Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder.

Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy caused by mutations or rearrangements in PLP1. It presents in infancy with nystagmus, jerky head movements, hypotonia and developmental delay evolving into spastic tetraplegia with optic atrophy and variable movement disorders. A clinically similar phenotype caused by recessive mutations in GJC2 is known as Pelizaeus-Merzbacher-like disease. Both genes encode proteins associated with myelin. We describe three siblings of a consanguineous family manifesting the typical infantile-onset Pelizaeus-Merzbacher disease-like phenotype slowly evolving into a form of complicated hereditary spastic paraplegia with mental retardation, dysarthria, optic atrophy and peripheral neuropathy in adulthood. Magnetic resonance imaging and spectroscopy were consistent with a demyelinating leukodystrophy. Using genetic linkage and exome sequencing, we identified a homozygous missense c.399C>G; p.S133R mutation in MAG. This gene, previously associated with hereditary spastic paraplegia, encodes myelin-associated glycoprotein, which is involved in myelin maintenance and glia-axon interaction. This mutation is predicted to destabilize the protein and affect its tertiary structure. Examination of the sural nerve biopsy sample obtained in childhood in the oldest sibling revealed complete absence of myelin-associated glycoprotein accompanied by ill-formed onion-bulb structures and a relatively thin myelin sheath of the affected axons. Immunofluorescence, cell surface labelling, biochemical analysis and mass spectrometry-based proteomics studies in a variety of cell types demonstrated a devastating effect of the mutation on post-translational processing, steady state expression and subcellular localization of myelin-associated glycoprotein. In contrast to the wild-type protein, the p.S133R mutant was retained in the endoplasmic reticulum and was subjected to endoplasmic reticulum-associated protein degradation by the proteasome. Our findings identify involvement of myelin-associated glycoprotein in this family with a disorder affecting the central and peripheral nervous system, and suggest that loss of the protein function is responsible for the unique clinical phenotype.

The potential application of a transcriptionally regulated oncolytic herpes simplex virus for human cancer therapy.

BACKGROUND: Emerging studies have shown the potential benefit of arming oncolytic viruses with therapeutic genes. However, most of these therapeutic genes are placed under the regulation of ubiquitous viral promoters. Our goal is to generate a safer yet potent oncolytic herpes simplex virus type-1 (HSV-1) for cancer therapy. METHODS: Using bacterial artificial chromosome (BAC) recombineering, a cell cycle-regulatable luciferase transgene cassette was replaced with the infected cell protein 6 (ICP6) coding region (encoded for UL39 or large subunit of ribonucleotide reductase) of the HSV-1 genome. These recombinant viruses, YE-PC8, were further tested for its proliferation-dependent luciferase gene expression. RESULTS: The ability of YE-PC8 to confer proliferation-dependent transgene expression was demonstrated by injecting similar amount of viruses into the tumour-bearing region of the brain and the contralateral normal brain parenchyma of the same mouse. The results showed enhanced levels of luciferase activities in the tumour region but not in the normal brain parenchyma. Similar findings were observed in YE-PC8-infected short-term human brain patient-derived glioma cells compared with normal human astrocytes. intratumoural injection of YE-PC8 viruses resulted in 77% and 80% of tumour regression in human glioma and human hepatocellular carcinoma xenografts, respectively. CONCLUSION: YE-PC8 viruses confer tumour selectivity in proliferating cells and may be developed further as a feasible approach to treat human cancers.

Investigating the neural correlates of psychopathy: a critical review.

In recent years, an increasing number of neuroimaging studies have sought to identify the brain anomalies associated with psychopathy. The results of such studies could have significant implications for the clinical and legal management of psychopaths, as well as for neurobiological models of human social behavior. In this article, we provide a critical review of structural and functional neuroimaging studies of psychopathy. In particular, we emphasize the considerable variability in results across studies, and focus our discussion on three methodological issues that could contribute to the observed heterogeneity in study data: (1) the use of between-group analyses (psychopaths vs non-psychopaths) as well as correlational analyses (normal variation in 'psychopathic' traits), (2) discrepancies in the criteria used to classify subjects as psychopaths and (3) consideration of psychopathic subtypes. The available evidence suggests that each of these issues could have a substantial effect on the reliability of imaging data. We propose several strategies for resolving these methodological issues in future studies, with the goal of fostering further progress in the identification of the neural correlates of psychopathy.

