Adult Hallervorden-Spatz syndrome simulating amyotrophic lateral sclerosis.

Hallervorden-Spatz syndrome (HSS) is a neurodegenerative disorder characterized by progressive dementia, dystonia, ataxia, and rigidity. An atypical form of adult-onset HSS was observed in a 36-year-old man presenting with progressive dysarthria. Markedly dysarthric speech and a weak atrophic tongue associated with a neurogenic pattern of motor unit recruitment in bulbar-supplied muscles on electromyography led to an initial impression of bulbar amyotrophic lateral sclerosis (ALS). Lack of expected progression of symptoms, however, prompted reinvestigation. Repeat brain magnetic resonance imaging demonstrated an "eye-of-the-tiger" pattern in the basal ganglia, characteristic of HSS, thus requiring genetic studies. DNA analyses of the pantothenate kinase gene (PANK2) was conducted and revealed two novel, disease-causing exon 3 missense mutations (Cys231Ser and Tyr251Cys). This case broadens the genotypic and phenotypic spectrum of HSS to include a late-onset syndrome resembling bulbar-onset ALS.

mtDNA analysis of Leber hereditary optic neuropathy associated with spondyloepiphyseal dysplasia.

A patient was diagnosed in 1974 with the unique combination of Leber hereditary optic neuropathy (LHON) and spondyloepiphyseal dysplasia. The entire mitochondrial DNA (mtDNA) sequence from this patient was determined in order to identify candidate pathogenic mutations. The patient's mtDNA carried the LHON mutation at nucleotide 14484, thus elucidating the etiology of his optic neuropathy. We also identified another ND6 mutation at nucleotide 14420. This latter mutation is probably a clinically benign private polymorphism, although a pathogenic role in his skeletal abnormalities or in his optic neuropathy cannot yet be ruled out.

Effects of 12-h tobacco deprivation on event-related potentials elicited by visual smoking cues.

RATIONALE: A cigarette smoker's reactivity to smoking cues, or cue-reactivity, traditionally has been indexed by self-report and/or measures of autonomic nervous system activity. Recent evidence suggests that measures of central nervous system activity in the form of event-related brain potentials (ERPs) may also index cue-reactivity in smokers. OBJECTIVE: The present study sought to confirm the sensitivity of ERPs to smoking cues and to investigate the question of whether 12 h of smoking deprivation would enhance ERP cue-reactivity to such stimuli. METHODS: Scalp ERPs were recorded to 80 smoking-related pictures and 80 neutral pictures, i.e., similar pictures with a nonsmoking theme, in 19 tobacco-deprived smokers, 17 nondeprived smokers, and 19 nonsmokers. RESULTS: Smokers' N300 amplitudes over fronto-central scalp were larger to neutral than to smoking-related stimuli, thus reflecting N300 smoking cue-reactivity. N300 cue-reactivity was greater for deprived than for nondeprived smokers. Smokers' P300 values were greater to smoking-related than to neutral stimuli, particularly over the centro-parietal area; however, nonsmokers also showed a P300 main effect to smoking cues. Smoking deprivation did not affect P300 cue-reactivity, nor did deprivation affect self-reported urges to smoking relative to neutral cues. CONCLUSIONS: These data confirm the sensitivity of ERPs to tobacco cues in smokers and suggest, additionally, that the cue-reactivity of the N300 component is modulated by smoking deprivation. N300 cue-reactivity may reflect an internally generated priming of the semantic network related to the smokers' need states. Stimulus-category differences in P300 may reflect cue-reactivity in smokers and/or nonaddiction-specific factors in both smokers and nonsmokers.

Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy.

