Diagnostic red flags: steroid‐treated malignant CNS lymphoma mimicking autoimmune inflammatory demyelination

The presence of inflammation and demyelination in a central nervous system (CNS) biopsy points towards a limited, yet heterogeneous group of pathologies, of which multiple sclerosis (MS) represents one of the principal considerations. Inflammatory demyelination has also been reported in patients with clinically suspected primary central nervous system lymphoma (PCNSL), especially when steroids had been administered prior to biopsy acquisition. The histopathological changes induced by corticosteroid treatment can range from mild reduction to complete disappearance of lymphoma cells. It has been proposed that in the absence of neoplastic B cells, these biopsies are indistinguishable from MS, yet despite the clinical relevance, no histological studies have specifically compared the two entities. In this work, we analyzed CNS biopsies from eight patients with inflammatory demyelination in whom PCNSL was later histologically confirmed, and compared them with nine well defined early active multiple sclerosis lesions. In the patients with steroid‐treated PCNSL (ST‐PCNSL) the interval between first and second biopsy ranged from 3 to 32 weeks; all of the patients had received corticosteroids before the first, but not the second biopsy. ST‐PCNSL patients were older than MS patients (mean age: ST‐PCNSL: 62 ± 4 years, MS: 30 ± 2 years), and histological analysis revealed numerous apoptoses, patchy and incomplete rather than confluent and complete demyelination and a fuzzy lesion edge. The loss of Luxol fast blue histochemistry was more profound than that of myelin proteins in immunohistochemistry, and T cell infiltration in ST‐PCNSL exceeded that in MS by around fivefold (P = 0.005). Our data indicate that in the presence of extensive inflammation and incomplete, inhomogeneous demyelination, the neuropathologist should refrain from primarily considering autoimmune inflammatory demyelination and, even in the absence of lymphoma cells, instigate close clinical follow‐up of the patient to detect recurrent lymphoma.     

Emotion categories and patterns of change in experiential therapy for depression

Objective: This investigation examined the relationship between in-session types of emotional experience operationalized by the emotion category coding system and the reduction of depressive symptoms in emotion-focused therapy (EFT). Method: Segments of videotaped sessions were coded and the different emotion categories were related to reduction in depressive symptoms in a sample of 30 clients who received EFT for depression. Results: Both fewer secondary and more primary adaptive emotions, in the working phases of therapy, were found to significantly predict outcome. Moderate levels of primary maladaptive emotion in the middle working session were associated with outcome and the frequency with which clients moved from primary maladaptive to primary adaptive emotions in this session-predicted outcome. Conclusions: Results of this study support a transformational model of changing emotion with emotion.     

Biological activity of two botulinum toxin type A complexes (Dysport® and Botox®) in volunteers

Journal of Neurology -     

Role of murine integrin alpha2beta1 in thrombus stabilization and embolization: contribution of thromboxane A2

Platelets stably interact with collagen via glycoprotein (GP)VI and alpha2beta1integrin. With alpha2-null mice, we investigated the role of alpha2beta1 in thrombus formation and stability in vivo and in vitro. Using a FeCl(3)-induced thrombosis model, in arteries from alpha2-null mice smaller thrombi were formed with more embolization compared to vessels from wild-type mice. Aspirin treatment of wild-type mice causes similar effects, while the thromboxane A(2) analogue U46619 was borderline effective in suppressing the embolisation in alpha2-null mice. In vitro, perfusion of alpha2-null blood over collagen resulted in formation of thrombi that were smaller and looser in appearance, regardless of the presence or absence of coagulation. Aspirin treatment or blockage of thromboxane receptors provoked embolus formation in wildtype blood, while U46619 normalized thrombus formation in blood from alpha2-null mice. We conclude that integrin alpha2beta1 plays a role in stabilizing murine thrombi, likely by enhancing GPVI activation and thromboxane A(2) release. The increased embolization in alpha2-null mice may argue against the use of alpha2beta1 integrin inhibitors for antithrombotic therapy.     

Reduced hippocampal neurogenesis in the GR<Superscript>+/−</Superscript> genetic mouse model of depression

Glucocorticoid receptor (GR) heterozygous mice (GR^+/− ) represent a valuable animal model for major depression. GR^+/− mice show a depression-related phenotype characterized by increased learned helplessness on the behavioral level and neuroendocrine alterations with hypothalamo-pituitary-adrenal (HPA) axis overdrive characteristic of depression. Hippocampal brain-derived neurotrophic factor (BDNF) levels have also been shown to be reduced in GR^+/− animals. Because adult hippocampal neurogenesis has been implicated in the pathophysiology of affective disorders, we studied here the effects of the GR^+/− genotype on neurogenesis in vivo. In a 2 × 2 design, GR^+/− mice and GR^+/+ littermate controls were either subjected to 1 h of restraint stress or left undisturbed in their home cages after intraperitoneal injection of BrdU. Stress exposure and BrdU injections were performed once daily for 7 days and neurogenesis analyzed 4 weeks later. BrdU cell counts were significantly reduced as an effect of GR^+/− genotype and as an effect of stress. Majority of the BrdU+ cells showed co-labeling with mature neuronal marker NeuN or astrocytic marker S100β with no further significant effect of either experimental condition or of genotype. In sum, this results in reduced neurogenesis in GR^+/− mice which is further repressed by restraint stress. Our results, thus, reinforce the link between reduced neurogenesis, stress, neurotrophins, and behavioral symptoms of and susceptibility to depression.     

