Polymerization of proteins into amyloid protofibrils shares common critical oligomeric states but differs in the mechanisms of their formation.

Amyloid protofibril formation of phosphoglycerate kinase (PGK) and Syrian hamster prion protein (SHaPrP(90-232)) were investigated by static and dynamic light scattering, size exclusion chromatography and electron microscopy. Changes in secondary structure were monitored by Fourier transform infrared spectroscopy and by circular dichroism. Protofibril formation of the two proteins is found to be a two-stage process. At the beginning, an ensemble of critical oligomers is built up. These critical oligomeric states possess a predominant beta-sheet structure and do not interact considerably with monomers. Initial oligomerization and transition to beta-sheet structure are coupled events differing in their details for both proteins. Intermediate oligomeric states (dimers, trimers, etc.) are populated in case of PGK, whereas SHaPrP(90-232) behaves according to an apparent two-state reaction between monomers and octamers rich in beta-structure with a reaction order varying between 2 and 4. All oligomers coalesce to PGK protofibrils in the second stage, while SHaPrP(90-232) protofibrils are only formed by a subpopulation. The rates of both growth stages can be tuned in case of PGK by different salts preserving the underlying generalized diffusion-collision mechanism. The different kinetics of the early misfolding and oligomerization events of the two proteins argue against a common mechanism of protofibril formation. A classification scheme for misassembly mechanisms of proteins based on energy landscapes is presented. It includes scenarios of downhill polymerization to which protofibril formation of PGK and SHaPrP(90-232) belong.     

Towards the genetic basis of periodic catatonia: pedigree sample for genome scan I and II

In a genome-wide linkage study, we mapped two major susceptibility loci for periodic catatonia, a phenotype with qualitative disturbances of the psychomotor sphere and a morbidity risk of 26.9 % in first-degree relatives of index cases, to chromosome 15q15, and to chromosome 22q13 using nonparametric as well as parametric (autosomal dominant model) analyses. The study included 12 multiplex pedigrees with 135 individuals, among them 57 affected persons. A second genome scan is in progress investigating four families with 21 affected individuals, aiming to confirm linkage results. Age at onset patterns as well as the clinical outcome were similar among affected individuals in both sets of families. Within the pedigrees we observed no physical diseases segregating with periodic catatonia. Under the assumption of genetic homogeneity, the statistical power to detect LOD scores ≥ 2.0 was 98.5 % in the first set of families, and 57.9 % in the second set. Thus, the panel of multiplex pedigrees segregating periodic catatonia seems to represent a homogenous clinical sample, and possesses sufficient statistical power to delineate and confirm linkage to major genetic loci for periodic catatonia.

     

Long-term follow-up, neurological outcome and survival rate in 28 Nordic patients with glutaric aciduria type 1.

All 28 patients, 13 females and 15 males, with glutaric aciduria type 1 diagnosed between 1975 and 2001 in Denmark, Finland, Norway and Sweden were identified and studied retrospectively until 2001. Mass screening was not performed. Three were sibling cases. Prenatal enzymatic diagnosis performed in 11 pregnancies led to termination in one. The median follow-up time was 14 years. Six patients had died. At 10 years of age the cumulative survival rate was 89% and at 35 years 44%. The dominating neurological sign was dystonia in 20 and dyskinesia in 4. Three had only slight spastic signs and information was missing in one. The head circumference at birth was significantly larger than normal and increased significantly until 6 months of age. The onset was acute encephalopathic in 24 patients and insidious in 3. From the time of diagnosis, all patients but one were prescribed protein restriction and/or a diet low in lysine and tryptophan. Riboflavine and/or carnitine supplementation were given to 25. Neurological deficits did not improve on the offered treatment. Deterioration may have been averted by intense acute metabolic treatment in a few patients. Dystonia correlated significantly to absence of speech but not to cognitive function. Severe disability, including motor, cognitive and speech functions, correlated significantly with acute onset, dystonia and mortality, and weakly with a deteriorating course, but not with age at onset, diagnosis, or follow-up, nor to head size. Results from future population studies derived from mass screening will have to relate to clinical diagnostic series of the kind presented here.     

