Anosognosia Is Associated With Greater Caregiver Burden and Poorer Executive Function in Huntington Disease.

BACKGROUND: Anosognosia, or unawareness of one's deficits, is estimated to occur in 25% to 50% of Huntington disease (HD). The relationship between anosognosia and increased caregiver burden found in other dementias has not been determined in HD. METHODS: Patient-caregiver dyads presenting to a statewide HD clinic were assessed using the Anosognosia Scale and grouped into "anosognosia" and "no anosognosia." Caregiver burden, measured by Zarit Burden Interview (ZBI) and Caregiver Burden Inventory (CBI), demographic data, and Unified Huntington's Disease Rating Scale, including Mini-Mental State Examination, Stroop, Trail Making, Verbal Fluency, and Symbol Digit Modalities Tests, were compared between groups. RESULTS: Of the 38 patients recruited, 10 (26.3%) met criteria for anosognosia. Patients with anosognosia elicited higher caregiver burden ratings on both the ZBI (mean difference 16.4 [12.1], P < .001) and CBI (16.7 [15.0], P < .005) while also demonstrating poorer executive function. Except for CAG burden score, between-group characteristics did not differ significantly. Stroop Interference predicted both anosognosia and caregiver burden. CONCLUSIONS: In HD, anosognosia is associated with greater caregiver burden and executive deficits. Its occurrence should prompt further patient assessment and increased caregiver support.

Radiation Damage of Myoglobin Crystals in Weak Stationary Electric and Magnetic Fields.

Radiation damage is one of the bottlenecks in the field of structural biology. Cryo-cooling of protein crystals provided a breakthrough in the 1980s and resulted in significant reductions in radiation damage. Other factors positively influencing the progression of damage include the application of radical scavengers and reductions in the experimental beam size. Here we study the impact on radiation damage of applying static magnetic and electric fields during protein diffraction experiments, ultimately probing the Lorenz force effect on primary photoelectrons and secondary Auger electrons, which both contribute to the damage process. The design of a special mounting pin using graphene for applying electric fields on a crystalline sample is described. Analyses of myoglobin protein crystals exposed to the fields of ~40 mT and -300 V show a slower global radiation damage rate and also changes in the progression of specific damage process on the molecular level, in particular at doses extending beyond the Garman limit of 30 MGy.

Genome-wide supported variant MIR137 and severe negative symptoms predict membership of an impaired cognitive subtype of schizophrenia.

Progress in determining the aetiology of schizophrenia (Sz) has arguably been limited by a poorly defined phenotype. We sought to delineate empirically derived cognitive subtypes of Sz to investigate the association of a genetic variant identified in a recent genome-wide association study with specific phenotypic characteristics of Sz. We applied Grade of Membership (GoM) analyses to 617 patients meeting ICD-10 criteria for Sz (n=526) or schizoaffective disorder (n=91), using cognitive performance indicators collected within the Australian Schizophrenia Research Bank. Cognitive variables included subscales from the Repeatable Battery for the Assessment of Neuropsychological Status, the Controlled Oral Word Association Test and the Letter Number Sequencing Test, and standardised estimates of premorbid and current intelligence quotient. The most parsimonious GoM solution yielded two subtypes of clinical cases reflecting those with cognitive deficits (CDs; N=294), comprising 47.6% of the sample who were impaired across all cognitive measures, and a cognitively spared group (CS; N=323) made up of the remaining 52.4% who performed relatively well on all cognitive tests. The CD subgroup were more likely to be unemployed, had an earlier illness onset, and greater severity of functional disability and negative symptoms than the CS group. Risk alleles on the MIR137 single-nucleotide polymorphism (SNP) predicted membership of CD subtype only in combination with higher severity of negative symptoms. These findings provide the first evidence for association of the MIR137 SNP with a specific Sz phenotype characterised by severe CDs and negative symptoms, consistent with the emerging role of microRNAs in the regulation of proteins responsible for neural development and function.

Promoter polymorphisms in two overlapping 6p25 genes implicate mitochondrial proteins in cognitive deficit in schizophrenia.

In a previous study, we detected a 6p25-p24 region linked to schizophrenia in families with high composite cognitive deficit (CD) scores, a quantitative trait integrating multiple cognitive measures. Association mapping of a 10 Mb interval identified a 260 kb region with a cluster of single-nucleotide polymorphisms (SNPs) significantly associated with CD scores and memory performance. The region contains two colocalising genes, LYRM4 and FARS2, both encoding mitochondrial proteins. The two tagging SNPs with strongest evidence of association were located around the overlapping putative promoters, with rs2224391 predicted to alter a transcription factor binding site (TFBS). Sequencing the promoter region identified 22 SNPs, many predicted to affect TFBSs, in a tight linkage disequilibrium block. Luciferase reporter assays confirmed promoter activity in the predicted promoter region, and demonstrated marked downregulation of expression in the LYRM4 direction under the haplotype comprising the minor alleles of promoter SNPs, which however is not driven by rs2224391. Experimental evidence from LYRM4 expression in lymphoblasts, gel-shift assays and modelling of DNA breathing dynamics pointed to two adjacent promoter SNPs, rs7752203-rs4141761, as the functional variants affecting expression. Their C-G alleles were associated with higher transcriptional activity and preferential binding of nuclear proteins, whereas the G-A combination had opposite effects and was associated with poor memory and high CD scores. LYRM4 is a eukaryote-specific component of the mitochondrial biogenesis of Fe-S clusters, essential cofactors in multiple processes, including oxidative phosphorylation. LYRM4 downregulation may be one of the mechanisms involved in inefficient oxidative phosphorylation and oxidative stress, increasingly recognised as contributors to schizophrenia pathogenesis.

