Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease

Recently, a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 was reported as the cause of chromosome 9p21‐linked frontotemporal dementia‐amyotrophic lateral sclerosis (FTD‐ALS). We here report the prevalence of the expansion in a hospital‐based cohort and associated clinical features indicating a wider clinical spectrum of C9ORF72 disease than previously described. We studied 280 patients previously screened for mutations in genes involved in early onset autosomal dominant inherited dementia disorders. A repeat‐primed polymerase chain reaction amplification assay was used to identify pathogenic GGGGCC expansions. As a potential modifier, confirmed cases were further investigated for abnormal CAG expansions in ATXN2. A pathogenic GGGGCC expansion was identified in a total of 14 probands. Three of these presented with atypical clinical features and were previously diagnosed with clinical olivopontocerebellar degeneration (OPCD), atypical Parkinsonian syndrome (APS) and a corticobasal syndrome (CBS). Further, the pathogenic expansion was identified in six FTD patients, four patients with FTD‐ALS and one ALS patient. All confirmed cases had normal ATXN2 repeat sizes. Our study widens the clinical spectrum of C9ORF72related disease and confirms the hexanucleotide expansion as a prevalent cause of FTD‐ALS disorders. There was no indication of a modifying effect of the ATXN2 gene.     

Differences in functional connectivity in major depression versus bipolar II depression

Background

Objective methods of differentiating unipolar versus bipolar depression would enhance our ability to treat these disorders by providing more accurate diagnoses. One first step towards developing diagnostic methodology is determining whether brain function as assessed by functional MRI (fMRI) and functional connectivity analyses might differentiate the two disorders.

Methods

Fourteen subjects with bipolar II depression and 26 subjects with recurrent unipolar depression were studied using fMRI and functional connectivity analyses.

Results

The first key finding of this study was that functional connectivity of the right posterior cingulate cortex differentiates bipolar II and unipolar depression. Additionally, results suggest that functional connectivity of this region is associated with suicidal ideation and depression severity in unipolar but not bipolar II depression.

Limitations

The primary limitation is the relatively small sample size, particularly for the correlational analyses.

Conclusions

The functional connectivity of right posterior cingulate cortex may differential unipolar from bipolar II depression. Further, connectivity of this region may be associated with depression severity and suicide risk in unipolar but not bipolar depression.     

Hodgkin disease: CT of the thymus

The computed tomography (CT) scans in two groups of patients with Hodgkin disease were reviewed to determine the frequency of thymic enlargement. In 50 CT scans from 50 patients with evidence of thoracic disease on CT scans who were examined for primary staging, the thymus was enlarged in 15 of 50 (30%). Fifty CT scans were obtained from 44 patients at the time of 50 separate episodes of known or suspected relapse. Relapse occurred in the mediastinum in 12 episodes, lung parenchyma in five, and both sites in one. Thymic enlargement thought to be due to involvement by disease was present in seven of 18 (38%). Mediastinal disease was associated with thymic enlargement in all but one patient in whom a thymic cyst developed after radiation therapy. Differentiation of thymic enlargement from enlarged superior mediastinal lymph nodes was easily made in all but two patients. Thymic enlargement in the absence of lymph node enlargement may indicate a different disease, since isolated Hodgkin disease of the thymus is uncommon. Primary thymic tumor should be considered initially, whereas after treatment, rebound hyperplasia of the thymus may be the cause of enlargement.     

New catheter design and placement technique for pulmonary arteriography

An improved catheter for pulmonary arteriography via the antecubital approach is described. The catheter has been used successfully in 56 patients.     

Malignant uveal melanoma and simulating lesions: MR imaging evaluation

Twenty-one patients with intraocular disease were studied by magnetic resonance (MR) imaging and computed tomography (CT). In 13 cases, malignant uveal melanoma was considered the likely diagnosis. Both imaging methods were accurate in determining the location and size of uveal melanomas. MR imaging was superior for the assessment of possible associated retinal detachment, for assessment of vitreous change, and for differentiating uveal melanoma from choroidal hemangioma and choroidal detachment. A case of retinal gliosis could not be differentiated from uveal melanoma by either technique. Uveal melanomas appeared as hyperintense lesions on T1-weighted images and as hypointense lesions on T2-weighted images. High signal intensity of the vitreous was observed in patients with vitritis and in those who were thought to have protein leaking into the vitreous as a result of impairment of the retinal-blood barrier.     

