Transcranial direct current stimulation of the primary motor cortex affects cortical drive to human musculature as assessed by intermuscular coherence

Intermuscular coherence analysis can be used to assess the common drive to muscles. Coherence in the β-frequency band (15–35 Hz) is thought to arise from common cortical sources. Intermuscular coherence analysis is a potentially attractive tool for the investigation of motor cortical excitability changes because it is non-invasive and can be done relatively quickly. We carried out this study to test the hypothesis that intermuscular coherence analysis was able to detect cortical excitability changes in healthy subjects following transcranial direct current stimulation (tDCS). tDCS has been shown to increase (anodal stimulation) or decrease (cathodal stimulation) the size of the muscle potential evoked by TMS. We found that anodal tDCS caused an increase in motor evoked potential (MEP) size that was paralleled by an increase in β-band intermuscular coherence. Similarly, the reduction in MEP size produced by cathodal tDCS was paralleled by a reduction in β-band intermuscular coherence, while sham stimulation did not result in any change in either MEP amplitude or β-band intermuscular coherence. The similar pattern of change observed for MEP and intermuscular coherence may indicate similar mechanisms of action, although this cannot be assumed without further investigation. These changes do suggest that at least some of the action of tDCS is on cortical networks, and that combined tDCS and intermuscular coherence analysis may be useful in the diagnosis of pathologies affecting motor cortical excitability.     

Residual cholesterol synthesis and simvastatin induction of cholesterol synthesis in Smith-Lemli-Opitz syndrome fibroblasts

Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive, malformation syndrome caused by mutations in the 3beta-hydroxysterol delta7-reductase gene (DHCR7). DHCR7 catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol. We report the mutation analysis and determination of residual cholesterol synthesis in 47 SLOS patients, and the effects of treatment of SLOS skin fibroblasts with simvastatin. Using deuterium labeling we have quantified the amount of synthesized cholesterol and 7DHC in homozygote, heterozygote, and control fibroblast cell lines. In SLOS fibroblasts, the fraction of synthesized cholesterol to total sterol synthesis ranged from undetectable to over 50%. This establishes that different mutant alleles encode enzymes with varying degrees of residual activity. There was a correlation between increased phenotypic severity and decreased residual cholesterol synthesis (r(2)=0.45, p<0.0001). Simvastatin treatment of SLOS fibroblasts with residual DHCR7 enzymatic activity decreased 7DHC levels and increased cholesterol synthesis. This increase in cholesterol synthesis is due to increased expression of a mutant allele with residual function. Determination of residual enzymatic activity for specific DHCR7 mutant alleles will help in understanding the processes underlying the broad phenotypic spectrum found in this disorder and will be useful in identifying patients who may benefit from simvastatin therapy.     

The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression.

Posttransplant lymphoproliferative disorders (PTLDs) were diagnosed in 43 patients from the Pittsburgh-Denver series between June 1980 and March 1987. This constitutes a detection rate of 1.7%. Major categories of clinical presentation included a mononucleosislike syndrome, gastrointestinal/abdominal disease, and solid organ disease. The median time of onset in patients initially immunosuppressed with cyclosporine-A (CsA)-containing regimens was 4.4 months after transplant, regardless of tumor clonality. A strong association of PTLD with Epstein-Barr virus (EBV) was observed. A histologic spectrum of lesions from polymorphic to monomorphic was observed. Whereas polymorphic lesions could be either clonal or nonclonal, monomorphic lesions appeared to be clonal in composition. The presence of large atypical cells (atypical immunoblasts) or necrosis did not appreciably worsen the prognosis. Twelve patients had clonal, 13 had nonclonal, and five had both clonal and nonclonal tumors. Clonality was indeterminate in 13 cases. Most patients were treated with a regimen based on reduced immunosuppression and supportive surgery. Almost all nonclonal and about half of the clonal lesions respond to this conservative therapy, indicating that it is an appropriate first line of treatment. This behavior suggests that a spectrum of lesions ranging from infectious mononucleosis to malignant lymphoma constitutes the entity known as PTLD. Some monoclonal tumors can undergo regression, however, apparently in response to host immune control mechanisms. Because of its short latency and strong association with EBV, PTLD is an important model for the study of virus-associated tumor progression in humans.     

