Differentiating societal costs of disability worsening in multiple sclerosis

Journal of Neurology - In multiple sclerosis (MS), confirmed disability progression (CDP) can be either the result of progression independent of relapse activity (PIRA) or relapse-associated...     

Correction to: Differentiating societal costs of disability worsening in multiple sclerosis

Journal of Neurology - The original version of this article unfortunately contained a mistake. The captions of Fig. 2 and Fig. 3 are mismatched.     

HgCl2 challenge in Brown Norway rats lead to dermatitis instead of arthritis

A wide range of methods are described to produce adjuvant arthritis in rats by antigen exposure. Studies using these methods are rarely controlled histologically though the result can be paw dermatitis instead of arthritis. Three male Brown Norway rats were injected s.c. with HgCl₂ (1 mg Hg/kg body weight) on five alternating days following closely a well described scheme for induction of adjuvant arthritis. Extent of paw oedema was assessed sonographically. Location and extent of inflammatory responses were inspected histologically. Swollen reddish and painful paw oedema started to develop on day 13 increasing until day 16. Oedema increased skin-to-bone and skin-to-skin distance across the inflamed paws significantly. Histological examination on day 16 revealed marked dermatitis with dense cellular infiltrates, single cell necrosis and fibrin exudation. In contrast, no inflammatory responses were observed in the joints. Use of a well described scheme for induction of adjuvant arthritis produced dermatitis of the paw with identical time course, clinical and sonographic appearance as expected for arthritis. This observation strongly suggests the need to check the histology on location and the kind of inflammatory response when a model for adjuvant arthritis is altered or used for the first time.     

Assessing and influencing the fractional contribution of erythrocyte-bound 59Fe to individual 59Fe tissue content in murine 59Fe distribution studies

BACKGROUND: Murine proteins of iron homoeostasis are frequently manipulated to investigate the mechanisms of iron-distribution and their toxicological consequences. Beyond subtracting erythrocyte-bound 59Fe of the residual blood content determined for each tissue (subtraction method), procedures are needed to determine 59Fe distribution in murine models of, e.g. inflammation or diabetes that cause local hyperaemia and changes in microcirculation. AIM: Two new methods were developed to correct total 59Fe tissue content individually for erythrocyte-bound 59Fe-labelled haem iron. METHODS: Iron-deficiency and iron-overload was induced in male C57BL6 mice by feeding of respective diets. Distribution of 59Fe between different tissues was determined 24h, 14, and 28 days after intravenous injection of 59Fe trace amounts. Haem-bound 59Fe was separated from non-haem 59Fe in homogenates from all tissues by dispersion in a mix of lipophilic cyclohexanone and hydrophilic H3PO4 (separation method). Moreover, the reduction of 59Fe-labelled tissue blood content was determined in all organs after in vivo saline perfusion via the left ventricle (perfusion method). RESULTS AND DISCUSSION: 59Fe-labelled non-haem iron determined by the separation method was not significantly different from values determined by the subtraction method, except for the iron-deficient spleen 14 and 28 days after 59Fe injection when the separation method yielded approximately 20% higher values. Approximately 20% of 59Fe-labelled haem iron spilled over into the hydrophilic phase. The impact of this error decreases in parallel to 59Fe radioactivity in the residual tissue blood content: thus, it is higher in iron-deficient mice which accumulate more 59Fe in their erythrocytes than iron-adequate and iron-rich mice. For the same reason this type of error is more marked after long distribution periods and in organs with high residual blood content. Saline perfusion via the left ventricle reduced total blood content in mice to less than 10%. Liver (95%) and duodenum (94%) showed the highest removal of blood while it is lowest in spleen (66%) and lungs (69%). CONCLUSIONS: The separation and the perfusion method can be used to correct the impact of erythrocyte-bound haem iron individually. A margin of error below 10% was determined for all organs except for spleen, lungs, and fat. Both methods can be applied sequentially to obtain satisfactory results in spleen, lungs, and fat.     

A method to assess 59Fe in residual tissue blood content in mice and its use to correct 59Fe-distribution kinetics accordingly

BACKGROUND: Dysregulation of body iron-distribution may induce oxidative damage. To investigate the molecular mechanisms of iron homeostasis, corresponding essential genes are manipulated by many working groups. This asks for a simple method to pursue the resulting impact on body iron-distribution in mice. AIM: To develop a method for the assessment of (59)Fe in residual tissue blood content and to correct this influence in (59)Fe body distribution studies. METHODS: Iron status in male adult C57BL6 mice was adjusted by feeding diets with different iron content. Fractional contribution of organs to total body weight was determined after dissection. (59)Fe-labelled blood was injected in recipient mice to estimate total blood volume and residual blood content in all organs and tissues. The main experiment used these data to correct total (59)Fe tissue content at six intervals after (59)Fe injection (12h-28 days). RESULTS AND DISCUSSION: The sum of (59)Fe in all organs was the same as determined in each mouse before dissection. (59)Fe in whole blood remained constant from the 4th day after injection on, and was highest in iron-deficiency. As in other species, residual blood content was highest in spleen and lungs. Nevertheless, (59)Fe in the iron-deficient spleen decreased to zero and intestinal (59)Fe-content also decreased significantly over time after correction for (59)Fe in residual blood. These findings suggest correct assessment of compartment sizes and (59)Fe in residual blood in each organ. CONCLUSIONS: Differences in (59)Fe-distribution between iron status reflected changes in the expression of proteins of iron-transport and its regulation correctly. Thus, the method seems suitable to analyse body iron-distribution in consequence to genetic manipulations of murine iron homeostasis which is a prerequisite to assess possible toxicological consequences of iron supplementation.     

