Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele‐Specific Expression

Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication‐based mechanisms such fork stalling and template switching or microhomology‐mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients’ fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele‐specific LMNB1 expression levels.     

Linear β-amino alcohol catalyst anchored on functionalized magnetite nanoparticles for enantioselective addition of dialkylzinc to aromatic aldehydes

A linear β-amino alcohol ligand, previously found to be a very efficient catalyst for enantioselective addition of dialkylzinc to aromatic aldehydes, has been anchored on differently functionalized superparamagnetic core–shell magnetite–silica nanoparticles (1a and 1b). Its catalytic activity in the addition of dialkylzinc to aldehydes has been evaluated, leading to promising results, especially in the case of 1b for which the recovery by simple magnetic decantation and reuse was successfully verified.

The catalytic activity of a linear β-amino alcohol ligand anchored on functionalized magnetite/silica core–shell nanoparticles has been evaluated in the addition of dialkylzinc to aldehydes leading to promising results.     

Secondary prevention of cryptogenic stroke in patients with patent foramen ovale: a systematic review and meta-analysis

The aim of our study is to compare patent foramen ovale (PFO) closure versus medical treatment and antiplatelet versus anticoagulant therapy in patients with cryptogenic stroke (CS) and PFO. We conducted a systematic review and meta-analysis with trial sequential analysis (TSA) of randomized trials. Primary outcomes are stroke or transient ischemic attack (TIA) and all-cause mortality. Secondary outcomes are peripheral embolism, bleeding, serious adverse events, myocardial infarction and atrial dysrhythmias. We performed an intention to treat meta-analysis with a random-effects model. We include six trials (3677 patients, mean age 47.3 years, 55.8% men). PFO closure is associated with a lower recurrence of stroke or TIA at a mean follow-up of 3.88 years compared to medical therapy [risk ratio (RR) 0.55, 95% CI 0.38–0.81; I²?=?40%]. The TSA confirms this result. No difference is found in mortality (RR 0.74, 95% CI 0.35–1.60; I²?=?0%), while PFO closure is associated with a higher incidence of atrial dysrhythmias (RR 4.55, 95% CI 2.16–9.60; I²?=?25%). The rate of the other outcomes is not different among the two groups. The comparison between anticoagulant and antiplatelet therapy shows no difference in terms of stroke recurrence, mortality and bleeding. There is conclusive evidence that PFO closure reduces the recurrence of stroke or TIA in patients younger than 60 years of age with CS. More data are warranted to assess the consequences of the increase in atrial dysrhythmias and the advantage of PFO closure over anticoagulants.     

Brentuximab vedotin as salvage treatment in Hodgkin lymphoma naïve transplant patients or failing ASCT: the real life experience of Rete Ematologica Pugliese (REP)

Brentuximab vedotin (BV) shows a high overall response rate (ORR) in relapsed/refractory (R/R) Hodgkin lymphoma (HL) after autologous transplant (ASCT). The aim of this multicenter study, conducted in nine Hematology Departments of Rete Ematologica Pugliese, was to retrospectively evaluate the efficacy and safety of BV as salvage therapy and as bridge regimen to ASCT or allogeneic transplant (alloSCT) in R/R HL patients. Seventy patients received BV. Forty-five patients (64%) were treated with BV as bridge to transplant:16 (23%) patients as bridge to ASCT and 29 (41%) as bridge to alloSCT. Twenty-five patients (36%), not eligible for transplant, received BV as salvage treatment. The ORR was 59% (CR 26%). The ORR in transplant naïve patients was 75% (CR 31%). In patients treated with BV as bridge to alloSCT, the ORR was 62% (CR 24%). In a multivariate analysis, the ORR was lower in refractory patients (p?<?0.005). The 2y-OS was 70%. The median PFS was 17 months. Ten of the 16 (63%) naïve-transplant patients received ASCT, with 50% in CR before ASCT. In the 29 patients treated with BV as bridge to alloSCT, 28 (97%) proceeded to alloSCT with 25% in CR prior to alloSCT. The most common adverse events were peripheral neuropathy (50%), neutropenia (29%) and anemia (12%). These data suggest that BV is well tolerated and very effective in R/R HL, producing a substantial level of CR. BV may also be a key therapeutic agent to achieve good disease control before transplant, improving post- transplant outcomes, also in refractory and heavily pretreated patients, without significant overlapping toxicities with prior therapies.     