Immunohistochemical characterization of amyloid proteins in sural nerves and clinical associations in amyloid neuropathy.

To test whether immunohistochemical characterization of proteins in amyloid deposits in biopsied sural nerves gives reliable and useful diagnostic information using commercially available reagents, biopsy specimens of sural nerves from 38 patients with amyloid neuropathy were studied. Transthyretin (TTR) was detected in the amyloid deposits of 11 nerves, lambda light chains (LC) in 8 nerves, kappa LC in 7 nerves, and both lambda and kappa LC in 3 nerves. In 9 nerves, the amyloid deposits were too small to allow adequate immunohistochemical characterization of amyloid proteins in serial sections. Evidence that immunohistochemical characterization was correct came from: 1) evaluation of kin, 2) search for monoclonal proteins in the plasma, and 3) sequencing of the gene abnormalities in TTR+ cases. In 9 of 11 TTR+ cases, in which DNA could be obtained, sequencing of the gene showed that each of the 9 cases was heterozygous for a gene mutation; 7 had previously described mutations and 2 undescribed mutations. Therefore, in the nine sporadic cases without plasma monoclonal light chains, the immunohistochemical characterization correctly identified the protein in amyloid as transthyretin. Likewise, there was a high concordance between immunoglobulin light chains in plasma and light chains in amyloid in primary amyloidosis. Evaluation of the type, distribution, and severity of the neurologic symptoms and deficits showed: 1) the sensorimotor and autonomic neuropathy of amyloidosis characteristically affects proximal as well as distal limbs, and 2) the type of amyloidosis probably cannot be determined from the characteristics or severity of the neuropathy alone or from the location or size of amyloid deposits in nerve.     

Lingual mechanoreceptors activated by muscle twitch

1. Two groups of mechanoreceptors in the tongue have been identified by recording afferent discharges in single nerve fibres dissected from the lingual nerves of anaesthetized cats. The group of superficially situated, rapidly adapting mechanoreceptors had faster conduction velocities than the presumed deeply situated, slowly adapting endings.2. Stretch of the tongue musculature did not prove to be as efficient in activating the endings as local deformation, although it was possible to excite some of the presumed deeply situated endings in this way.3. No mechanoreceptor fibres could be identified in filaments dissected from the hypoglossal nerves in the same experiments.4. Twitches of the tongue musculature produced by stimulation of the hypoglossal nerve were able to cause discharge of superficial and presumed deeply situated mechanoreceptors during the tension change.5. The timing of the discharges in response to twitch was such that it could account for the delay in synaptic potentials produced in hypoglossal motoneurones when supramaximal stimuli were applied to the hypoglossal nerve.6. The possible significance of mechanoreceptor discharges in reflex activation of tongue motor units is discussed.     

Pulmonary marginal zone lymphoma of MALT type as a cause of localised pulmonary amyloidosis

AIM: To describe six patients with pulmonary marginal zone lymphoma in whom amyloid deposition was identified. Marginal zone lymphoma is a recently recognised type of low grade non-Hodgkin's lymphoma. METHODS: A computerised search was performed of all patients seen at the Mayo Clinic with a diagnosis of pulmonary amyloidosis. Six patients with pulmonary amyloidosis who had biopsy confirmed extranodal marginal zone lymphoma of mucosa associated lymphoid tissue type were identified. All were women, ranging in age from 45 to 85 years. RESULTS: Five patients had amyloid deposition in conjunction with pulmonary marginal zone lymphoma at the time of the original diagnosis. One patient was referred for evaluation of localised pulmonary amyloidosis and was found to have coexisting pulmonary marginal zone lymphoma. Clinical presentation was limited to pulmonary symptoms (two of the six) or constitutional symptoms (two), or was asymptomatic (two). In all six cases, initial findings of nodular densities on screening chest roentgenograms led to further evaluation and eventual lobectomy; these findings included multiple pulmonary nodules (four), single nodule (one), and single nodule with diffuse bilateral interstitial infiltrates (one). Bone marrow was examined in five patients and was normal in all. Protein studies performed in four patients revealed no monoclonal protein. No patients had manifestations of systemic amyloidosis, such as renal, neurological, or cardiac involvement, at a median follow up of 50 months. Four of the six patients remain alive at a median of five years. CONCLUSIONS: Pulmonary marginal zone lymphoma may be found in association with localised amyloid deposition and should be considered in the differential diagnosis of localised pulmonary amyloidosis.     