Lateral Balance Factors Predict Future Falls in Community-Living Older Adults

Hilliard MJ, Martinez KM, Janssen I, Edwards B, Mille M-L, Zhang Y, Rogers MW. Lateral balance factors predict future falls in community-living older adults.

Objective

To prospectively determine the capacity of measures of mediolateral (ML) protective stepping performance, maximum hip abduction torque, and trunk mobility, in order to predict the risk of falls among community-living older people.

Design

Cross-sectional study.

Setting

A balance and falls research laboratory.

Participants

Medically screened and functionally independent community-living older adult volunteers (N=51).

Interventions

Not applicable.

Main Outcome Measures

Measures included: (1) protective stepping responses: percentage of trials with multiple balance recovery steps and sidestep/crossover step recovery patterns, and first step length following motor-driven waist-pull perturbations of ML standing balance; (2) hip abduction strength and axial mobility: (3) peak isokinetic hip abduction joint torque and trunk functional axial rotation (FAR) range of motion; and (4) fall incidence: monthly mail-in reporting of fall occurrences with follow-up contact for 1 year post-testing. One- and 2-variable logistic regression analysis models determined which single and combined measures optimally predicted fall status.

Results

The single variable model with the strongest predictive value for falls was the use of multiple steps in all trials (100% multiple steps) (odds ratio, 6.2; P=.005). Two-variable models, including 100% multiple steps and either hip abduction torque or FAR variables, significantly improved fall prediction over 100% multiple steps alone. The hip abduction and FAR logistic regression optimally predicted fall status.

Conclusions

The findings identify new predictor variables for risk of falling that underscore the importance of dynamic balance recovery performance through ML stepping in relation to neuromusculoskeletal factors contributing to lateral balance stability. The results also highlight focused risk factors for falling that are amenable to clinical interventions for enhancing lateral balance function and preventing falls.     

Criteria in Sentinel Lymph Nodes of Melanoma Patients that Predict Involvement of Nonsentinel Lymph Nodes

Background Previous studies described various criteria in sentinel lymph nodes (SLN) of melanoma patients that predict the involvement of further, nonsentinel lymph nodes (NSLN). Such criteria may facilitate the selection of patients who might benefit from a completion lymph node dissection (CLND). However, it is currently unclear which parameters are most important. Methods A total of 180 melanoma patients with positive SLNB and subsequent CLND were investigated. Histopathologic parameters in the SLN were systematically evaluated and compared with regard to NSLN positivity. Twenty-eight of these patients (16.0%) had positive NSLN. Results By univariate analysis several criteria with regard to tumor burden and location of melanoma cells in the SLN correlated with NSLN involvement, such as positivity by hematoxylin-eosin (H&E) staining (P < .001), largest diameter of clusters (P < .001), capsular involvement (P = .001), extranodal extension (P < .001), and tumor penetrative depth (P < .001). Multivariate analysis revealed three independent parameters: (1) positivity of the SLN by H&E staining (versus by immunohistochemistry alone), (2) relative tumor burden >10% of total lymph node tissue, and (3) perinodal intralymphatic tumor. In 23 of 28 patients with positive NSLN the SLN was positive by H&E staining, in 15 of 28 patients the relative tumor burden was >10%, and 13 of 28 showed perinodal intralymphatic tumor. In 5 of 28 patients with NSLN involvement, these three parameters were negative. Conclusions Histopathologic examination of the SLN can identify patients at risk for NSLN positivity.     

A new large animal model of CLN5 neuronal ceroid lipofuscinosis in Borderdale sheep is caused by a nucleotide substitution at a consensus splice site (c.571+1G>A) leading to excision of exon 3

Batten disease (neuronal ceroid lipofuscinoses, NCLs) are a group of inherited childhood diseases that result in severe brain atrophy, blindness and seizures, leading to premature death. To date, eight different genes have been identified, each associated with a different form. Linkage analysis indicated a CLN5 form in a colony of affected New Zealand Borderdale sheep. Sequencing studies established the disease-causing mutation to be a substitution at a consensus splice site (c.571+1G>A), leading to the excision of exon 3 and a truncated putative protein. A molecular diagnostic test has been developed based on the excision of exon 3. Sequence alignments support the gene product being a soluble lysosomal protein. Western blotting of isolated storage bodies indicates the specific storage of subunit c of mitochondrial ATP synthase. This flock is being expanded as a large animal model for mechanistic studies and trial therapies.