Transcranial sonography for diagnosis of Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>In idiopathic Parkinson's disease (IPD) transcranial sonography (TCS) represents an alternative diagnostic method to verify clinical diagnosis. Although the phenomenon of an increased echogenicity of the Substantia nigra (SN) is well known this method is still not widly used in the diagnostic workup. Until now reliability of this method is still a matter of debate, partly because data only existed from a few laboratories using the same ultrasound machine. Therefore our study was conducted to test the reliability of this method by using a different ultrasound device and examining a large population of control and IPD subjects by two examiners to calculate interobserver reliability.</p> <p>Method</p> <p>In this study echogenicity of SN was examined in 199 IPD patients and 201 control subjects. All individuals underwent a neurological assessment including Perdue pegboard test and Webster gait test. Using a Sonos 5500 ultrasound device area of SN was measured, echogenicity of raphe, red nuclei, thalamus, caudate and lenticular nuclei, width of third and lateral ventricle were documented.</p> <p>Results</p> <p>We found a highly characteristic enlargement of the SN echogenic signal in IPD. The cut-off value for the SN area was established using a ROC curve with a sensitivity of 95% corresponding to an area of SN of 0.2 cm²and was found to be equivalent to the cut-off values of other studies using different ultrasound devices.</p> <p>Conclusions</p> <p>Our study shows that TCS is a reliable and highly sensitive tool for differentiation of IPD patients from individuals without CNS disorders.</p

Intravenous Immunoglobulin Prevents Murine Antibody-Mediated Acute Lung Injury at the Level of Neutrophil Reactive Oxygen Species (ROS) Production

Transfusion-related acute lung injury (TRALI) is a leading cause of transfusion-associated mortality that can occur with any type of transfusion and is thought to be primarily due to donor antibodies activating pulmonary neutrophils in recipients. Recently, a large prospective case controlled clinical study of cardiac surgery patients demonstrated that despite implementation of male donors, a high incidence of TRALI still occurred and suggested a need for additional interventions in susceptible patient populations. To examine if intravenous immunoglobulin (IVIg) may be effective, a murine model of antibody-mediated acute lung injury that approximates human TRALI was examined. When BALB/c mice were injected with the anti-major histocompatibility complex class I antibody 34-1-2s, mild shock (reduced rectal temperature) and respiratory distress (dyspnea) were observed and pre-treatment of the mice with 2 g/kg IVIg completely prevented these symptoms. To determine IVIg's usefulness to affect severe lung damage, SCID mice, previously shown to be hypersensitive to 34-1-2s were used. SCID mice treated with 34-1-2s underwent severe shock, lung damage (increased wet/dry ratios) and 40% mortality within 2 hours. Treatment with 2 g/kg IVIg 18 hours before 34-1-2s administration completely protected the mice from all adverse events. Treatment with IVIg after symptoms began also reduced lung damage and mortality. While the prophylactic IVIg administration did not affect 34-1-2s-induced pulmonary neutrophil accumulation, bone marrow-derived neutrophils from the IVIg-treated mice displayed no spontaneous ROS production nor could they be stimulated in vitro with fMLP or 34-1-2s. These results suggest that IVIg prevents murine antibody-mediated acute lung injury at the level of neutrophil ROS production and thus, alleviating tissue damage

Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants

Background:Genomic structural variants (SVs) can affect many genes and regulatory elements. Therefore, the molecular mechanisms driving the phenotypes of patients carrying de novo SVs are frequently unknown. Methods:We applied a combination of systematic experimental and bioinformatic methods to improve the molecular diagnosis of 39 patients with multiple congenital abnormalities and/or intellectual disability harboring apparent de novo SVs, most with an inconclusive diagnosis after regular genetic testing. Results: In 7 of these cases (18%), whole-genome sequencing analysis revealed disease-relevant complexities of the SVs missed in routine microarray-based analyses. We developed a computational tool to predict the effects on genes directly affected by SVs and on genes indirectly affected likely due to the changes in chromatin organization and impact on regulatory mechanisms. By combining these functional predictions with extensive phenotype information, candidate driver genes were identified in 16/39 (41%) patients. In 8 cases, evidence was found for the involvement of multiple candidate drivers contributing to different parts of the phenotypes. Subsequently, we applied this computational method to two cohorts containing a total of 379 patients with previously detected and classified de novo SVs and identified candidate driver genes in 189 cases (50%), including 40 cases whose SVs were previously not classified as pathogenic. Pathogenic position effects were predicted in 28% of all studied cases with balanced SVs and in 11% of the cases with copy number variants. Conclusions:These results demonstrate an integrated computational and experimental approach to predict driver genes based on analyses of WGS data with phenotype association and chromatin organization datasets. These analyses nominate new pathogenic loci and have strong potential to improve the molecular diagnosis of patients with de novo SVs