BACKGROUND: The molecular basis of idiopathic dilated cardiomyopathy, a primary myocardial disorder that results in reduced contractile function, is largely unknown. Some cases of familial dilated cardiomyopathy are caused by mutations in cardiac cytoskeletal proteins; this finding implicates defects in contractile-force transmission as one mechanism underlying this disorder. To elucidate this important cause of heart failure, we investigated other genetic causes of dilated cardiomyopathy. METHODS: Clinical evaluations were performed in 21 kindreds with familial dilated cardiomyopathy. A genome-wide linkage study prompted a search of the genes encoding beta-myosin heavy chain, troponin T, troponin I, and alpha-tropomyosin for disease-causing mutations. RESULTS: A genetic locus for mutations associated with dilated cardiomyopathy was identified at chromosome 14q11.2-13 (maximal lod score, 5.11; theta=0), where the gene for cardiac beta-myosin heavy chain is encoded. Analyses of this and other genes for sarcomere proteins identified disease-causing dominant mutations in four kindreds. Cardiac beta-myosin heavy-chain missense mutations (Ser532Pro and Phe764Leu) and a deletion in cardiac troponin T (deltaLys210) caused early-onset ventricular dilatation (average age at diagnosis, 24 years) and diminished contractile function and frequently resulted in heart failure. Affected persons had neither antecedent cardiac hypertrophy (average maximal left-ventricular-wall thickness, 8.5 mm) nor histopathological findings characteristic of hypertrophy. CONCLUSION: Mutations in sarcomere protein genes account for approximately 10 percent of cases of familial dilated cardiomyopathy and are particularly prevalent in families with early-onset ventricular dilatation and dysfunction. Because distinct mutations in sarcomere proteins cause either dilated or hypertrophic cardiomyopathy, the effects of mutant sarcomere proteins on muscle mechanics must trigger two different series of events that remodel the heart.

Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.

BACKGROUND: Inherited mutations cause approximately 35 percent of cases of dilated cardiomyopathy; however, few genes associated with this disease have been identified. Previously, we located a gene defect that was responsible for autosomal dominant dilated cardiomyopathy and conduction-system disease on chromosome 1p1-q21, where nuclear-envelope proteins lamin A and lamin C are encoded by the LMNA (lamin A/C) gene. Mutations in the head or tail domain of this gene cause Emery-Dreifuss muscular dystrophy, a childhood-onset disease characterized by joint contractures and in some cases by abnormalities of cardiac conduction during adulthood. METHODS: We evaluated 11 families with autosomal dominant dilated cardiomyopathy and conduction-system disease. Sequences of the lamin A/C exons were determined in probands from each family, and variants were confirmed by restriction-enzyme digestion. The genotypes of the family members were ascertained. RESULTS: Five novel missense mutations were identified: four in the alpha-helical-rod domain of the lamin A/C gene, and one in the lamin C tail domain. Each mutation caused heritable, progressive conduction-system disease (sinus bradycardia, atrioventricular conduction block, or atrial arrhythmias) and dilated cardiomyopathy. Heart failure and sudden death occurred frequently within these families. No family members with mutations had either joint contractures or skeletal myopathy. Serum creatine kinase levels were normal in family members with mutations of the lamin rod but mildly elevated in some family members with a defect in the tail domain of lamin C. CONCLUSIONS: Genetic defects in distinct domains of the nuclear-envelope proteins lamin A and lamin C selectively cause dilated cardiomyopathy with conduction-system disease or autosomal dominant Emery-Dreifuss muscular dystrophy. Missense mutations in the rod domain of the lamin A/C gene provide a genetic cause for dilated cardiomyopathy and indicate that this intermediate filament protein has an important role in cardiac conduction and contractility.

Event-related brain potentials as indicators of smoking cue-reactivity.