Successful parathyroidectomy improves cognition in patients with primary hyperparathyroidism: A prospective study in a tertiary medical center and comprehensive review of the literature.

Context: The recent American and European guidelines on management of patients with primary hyperparathyroidism (PHPT) did not endorse neurocognitive evaluation as part of standard work-up and did not consider it as a surgery criterion.The neurocognitive deleterious effects of hyperparathyroidism and impact of parathyroidectomy on PHPT patients is yet to be elucidated. Objective: To evaluate specific neurocognitive functions in PHPT patients prior to parathyroidectomy and describe the changes during follow-up with serial evaluations. Design: A prospective case-control study including parathyroidectomy candidates evaluated at a tertiary teaching university hospital. Thorough neurocognitive evaluation was conducted before and 1- & 6-months following parathyroidectomy: Rey Auditory Verbal Learning Test (RAVLT), Rey-Osterrieth Complex Figure Test (ROCF), Trail Making Test A, Trail Making Test B, Addenbrooke's Cognitive Examination-III (ACE), Frontal Assessment Battery (FAB), Beck Depression Inventory (BDI). Results: 18 consecutive patients underwent successful parathyroidectomy. Various neurocognitive functions improved significantly after successful parathyroidectomy: long term auditory memory (RAVLT, p=0.008), short- and long-term visual memory (ROCF, p=0.006 and p=0.002 respectively), visual attention and complex concentration skills (trail making A, p<0.001) and executive abilities (trail making B, p=0.005). No change was identified in frontal-lobe abilities. Depression symptoms were absent or minimal prior to surgery and no significant change was observed after surgery. Conclusions: PHPT is associated with significant various neurocognitive dysfunctions when mindfully evaluated before surgery. Successful parathyroidectomy results in several neurocognitive aspect improvements. The data suggest that neurocognitive deterioration may be considered an added parathyroidectomy criterion when surgical decision is not straightforward.

Hereditary spastic paraplegia with thin corpus callosum: reduction of the SPG11 interval and evidence for further genetic heterogeneity.

BACKGROUND: Hereditary spastic paraplegia (HSP) with thin corpus callosum (TCC) is an autosomal recessive form of complicated HSP mainly characterized by slowly progressive spastic paraparesis and mental deterioration beginning in the second decade of life. The locus for HSP-TCC, designated SPG11, was mapped to chromosome 15q13-15 in some of the affected families from Japan, Europe, and North America, spanning an interval of 17.5 megabases (Mb). OBJECTIVE: To perform a clinical and genetic study of HSP-TCC. DESIGN AND SETTING: Case series; multi-institutional study. PATIENTS: Seven patients with HSP-TCC who belong to 3 consanguineous families of Arab origin residing in Israel. RESULTS: The 7 patients manifested a relatively similar combination of adolescence-onset cognitive decline and spastic paraparesis with TCC on brain magnetic resonance imaging. After excluding the SPG7 locus, we tested the 3 families for linkage to the SPG11, SPG21/MAST, and ACCPN loci associated with autosomal recessive disorders with TCC. Two families showed evidence for linkage to SPG11 (Z(max) = 5.55) and reduced the candidate region to 13 Mb. CONCLUSIONS: Our findings in HSP-TCC further confirm its worldwide distribution and genetic heterogeneity, and they significantly reduce the candidate SPG11 interval.

Early clinical heterogeneity in choreoacanthocytosis.

BACKGROUND: Choreoacanthocytosis (CHAC) is a slowly progressive multisystem disorder with involuntary movements, cognitive decline, behavioral changes, seizures, and polyneuropathy caused by mutations in the VPS13A gene. OBJECTIVE: To describe the early clinical features and possible genotype-phenotype correlation in CHAC. DESIGN AND SETTING: Case series in a tertiary care center. PATIENTS AND MAIN OUTCOME METHODS: Choreoacanthocytosis was diagnosed in 3 patients of Jewish origin from 3 unrelated families. We reviewed their medical histories and performed molecular analysis by screening all 73 exons of VPS13A. RESULTS: Trichotillomania, hypertrophic cardiomyopathy, and idiopathic hyperCKemia, in 1 patient each, preceded the development of the full clinical spectrum of CHAC by 2 to 20 years. At diagnosis, 2 patients manifested signs of overt neuromuscular involvement and were homozygous for the 6059delC mutation, whereas 1 patient had only hyporeflexia and was homozygous for the EX23del mutation. Because only 1 of the 2 patients with 6059delC had cardiomyopathy, its relevance to CHAC is unclear. CONCLUSIONS: These findings extend the knowledge of significant early clinical heterogeneity in CHAC and suggest a possible genotype-phenotype correlation. Awareness of the early manifestations may prevent misdiagnosis and enable appropriate genetic counseling.

