-release levodopa/carbidopa in patients with fluctuating Parkinson's disease on a protein redistribution diet. A preliminary report.

Ten patients with Parkinson's disease (PD) with motor fluctuations that responded to a protein redistribution diet were studied. All 10 patients were receiving standard Sinemet (levodopa/carbidopa). Five randomly selected patients were changed from standard Sinemet to a controlled-release form of Sinemet. The other five patients continued to receive standard Sinemet. To maintain the same degree of control of PD in the five patients switched to the controlled-release form of Sinemet, the daily levodopa intake increased. While receiving optimal therapy (standard Sinemet or controlled-release Sinemet) and a protein redistribution diet, all 10 patients then underwent hourly videotaping and blood sampling (for plasma levodopa levels) during 2 consecutive days. Videotapes were blindly reviewed for PD disability, dyskinesia, and the time required to walk a measured distance. Comparing the two groups, standard Sinemet with controlled-release Sinemet, respectively, mean levodopa requirements were 505 and 1895 mg, plasma levodopa levels were 6.1 and 17.6 mumol/L, and abnormal involuntary movement scale scores were 14 and 26. Their mean PD disability scores did not differ statistically or clinically. Also no statistically significant differences were noted in either their mean walking times or their mean daily dose frequencies.

Thiamine triphosphate levels and histopathology. Correlation in Leigh disease.

Thiamine and thiamine triphosphate (TTP) values were assayed in various brain regions in 11 controls and 13 patients with subacute necrotizing encephalomyelopathy (SNE, Leigh disease). The TTP values of normal brain were 5% of the total thiamine value. The relative TTP (or % TTP) level was consistently low in the pons, midbrain, and cerebellum of all the SNE brains. Twenty-five percent of the SNE brains had normal TTP levels in the frontal region. The TTP values correlated with the degrees of pathologic involvement in all sampled regions of the brain except the cerebellum. The concentration of thiamine in the mammillary bodies exceeded its concentration elsewhere in both control and SNE brains. The finding of low TTP levels in morphologically abnormal regions supports the hypothesis that TTP deficiency is etiologically related to SNE.

Aspartame use in Parkinson's disease.

The artificial sweetener aspartame (NutraSweet) is hydrolyzed in the gut as phenylalanine (PA), a large neutral amino acid (LNAA). LNAAs compete with levodopa for uptake into the brain. To determine the effect of aspartame on levodopa-treated Parkinson's disease (PD) patients, we studied 18 PD patients with protein-sensitive motor fluctuations by administering in a double-blind and single-crossover design, on alternate days, aspartame (600 or 1,200 mg) and placebo. Every hour, we performed a motor examination and drew blood to estimate plasma LNAA, PA, and levodopa levels. Six-hundred mg of aspartame had no effect on plasma PA or motor status. Although 1,200 mg of aspartame significantly increased plasma PA, motor performance did not deteriorate. Aspartame consumption in amounts well in excess of what would be consumed by heavy users of aspartame-sweetened products has no adverse effect on PD patients.

Protein redistribution diet restores motor function in patients with dopa-resistant "off" periods.

Sixteen parkinsonians with acquired drug-resistant "off" periods without dyskinesia were placed on a diet in which virtually all protein was concentrated in the evening meal. Restoration of sensitivity to levodopa resulted in 88%. Ten patients (62%) have continued to comply with the diet for 7 months (mean). Two patients were studied in detail. Immobility correlated with elevated plasma levels of large neutral amino acids (LNAA), normality with low LNAA.

Neurologic abnormalities in murderers.

Thirty-one individuals awaiting trial or sentencing for murder or undergoing an appeal process requested a neurologic examination through legal counsel. We attempted in each instance to obtain EEG, MRI or CT, and neuropsychological testing. Neurologic examination revealed evidence of "frontal" dysfunction in 20 (64.5%). There were symptoms or some other evidence of temporal lobe abnormality in nine (29%). We made a specific neurologic diagnosis in 20 individuals (64.5%), including borderline or full mental retardation (9) and cerebral palsy (2), among others. Neuropsychological testing revealed abnormalities in all subjects tested. There were EEG abnormalities in eight of the 20 subjects tested, consisting mainly of bilateral sharp waves with slowing. There were MRI or CT abnormalities in nine of the 19 subjects tested, consisting primarily of atrophy and white matter changes. Psychiatric diagnoses included paranoid schizophrenia (8), dissociative disorder (4), and depression (9). Virtually all subjects had paranoid ideas and misunderstood social situations. There was a documented history of profound, protracted physical abuse in 26 (83.8%) and of sexual abuse in 10 (32.3%). It is likely that prolonged, severe physical abuse, paranoia, and neurologic brain dysfunction interact to form the matrix of violent behavior.

Gender and pramipexole effects on levodopa pharmacokinetics and pharmacodynamics.

The authors studied the pharmacokinetics of levodopa (LD) with and without pramipexole (PPX) in men and postmenopausal women with PD. Patients on stable dose of carbidopa/LD were randomized to receive escalating doses of placebo or PPX over 7 weeks. LD and PPX pharmacokinetics were performed after a single test dose 25/100 of carbidopa/LD, before initiation of PPX or placebo, at 1.5 mg/d and 4.5 mg/d of PPX or placebo. Compared to men, women had greater LD bioavailability. PPX did not alter LD bioavailability, and PPX pharmacokinetics were equivalent in men and women.