Polymorphisms associated with normal memory variation also affect memory impairment in schizophrenia.

Neurocognitive dysfunction is a core feature of schizophrenia with particularly prominent deficits in verbal episodic memory. The molecular basis of this memory impairment is poorly understood and its relatedness to normal variation in memory performance is unclear. In this study, we explore, in a sample of cognitively impaired schizophrenia patients, the role of polymorphisms in seven genes recently reported to modulate episodic memory in normal subjects. Three polymorphisms (GRIN2B rs220599, GRM3 rs2189814 and PRKCA rs8074995) were associated with episodic verbal memory in both control and patients with cognitive deficit, but not in cognitively spared patients or the pooled schizophrenia sample. GRM3 and PRKCA acted in opposite directions in patients compared to controls, possibly reflecting an abnormal brain milieu and/or adverse environmental effects in schizophrenia. The encoded proteins balance glutamate signalling vs. excitotoxicity in complex interactions involving the excitatory amino acid transporter 2 (EAAT2), implicated in the dysfunctional glutamatergic signalling in schizophrenia. Double carrier status of the GRM3 and PRKCA minor alleles was associated with lower memory test scores and with increased risk of schizophrenia. Single nucleotide polymorphism (SNP) rs8074995 lies within the PRKCA region spanned by a rare haplotype associated with schizophrenia in a recent UK study and provides further evidence of PRKCA contribution to memory impairment and susceptibility to schizophrenia. Our study supports the utility of parsing the broad phenotype of schizophrenia into component cognitive endophenotypes that reduce heterogeneity and enable the capture of potentially important genetic associations.

'Social dysmetria' in first-episode psychosis patients.

OBJECTIVE: The 'embodied cognition' hypothesis suggests a close relationship between internal self-representations and the outward expression of social behaviours and emotions. Given self-awareness disturbances in patients with first-rank symptoms (FRS), we hypothesized that these patients would show abnormal social behaviours. In this study, we examined the social interactive skills of patients with first-episode psychosis during an interview, together with changes in performance over time. METHOD: We analysed previously unreported data from 227 patients with first-episode psychosis (90 with, and 137 without, FRS) who took part in the WHO multicentre study on the Determinants of Outcome of Severe Mental Disorders. They were assessed on the Psychological Impairment Rating Schedule (PIRS) and examined again after 2 years. RESULTS: A principal component analysis on the Psychosocial Impairment Rating Schedule produced two factors (interactive skills; withdrawal from interactions). Patients with FRS showed greater impairments in the domain linked to 'interactive skills', which remained 2 years after the first experience of a psychotic illness. These findings were not explained by clinical characteristics, or presence of non-FRS delusions. CONCLUSION: Self-awareness deficits, as indexed by the FRS symptom cluster, are linked to deficits in social interactive behaviours. These abnormalities are indicative of 'social dysmetria' in this group, which involves difficulties conveying motor aspects of behaviours, volition and affect to facilitate mutual communication. These findings point to the utility of behavioural assessment scales in clinical and research settings.

Neuregulin 3 (NRG3) as a susceptibility gene in a schizophrenia subtype with florid delusions and relatively spared cognition.

Linkage of 10q22-q23 to schizophrenia and the recently reported association of Neuregulin 3 (NRG3) polymorphisms with high 'delusion factor' scores led us to attempt replication and further refinement of these findings in a sample of 411 schizophrenic patients and 223 nonpsychiatric control subjects. Using quantitative cognitive traits, patients were grouped into a cluster with pervasive cognitive deficit (CD) and a cluster with relatively spared cognition (CS). We found a significant association between rs6584400 and schizophrenia, with a trend for rs10883866. Post hoc analysis revealed that this result was mainly due to the CS cluster, characterized by elevated scores on Schneiderian first-rank symptoms, salience of complex delusions and positive thought disorder--thus closely related to the 'delusion factor'. In addition, both rs6584400 and rs10883866 were associated with the degraded-stimulus continuous performance task in which 'risk' alleles were associated with better than average performance in patients and worse performance in controls. This suggests that NRG3 may be modulating early attentional processes for perceptual sensitivity and vigilance, with opposite effects in affected individuals and healthy controls. The two single-nucleotide polymorphisms are in close proximity to the alternative first exons of the NRG3-a, -b and -d isoforms, of which the human brain-specific NRG-b appears to be the most interesting candidate.

