Genome sequencing for detection of pathogenic deep intronic variation: A clinical case report illustrating opportunities and challenges.

Variants in JAM3 have been reported in four families manifesting a severe autosomal recessive disorder characterized by hemorrhagic destruction of the brain, subependymal calcification, and cataracts. We describe a 7-year-old male with a similar presentation found by research-based quad genome sequencing to have two novel splicing variants in trans in JAM3, including one deep intronic variant (NM_032801.4: c.256+1260G>C) not detectable by standard exome sequencing. Targeted sequencing of RNA isolated from transformed lymphoblastoid cell lines confirmed that each of the two variants has a deleterious effect on JAM3 mRNA splicing. The role for genome sequencing as a clinical diagnostic test extends to those patients with phenotypes strongly suggestive of a specific Mendelian disorder, especially when the causal genetic variant(s) are not found by a more targeted approach. Barriers to diagnosis via identification of pathogenic deep intronic variation include lack of laboratory consensus regarding in silico splicing prediction tools and limited access to clinically validated confirmatory RNA experiments.

Decompressive Craniectomy for Ischemic Stroke: Effect of Hemorrhagic Transformation on Outcome.

BACKGROUND: Decompressive hemicraniectomy (DhC) is a life-saving surgical procedure being increasingly employed for malignant middle cerebral artery strokes. We examined the incidence of hemorrhagic transformation following DhC. METHODS: We retrospectively reviewed the charts and radiological images of patients who underwent DhC for malignant middle cerebral artery strokes. We classified the hemorrhagic events and assessed the short-term 30-day outcome associated with these events. RESULTS: A total of 23 DhCs were performed for supratentorial ischemic strokes in 22 patients. There were 16 males and 6 females with an average age of 47 years (21-69 years). Of the 22 patients, 13 (59%) developed a new hemorrhage following DhC. There were 3 mortalities (14%). Of the survivors, 6 (27%) were discharged home with a modified Rankin Scale (mRS) score of 2. The remaining 13 patients (59%) recovered to a degree wherein they were discharged to a rehabilitation center (mRS score 3-4). No patient persisted in a vegetative or semivegetative state (mRS score 5). CONCLUSIONS: In this study, the rate of hemorrhagic transformation following DhC for ischemic stroke was 59%. This is much higher than that reported in the stroke thrombolysis literature. The presence of any type of new hemorrhagic transformation in this patient population does not appear to alter the natural history of their ischemic strokes in terms of Glasgow outcome scores or destination of disposition.

Hepatic cysts treated with percutaneous ethanol sclerotherapy: time to extend the indications to haemorrhagic cysts and polycystic liver disease.

OBJECTIVES: To describe the long-term clinical and morphological outcome of symptomatic hepatic cysts treated with percutaneous ethanol sclerotherapy (PES). METHODS: From December 2003 to September 2011, all patients with hepatic cysts undergoing PES with a follow-up after 12 months were included. Evolution of the volume of the cysts and clinical and biological data were recorded. Features of the cyst were evaluated in each patient: simple, haemorrhagic or developed on underlying polycystic liver disease (PCLD). RESULTS: Fifty-eight cysts (median volume 666 mL) were treated in 57 patients (52 women, mean age 58 years (18-80)). Twenty-two patients (39 %) had simple hepatic cysts, 19 (33 %) had dominant cysts on PCLD and 20 had haemorrhagic cysts (34.5 %), including 4 with PCLD. After a mean 27.3 months of follow-up, the final median cystic volume was 13.5 mL (p < 0.0001), and the median reduction in cyst volume was 94 % (58-100 %). Treatment was satisfactory in 95 % of the patients (54/57) (symptoms disappeared in 45/57 (79 %), decreased in 9/57 (16 %)). There was no clinical or morphological difference between patients with PCLD, haemorrhagic cysts or simple cysts. CONCLUSION: The clinical and morphological efficacy of a single session of PES is very high, regardless of the presence of intracystic haemorrhage or underlying PCLD. KEY POINTS: • The clinical efficacy of percutaneous ethanol sclerotherapy is very high. • Haemorrhagic content should not be a contraindication for percutaneous sclerotherapy. • Dominant cysts on polycystic liver disease should be treated with PES. • Imaging follow-up should not be performed shortly after the procedure.

D-dimer as a predictor of progressive hemorrhagic injury in patients with traumatic brain injury: analysis of 194 cases.

