Wild type Huntingtin reduces the cellular toxicity of mutant Huntingtin in mammalian cell models of Huntington's disease.

OBJECTIVES: Recent data suggest that wild type huntingtin can protect against apoptosis in the testis of mice expressing full length huntingtin transgenes with expanded CAG repeats. It is not clear if this protective effect was confined to particular cell types, or if wild type huntingtin exerted its protective effect in this model by simply reducing the formation of toxic proteolytic fragments from mutant huntingtin. METHODS: We cotransfected neuronal (SK-N-SH, human neuroblastoma) and non-neuronal (COS-7, monkey kidney) cell lines with HD exon 1 (containing either 21 or 72 CAG repeats) construct DNA and either full length wild type huntingtin or pFLAG (control vector). RESULTS: Full length wild type huntingtin significantly reduced cell death resulting from the mutant HD exon 1 fragments containing 72 CAG repeats in both cell lines. Wild type huntingtin did not significantly modulate cell death caused by transfection of HD exon 1 fragments containing 21 CAG repeats in either cell line. CONCLUSIONS: Our results suggest that wild type huntingtin can significantly reduce the cellular toxicity of mutant HD exon 1 fragments in both neuronal and non-neuronal cell lines. This suggests that wild type huntingtin can be protective in different cell types and that it can act against the toxicity caused by a mutant huntingtin fragment as well as against a full length transgene.

Genetic associations with clinical characteristics in bipolar affective disorder and recurrent unipolar depressive disorder.

Genetic factors may be associated with disease subtype as well as susceptibility. We have therefore typed polymorphisms at the serotonin transporter, dopamine receptor, tryptophan hydroxylase, tyrosine hydoxylase, and monoamine oxidase A (MAOA) loci in 139 unipolar and 131 bipolar patients and investigated associations with gender, number of episodes, age of onset, history of psychotic symptoms, history of suicidal behavior, and history of substance abuse. In bipolar subjects, the promoter variable number tandem repeat (VNTR) allele 132 of MAOA was associated with history of suicide attempts, P = 0.029, particularly in females, P = 0.006. The Fnu4HI allele 1 of MAOA was also associated with history of suicide attempts in females, P = 0.0162. The serotonin transporter promoter allele 2 was associated with increasing number of manic episodes, P = 0.02, and history of psychotic symptoms, P = 0.0243. One significant association was found in the unipolar group: dopamine D2 receptor promoter allele 2 with history of psychotic symptoms, P = 0. 0165. We have tested multiple loci for a variety of different clinical variables and performed 228 tests of significance in total. It is possible that these preliminary findings are type 1 errors, because one would expect 11 of the 228 tests to reach a nominal significance level of P < 0.05 by chance alone if all the tests were independent. The associations with the MAOA and serotonin transporter loci are consistent with previous data suggesting associations with susceptibility to bipolar affective disorder. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:36-42, 2000

No association of an insertion/deletion polymorphism in the angiotensin I converting enzyme gene with bipolar or unipolar affective disorders.

A recent Japanese study on the angiotensin I converting enzyme gene (ACE) insertion/deletion polymorphism reported that both the D allele (P < 0.02) and the DD genotype (P < 0.002) were significantly more frequent in affective disorder cases than in controls [Arinami et al., 1996: Biol Psychiatry 40:1122-1127]. A replication study was performed by using 157 bipolar I affective disorder cases, 169 major depressive disorder cases, and 313 controls. No significant association with this polymorphism was found in either disorder or in a combined affective disorder group. These results do not support the ACE gene having a major role in the etiology of either bipolar or unipolar affective disorders. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:733-735, 2000.

A rare coding variant within the wolframin gene in bipolar and unipolar affective disorder cases.

A recent report has shown that Wolfram syndrome carriers (heterozygotes) are 26-fold more likely to require psychiatric hospitalization compared with non-carriers, and that Wolfram syndrome heterozygotes may constitute approximately 25% of individuals hospitalized with depression and suicide attempts. We analyzed a His611Arg polymorphism of the wolframin gene by the polymerase chain reaction (PCR) and HhaI restriction digestion, in 158 bipolar I and 163 unipolar major affective disorder cases, and 316 controls. Statistical analyses of allele or genotype frequencies do not support a major role for wolframin in affective disorder. HhaI restriction digestion and sequencing of PCR products from four affective disorder cases showed a heterozygous Ala559Thr change. The Ala559Thr variant was not detectable in 382 controls tested. Thus, the rare wolframin 559Thr allele deserves consideration as a risk allele for affective disorder.

Psychiatric symptoms and CAG repeats in neurologically asymptomatic Huntington's disease gene carriers.

The putative relationship between the psychiatric profile of a sample of neurologically asymptomatic Huntington's disease gene carriers and CAG repeats was investigated. The psychiatric assessments (by consultant psychiatrist and computerised battery) were undertaken before the genetic testing was carried out. In this way, the informational distortions caused by neurological and cognitive deficits were avoided. The hypothesis that there is a relationship between psychiatric and CAG repeats was tested by seeking direct correlations between psychiatric systems and CAG repeats, and also by correcting the correlation by the number of years above or below the estimated age of onset in Huntington's disease. Scores for irritability and cognitive failures were high in the sample. There was no correlation between any psychiatric variable and CAG repeats. Possible explanations for this lack of correlations are discussed.

Palpable asymmetrical thickening of the breast: a clinical, radiological and pathological study.