The predictive value of transcranial duplex sonography for the clinical diagnosis in undiagnosed parkinsonian syndromes: comparison with SPECT scans

<p>Abstract</p> <p>Background</p> <p>Transcranial duplex sonography (TCD) of the substantia nigra has emerged as a promising, non-invasive tool to diagnose idiopathic Parkinson's disease (IPD). However, its diagnostic accuracy in patients with undefined parkinsonism remains to be determined.</p> <p>In this study we determined the predictive value of TCD for the clinical diagnosis in undiagnosed parkinsonian syndromes. Additionally we compared the predictive value of TCD with that of presynaptic and postsynaptic single photon emission computer tomography (SPECT) scans.</p> <p>Methods</p> <p>We studied 82 patients with an unclassified parkinsonian syndrome. All 82 patients were subjected to a TCD, 59 of them underwent a presynaptic SPECT scans and 32 underwent a postsynaptic SPECT scan.</p> <p>We determined the diagnostic accuracy of TCD and SPECT scans in differentiating:</p> <p>1) IPD patients from patients without nigrostriatal degeneration and 2) IPD patients from patients with atypical parkinsonian syndromes (APS).</p> <p>To compare the diagnostic accuracy of TCD and SPECT scans, we used the clinical diagnosis after follow-up according to generally accepted clinical criteria as the gold standard. This clinical diagnosis was determined by a movement disorder specialist.</p> <p>3) Finally, we ascertained the predictive value of the TCD for the SPECT result.</p> <p>Results</p> <p>The clinical diagnoses after follow-up resulted in 51 cases of IPD, 7 patients with APS and 17 patients without nigrostriatal degeneration. In total 7 patients remained undiagnosed.</p> <p>1) The accuracy of TCD, assessed by sensitivity and specificity, to differentiate IPD patients from patients without nigrostriatal degeneration was 50% and 82% respectively.</p> <p>For the presynaptic SPECT scans sensitivity was 97% and specificity 100%.</p> <p>2) In differentiating IPD patients from APS patients, the sensitivity and specificity of TCD was 50% and 43% respectively. For presynaptic SPECT scans this was 97% and 0%. For the postsynaptic SPECT scans the sensitivity was 75% and the specificity 81%.</p> <p>3) The positive predictive value (PPV) of an abnormal TCD for an abnormal presynaptic SPECT scan was 88%.</p> <p>Conclusion</p> <p>Presynaptic SPECT scanning has a higher predictive value for the clinical diagnosis than TCD. However, since the PPV of an abnormal TCD for parkinsonism with nigrostriatal degeneration is high, TCD might be used as screening tool, before ordering a presynaptic SPECT.</p

A Mutation in the Golgi Qb-SNARE Gene GOSR2 Causes Progressive Myoclonus Epilepsy with Early Ataxia

The progressive myoclonus epilepsies (PMEs) are a group of predominantly recessive disorders that present with action myoclonus, tonic-clonic seizures, and progressive neurological decline. Many PMEs have similar clinical presentations yet are genetically heterogeneous, making accurate diagnosis difficult. A locus for PME was mapped in a consanguineous family with a single affected individual to chromosome 17q21. An identical-by-descent, homozygous mutation in GOSR2 (c.430G>T, p.Gly144Trp), a Golgi vesicle transport gene, was identified in this patient and in four apparently unrelated individuals. A comparison of the phenotypes in these patients defined a clinically distinct PME syndrome characterized by early-onset ataxia, action myoclonus by age 6, scoliosis, and mildly elevated serum creatine kinase. This p.Gly144Trp mutation is equivalent to a loss of function and results in failure of GOSR2 protein to localize to the cis-Golgi