Medullary and papillary tumors are frequently associated in the same thyroid gland without evidence of reciprocal influence in their biologic behavior.

Papillary thyroid microcarcinoma (mPTC), is a very frequent incidental finding with a frequency varying from a few percent to 35% at postmortem histopathologic examinations. However, the presence of mPTC in patients undergoing thyroidectomy for multinodular goiter (MNG) and for Graves' disease (GD) has been found to be lower. Patients with medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) association have been published as anecdotal case reports, as well as kindred with familial MTC or multiple endocrine neoplasia (MEN) 2A with some members simultaneously affected by MTC and PTC. We studied the prevalence and the biological behavior of MTC associated with PTC, with particular attention to those cases in which a mPTC was incidentally found. Twenty-seven of 196 (13.8%) MTC cases showed an association with PTC and in particular 21 of 190 (11.05%) with an incidental mPTC. This percentage is higher than that reported in the literature on the association of mPTC with GD (2.8%-4.5%) and MNG (3%). Also the percentage of the more general association of MTC/PTC, not restricted to mPTC, found in our series (13.8%) is higher than that reported in studies that analyzed the prevalence of PTC (any size) in patients treated for MNG (7.5%). A similarly high percentage of MTC/PTC had not been reported before and in particular there are no reports on large series of MTC/PTC. We also analyzed the epidemiologic, clinical, and pathologic features of MTC associated and not associated with PTC without finding any difference. In particular the outcome of the MTC did not appear to be influenced by the presence of the PTC and the specific radioiodine treatments. Moreover, although we cannot completely exclude a shared pathogenic event as the cause of both MTC and PTC, the molecular analysis of RET gene alterations did not show any common mutation.     

IL-4 in vitro production is upregulated in Alzheimer's disease patients treated with acetylcholinesterase inhibitors

Cytokines appear to be involved in the pathogenesis of Alzheimer's Disease (AD). Their modulation by treatment has been investigated only in a few studies. The aim of our study was to evaluate the effect of acetylcholinesterase inhibitors (AChEI) on Interleukin-4 (IL-4) production in AD patients. IL-4 levels were measured by ELISA on peripheral blood mononuclear cell cultures in the presence or absence of Concanavalin A or Phytohaemagglutinin. Linear regression analysis shows that patients who have been treated, have higher levels of IL-4 independently from age, gender and comorbidity. The increased production of IL-4 in AChEI treated patients might represent an additional mechanism through which AChEI act on AD progression.     

Prevalence of rheumatoid arthritis in Tucumán,Argentina

OBJECTIVE: To ascertain the prevalence of rheumatoid arthritis (RA) in Tucumán, Argentina. METHODS: The study was conducted between January 1, 1998, and December 31, 1999, in Tucumán province in northwest Argentina. Outpatient and hospitalization medical records for all patients with RA aged > or = 16 years were reviewed. Diagnosis was by 1987 American College of Rheumatology (ACR) criteria for RA and the population data were based on the 1991 national census. Prevalence rates, with 95% CI, were calculated using the number of San Miguel de Tucumán residents who fulfilled the 1987 ACR criteria for RA as numerator, and the city population aged > or = 16 as denominator. Crude and age-specific prevalence rates were calculated as number of cases/1,000 inhabitants. RESULTS: We identified 695 cases of RA. Sex-specific and overall prevalence rates (per 1,000) were 1.97 (95% CI 1.8-2) for all, 0.6 (95% CI 0.49-0.73) for men, 3.2 (95% CI 2.9-3.5) for women. CONCLUSION: Prevalence of RA is low in residents of Tucumán, Argentina, and comparable with rates observed in epidemiological surveys from Southern European countries.