Brief assessment of cognitive mental status in Hebrew: Addenbrooke's Cognitive Examination.

We describe a new brief neurocognitive assessment instrument, Addenbrooke's Cognitive Examination, which is built around the shell of the Mini-Mental State Examination but which assesses a wider range of cognitive functions specific to various dementing diseases such as Alzheimer's disease and frontotemporal dementia. A Hebrew-language adaptation of the instrument is also provided.

Reflectivity and learning from aversive events: toward a psychological mechanism for the syndromes of disinhibition.

Gorenstein and Newman (1980) proposed that poorly modulated responding for reward is the common diathesis underlying disinhibited behavior in several traditionally distinct person categories: psychopathy, hysteria, early onset alcoholism, childhood hyperactivity, and nonpathological impulsivity (e.g., extraversion). The authors extend this proposal by theorizing a psychological mechanism that highlights relations among disinhibition, reflection, and failures to learn from aversive feedback. The hypothesized mechanism is presented as 4 generic stages of response modulation: the dominant response set, the reaction to an aversive event, the subsequent behavioral adaptation, and the immediate and long-term consequences of reflection, or the lack thereof. The mechanism has implications for disinhibited individuals' impulsivity and provides a point of departure to study factors responsible for similarities and differences among these syndromes.

Sucrose and delinquency: oral sucrose tolerance test and nutritional assessment.

Claims that juvenile delinquency may be associated with reactive hypoglycemia or nutritional deficiencies have received widespread attention but little objective evaluation. To assess the validity of these claims, nutritional and psychological indices of juvenile delinquents have been measured. Serum glucose and insulin profiles during an oral sucrose tolerance test were measured in 137 delinquent and 41 nondelinquent male adolescents aged 14 to 19. In addition, nutritional status of both populations was assessed by anthropometry (height, weight, arm circumference, triceps skin fold) and biochemical measures (hematocrit, red-blood cell thiamin, and serum copper, ferritin, and zinc). Delinquent subjects had slightly but significantly lower serum glucose values at four of six time points (fasting, 60 minutes, 120 minutes, 180 minutes) and higher serum insulin values at one time point (30 minutes) compared with nondelinquent subjects. Changes in glucose from fasting levels indicate that these subjects were regulating serum glucose adequately, but doing so at lower values; changes in insulin from fasting levels indicate that black delinquents initially secreted more insulin than either white subject group. There were no significant associations between excursions in serum glucose or insulin and any adrenergic signs or symptoms of low blood glucose levels. Nutritional status of incarcerated delinquents did not differ from that of nonincarcerated subjects on most measures. Although the significantly lower serum glucose levels and higher serum insulin levels are intriguing, no support is offered by results of this study for allegations that sucrose ingestion causes reactive hypoglycemia in juvenile delinquents or that delinquent male adolescents are at greater risk nutritionally than male adolescents of the same age who are not delinquent.(ABSTRACT TRUNCATED AT 250 WORDS)

Sucrose and delinquency: behavioral assessment.

In this study, a double-blind challenge design was used to evaluate the hypothesis that sucrose ingestion may compromise the behavioral performance of juvenile delinquents. Subjects were 58 white delinquents, 57 black delinquents, and 39 white nondelinquents. The behavioral assessment included tasks that are relevant to delinquency and that might be expected to be disrupted following sucrose ingestion. The results provide no evidence that sucrose ingestion impairs the performance of juvenile delinquents. In fact, the results of several analyses indicated that the sucrose breakfast was associated with improved performance. In additional analyses the effect of sucrose on particular subgroups of juvenile delinquents was evaluated. Statistical interactions indicated that the performance of delinquents rated as more behaviorally disturbed benefited from sucrose ingestion, whereas those delinquents with less pronounced behavior problems tended to show impaired performance following a sucrose-loaded breakfast. These results indicate that simple statements regarding the effects of sucrose ingestion on behavior are likely to be misleading and highlight the need to consider individual difference variables when investigating the effects of sucrose on juvenile delinquents.

