McLeod syndrome is caused by mutations of XK, an X‐chromosomal gene of unknown function. Originally defined as a peculiar Kell blood group variant, the disease affects multiple organs, including the ...nervous system, but is certainly underdiagnosed. We analyzed the mutations and clinical findings of 22 affected men, aged 27 to 72 years. Fifteen different XK mutations were found, nine of which were novel, including the one of the eponymous case McLeod. Their common result is predicted absence or truncation of the XK protein. All patients showed elevated levels of muscle creatine phosphokinase, but clinical myopathy was less common. A peripheral neuropathy with areflexia was found in all but 2 patients. The central nervous system was affected in 15 patients, as obvious from the occurrence of seizures, cognitive impairment, psychopathology, and choreatic movements. Neuroimaging emphasized the particular involvement of the basal ganglia, which was also detected in 1 asymptomatic young patient. Most features develop with age, mainly after the fourth decade. The resemblance of McLeod syndrome with Huntington's disease and with autosomal recessive chorea‐acanthocytosis suggests that the corresponding proteins—XK, huntingtin, and chorein—might belong to a common pathway, the dysfunction of which causes degeneration of the basal ganglia.
Objectives Uncomplicated acute type B aortic dissection (AD) treated conservatively has a 10% 30-day mortality and up to 25% need intervention within 4 years. In complicated AD, stent grafts have ...been encouraging. The aim of the present prospective randomised trial was to compare best medical treatment (BMT) with BMT and Gore TAG stent graft in patients with uncomplicated AD. The primary endpoint was a combination of incomplete/no false lumen thrombosis, aortic dilatation, or aortic rupture at 1 year. Methods The AD history had to be less than 14 days, and exclusion criteria were rupture, impending rupture, malperfusion. Of the 61 patients randomised, 80% were DeBakey type IIIB. Results Thirty-one patients were randomised to the BMT group and 30 to the BMT+TAG group. Mean age was 63 years for both groups. The left subclavian artery was completely covered in 47% and in part in 17% of the cases. During the first 30 days, no deaths occurred in either group, but there were three crossovers from the BMT to the BMT+TAG group, all due to progression of disease within 1 week. There were two withdrawals from the BMT+TAG group. At the 1-year follow up there had been another two failures in the BMT group: one malperfusion and one aneurysm formation ( p = .056 for all). One death occurred in the BMT+TAG group. For the overall endpoint BMT+TAG was significantly different from BMT only ( p < .001). Incomplete false lumen thrombosis, was found in 13 (43%) of the TAG+BMT group and 30 (97%) of the BMT group ( p < .001). The false lumen reduced in size in the BMT+TAG group ( p < .001) whereas in the BMT group it increased. The true lumen increased in the BMT+TAG ( p < .001) whereas in the BMT group it remained unchanged. The overall transverse diameter was the same at the beginning and after 1 year in the BMT group (42.1 mm), but in the BMT+TAG it decreased (38.8 mm; p = .062). Conclusions Uncomplicated AD can be safely treated with the Gore TAG device. Remodelling with thrombosis of the false lumen and reduction of its diameter is induced by the stent graft, but long term results are needed.
The disease complex medullary cystic disease/familial juvenile hyperuricemic nephropathy (MCKD/FJHN) is characterized by alteration of urinary concentrating ability, frequent hyperuricemia, ...tubulo-interstitial fibrosis, cysts at the cortico-medullary junction and renal failure. MCKD/FJHN is caused by mutations of the gene encoding uromodulin, the most abundant protein in urine. Here, we describe new missense mutations in three families with MCKD/FJHN and demonstrate allelism with a glomerulocystic kidney disease (GCKD) variant, showing association of cyst dilatation and collapse of glomeruli with some clinical features similar to MCKD/FJHN as hyperuricemia and impairment of urine concentrating ability. Furthermore, we provide the first functional characterization of uromodulin mutations. The four newly identified mutants were characterized by immunofluorescence and FACS analysis on transfected cells. These experiments showed that all uromodulin mutations cause a delay in protein export to the plasma membrane due to a longer retention time in the endoplasmic reticulum. Immunohistochemistry on GCKD and MCKD/FJHN kidney biopsies revealed dense intracellular accumulation of uromodulin in tubular epithelia of the thick ascending limb of Henle's loop. Electron microscopy demonstrated accumulation of dense fibrillar material within the endoplasmic reticulum. Consistently, patient urines show a severe reduction of excreted uromodulin. The maturation impairment is consistent with the clinical findings and suggests a pathogenetic mechanism leading to these kidney diseases.
