Novel mutations in KARS cause hypertrophic cardiomyopathy and combined mitochondrial respiratory chain defect.

Mutations in KARS, which encodes for both mitochondrial and cytoplasmic lysyl-tRNA synthetase, have been so far associated with three different phenotypes: the recessive form of Charcot-Mary-Tooth polyneuropathy, the autosomal recessive nonsyndromic hearing loss and the last recently described condition related to congenital visual impairment and progressive microcephaly. Here we report the case of a 14-year-old girl with severe cardiomyopathy associated to mild psychomotor delay and mild myopathy; moreover, a diffuse reduction of cytochrome C oxidase (COX, complex IV) and a combined enzymatic defect of complex I (CI) and complex IV (CIV) was evident in muscle biopsy. Using the TruSight One sequencing panel we identified two novel mutations in KARS. Both mutations, never reported previously, occur in a highly conserved region of the catalytic domain and displayed a dramatic effect on KARS stability. Structural analysis confirmed the pathogenic role of the identified variants. Our findings confirm and emphasize that mt-aminoacyl-tRNA synthetases (mt-ARSs) enzymes are related to a broad clinical spectrum due to their multiple and still unknown functions.

A novel mutation in NDUFB11 unveils a new clinical phenotype associated with lactic acidosis and sideroblastic anemia.

NDUFB11, a component of mitochondrial complex I, is a relatively small integral membrane protein, belonging to the "supernumerary" group of subunits, but proved to be absolutely essential for the assembly of an active complex I. Mutations in the X-linked nuclear-encoded NDUFB11 gene have recently been discovered in association with two distinct phenotypes, i.e. microphthalmia with linear skin defects and histiocytoid cardiomyopathy. We report on a male with complex I deficiency, caused by a de novo mutation in NDUFB11 and displaying early-onset sideroblastic anemia as the unique feature. This is the third report that describes a mutation in NDUFB11, but all are associated with a different phenotype. Our results further expand the molecular spectrum and associated clinical phenotype of NDUFB11 defects.

DJ-1 modulates mitochondrial response to oxidative stress: clues from a novel diagnosis of PARK7.

DJ-1 mutations are associated to early-onset Parkinson's disease and accounts for about 1-2% of the genetic forms. The protein is involved in many biological processes and its role in mitochondrial regulation is gaining great interest, even if its function in mitochondria is still unclear. We describe a 47-year-old woman affected by a multisystem disorder characterized by progressive, early-onset parkinsonism plus distal spinal amyotrophy, cataracts and sensory-neural deafness associated with a novel homozygous c.461C>A [p.T154K] mutation in DJ-1. Patient's cultured fibroblasts showed low ATP synthesis, high ROS levels and reduced amount of some subunits of mitochondrial complex I; biomarkers of oxidative stress also resulted abnormal in patient's blood. The clinical pattern of multisystem involvement and the biochemical findings in our patient highlight the role for DJ-1 in modulating mitochondrial response against oxidative stress.

[Endovascular treatment for recurrent carotid stenosis]. / Il trattamento endovascolare della restenosi carotidea.

PURPOSE: Surgery of recurrent carotid stenosis (RCS) has higher complication rates than primary carotid endoarterectomy (CEA). Percutaneous transluminal angioplasty (PTA) and stent placement were evaluated retrospectively with a view to proposing then as alternative procedures for RCS. METHODS: In the last 10 years, 19 patients underwent 20 endovascular procedures for RCS at our Department. The mean interval between CEA and PTA was 21 months (range 4-96): 14 patients had PTA within 2 years, 3 patients within 2 and 3 years,and 2 after 3 years. The mean degree of stenosis was 92% (range 80-95%). PTA was performed by balloon catheters (size 4-7 mm) without using cerebral protection device; one self-expanding stent was used to treat RCS after PTA. All patients underwent physical examination and carotid color-coded Doppler sonography in autumn 1999 RESULTS: The procedure was technically successful, with residual stenosis lower than 50%, in 17 of 19 patients; 10 patients showed residual stenosis lower than 30%. Carotid PTA was stopped due to transient neurological deficit in one case. One RCS proved uncompliant even though high-pressure balloon catheters were used. The mean follow-up period in 16 patients was 37.4 months (range 3-99 months). Carotid restenosis after PTA developed in 3 patients, respectively after 29,18 and 7 months. In the last case RCS was successfully treated by stent placement (Wallstent). The primary patency rate was 81%, the secondary patency rate was 88% and the late clinical success rate was of 94%. CONCLUSIONS: In selected cases, PTA without the use of cerebral protection devices and stent placement proved to be a safe and effective alternative treatment for early RCS. When an atherosclerotic lesion is suspected surgery or endovascular treatment with cerebral protection devices are recommended.

[Power Doppler signals produced by static structures: a frequent cause of interpretation errors in the study of slow flows]. / Segnali con power Doppler prodotti da strutture statiche: causa frequente di errori interpretativi nello studio dei flussi lenti.