Regional cerebral blood flow in patients with mild hypothyroidism.

UNLABELLED: Emotional and cognitive abnormalities are common in adult hypothyroidism. Few studies, however, have evaluated cerebral perfusion and metabolism in this disorder. The aims of this study were to compare regional cerebral blood flow (rCBF) between hypothyroid patients and healthy subjects and assess flow during the euthyroid state after treatment. METHODS: Ten mildly hypothyroid patients, before and after thyroxine treatment, and 10 healthy controls underwent 99mTc-hexamethylpropyleneamine oxime brain SPECT, MRI, and psychometric testing. SPECT images were analyzed using statistical parametric mapping. RESULTS: Compared with controls, rCBF in patients before treatment was lower in right parietooccipital gyri, cuneus, posterior cingulate, lingual gyrus, fusiform, insula, and pre- and postcentral gyri. Perfusion did not normalize on a return to the euthyroid state. CONCLUSION: Decreased rCBF in mild hypothyroidism is found in regions mediating attention, motor speed, memory, and visuospatial processing, faculties affected in hypothyroidism. Follow-up studies are needed to determine the longer-term persistence of perfusion abnormalities in this disorder.

Hemodynamic and metabolic responses to moderate asphyxia in brain and skeletal muscle of late-gestation fetal sheep.

The purpose of this study was to investigate metabolic and hemodynamic responses in two fetal tissues, hindlimb muscle and brain, to an episode of acute moderate asphyxia. Near-infrared spectroscopy was used to measure changes in total hemoglobin concentration ([tHb]) and the redox state of cytochrome oxidase (COX) simultaneously in the brain and hindlimb of near-term unanesthetized fetal sheep in utero. Oxygen delivery (DO(2)) to, and consumption (VO(2)) by, each tissue was derived from the arteriovenous difference in oxygen content and blood flow, measured by implanted flow probes. One hour of moderate asphyxia (n = 11), caused by occlusion of the maternal common internal iliac artery, led to a significant fall in DO(2) to both tissues and to a significant drop in VO(2) by the head. This was associated with an initial fall in redox state COX in the leg but an increase in the brain. [tHb], and therefore blood volume, fell in the leg and increased in the brain. These data suggest the presence of a fetal metabolic response to hypoxia, which, in the brain, occurs rapidly and could be neuroprotective.

Generality of Psychopathy Checklist-Revised factors over prisoners and substance-dependent patients.

The Psychopathy Checklist-Revised (PCL-R; R. D. Hare, 1991) is an often-used device for assessment of adult antisociality. This research examined generalizability by replicating the 2-factor model for a sample of 326 male prisoners and assessing its congruence and relative reliability and specificity among 620 substance-dependent patients. Generality was assessed also across addiction subtypes (opioid, cocaine, and alcohol), age, gender, and ethnicity. The 2-factor model was found inappropriate for the substance-dependent samples, whereas a unidimensional model represented by the PCL-R total score was found generalizable across prison and substance-dependent samples.

Alcohol and drug abuse-dependence disorders in psychopathic and nonpsychopathic criminal offenders.

Co-occurrence of psychopathy (assessed with the Psychopathy Checklist) and lifetime Diagnostic and Statistical Manual of Mental Disorders (3rd ed.) alcohol and drug disorders (assessed with the National Institute of Mental Health Diagnostic Interview Schedule) was examined in a sample of 360 male inmates. Consistent with previous research that used diagnoses of antisocial personality disorder, psychopaths were more likely than nonpsychopaths to have lifetime diagnoses of alcoholism, any drug disorder, and multiple drug disorders. We also examined the relation between substance abuse and the 2 factors of the Psychopathy Checklist. Substance abuse was significantly related to general social deviance (Factor 2) but was unrelated to core personality features of psychopathy (Factor 1). We present two possible models of psychopathy (unitary syndrome vs. dual-diathesis model) that may account for the association between psychopathy and substance abuse.

Response perseveration in psychopathic women.

Recent attempts to validate the Psychopathy Checklist-Revised (PCL-R) as a measure of psychopathy in female offenders have been limited by a failure to examine laboratory correlates of the syndrome. We assessed 112 incarcerated women by using the PCL-R and examined their performance on a card perseveration task that has been used to demonstrate response perseveration in psychopathic men. Contrary to prediction, psychopathic women did not perseverate responding when the PCL-R was used either dimensionally or categorically. The authors discuss the implications of the results for the PCL-R and for female psychopathy more generally.