Laparoscopic liver resection (LLR) and radiofrequency ablation (RFA) represented potential treatments for patients with a single hepatocellular carcinoma (HCC) smaller than 3 cm. As the aging ...population soared, our study aimed to examine the advantage/drawback balance for these treatments, which should be reassessed in elderly patients.
A multicentric retrospective study compared 184 elderly patients (aged >70 years) (86 patients underwent LLR and 98 had RFA) with single ≤3 cm HCC, observed from January 2009 to January 2019.
After propensity score matching (PSM), the estimated 1- and 3-year overall survival rates were 96.5 and 87.9% for the LLR group, and 94.6 and 68.1% for the RFA group (p = 0.001) respectively. The estimated 1- and 3-year disease-free survival rates were 92.5 and 67.4% for the LLR group, and 68.5 and 36.9% for the RFA group (p = 0.001). Patients with HCC of anterolateral segments were more often treated with laparoscopic resection (47 vs. 36, p = 0.04). The median operative time in the resection group was 205 min and 25 min in the RFA group (p = 0.01). Length of hospital stay was 5 days in the resection group and 3 days in the RFA group (p = 0.03).
Despite a longer length of hospital stay and operative time, LLR guarantees a comparable postoperative course and a better overall and disease-free survival in elderly patients with single HCC (≤3 cm), located in anterolateral segments.
Surgical mortality for acute type A aortic dissection reported in different experiences from single centers or surgeons varies from 7% to 30%. The International Registry of Acute Aortic Dissection, ...collecting patients from 18 referral centers worldwide, identifies a preoperative risk stratification scheme and a real average surgical mortality for acute type A aortic dissection in the current era.
A comprehensive analysis was completed of 290 clinical variables and their relationship to surgical outcomes in 526 of 1032 patients enrolled in the International Registry of Acute Aortic Dissection from 1996 through 2001. Extracted cases, categorized according to risk profile, were defined as unstable (group I) in the presence of cardiac tamponade; shock; congestive heart failure; cerebrovascular accident; stroke; coma; myocardial ischemia, infarction, or both; electrocardiograms with new Q waves or ST elevation; acute renal failure; or mesenteric ischemia-infarction at the time of the operation. Outside of an unstable condition, patients were categorized as stable (group II).
The overall in-hospital mortality was 25.1%. Mortality in group I was 31.4% compared with 16.7% in group II (
P < .001). Independent preoperative predictors of operative mortality were history of aortic valve replacement (odds ratio = 3.12), migrating chest pain (odds ratio = 2.77), hypotension as sign of acute type A aortic dissection (odds ratio = 1.95), shock or tamponade (odds ratio = 2.69), preoperative cardiac tamponade (odds ratio = 2.22), and preoperative limb ischemia (odds ratio = 2.10).
The International Registry of Acute Aortic Dissection experience confirms that patient selection plays an important role in determining surgical outcomes in patients with acute type A aortic dissection. Knowledge of significant risk factors for operative mortality can contribute to better management and a more defined risk assessment in patients affected by acute type A aortic dissection.