INTRODUCTION: The main characteristic of power Doppler US is its high sensitivity in showing blood vessels with small caliber and slow flow. However, artifacts are a common problem with this technique and they lead to impaired and subjective image reading. We analyzed the artifacts from Power Doppler signals from static structures both in vitro and in vivo. MATERIAL AND METHODS: Some samples of different tissues (liver, muscle, fat) positioned into a water bath were studied with Power Doppler in vitro. The static structures were imaged with a 10 MHz transducer (Esaote AU4, Genoa, Italy) both through water and with the transducer resting directly on the tissue. PRF and WF were set differently every time and their individual/combined role in causing artifacts was assessed. Then we examined different organs in vivo to investigate if the same setting as in vitro would cause the same artifacts. RESULTS: All our tissue samples exhibited strong and persistent color signals at low PRF and WF settings, with stronger signals at the solid/liquid interface and no signals from the liquid color box. Comparison of images acquired with same setting, particularly color gain, but different PRF (750 Hz to 3 KHz) or WF (50 to 600 Hz) showed that artifacts are mainly related to the latter. In vivo examinations showed similar findings, especially relative to the liquid/solid and solid hypoechoic/solid hyperechoic interfaces. CONCLUSIONS: Persistent and fairly strong Power Doppler signals can be produced by echogenic structures with no flow; these artifacts are frequent at low PRF, but are mainly caused by incorrect WF setting. They are most frequent along interfaces with specular reflection. To conclude, we would like to stress that, in addition to motion artifacts, which are easier to recognize, other potentially misleading signals may come from static structures.

Excess prevalence of supraaortic artery lesions in renovascular hypertension: an arteriographic study.

PURPOSE: High renin or renovascular hypertension (RVH) has been associated with a higher risk of stroke than low-to-normal renin hypertension. Our present purpose was to investigate the angiographic prevalence and distribution of lesions of the supraaortic arteries in a series of consecutive patients with RVH compared with control patients with low-to-normal renin primary hypertension (PH). METHODS: Thirty-two consecutive hypertensives (21 females, 11 males, aged 23-72 years) were investigated by renal and aortic arch digital subtraction arteriography (DSA). None of them had any history or symptoms of cerebrovascular disease. In each, the presence and severity of lesions at 17 different segments of the supraaortic arteries were evaluated and a score for supraaortic lesions was then calculated based on the number and severity of lesions. RVH was diagnosed in 16 patients with renal artery stenoses and normalization of blood pressure after percutaneous transluminal renal angioplasty (PTRA) (n = 12) or surgery (n = 4). The cause of renal artery obstruction was fibrodysplasia in 5 patients (31%) and atherosclerosis in 11 (69%). PH was diagnosed in 16 patients based on a normal renal DSA and exclusion of all other possible causes of hypertension. RESULTS: The RVH and PH groups were similar with respect to age, sex, body mass index, diabetes, smoking habits, serum triglycerides, cholesterol, and blood pressure values, and differed only in plasma renin activity (6.0 +/- 1.7 ng AngI/ml/h in RVH vs. 1.4 +/- 0.3 in PH, mean +/- SEM, p = 0.008). The score for supraaortic arterial lesions was significantly higher in RVH than in PH (181 +/- 32 vs. 17 +/- 9, p = 0.001). This difference was also evident when the five patients with fibrodysplasia were compared with five age- and sex-matched PH patients. The sites most frequently involved were the carotid artery bulb and the internal carotid artery sinus. At each affected site the score was higher for RVH than for PH. CONCLUSION: For the same demographic features and risk profile, RVH was associated with a higher prevalence and severity of supraaortic artery lesions than PH.

Intravascular ultrasound evaluation for assessment and therapeutic decisions in aortic diseases.

Intravascular sonography (IVS) was employed in several aortic pathologies. Acute dissecting aneurysm, chronic or recurrent dissection in previously repaired aneurysm, iatrogenic (postcatheterism) dissection, noncommunicating dissection (mural hematoma), chronic and acute partial thrombosis, and mural fibrosis following aspecific aortitis were studied. The stationary and dynamic observations combined with angiographic findings provided useful information for characterization of the lesions and for therapeutic decisions. In all 14 patients studied, supplemental data achieved from IVS suggest that a combination of angiography and IVS is the most nearly complete examination for concomitant and fast diagnostic workup.

[Chemoembolization in the therapy of hepatocarcinoma. A 3-year experience]. / La chemioembolizzazione nella terapia dell'epatocarcinoma. Esperienza di 3 anni.

This study was aimed at evaluating the efficacy of chemoembolization (CE) to improve survival in patients with hepatocellular carcinoma (HCC). Our results were compared with the natural history of HCC. Sixty-two consecutive patients with HCC in Okuda's stages I and II underwent CE. Forty-seven patients were treated with CE alone; 9 patients had CE prior to surgery, and 6 patients had it after surgery because of recurrent HCC. One hundred and nine CEs (mean: 1.8 CEs/patient) were performed with Lipiodol UF, epirubicin and gelatin sponge. Actuarial survival was calculated considering Okuda's stage, neoplasm size, and evidence of pseudocapsule. The mean cumulative survival of the 47 patients treated with CE alone was 13.2 months; survival (+/- SE) at 12, 24 and 36 months was 0.75 (+/- 0.07), 0.46 (+/- 0.10) and 0.28 (+/- 0.12). Survival was not affected by Okuda's stage, neoplasm size, evidence of pseudocapsule (p > 0.05). Nevertheless, the patients with early HCC had better prognosis. Eighteen patients (42.9%) died during follow-up, 12 of whom (66.7%) from hepatic failure. The mean survival of patients with recurrence of HCC after surgery was 41 months (range: 24.8-74.9 months) since initial diagnosis of HCC, and 14.8 months (range: 7.1-29.6 months) since diagnosis of recurrence. Two of these patients died from hepatic failure. All the patients who underwent also surgery after CE are still alive (mean survival: 14.7 months). Histologic findings of resected specimens revealed viable neoplastic cells in all cases. Twenty-one major complications (20.2%) occurred in 18 patients (29%); the outcome of complications was favorable in all but one patient who died from sepsis. CE is a reliable and safe treatment for unresectable HCC. Small HCCs should be preferably treated with surgery or, alternatively, with percutaneous alcohol injection.