Passive avoidance in psychopathic offenders: a replication and extension.

A passive avoidance task was administered to 97 Caucasian and 110 African American offenders to (a) replicate prior research demonstrating poor passive avoidance in psychopathic individuals (Ps) with low anxiety, (b) compare the effects of anxiety, neuroticism, and fear in identifying subgroups of Ps and controls who differ in passive avoidance, and (c) reevaluate the generalizability of this finding to African American offenders. Replicating past research with Caucasian offenders, low-anxious Ps committed significantly more passive avoidance errors than low-anxious controls. Although this difference was also found in Ps and controls with low neuroticism scores, the comparison involving low-fear offenders failed to reach significance. As in past research, comparable comparisons involving African American offenders were not statistically significant.

Are all psychopathic individuals low-anxious?

Theorists commonly assume that true or primary psychopathic individuals experience little anxiety or neurotic conflict. This study examined the relationship between psychopathy and anxiety in 104 Caucasian and 113 African American incarcerated men using the Psychopathy Checklist--Revised (PCL-R; R. D. Hare, 1991) and multiple self-report measures to tap diverse interpretations of the anxiety construct (i.e., neuroticism, traditional definitions of anxiety, and fear). Analyses involving zero-order, semipartial, and point-biserial correlations indicate that PCL-R psychopathy and the anxiety construct are essentially independent. These findings suggest that either (a) the traditional belief that all psychopathic individuals are low-anxious is incorrect or (b) the PCL-R is not an adequate measure of primary psychopathy.

Evaluating the construct validity of psychopathy in black and white male inmates: three preliminary studies.

Although Black inmates represent almost half the population of United States prisons and have been included in several studies of psychopathy, there appear to be no published studies to date addressing the validity of the psychopathy construct in Black inmates. Three studies were conducted to assess the validity of the construct in Black male inmates using Hare's Psychopathy Checklist (PCL). In Study 1, we examined the internal structure of the PCL and the relation of checklist scores to several constructs relevant to psychopathy. We observed differences between Blacks and Whites in the distribution of psychopathy scores, in the relation of psychopathy to measures of impulsivity, and in the congruence of the underlying factor structure of the PCL. In Study 2, Black psychopaths were found to manifest a pattern of passive avoidance deficits similar but not identical to that reported for White psychopaths in Newman and Kosson's study. Study 3 demonstrated that psychopaths of both races receive more criminal charges in a wider variety of offense categories than do nonpsychopaths. The psychopathy construct appears tentatively applicable to Blacks, although its components may be somewhat different than for Whites.

Delay of gratification in psychopathic and nonpsychopathic offenders.

Delay of gratification is a prototypical measure of self-control that merits systematic investigation in psychopaths. White male prisoners were provided with repeated opportunities to select an immediate response with uncertain reward or a delayed response with a higher rate of reward under one of three incentive conditions. Psychopaths' performance depended on their level of trait anxiety and incentive condition: Whereas low-anxious psychopaths were relatively unwilling to delay when omission of expected rewards also incurred monetary punishments, they displayed relatively superior performance when the task involved rewards only. Findings complement those for passive avoidance learning in psychopaths and suggest that inhibitory self-control in low-anxious psychopaths is somewhat impaired under conditions involving a combination of monetary rewards and punishments.

The impact of motivationally neutral cues on psychopathic individuals: assessing the generality of the response modulation hypothesis.

Psychopathic individuals' lack of responsiveness to punishment cues and poor self-regulation have been attributed to fearlessness (D. T. Lykken, 1957, 1982, 1995). Alternatively, deficient response modulation (RM) may hinder the psychopathic individual's processing of peripheral information and self-regulation when they are engaged in goal-directed behavior (C. M. Patterson & J. P. Newman, 1993). Although more specific than the fearlessness hypothesis in some respects, the RM hypothesis makes the more general prediction that psychopathic individuals will have difficulty processing motivationally neutral as well as fear-related stimuli. The authors assessed this prediction by using psychopathic and nonpsychopathic male inmates subdivided by level of anxiety/negative affectivity (NA). As predicted by the RM hypothesis, peripheral presentation of motivationally neutral cues produced significantly less interference in low-NA psychopathic individuals than in low-NA controls.