Immunophenotypic and genotypic characterisation of multiple myelomas with adverse prognosis characterised by immunohistological expression of the T cell related antigen CD45RO (UCHL-1).

AIMS: To investigate whether plasma cell expression of early B cell, late B cell/preplasma cell, T cell, and myelomonocytic antigens or myeloma associated lymphocytic infiltrates correlated with prognosis in bone marrow biopsy specimens of patients with multiple myeloma. METHODS: Bone marrow biopsy specimens of 23 patients with multiple myeloma were investigated for plasma cell expression and interstitial lymphocyte expression of T cell related antigen CD45RO (UCHL-1). RESULTS: Eight patients showed plasma cell expression of CD45RO and 16 showed increased tumour infiltrating CD45RO positive lymphocytes, which were correlated with poor survival by multivariate analyses (p = 0.005 and p = 0.04, respectively). B cell antigens (MB2, CD20) but no T cell specific antigens (CD3) or T cell receptor gene rearrangements were expressed by plasma cells in CD45RO positive myelomas. Of 16 patients with myeloma who had increased tumour infiltrating CD45RO positive lymphocytes, four had interstitial lymphocyte expression of B cell antigens and two had interstitial lymphocyte expression of the T cell specific antigen CD3. CONCLUSIONS: The recognition of plasma cell expression of CD45RO and increased interstitial CD45RO lymphocytes in bone marrow biopsy specimens of patients with multiple myeloma is an adverse prognostic finding not indicative of an aberrant T cell phenotype or genotype; it is consistent with B cell/pre-plasma cell antigen expression by myeloma cells and their lymphocytic precursors.     

Non-isotopic in situ hybridisation and immunophenotyping of infected cells in the investigation of human fetal parvovirus infection.

AIMS: To compare the use of biotinylated and digoxigenin labelled probes for diagnosis of human fetal parvovirus B19 infection in formalin fixed, paraffin wax embedded tissues; and to assess the cellular distribution of the virus in positive cases. METHODS: Sections of lung tissue from 23 cases of anatomically normal non-immune fetal hydrops presenting between 1984 and 1989, and from 13 control cases of hydrops due to chromosomal abnormality were probed for B19 DNA by in situ hybridisation using both biotinylated and digoxigenin labelled probes. The distribution of the virus was then investigated in all cases of fetal B19 infection confirmed in this laboratory to date (n = 11) by combining in situ hybridisation for viral DNA (using the digoxigenin system) with immunohistological labelling for a range of cellular antigens. RESULTS: Five unequivocal cases of B19 infection were identified among the 23 fetuses with unexplained hydrops using both probe labels. When combined with data from previous studies of the period 1974-1983, the results indicate that B19 infection was responsible for 27% of cases of anatomically normal non-immune hydrops and 8% of all cases, of non-immune hydrops presenting to this hospital over 15 years. False positive signal was seen in an additional three cases, using biotinylated probes. Digoxigenin labelled probes gave greater specificity and permitted detailed investigation of tissues high in endogenous biotin. Though most cells containing B19 DNA colabelled as erythroid precursors, viral DNA was frequently detected within mononuclear-phagocytic cells. In three cases viral signal was also found within occasional myocardial cells labelled by antibody to desmin. CONCLUSIONS: A relatively high proportion of cases of anatomically normal, non-immune hydrops are caused by B19 infection. Digoxigenin is a more reliable probe label than biotin for in situ hybridisation in archival fetal tissues. Double labelling for cellular antigens and viral nucleic acid is a powerful technique for investigating virus-host cell interactions, and provides evidence that cell types other than those of erythroid lineage may have a role in human fetal parvovirus infection.