Manganese is essential for several metabolic pathways but becomes toxic in excessive amounts. Manganese levels in the body are therefore tightly regulated, but the responsible protein(s) remain incompletely known. We studied two consanguineous families with neurologic disorders including juvenile-onset dystonia, adult-onset parkinsonism, severe hypermanganesemia, polycythemia, and chronic hepatic disease, including steatosis and cirrhosis. We localized the genetic defect by homozygosity mapping and then identified two different homozygous frameshift SLC30A10 mutations, segregating with disease. SLC30A10 is highly expressed in the liver and brain, including in the basal ganglia. Its encoded protein belongs to a large family of membrane transporters, mediating the efflux of divalent cations from the cytosol. We show the localization of SLC30A10 in normal human liver and nervous system, and its depletion in liver from one affected individual. Our in silico analyses suggest that SLC30A10 possesses substrate specificity different from its closest (zinc-transporting) homologs. We also show that the expression of SLC30A10 and the levels of the encoded protein are markedly induced by manganese in vitro. The phenotype associated with SLC30A10 mutations is broad, including neurologic, hepatic, and hematologic disturbances. Intrafamilial phenotypic variability is also present. Chelation therapy can normalize the manganesemia, leading to marked clinical improvements. In conclusion, we show that SLC30A10 mutations cause a treatable recessive disease with pleomorphic phenotype, and provide compelling evidence that SLC30A10 plays a pivotal role in manganese transport. This work has broad implications for understanding of the manganese biology and pathophysiology in multiple human organs.
The spectrum of clinical and neuroradiological evaluation shows that intracranial involvement from plasmacytoma and multiple myeloma must be taken into account in the differential diagnosis of cranial osseous and meningeal disease.
Recent studies have revealed the possible role of choroid plexus (ChP) in Alzheimer's disease (AD). T1-weighted MRI is the modality of choice for the segmentation of ChP in humans. Manual segmentation is considered the gold-standard technique, but given its time-consuming nature, large-scale neuroimaging studies of ChP would be impossible. In this study, we introduce a lightweight segmentation algorithm based on the Gaussian Mixture Model (GMM). We compared its performance against manual segmentation as well as automated segmentation by Freesurfer in three separate datasets: 1) patients with structural MRIs enhanced with contrast (n = 19), 2) young healthy subjects (n = 20), and 3) patients with AD (n = 20). GMM outperformed Freesurfer and showed high similarity with manual segmentation. To further assess the algorithm's performance in large scale studies, we performed GMM segmentations in young healthy subjects from the Human Connectome Project (n = 1,067), as well as healthy controls, mild cognitive impairment (MCI), and AD patients from the Alzheimer's Disease Neuroimaging Initiative (n = 509). In both datasets, GMM segmented ChP more accurately than Freesurfer. To show the clinical importance
Cerebrotendinous xanthomatosis (CTX) is a metabolic disease characterized by systemic signs and neurological impairment, which can be prevented if chenodeoxycholic acid (CDCA) treatment is started early. Despite brain MRI represents an essential diagnostic tool, the spectrum of findings is worth to be reappraised, and follow-up data are needed. We performed clinical evaluation and brain MRI in 38 CTX patients. Sixteen of them who were untreated at baseline examination underwent clinical and MRI follow-up after long-term treatment with CDCA. Brain MRI abnormalities included cortical and cerebellar atrophy, and T2W/FLAIR hyperintensity involving subcortical, periventricular, and cerebellar white matter, the brainstem and the dentate nuclei. Regarding the dentate nuclei, we also observed T1W/FLAIR hypointensity consistent with cerebellar vacuolation and T1W/FLAIR/SW hypointense alterations compatibly with calcification in a subgroup of patients. Long-term follow-up showed that clinical and neuroradiological stability or progression were almost invariably associated. In patients with cerebellar vacuolation at baseline, a worsening over time was observed, while subjects lacking vacuoles were clinically and neuroradiologically stable at follow-up. The brains of CTX patients very often show both supratentorial and infratentorial abnormalities at MRI, the latter being related to clinical disability and including a wide spectrum of dentate nuclei alterations. The presence of cerebellar vacuolation may be regarded as a useful biomarker of disease progression and unsatisfactory response to therapy. On the other hand, the absence of dentate nuclei signal alteration should be considered an indicator of better prognosis.