OBJECTIVE: Reactivity to smoking cues, shown previously by autonomic and self-report variables, was investigated in smokers and nonsmokers using event-related brain potentials (ERPs). METHODS: Average ERPs to 20 color pictures of people smoking and 20 neutral pictures depicting nonsmoking themes, randomly mixed with 4 repetitions/stimulus, were measured from 20 light-moderate smokers and 18 nonsmokers, following a stressor. Smoker status and stimulus type effects on ERPs and principal components factor scores (FS) were tested by repeated-measures ANOVAs. RESULTS: Smokers' N268 showed significant medial and midline smoking cue-reactivity (ERP to smoking-related minus neutral stimuli); while a P300-like, P412, showed significant smoking cue-reactivity over medial and left hemisphere scalp. FS analyses confirmed most of the foregoing. P412 smoking cue-reactivity was correlated with unpleasantness-pleasantness cue-reactivity but not with urge-to-smoke cue-reactivity. Nonsmokers' N268 stimulus differences were not significant, but significant P412 stimulus effects (unconfirmed by FS analyses) were found in central-to-posterior and in left parietal-temporal areas. CONCLUSIONS: Smokers' N268 is identified with a process detecting stimuli incongruent with tobacco-addicted states; and P412 smoking cue-reactivity is discussed in terms of an automatic, perceptual-categorization system, consistent with Tiffany's drug-use and Johnson's P300 models. Implications of ERP smoking cue-reactivity for study of tobacco and other addictions are discussed.

Prevalence of hypertension in a hemodialysis population.

BACKGROUND: Accurate information on prevalence and status of blood pressure (BP) control in hemodialysis patients is lacking. Our Hemodialysis Quality Improvement Program, sought to determine: 1) The extent and control of hypertension (HTN), 2) whether Erythropoietin (EPO) dose or intradialytic fluid loss had any effect on BP and 3) a means to follow the severity of HTN. PATIENTS AND METHODS: The pre/post mid-week dialysis BP readings of 190 patients (64+/-14.1 years, 53% males, 77% whites) were evaluated over a 3 month period. HTN was defined as BP >150/90. Hypertension was further characterized according to whether the patients had normal or elevated pre-dialysis systolic, pre-dialysis diastolic, post-dialysis systolic or post-diastolic BP readings on more than 6 of the possible 13 recordings. The average EPO dose and weight loss during dialysis was correlated with BP. To better understand the extent of HTN, systolic and diastolic pressures were separately graded from 0 to 3 and a number designated as hypertension sensitivity index (HSI) was assigned to each patient. RESULTS: Of the 190 patients, 146 (76.8%) were hypertensive. 117 out of 146 hypertensive patients (80.1%) had persistent elevation of BP despite being on one or more antihypertensive medications. Most patients were on calcium channel blockers (39%) with 27% being on beta-blockers and 14% on Angiotensin converting enzyme inhibitors. There was no correlation between the number of medications used and the control of HTN. The dose of EPO also had no effect on the degree of HTN. 69.8% of all HTN was systolic. Of this, 64.7% was pre-dialysis and 35.3% post-dialysis. Multiple regression analysis demonstrated a significant correlation with loss of weight during dialysis and lowering of systolic BP (r = 0.33, p = 0.0001). The mean HSI for this population was 2.3+/-1.8. CONCLUSION: HTN was a frequent finding in our hemodialysis population and it was controlled in only 19.9% of hypertensive patients. Most of this HTN was pre-dialysis systolic. There was a significant correlation between fluid loss during dialysis and lowering of blood pressure. The use of the HSI has proven to be helpful in differentiating type and severity of HTN.

Reduced penetrance, variable expressivity, and genetic heterogeneity of familial atrial septal defects.

BACKGROUND: Secundum atrial septal defect (ASD) is a common congenital heart malformation that occurs as an isolated anomaly in 10% of individuals with congenital heart disease. Although some embryological pathways have been elucidated, the molecular etiologies of ASD are not fully understood. Most cases of ASD are isolated, but some individuals with ASD have a family history of this defect or other congenital heart malformations. METHODS AND RESULTS: Clinical evaluation of three families identified individuals with ASD in multiple generations. ASD was transmitted as an autosomal dominant trait in each family. ASD was the most common anomaly, but other heart defects occurred alone or in association with ASD in individuals from each kindred. Genome-wide linkage studies in one kindred localized a familial ASD disease gene to chromosome 5p (multipoint LOD score=3.6, theta=0.0). Assessment of 20 family members with the disease haplotype revealed that 9 had ASD, 8 were clinically unaffected, and 3 had other cardiac defects (aortic stenosis, atrial septal aneurysm, and persistent left superior vena cava). Familial ASD did not map to chromosome 5p in two other families. CONCLUSIONS: Familial ASD is a genetically heterogeneous disorder; one disease gene maps to chromosome 5p. Recognition of the heritable basis of familial ASD is complicated by low disease penetrance and variable expressivity. Identification of ASD or other congenital heart defects in more than one family member should prompt clinical evaluation of all relatives.