This study sought to describe and evaluate any relationship between D-dimer values and progressive hemorrhagic injury (PHI) after traumatic brain injury (TBI). In patients with TBI, plasma D-dimer was measured while a computed tomography (CT) scan was conducted as soon as the patient was admitted to the emergency department. A series of other clinical and laboratory parameters were also measured and recorded. A logistic multiple regression analysis was used to identify risk factors for PHI. A cohort of 194 patients with TBI was evaluated in this clinical study. Eighty-one (41.8%) patients suffered PHI as determined by a second CT scan. The plasma D-dimer level was higher in patients who demonstrated PHI compared with those who did not (P < 0.001. Using a receiver-operator characteristic curve to predict the possibility by measuring the D-dimer level, a value of 5.00 mg/L was considered the cutoff point, with a sensitivity of 72.8% and a specificity of 78.8%. Eight-four patients had D-dimer levels higher than the cut point value (5.0 mg/L); PHI was seen in 71.4% of these patients and in 19.1% of the other patients (P < 0.01). Factors with P < 0.2 on bivariate analysis were included in a stepwise logistic regression analysis to identify independent risk factors for TBI coagulopathy. Logistic regression analysis showed that the D-dimer value was a predictor of PHI, and the odds ratio (OR) was 1.341 with per milligram per liter (P = 0.020). The stepwise logistic regression also identified that time from injury to the first CT shorter than 2 h (OR = 2.118, P = 0.047), PLT counts lesser than 100 x 109/L (OR = 7.853, P = 0.018), and Fg lower than 2.0 g/L (OR = 3.001, P = 0.012) were risk factors for the development of PHI. When D-dimer values were dichotomized at 5 mg/L, time from injury to the first CT scan was no longer a risk factor statistically while the OR value of D-dimer to the occurrence of PHI elevated to 11.850(P < 0.001). The level of plasma D-dimer after TBI can be a useful prognostic factor for PHI and should be considered in the clinical management of patients in combination with neuroimaging and other data.

Relation of common carotid artery lumen diameter to general arterial dilating diathesis and abdominal aortic aneurysms: the Tromsø Study.

In a cross-sectional, population-based study in Tromsø, Norway, the authors investigated correlations between lumen diameter in the right common carotid artery (CCA) and the diameters of the femoral artery and abdominal aorta and whether CCA lumen diameter was a risk factor for abdominal aortic aneurysm (AAA). Ultrasonography was performed in 6,400 men and women aged 25-84 years during 1994-1995. An AAA was considered present if the aortic diameter at the level of renal arteries was greater than or equal to 35 mm, the infrarenal aortic diameter was greater than or equal to 5 mm larger than the diameter of the level of renal arteries, or a localized dilation of the aorta was present. CCA lumen diameter was positively correlated with abdominal aortic diameter (r = 0.3, P < 0.01) and femoral artery diameter (r = 0.2, P < 0.01). In a multivariable adjusted model, CCA lumen diameter was a significant predictor of AAA in both men and women (for the fifth quintile vs. the third, odds ratios were 1.9 (95% confidence interval: 1.2, 2.9) and 4.1 (95% confidence interval: 1.5, 10.8), respectively). Thus, CCA lumen diameter was positively correlated with femoral and abdominal aortic artery diameter and was an independent risk factor for AAA.

Percutaneous biopsy of liver tumors with color Doppler US guidance.

BACKGROUND: Percutaneous liver biopsy is a well-established procedure. Aim of this study was to investigate the usefulness of color Doppler ultrasound (US) for guiding percutaneous biopsy of liver tumors in patients at high risk of bleeding. METHODS: Forty-seven patients with severe, uncorrectable coagulopathy (platelet count < 50 x 10(9)/L and/or prothrombin time ratio [normal/patient] < 50%) were submitted to percutaneous biopsy of focal liver lesions using a 21 G cutting needle. The procedure was guided by color Doppler US, avoiding the needle cross into any liver or tumor vessel. RESULTS: Biopsy material was adequate for pathological reading in 46/47 cases (97.9%). No major post-biopsy complication was observed. In particular, no case of hemoperitoneum was detected on US examinations performed 2 hours after biopsy. Minor complications (including one subcapsular hematoma) occurred in 4 patients (8.5%). CONCLUSIONS: Color Doppler US can safely guide percutaneous liver biopsy in patients at high-risk of bleeding.