Two groups of patients, with laparoscopic cholecystectomy (LC) were prospectively studied. All patients had serial plain abdominal X-ray examinations at various intervals after operation, to record the position of clips placed during LC. Seventy-one patients had less cystic duct (CD) dissection and > or =4 clips placed during the procedure. One hundred and fifteen patients had a larger CD dissection and only 4 clips placed (2 on the cystic artery and 2 on the CD, without additional clips on smaller vessels). In the former group, 7 patients had clip migration within 1 month and 11 within 1 year vs 1 either at 1 month or 1 year in the latter group (p = 0.01 and <0.001, respectively). During the follow-up, a 72-year-old man belonging to the former group had a recurrent common duct brown pigment stone containing a metallic clip 26 months after operation. He was treated successfully by endoscopic sphincterotomy. Factors predisposing to clip migration were short cystic stump, inadvertent clip dislodgment or incorrect placement, cystic duct ischemic necrosis, and local suppurative complications. Data from 29 patients with GS formed around suture material or phytobezoars observed during a prospective study and from the physicochemical and structural analysis of a cumulative series of 64 GS containing foreign bodies are also presented and discussed. It is suggested that metallic clips can migrate from their initial sites at various intervals within the peritoneal cavity or into the common duct and serve as a nidus for GS formation. Metallic clip migration in most cases is due to technical factors and can usually be prevented. However, it is not possible to prevent either clip migration or GS formation in every case, since even well-placed clips can migrate due to suppurative complications or local ischemic damage, and, once that penetration within the bile tract has occurred, GS are usually going to form, irrespective of the nature and the shape of the foreign body.
Abnormal gadolinium enhancement of the anterior segments of eyes harboring retinoblastoma seems to indicate more aggressive tumor behavior.
BackgroundInternal Jugular Veins (IJVs) are the principle outflow pathway for intracranial blood in clinostatism condition. In the seated position, IJVs collapse, while Vertebral Veins (VVs) increase the venous outflow and partially compensate the venous drainage. Spinal Epidural Veins are an additional drainage pathway in the seated position. Colour- Doppler-Sonography (CDS) examination is able to demonstrate IJVs and VVs outflow in different postural and respiratory conditions. The purpose of this study was to evaluate CDS quantification of the cerebral venous outflow (CVF) in healthy subjects and patients with multiple sclerosis (MS).Methodology/Principal FindingsIn a group of 27 healthy adults (13 females and 14 males; mean age 37.8±11.2 years), and 52 patients with MS (32 females and 20 males; mean age 42.6±12.1 years), CVF has been measured in clinostatism and in the seated position as the sum of the flow in IJVs and VVs. The difference between CVF in clinostatism and CVF in the seated position (ΔCVF) has been correlated with patients' status (healthy or MS), and a number of clinical variables in MS patients. Statistical analysis was performed by Fisher's exact test, non-parametric Mann-Whitney U test, ANOVA Kruskal-Wallis test, and correntropy coefficient.The value of ΔCVF was negative in 59.6% of patients with MS and positive in 96.3% of healthy subjects. Negative ΔCVF values were significantly associated with MS (p<0.0001). There was no significant correlation with clinical variables.Conclusions/SignificanceNegative ΔCVF has a hemodynamic significance, since it reflects an increased venous return in the seated position. This seems to be a pathologic condition. In MS patients, a vascular dysregulation resulting from involvement of the autonomous nervous system may be supposed. ΔCVF value should be included in the quantitative CDS evaluation of the cerebral venous drainage, in order to identify cerebral venous return abnormalities.
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