The Bjornstad syndrome (sensorineural hearing loss and pili torti) disease gene maps to chromosome 2q34-36.

We report that the Bjornstad syndrome gene maps to chromosome 2q34-36. The clinical association of sensorineural hearing loss with pili torti (broken, twisted hairs) was described >30 years ago by Bjornstad; subsequently, several small families have been studied. We evaluated a large kindred with Bjornstad syndrome in which eight members inherited pili torti and prelingual sensorineural hearing loss as autosomal recessive traits. A genomewide search using polymorphic loci demonstrated linkage between the disease gene segregating in this kindred and D2S434 (maximum two-point LOD score = 4.98 at theta = 0). Haplotype analysis of recombination events located the disease gene in a 3-cM region between loci D2S1371 and D2S163. We speculate that intermediate filament and intermediate filament-associated proteins are good candidate genes for causing Bjornstad syndrome.

Effects of Ayahuasca on the human EEG.

EEG data were recorded under field conditions from 11 members of the Santo Daime Doctrine, a Brazilian shamanistic religion, before and after ingesting the psychoactive alkaloid preparation, ayahuasca, or daime, as they term it. Post-ingestion, we observed increases in power in the 36-44 Hz frequency band ("40 Hz") from the left occipital-temporal-parietal scalp electrodes in the eyes-closed condition, which extended to most of the posterior scalp in the eyes-open condition. The results are consistent with many reports that ayahuasca intensifies visual imagery. These results are discussed in terms of a thalamocortical model of the role of 40 Hz activity in brain function and conscious experience. We also noted tendencies toward decreases in the power of slow (theta and alpha) brain rhythms, and increases in the 14-30 Hz beta band, in accord with studies reported 30 years ago with other consciousness-altering compounds. Analysis of four ayahuasca samples yielded an average composition per ingested dose (75 ml) of 55.6 mg harmine, 43.9 mg tetrahydroharmine, 41.3 mg N,N-dimethyltryptamine (DMT), 4.6 mg harmaline, and 3.1 mg harmol. The DMT appeared to be of sufficient concentration to promote psychoactive effects, while the ß-carbolines functioned to supply MAO inhibitors necessary to prevent degradation of DMT and to maintain its oral activity.

P3B and positive slow wave following real and dummy feedback on arithmetic rule-learning and perceptuomotor tasks.

Event-related Potentials (ERPs) were recorded to feedback during a cognitively demanding, arithmetic rule-learning task and a relatively simple, skill-oriented, perceptuomotor task. For both tasks, a compound feedback display was employed. It consisted of numeric feedback information presented simultaneously with a red or green light (50% each) which indicated whether the numeric information was real (valid) or dummy (invalid). The task and feedback-validity manipulations showed a functional dissociation between the P3b (350-450 msec.) and a Positive Slow Wave (600-900-msec.). P3b was larger for real than for dummy feedback; Positive Slow Wave was larger for rule-learning than for perceptuomotor tasks.

Positive event-related potentials to real and dummy rule-learning feedback and to perceptuomotor feedback.

Amplitudes of 5 event-related potentials (ERPs) were recorded at 5 sites of 10 males to real (R-) and dummy (D-) feedback (FB) over two difficulty levels of a rule-learning task, with interspersed perceptuomotor (PM) task trials. Rule-learning R-FB for positive slow wave (PSW) and P3b was greater than for D-FB for both mean time-window and principal component factor score measures. FB effects varied by site for P2/P3a (mainly Fz-C4-Pz) and for a late PSW (LPSW; mainly C4-C3-Fz). A new ERP, P508, showed the greatest topographic differentiation, but no FB main effect. The following ERPs may reflect different sources: PSW versus P3b; P2/P3a versus LPSW; R-FB versus D-FB P2/P3a; R-FB versus D-FB LPSW; and P508 versus all others. LPSW was greater to simple than complex task difficulty; while the "P508" factor score trended towards being greater for complex than simple. ERP interpretation is in terms of stimulus recognition classification, comparative evaluation and development elaboration of mental models. Rule-learning D-FB exceeded PM accuracy R-FB for all ERPs but P2/P3a. Strongly implicated in these differences are preparatory acts in the former task as reflected by the PSW and LPSW.

