Identification of regions critical for the integrity of the TSC1-TSC2-TBC1D7 complex

The TSC1-TSC2-TBC1D7 complex is an important negative regulator of the mechanistic target of rapamycin complex 1 that controls cell growth in response to environmental cues. Inactivating TSC1 and TSC2 mutations cause tuberous sclerosis complex (TSC), an autosomal dominant disorder characterised by the occurrence of benign tumours in various organs and tissues, notably the brain, skin and kidneys. TBC1D7 mutations have not been reported in TSC patients but homozygous inactivation of TBC1D7 causes megaencephaly and intellectual disability. Here, using an exon-specific deletion strategy, we demonstrate that some regions of TSC1 are not necessary for the core function of the TSC1-TSC2 complex. Furthermore, we show that the TBC1D7 binding site is encoded by TSC1 exon 22 and identify amino acid residues involved in the TSC1-TBC1D7 interaction

High-grade infarct-related stenosis after successful thrombolysis: strong predictor of reocclusion, but not of clinical reinfarction.

Contains fulltext : 58311.pdf (publisher's version ) (Closed access)BACKGROUND: After successful thrombolysis, a high-grade stenosis at 24-hour angiography is strongly predictive of reocclusion and is often believed to result in high reinfarction rates. However, routine angioplasty did not reduce death or reinfarction in past trials. Systematic angiographic follow-up shows that reocclusion often occurs without clinical reinfarction. This study investigates whether the increased risk for reocclusion associated with a high-grade lesion translates into impaired clinical outcome. METHODS: In the ischemia-guided Antithrombotics in the Prevention of Reocclusion in COronary Thrombolysis (APRICOT-1) trial, 240 patients with ST-elevation MI who had an open infarct artery 24 hours after thrombolysis had 3-month repeat angiography to assess reocclusion, with clinical follow-up at 3 months and 3 years. RESULTS: On the basis of the optimal discriminative stenosis severity, the reocclusion rate was 40% (47/118) in patients with a high-grade residual stenosis and 16% (20/122) in patients with a low-medium-grade lesion (risk ratio [RR], 2.43; 95% CI, 1.54-3.84; P <.01). Three-month death and reinfarction rates did not differ: 6% (7/118) versus 9% (11/122; RR, 0.66; 95% CI, 0.26-1.64; P = not significant). Systematic angiographic follow-up revealed that reocclusion of a high-grade lesion occurred in the absence of clinical reinfarction in 85% (40/47) of patients, as compared with 45% (9/20) in patients with a low-medium-grade stenosis (RR, 1.89; 95% CI, 1.15-3.12; P <.01). Despite an independent association with reocclusion, a high-grade stenosis was not predictive of either short- or long-term death and reinfarction. CONCLUSIONS: After successful thrombolysis and adopting an ischemia-guided revascularization strategy, patients with a high-grade stenosis experience death/reinfarction rates similar to that of patients with a low-medium-grade lesion. This is true despite a 2- to 3-fold higher risk for reocclusion. The finding that reocclusion of a high-grade lesion often occurs without clinical reinfarction explains the absence of a relationship between a severe stenosis and death/reinfarction. Appreciation of these observations may contribute to an optimal design of a future randomized trial to re-evaluate the impact of a routine invasive strategy

Ectopia lentis et pupillae in four generations caused by novel mutations in the ADAMTSL4 gene

Item does not contain fulltextOBJECTIVES: To identify the phenotype, genetic defect and inheritance pattern of ectopia lentis et pupillae (ELP) in a large Dutch family, previously diagnosed as presumed autosomal dominant ELP because of the occurrence of ELP in three generations. DESIGN: A clinical and genetic study of children and adults. PARTICIPANTS: Eight patients of the ELP family, including five new patients from the youngest generation. METHODS: Standard ophthalmological examinations were performed. For molecular genetic analysis, the coding region of ADAMTSL4 was sequenced. Main outcome measures were the ocular phenotype of the new ELP patients, the inheritance pattern and the identification of mutations in the ADAMTSL4 gene in the family. RESULTS: Of the eight patients with ectopia lentis, seven fulfilled the clinical diagnostic criteria of ELP. Molecular genetic analysis of these seven patients disclosed two novel mutations in the ADAMTSL4 gene: homozygous (p.Q752X/p.Q752X) in six patients and compound heterozygous (p.Q752X/p.Q758fs) in one patient. Heterozygosity in phenotypically normal parents proved autosomal recessive (AR) inheritance. The pseudodominant inheritance pattern can be explained by high carrier frequency in this small community and/or consanguinity. CONCLUSIONS: Patients from a family with ELP in four generations have AR ELP caused by novel mutations in ADAMTSL4. The clinical presentation of ELP can be variable, but all patients of our study with homozygous p.Q752X mutation have ectopia lentis and pupillary dysfunction in common

Sustained coronary patency after fibrinolytic therapy as independent predictor of 10-year cardiac survival Observations from the Antithrombotics in the Prevention of Reocclusion in COronary Thrombolysis (APRICOT) trial.

Contains fulltext : 70887.pdf (publisher's version ) (Closed access)BACKGROUND: Whether late coronary patency after myocardial infarction has prognostic impact independent of left ventricular function remains a matter of debate. Reocclusion rates in the first year after fibrinolysis vary between 20% and 30%. Of all reocclusions, about 30% present as clinical reinfarction, associated with a 2-fold-increased risk of mortality. The clinical impact of reocclusion that presents without reinfarction has not been studied; but an association has been demonstrated with impaired contractile recovery of left ventricular function, the strongest prognosticator of long-term outcome. We therefore studied the impact of 3-month coronary patency after successful fibrinolysis on 10-year cardiac survival. METHODS: In the APRICOT-1 trial, 248 ST-elevation myocardial infarction patients with an open infarct artery 24 hours after fibrinolysis had 3-month repeated angiography. Ten-year clinical follow-up was complete in 99.6%. RESULTS: The reocclusion rate was 29% (71/248). Of these reocclusions, 24% presented as clinical reinfarction (17/71). Cardiac survival at 10 years was 73% in patients with a reoccluded infarct artery and 88% in patients with sustained patency (P < .01). This difference was also present in patients in whom reocclusion was only detected as a result of systematic repeated angiography, that is, in the absence of reinfarction or ischemic symptoms between angiograms (70% vs 86%, P < .03). Multivariable analysis identified sustained patency at 3-month angiography as independent predictor of 10-year cardiac survival (hazard ratio 2.10, 95% CI 1.10-4.02) together with left ventricular ejection fraction. CONCLUSIONS: Sustained infarct artery patency in the first 3 months after successful fibrinolysis is a strong predictor of 10-year cardiac survival, independent of left ventricular function. Notably, this also holds true when reocclusion occurs without signs of clinical reinfarction or recurrent ischemia. Therefore, future preventive strategies should also focus on "clinically silent" reocclusions. Additional studies on better antithrombotic regimens and the combination with a routine invasive strategy early after successful fibrinolysis are warranted

Contamination control: removing small particles from increasingly large wafers

With the introduction of 450 mm wafers, which are considerably larger than the currently largest wafers of 300mm, handling with side grippers is no longer possible and backside grippers are required. Backside gripping increases the possible buildup of particles on the backside of the wafers with possible cross-contamination to the front-side. Therefore, regular backside cleaning is required. Three vacuum compatible cleaning methods were selected. Tacky rollers and highvoltage cleaning were selected for particles and plasma cleaning for molecular layers. A test-bench was designed and constructed implementing these three cleaning methods. The first experiments show promising results for the plasma cleaner and the tacky roller. © 2012 SPIE