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a genetically heterogeneous renal disorder leading to progressive loss of renal function. ADTKD-REN is due to rare mutations in renin, ...all localized in the protein leader peptide and affecting its co-translational insertion in the endoplasmic reticulum (ER). Through exome sequencing in an adult-onset ADTKD family we identified a new renin variant, p.L381P, mapping in the mature protein. To assess its pathogenicity, we combined genetic data, computational and predictive analysis and functional studies. The L381P substitution affects an evolutionary conserved residue, co-segregates with renal disease, is not found in population databases and is predicted to be deleterious by in silico tools and by structural modelling. Expression of the L381P variant leads to its ER retention and induction of the Unfolded Protein Response in cell models and to defective pronephros development in zebrafish. Our work shows that REN mutations outside of renin leader peptide can cause ADTKD and delineates an adult form of ADTKD-REN, a condition which has usually its onset in childhood. This has implications for the molecular diagnosis and the estimated prevalence of the disease and points at ER homeostasis as a common pathway affected in ADTKD-REN, and possibly more generally in ADTKD.
OBJECTIVES: An innovative diagnostic procedure (MRgFUS) is used for the treatment of uterine fibroids (UF), a disease affecting 13.80% of all ages Italian women. The study aim was a multi-dimensional ...evaluation of the benefits concerning the introduction of MRgFUS, in comparison with conservative procedures: myomectomy, and uterine artery embolization (UAE). METHODS: In 2017, a Health Technology Assessment was conducted, considering the Lombardy Region perspective. Data were gathered using specific questionnaires, self-reported interviews and systematically searching medical literature, considering the 9 EUnetHTA dimensions and the MCDA approach. RESULTS: MRgFUS introduction would lead to: i) a decrease in the adverse events incidence (p-value<0.001); ii) an effectiveness improvement (symptoms' relief); iii) a best cost-effectiveness trade-off; iv) a significant decrease in the length of hospital stay (p-value<0.001), with the possibility to perform a day-hospital procedure; v) a generation of health migration phenomena; vi) a significant decrease in patients' productivity loss, reporting a saving of -54.60% compared with surgical procedures (p-value<0.001) and -20.37% compared with UAE (p-value=0.024); vii) an improvement in the quality of life for both patients and caregivers, with a shorter recovery-time period. While the new equipment introduction, in the short term, requires training courses productivity losses, in the long run, there would be a reduction in the areas described above, thus making it the preferred technology, with an average organisational value of 0.32, followed by UAE (0.12). Lombardy Region could benefit from economic and organizational advantages with the adoption of MRgFUS into the clinical practice (-6.29%), thus being able to perform, on average, 57,181 additional DRGs, within three years. CONCLUSIONS: The results suggested that MRgFUS could be considered an advantageous technological alternative in the UF target population, providing a potential overall benefit with its acquisition, thus supporting the definition of a future dedicated national reimbursement tariff.
Objective The increasing life expectancy of the population will likely be accompanied by a rise in the incidence of acute type A aortic dissection. However, because of an increased risk of cardiac ...surgery in an elderly population, it is important to define when, if at all, the risks of aortic repair outweigh the risk of death from unoperated type A aortic dissection. Methods We analyzed 936 patients with type A aortic dissection enrolled in the International Registry of Acute Aortic Dissection from 1996 to 2004. Patients with type A aortic dissection were categorized according to patient age by decade and by surgical versus medical management, and outcomes of both management types were investigated in the different age groups. Results The rate of surgical aortic repair decreased progressively with age, whereas surgical mortality significantly increased with age. Age 70 years or more was an independent predictor for mortality (38.2% vs 26.0%; P < .0001, odds ratio 1.73). The in-hospital mortality rate was significantly lower after surgical management compared with medical management until the age of 80 years. For patients aged 80 to 90 years, the in-hospital mortality appeared to be lower after surgical management (37.9% vs 55.2%; P = .188); however, this failed to reach clinical significance owing to the limited patient number in this age group. Conclusions Although the surgical mortality significantly increased with increased age, surgical management was still associated with significantly lower in-hospital mortality rates compared with medical management until the age of 80 years. Surgery may decrease the in-hospital mortality rate for octogenarians with type A aortic dissection and might be considered in all patients with type A aortic dissection regardless of age.
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