Aggression in mentally handicapped psychiatric patients during inpatient psychiatric stay. Preliminary results of a 2-year follow-up study

The preliminary results of a 2-year study of aggressive behaviour in psychiatric patients with an additional learning impairment or mental retardation in a specialized department of a psychiatric hospital are introduced. The study is concerned about the correlation between aggressive behaviour and different factors, as quality of life, number of patients in the ward, age, duration of stay, self-assessment and assessment by the CGI on admission.     

Dietary preferences for feeds varying in threonine concentration by the piglet

Two choice feeding trials were carried out to investigate if weaned piglets prefer feeds varying in threonine (Thr) content. In exp 1, two control groups were fed either a 0.57% Thr (negative control) or a 0.67% Thr (positive control) feed. Two other groups had the choice from 2 feeds containing 0.57% or 0.62% Thr (Thr-choice 1) and 0.57% or 0.67% Thr (Thr-choice 2). In exp 2 the two control groups were fed either a 0.50% Thr (negative control) or a 0.62% Thr (positive control) feed and the Thr-choice groups had the choice from 2 feeds containing 0.50% or 0.56% (Thr-choice 1) and 0.50% or 0.62% Thr (Thr-choice 2), respectively. In exp 1, animals of the Thr-choice 1 showed a significant preference for the feed with the higher Thr content but in the Thr-choice 2, both feeds on offer were chosen at random. In exp 2 the preference for the higher Thr feeds in the Thr-choice groups 1 and 2 was on average 71% and 72%, respectively. In both experiments, the data of growth performance and plasma amino acid and urea pattern indicated a suboptimal Thr supply in the negative control and the Thr-choice 1 group. It is concluded that piglets are able to detect metabolic changes caused by a marginal Thr supply and that they change their feeding behaviour in order to overcome deficiency.     

α-Synuclein impairs oligodendrocyte progenitor maturation in multiple system atrophy

Multiple system atrophy (MSA), an atypical parkinsonian disorder, is characterized by α-synuclein (α-syn⁺) cytoplasmatic inclusions in mature oligodendrocytes. Oligodendrocyte progenitor cells (OPCs) represent a distinct cell population with the potential to replace dysfunctional oligodendrocytes. However, the role of OPCs in MSA and their potential to replace mature oligodendrocytes is still unclear. A postmortem analysis in MSA patients revealed α-syn within OPCs and an increased number of striatal OPCs. In an MSA mouse model, an age-dependent increase of dividing OPCs within the striatum and the cortex was detected. Despite of myelin loss, there was no reduction of mature oligodendrocytes in the corpus callosum or the striatum. Dissecting the underlying molecular mechanisms an oligodendroglial cell line expressing human α-syn revealed that α-syn delays OPC maturation by severely downregulating myelin-gene regulatory factor and myelin basic protein. Brain-derived neurotrophic factor was reduced in MSA models and its in vitro supplementation partially restored the phenotype. Taken together, efficacious induction of OPC maturation may open the window to restore glial and neuronal function in MSA.     

Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD

The olfactory bulb (OB) is one of the first brain regions in Parkinson’s disease (PD) to contain alpha-synuclein (α-syn) inclusions, possibly associated with nonmotor symptoms. Mechanisms underlying olfactory synucleinopathy, its contribution to progressive aggregation pathology and nigrostriatal dopaminergic loss observed at later stages, remain unclear. A second hit, such as environmental toxins, is suggestive for α-syn aggregation in olfactory neurons, potentially triggering disease progression. To address the possible pathogenic role of olfactory α-syn accumulation in early PD, we exposed mice with site-specific and inducible overexpression of familial PD-linked mutant α-syn in OB neurons to a low dose of the herbicide paraquat. Here, we found that olfactory α-syn per se elicited structural and behavioral abnormalities, characteristic of an early time point in models with widespread α-syn expression, including hyperactivity and increased striatal dopaminergic marker. Suppression of α-syn reversed the dopaminergic phenotype. In contrast, paraquat treatment synergistically induced degeneration of olfactory dopaminergic cells and opposed the higher reactive phenotype. Neither neurodegeneration nor behavioral abnormalities were detected in paraquat-treated mice with suppressed α-syn expression. By increasing calpain activity, paraquat induced a pathological cascade leading to inhibition of autophagy clearance and accumulation of calpain-cleaved truncated and insoluble α-syn, recapitulating biochemical and structural changes in human PD. Thus our results underscore the primary role of proteolytic failure in aggregation pathology. In addition, we provide novel evidence that olfactory dopaminergic neurons display an increased vulnerability toward neurotoxins in dependence to presence of human α-syn, possibly mediating an olfactory-striatal dopaminergic network dysfunction in mouse models and early PD.