Excess of high frequency electroencephalogram oscillations in boys with autism.

BACKGROUND: An elevated excitation/inhibition ratio has been suggested as one mechanism underpinning autism. An imbalance between cortical excitation and inhibition may manifest itself in electroencephalogram (EEG) abnormalities in the high frequency range. The aim of this study was to investigate whether beta and gamma range EEG abnormalities are characteristic for young boys with autism (BWA). METHODS: EEG was recorded during sustained visual attention in two independent samples of BWA from Moscow and Gothenburg, aged 3 to 8 years, and in age matched typically developing boys (TDB). High frequency EEG spectral power was analyzed. RESULTS: In both samples, BWA demonstrated a pathological increase of gamma (24.4-44.0 Hz) activity at the electrode locations distant from the sources of myogenic artefacts. In both samples, the amount of gamma activity correlated positively with degree of developmental delay in BWA. CONCLUSIONS: The excess of high frequency oscillations may reflect imbalance in the excitation-inhibition homeostasis in the cortex. Given the important role of high frequency EEG rhythms for perceptual and cognitive processes, early and probably genetically determined abnormalities in the neuronal mechanisms generating high frequency EEG rhythms may contribute to development of the disorder. Further studies are needed to investigate the specificity of the findings for autism.     

Treatment of fungal infections in hematology and oncology--guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

The Infectious Diseases Working Party of the German Society of Haematology and Oncology presents their guidelines for the treatment of fungal infections in patients with hematological and oncological malignancies. These guidelines are evidence-based, considering study results, case reports and expert opinions, using the evidence criteria of the Infectious Diseases Society of America (IDSA). The recommendations for major fungal complications in this setting are summarized here. The primary choice of therapy for chronic candidiasis should be fluconazole, reserving caspofungin or amphotericin B (AmB) for use in case of progression of the Candida infection. Patients with candidemia (except C. krusei or C. glabrata) who are in a clinically stable condition without previous azole prophylaxis should receive fluconazole, otherwise AmB or caspofungin. Voriconazole is recommended for the first-line treatment of invasive aspergillosis. The benefit of a combination of AmB and 5-flucytosine has not been demonstrated except in patients with cryptococcal meningitis. Mucormycosis is relatively rare. The drug therapy of choice consists of AmB, desoxycholate or liposomal formulation, in the highest tolerable dosage. Additional surgical intervention has been shown to achieve a lower fatality rate than with antifungal therapy alone. The role of interventional strategies, cytokines/G-CSF, and granulocyte transfusions in invasive fungal infections are further reviewed. These guidelines offer actual standards and discussions on the treatment of oropharyngeal and esophageal candidiasis, invasive candidiasis, cryptococcosis and mould infections.     

Pharmacotherapy for thyroid nodules. A systematic review and meta-analysis.

The review highlights the uncertainty in the management of nodular thyroid disease. Thyroxine suppressive treatment is given in the hope that nodules might decrease in size, sometimes assuming that dependency on TSH is different in benign and malignant nodular disease. Follow-up of benign nodules over 10 years suggested that most remain the same, shrink, or disappear [14]. TSH suppression may lead to hyperthyroidism, reduced bone density [37.39], and atrial fibrilation; however, apart from reduction of nodule size or arrest in nodule growth, thyroxine therapy may benefit patients by reducing perinodular volume. Consequently, both pressure symptoms and cosmetic complaints could improve. Unfortunately, no information concerning symptoms or well-being is available from published randomized trials. In conclusion, more high quality studies of sufficient duration with adequate power estimation are needed. Uncertainty about predictors of response or the impact on outcomes that are important to patients leaves considerable doubt about the wisdom of applying suppressive therapy. Future studies shoudl include patient-important outcomes including thyroid cancer incidence, health-related quality of life and costs.