Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.

Background Riluzole is approved for the treatment of amyotrophic lateral sclerosis in most countries. Questions persist about its clinical utility because of high cost and modest e icacy. Objectives To examine the e icacy of riluzole in prolonging survival and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival, and to assess the e ect of riluzole upon functional health.

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Patients with M. abscessus pulmonary disease who are treated with multidrug antibiotic therapy and surgery or antibiotic therapy alone had similar clinical outcomes. However, surgical resection, in addition to antibiotics, may offer a prolonged microbiologic response.

Internal thoracic arteries (ITAs) should be used to bypass the left anterior descending (LAD) artery when bypass of the LAD is indicated (class of recommendation [COR] I, level of evidence [LOE] B). As an adjunct to left internal thoracic artery (LITA), a second arterial graft (right ITA or radial artery [RA]) should be considered in appropriate patients (COR IIa, LOE B). Use of bilateral ITAs (BITAs) should be considered in patients who do not have an excessive risk of sternal complications (COR IIa, LOE B). To reduce the risk of sternal infection with BITA, skeletonized grafts should be considered (COR IIa, LOE B), smoking cessation is recommended (COR I, LOE C), glycemic control should be considered (COR IIa, LOE B), and enhanced sternal stabilization may be considered (COR IIb, LOE C). As an adjunct to LITA to LAD (or in patients with inadequate LITA grafts), use of a RA graft is reasonable when grafting coronary targets with severe stenoses (COR IIa, LOE: B). When RA grafts are used, it is reasonable to use pharmacologic agents to reduce acute intraoperative and perioperative spasm (COR IIa, LOE C). The right gastroepiploic artery may be considered in patients with poor conduit options or as an adjunct to more complete arterial revascularization (COR IIb, LOE B). Use of arterial grafts (specific targets, number, and type) should be a part of the discussion of the heart team in determining the optimal approach for each patient (COR I, LOE C).

Objective The recent increased detection of small-sized peripheral non-small cell lung cancer (NSCLC) has renewed interest in sub-lobar resection in-lieu of lobectomy, the traditional standard of care. CALGB/ALLIANCE 140503 is a multicenter international non-inferiority phase III trial in which NSCLC patients clinically staged as T1aN0 were randomly assigned to lobar or sub-lobar resection. The primary endpoint is disease-free survival. We conducted an exploratory comparative analysis of the perioperative mortality and morbidity associated with both arms of the trial. Patients and Methods Between June 15/2007 and March 13/2017, 697 patients with peripheral NSCLC clinically staged as T1aN0 were intraoperatively randomized (after pathological confirmation of absence of nodal metastases in major hilar and mediastinal nodes) to either lobar (Arm A: 357) or sublobar resection (Arm B: 340; 58% wedge resections). Randomization assignment was based on a stratified permuted-block randomization scheme without concealment. Randomized was stratified according to radiographic tumor size (< 1 cm, 1–1.5 cm, and > 1.5– 2.0 cm), histology (squamous carcinoma, adenocarcinoma and other) and smoking status (never, former, current). The assignment was not concealed. Perioperative mortality was defined as death from any cause within 30 and 90 days of surgical intervention and was calculated on all randomized patients. Morbidity was graded using the Common Terminology Criteria for Adverse Events (CTCAE v4.0). All analyses were done on an intention to treat basis. Results Overall 30 and 90- day mortality for 697 randomized patients were 0.86% (n=6) and 1.4% (n=10). Thirty and 90-day mortality were 1.1% (n=4) and 1.7% (n=6) after lobar resection and 0.6% (n=2) and 1.2% (n=4) after sub-lobar resection yielding a difference between arms of 0.5% (95%CI: −1.1,2.3) and 0.5% (95%CI: −1.5,2.6), respectively, without reaching statistical significance. No complications were observed in 47% of patients (Arm A: 46%, Arm B: 49%). Grade 3/4/5 AEs occurred in 15.2% in Arm A and 14.2% in Arm B. There were no differences between the two arms in cardiac or pulmonary complications. Grade 3 hemorrhage (requiring transfusion) occurred in 6 patients (1.6%) in Arm A and 8 patients (2.3%) in Arm B. Prolonged air leak occurred in 9 patients (2.5%) in Arm A and 2 patients (0.6%) in Arm B. Conclusions In this large, multicenter randomized international trial, post-hoc analysis showed no significant differences in perioperative mortality and morbidity between lobar and sub-lobar resection in physically and functionally fit patients with clinical T1aN0 NSCLC. These data may impact the daily choices made by patients and their physicians in determining the optimal treatment approach for stage I lung cancer. Trial registration This trial is registered as an international standard randomized trial with ClinicalTrials.gov Identifier: NCT00499330 Role of funding source The Cancer Therapy Evaluation Program of the National Cancer Institute (CTEP) approved the t...

Parkinson's disease (PD) is characterized by the presence of Lewy bodies containing phosphorylated and aggregated α-synuclein (α-syn). α-Syn is present in human body fluids, including blood plasma, and is a potential biomarker for PD. Immunoassays for total and oligomeric forms of both normal and phosphorylated (at Ser-129) α-syn have been used to assay plasma samples from a longitudinal cohort of 32 patients with PD (sampled at mo 0, 1, 2, 3), as well as single plasma samples from a group of 30 healthy control participants. The levels of α-syn in plasma varied greatly between individuals, but were remarkably consistent over time within the same individual with PD. The mean level of phospho-α-syn was found to be higher (P=0.053) in the PD samples than the controls, whereas this was not the case for total α-syn (P=0.244), oligo-α-syn (P=0.221), or oligo-phospho-α-syn (P=0.181). Immunoblots of plasma revealed bands (at 21, 24, and 50-60 kDa) corresponding to phosphorylated α-syn. Thus, phosphorylated α-syn can be detected in blood plasma and shows more promise as a diagnostic marker than the nonphosphorylated protein. Longitudinal studies undertaken over a more extended time period will be required to determine whether α-syn can act as a marker of disease progression.

There have been no longitudinal studies on α-synuclein as a potential biomarker for the progression of Parkinson's disease (PD). Here, blood plasma ‘total α-synuclein’ and ‘Ser-129 phosphorylated α-synuclein’ were assayed at 4–6 monthly intervals from a cohort of 189 newly-diagnosed patients with PD. For log-transformed data, plasma total α-synuclein levels increased with time for up to 20 yrs after the appearance of initial symptoms (p = 0.012), whereas phosphorylated α-synuclein remained constant over this same period. The mean level of phosphorylated α-synuclein, but not of total α-synuclein, was higher in the PD plasma samples taken at first visit than in single samples taken from a group of 91 healthy controls (p = 0.012). Overall, we conclude that the plasma level of phosphorylated α-synuclein has potential value as a diagnostic tool, whereas the level of total α-synuclein could act as a surrogate marker for the progression of PD.