While management protocols for a discrete palpable breast lump are standardized in most centres, the approach to an area of palpable asymmetrical thickening in the breast has seldom been addressed. A diagnostic algorithm for palpable asymmetrical thickening of the breast was prospectively evaluated in 116 Oriental women, followed by a retrospective review of their mammograms and histology specimens. Most women (86%) were pre-menopausal and 82% complained of a lump. The thickening eventually resolved spontaneously in 93 (80%) women. None of these 93 women developed cancer at a median follow-up of 41 months. A total of 9 (7.8%) cancers were found in the series of 116 women, including two with a lobular component. The occurrence of cancer was more likely when the woman was older than 43 years or when the thickening was marked (p<0.04). Mammographic review showed correlation of the palpable thickening with localized increase in breast tissue density and/or microcalcifications in 18% of cases. Histology review suggested fibrosis as an explanation for the clinical presentation. Although most cases of thickening tend to resolve with time, a significant number of cancers present in this way. A diagnostic approach with early and liberal imaging and biopsy for high risk women is required.

Nonmammary malignancies of the breast: ultrasound, CT, and MRI.

The three major categories of nonmammary malignancies of the breast include primary and secondary lymphoreticular malignancy, primary and secondary sarcoma, and hematogenous metastasis. This article describes the imaging features of 35 nonmammary malignancies of the breast and axilla with histopathologic confirmation. These include primary and secondary breast lymphoma, primary axillary nodal lymphoma, metastatic acute lymphatic leukemia, metastatic plasmacytoma, granulocytic sarcoma, primary angiosarcoma, metastatic rhabdomyosarcoma, hematogenous metastasis from primary lung, ovarian, cervical, thyroid, and colonic carcinoma, malignant melanoma, carcinoma of the nasal cavity, and adenocarcinoma of unknown primary. Wherever possible, correlation between mammography and ultrasound, computed tomography (CT), and/or magnetic resonance (MR) imaging is made.

Psychometric behaviour of BDI in Alzheimer's disease patients with depression.

The psychometric properties of the Beck Depression Inventory (BDI) in subjects with Alzheimer's disease (AD) and depression have not been fully evaluated. Item endorsement patterns may be distorted by the presence of AD. This was tested by applying the BDI to a sample of 129 subjects with probable AD without depression and to 57 subjects with both probable AD and depression. It was found that the BDI under diagnoses depression in the context of AD. ROC curves for total BDI and cognitive and somatic items subsets showed low sensitivity and low areas under the curve indices. The results suggest that the BDI is not an ideal instrument to measure depression in AD. This may not result solely from the swing of the somatic items subset, but from other aspects which require further investigation.

The molecular biology of Huntington's disease.

BACKGROUND: Huntington's disease (HD) is a fatal neurodegenerative disorder with an autosomal dominant mode of inheritance. It leads to progressive dementia, psychiatric symptoms and an incapacitating choreiform movement disorder, culminating in premature death. HD is caused by an increased CAG repeat number in a gene coding for a protein with unknown function, called huntingtin. The trinucleotide CAG codes for the amino acid glutamine and the expanded CAG repeats are translated into a series of uninterrupted glutamine residues (a polyglutamine tract). METHODS: This review describes the epidemiology, clinical symptomatology, neuropathological features and genetics of HD. The main aim is to examine important findings from animal and cellular models and evaluate how they have enriched our understanding of the pathogenesis of HD and other diseases caused by expanded polyglutamine tracts. RESULTS: Selective death of striatal and cortical neurons occurs. It is likely that the HD mutation confers a deleterious gain of function on the protein. Neuronal intranuclear inclusions containing huntingtin and ubiquitin develop in patients and transgenic mouse models of HD. Other proposed mechanisms contributing to neuropathology include excitotoxicity, oxidative stress, impaired energy metabolism, abnormal protein interactions and apoptosis. CONCLUSIONS: Although many interesting findings have accumulated from studies of HD and other polyglutamine diseases, there remain many unresolved issues pertaining to the exact roles of intranuclear inclusions and protein aggregates, the mechanisms of selective neuronal death and delayed onset of illness. Further knowledge in these areas will inspire the development of novel therapeutic strategies.

MR imaging of breast paraffinomas.

OBJECTIVE: Our objective is to present the MR appearance of breast paraffinoma, a late complication of breast augmentation by liquid paraffin wax, and to correlate this appearance with the histopathologic findings that were available for three of the 11 breasts we studied. CONCLUSION: Breast paraffinomas have a characteristic MR appearance that correlates well with histopathologic findings. With MR imaging, we were able to visualize the location and extent of the paraffinoma, best seen on the fat-suppression sequence, and to evaluate the surrounding fibroglandular breast tissue.

Decision-making in mania: a PET study.

Poor decision-making is often observed clinically in the manic syndrome. In normal volunteers, decision-making has been associated with activation in the ventral prefrontal cortex and the anterior cingulate gyrus. The aim of this study was to evaluate task-related activation in bipolar manic patients in these regions of the prefrontal cortex using PET. Six subjects with mania, 10 controls and six subjects with unipolar depression (an affective patient control group) were scanned using the bolus H(2)(15)O method while they were performing a decision-making task. Activations associated with the decision-making task were observed at two levels of difficulty. Task-related activation was increased in the manic patients compared with the control patients in the left dorsal anterior cingulate [Brodmann area (BA) 32] but decreased in the right frontal polar region (BA 10). In addition, controls showed greater task-related activation in the inferior frontal gyrus (BA 47) than manic patients. A positive correlation (r(s) = 0.88) between task-related activation in the anterior cingulate and increasing severity of manic symptoms was found. Depressed patients did not show significant task-related differences in activation compared with control subjects in the regions of interest. In conclusion, these patterns of activation point to abnormal task-related responses in specific frontal regions in manic patients. Moreover, they are consistent with neuropsychological observations in patients with lesions in the ventromedial prefrontal cortex, who show similar difficulties with decision-making and provide early evidence for context-specific neural correlates of mania.