Handedness in schizophrenia: a quantitative review of evidence.

OBJECTIVE: The prevalence of various anomalous handedness subtypes in schizophrenia patients remains ambiguous. Although current literature favours the notion that the shift in lateral preferences seen is because of an increase of mixed-handedness, several studies suggest that exclusive left handedness is more prevalent than in the general population. METHOD: Over 40 studies with reported prevalence data on various handedness subtypes in a schizophrenia population were evaluated by meta-analysis. Combined odds ratios for the three common handedness subtypes (left, mixed, and right) were separately calculated. RESULTS: Each of the three atypical hand dominance patterns were significantly greater in schizophrenia patients than in control subjects, showing that the leftward shift in handedness distribution is not entirely because of an increase in mixed-handedness alone. CONCLUSION: An increase of exclusive left-handedness is at variance with the prevailing assertion that the handedness shift in schizophrenia patients is because of a diffuse and bilateral hemispheric insult.

Linkage analysis of candidate regions using a composite neurocognitive phenotype correlated with schizophrenia.

As schizophrenia is genetically and clinically heterogeneous, systematic investigations are required to determine whether ICD-10 or DSM-IV categorical diagnoses identify a phenotype suitable and sufficient for genetic research, or whether correlated phenotypes incorporating neurocognitive performance and personality traits provide a phenotypic characterisation that accounts better for the underlying variation. We utilised a grade of membership (GoM) model (a mathematical typology developed for studies of complex biological systems) to integrate multiple cognitive and personality measurements into a limited number of composite graded traits (latent pure types) in a sample of 61 nuclear families comprising 80 subjects with ICD-10/DSM-IV schizophrenia or schizophrenia spectrum disorders and 138 nonpsychotic first-degree relatives. GoM probability scores, computed for all subjects, allowed individuals to be partly assigned to more than one pure type. Two distinct and contrasting neurocognitive phenotypes, one familial, associated with paranoid schizophrenia, and one sporadic, associated with nonparanoid schizophrenia, accounted for 74% of the affected subjects. Combining clinical diagnosis with GoM scores to stratify the entire sample into liability classes, and using variance component analysis (SOLAR), in addition to parametric and nonparametric multipoint linkage analysis, we explored candidate regions on chromosomes 6, 10 and 22. The results indicated suggestive linkage for the familial neurocognitive phenotype (multipoint MLS 2.6 under a low-penetrance model and MLS>3.0 under a high-penetrance model) to a 14 cM area on chromosome 6, including the entire HLA region. Results for chromosomes 10 and 22 were negative. The findings suggest that the familial neurocognitive phenotype may be a pleiotropic expression of genes underlying the susceptibility to paranoid schizophrenia. We conclude that use of composite neurocognitive and personality trait measurements as correlated phenotypes supplementing clinical diagnosis can help stratify the liability to schizophrenia across all members of families prior to linkage, allow the search for susceptibility genes to focus selectively on subsets of families at high genetic risk, and augment considerably the power of genetic analysis.

New cyclization reaction at the amino terminus of peptides and proteins.

Mild oxidation with periodate of the 1-amino-2-ol moiety of N-terminal seryl or threonyl peptides and proteins leads to a terminal aldehyde function O=CH-CO- which usually may be exploited for bioconjugate formation (e.g., via oximation with an O-alkyl hydroxylamine). We report that, when followed by a prolyl residue, the O=CH-CO- group can undergo a rapid cyclization and dehydration reaction through nucleophilic attack by the amide nitrogen of the third amino acid residue of the chain. We have characterized the resulting heterocycle, which is stable in aqueous acid, by mass spectrometry and NMR. Quantitative oximation can nevertheless be achieved in such cases by performing a one-pot oxidation-oximation without isolation of the intermediate aldehyde, as is demonstrated with cholera toxin B subunit.

[Surgical procedures in acute pancreatitis]. / Operativni postupci pri akutnom pankreatitsu.

The author points out the increased hepatobiliar intracanalicular pressure represents one of the factors responsible for the development of acute pancreatitis. Decompression of ductus choledochus by T-drainage or by reestablishment of the flow of pancreatico-biliary secretion through the Vater's papilla leads to the fall of the pressure in ductus choledochus, and probably to the decrease of intracanalicular pressure in the pancreas. They think that gastro-jejunostomy plays a significant role in the decrease of reflectory mediatory gastro-antral-duodenal influence upon a pancreatic secretion as well as on gastric decompression. Further, they think that one should not wait for a progressive pancreatic tissue necrosis to happen before operation, since this increases the risks involved; but the patient with acute pancreatitis should be operated on, when conservative treatment has not give the expected results. The number of the operations performed in cases of acute pancreatitis, their postoperative course, as well as the absence of the common complications give hope, that by the mentioned surgical procedures the present high mortality rate of this severe disease will be decreased.