Relationship between parathyroid hormone secretion and cytosolic calcium concentration in dispersed bovine parathyroid cells.

The parathyroid cell is unusual among exocytotic systems in that low extracellular Ca2+ concentrations stimulate, while high Ca2+ concentrations inhibit, parathyroid hormone (PTH) release, suggesting that this cell might have unique secretory mechanisms. In the present studies, we used the Ca2+-sensitive fluorescent dye QUIN -2 to examine the relationship between cytosolic Ca2+ concentration and PTH release in dispersed bovine parathyroid cells. The secretagogue dopamine, which enhances PTH release 2- to 3-fold in association with 20- to 30-fold increases in cellular cAMP, had no effect on the cytosolic Ca2+ level (261 +/- 28 vs. 236 +/- 22 nM for control cells at 1 mM extracellular Ca2+; P greater than 0.05). Dibutyryl-cAMP, which produces a comparable stimulation of PTH release, likewise did not modify the level of cytosolic Ca2+. Removal of extracellular Ca2+ produced a further decrease of the cytosolic Ca2+ to 82 +/- 10 nM. However, PTH secretion persisted at a near maximal rate despite this decrease of extracellular and cytosolic Ca2+ and was 95 +/- 2.5% of the rate of hormonal release at 0.5 mM extracellular Ca2+. In contrast, addition of the divalent cation ionophore ionomycin to parathyroid cells at 1.0 mM extracellular Ca2+ inhibited PTH secretion in association with an increase in cytosolic Ca2+ from 230 +/- 13 nM to 570 +/- 50 nM. Moreover, the magnitude of the ionomycin-induced reduction in PTH secretion (64 +/- 4% relative to the secretory rate at 0.5 mM Ca2+) was equivalent to the inhibition of PTH release caused by 1.5 mM extracellular Ca2+ (64 +/- 6%), which increased the cytosolic Ca2+ to similar levels (450 +/- 48 nM). Thus, the parathyroid cell differs from secretory cells thought to operate by stimulus-secretion coupling in the following ways: changes in PTH release can occur without detectable alterations in the cytosolic Ca2+ concentration, maximal rates of PTH secretion occur at cytosolic Ca2+ concentrations that fail to support exocytosis in other cell types, and increases in the cytosolic Ca2+ concentration due to ionomycin inhibit rather than stimulate PTH release. Therefore, the control of PTH secretion by Ca2+ and other secretagogues may involve previously undefined mechanisms whereby hormonal release is relatively independent of the cytosolic Ca2+ at low levels of this parameter and is inversely related to cytosolic Ca2+ at higher levels of intracellular Ca2+.     

Percutaneous Endoscopic Gastrostomy: A Preferred Method of Feeding Tube Gastrostomy

Percutaneous endoscopic gastrostomy was attempted in 16 patients using local anesthesia and intravenous meperidine and diazepam sedation. The procedure was shown to be safe, easy to perform, and avoided the need for laparotomy. We suggest percutaneous endoscopic gastrostomy be the preferred route of alimentation in those patients requiring feeding gastrostomy.     

Pulmonary histiocytosis X: comparison of radiographic and CT findings

The authors retrospectively evaluated radiographs, computed tomographic (CT) scans, and results of pulmonary function tests (when available) for 17 patients with biopsy-proved pulmonary histiocytosis X. In 11 patients, high-resolution CT was used. In 12 patients, CT demonstrated cystic air spaces, usually less than 10 mm in diameter. In three of these 12, cysts were the only abnormality, but in six others, nodules (usually less than 5 mm in diameter) were also present. Two patients had only nodules and one, only emphysema. CT showed that many lesions that appeared reticular on plain radiographs were actually cysts. CT showed no central or peripheral concentration of lesions, but it did reveal that many small nodules were distributed in the centers of secondary lobules around small airways. CT findings correlated better with the diffusing capacity (rho = -0.71) than did the plain radiographic findings (rho = -0.57). Thus, CT was better than radiography at showing the morphology and distribution of lung abnormalities.