Event-related potentials in a guessing task: the gleam in the eye effect.

Event-related potentials (ERPs) were recorded from a single subject performing a forced-choice guessing task. On each trial, ERPs were elicited by four, sequential, graphic images; 2 1/2 seconds after the last stimulus was delivered, the subject guessed which of the four images was experimentally (randomly) designated as the target. P200 had greater amplitude over the posterior scalp for stimuli which were guessed by the subject to be targets than for not-guessed stimuli. The amplitude of the P100, N100, and P300 components was unrelated to the subject's guess. A positive displacement evident in the waveforms from about 150-500 ms post-stimulus onset suggested that Slow Wave may have been partially responsible for the observed differences. These results suggest that ERPs may contain predictive information about a subject's subsequent responses in forced-choice guessing tasks. We termed this the "gleam in the eye" effect.

Manganese superoxide dismutase is induced by IFN-gamma in multiple cell types. Synergistic induction by IFN-gamma and tumor necrosis factor or IL-1.

We have previously characterized more than 20 proteins induced by the immunoregulatory lymphokine IFN-gamma in human fibroblasts by their m.w. and isoelectric points determined in two-dimensional gels. Some of these proteins are induced uniquely by IFN-gamma, whereas others are also induced by IFN-alpha, TNF, or IL-1. Recent technologic advances have allowed us to begin to rapidly identify proteins induced by IFN-gamma and other cytokines by sequencing the induced proteins from blots of preparative two-dimensional gels of total cell lysates. In this study, we show that the approximately 21 kDa, isoelectric point greater than 7 protein induced by IFN-gamma is manganese superoxide dismutase (Mn-SOD), a mitochondrial protective enzyme encoded by a nuclear gene. Mn-SOD is induced by IFN-gamma and also by TNF in all four human cell lines examined: HS153 fibroblasts, ACHN renal carcinoma, A549 lung carcinoma, and A375 melanoma. Induction of Mn-SOD mRNA is a primary, rapid, and dose-dependent response to IFN-gamma. In ACHN renal carcinoma cells, Mn-SOD mRNA and protein are induced synergistically by IFN-gamma in combination with either TNF or IL-1, and the induced protein is enzymatically active. IFN-gamma and TNF together induce Mn-SOD mRNA by more than 100-fold relative to its level in untreated ACHN cells. The induction of Mn-SOD by IFN-gamma and its synergistic induction by IFN-gamma in combination with TNF and IL-1 should protect healthy cells from the toxicity of O2- during an immune response, and may provide a mechanism for selective killing of infected cells.

Medicine and the media.

Whether physicians like it or not, the media is playing a growing role in the care of patients. Physicians must be prepared to deal with growing patient awareness of their health, and they must provide balance for inaccurate information when it is presented. For the physician grappling with this emerging situation, a careful understanding of medicine and the media is essential.

Experience with 11,916 designated donors.

From June, 1984, through December, 1985, Irwin Memorial Blood Bank drew 11,916 designated donors. The original protocol, filled with barriers that the donors and patients had to follow, was changed to an open protocol that was easy to follow. Patients wanted to participate in the program regardless of the obstacles so we removed them, making it easier for the patients and donors as well as the staff at the blood bank. 3063 designated donors were compared to 3201 homologous and 3439 first-time, non-designated donors. The three groups did not differ in any of the comparisons, deferral rate, age, sex, race, blood type, and test results. We conclude that these designated donations were no safer but no less safe than donations not designated.