Citations

Antisense oligonucleotides can correct disease-specific phenotypes in cultured motor neurons differentiated from iPSCs derived from ALS patients with a C9ORF72 repeat expansion.

Many neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis and Polyglutamine disorders are characterized by conformational change in proteins that result in misfolding, aggregation and accumulation of amyloid fibrils. These misfolded species result in toxicity in cells and ultimately lead to the death of specific neuronal populations. The cellular pathways involved in these neurological disorders are still unclear but a large body of evidence suggests that molecular chaperones, regulators of cellular protein quality control, may play a critical role in neurodegeneration. Indeed in patient post-mortem brain, chaperones are found in the hallmark neuronal inclusions. Molecular chaperones are able to inhibit the aggregation of denatured proteins and facilitate refolding of different disease-causing proteins. Experimental approaches in animal and cellular models have shown prevention of protein misfolding and facilitation of clearance mechanisms via up-regulation of molecular chaperones. Therefore manipulating the molecular chaperone system may be a successful strategy to counter the conformational changes occurring in protein misfolding diseases and may offer new therapeutic promise. Here we review the evidence for the involvement of various molecular chaperones in several neurodegenerative disorders and examine the current research investigating the role of the chaperones as novel targets for therapy of these devastating diseases.

Background and Purpose— The prognostic significance of subarachnoid extension of intracerebral hemorrhage was determined in the INTEnsive blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT2) study. Methods— INTERACT2 was an open randomized controlled trial of early intensive compared with guideline-recommended blood pressure lowering in patients with elevated systolic blood pressure within 6 hours of intracerebral hemorrhage. Independent predictors of death or major disability (scores 3–6 on the modified Rankin Scale) at 90 days were analyzed in logistic regression models. Results— Of 2582 participants, 192 (7%) had subarachnoid extension, which was associated with larger hematoma volumes ( P <0.0001) and higher National Institute of Health Stroke Scale score ( P <0.0001). Subarachnoid extension predicted death or major disability at 90 days (71% versus 53%; unadjusted odds ratio, 2.25; 95% confidence interval, 1.63–3.10; P <0.0001). The association remained significant after adjusting for age, region, lipid-lowering therapy, systolic blood pressure, glucose, location of hematoma, intraventricular extension, and randomized treatment (odds ratio, 2.17; 95% confidence interval, 1.50–3.14; P <0.0001), but not after further adjustment for baseline hematoma volume ( P =0.62). Conclusions— Subarachnoid extension of intracerebral hemorrhage is associated with poor prognosis, which is determined by a larger volume of the underlying intraparenchymal hematoma. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00716079.

Background— Sex-specific differences affect the evaluation, treatment, and prognosis of coronary artery disease. We tested the hypothesis that long-term outcomes of fractional flow reserve (FFR)–guided percutaneous coronary intervention (PCI) are different between women and men. Methods and Results— Consecutive 1090 patients, referred for PCI and undergoing FFR measurements at the Mayo Clinic between October 2002 and December 2009, were included in this registry study. Clinical events were compared between the sexes during a median follow-up of 50.9 months. Of all patients, women had higher FFR adjusted by visual coronary stenosis than men ( P =0.03). The Kaplan–Meier percent of major adverse cardiac events at 5 years was 35% in women and 38% in men ( P =0.54). Interestingly, in patients undergoing PCI with an FFR <0.75, the incidence of death or myocardial infarction was significantly higher in women than in men (hazard ratio, 2.16; 95% confidence interval, 1.04–4.51; P =0.04). Moreover, compared with patients with FFR >0.80, deferral of PCI for those with FFR between 0.75 and 0.80 was associated with an increased rate of major adverse cardiac events, particularly death or myocardial infarction in women (hazard ratio, 3.25; 95% confidence interval, 1.56–6.74; P =0.002) and revascularization in men (hazard ratio, 2.66; 95% confidence interval, 1.66–4.54; P <0.001). Conclusions— Long-term outcome differs between women and men undergoing FFR-guided PCI. Our data suggest that the sex-based treatment strategy is necessary to further optimize prognosis of patients with coronary artery disease.

S ‐transform (ST) is a time–frequency representation (TFR) that is popularly used in a variety of applications, but prohibitive in both storage and computation for large time series. This study proposes a one‐dimensional fast time–frequency transform (FTFT‐1D) which generates a highly compressed form of the ST directly, without the need to compute the complete ST matrix initially and compress it subsequently. The compression technique used in the FTFT‐1D helps in storage, transmission and visualisation of the ST. The FTFT‐1D encodes the TFR information uniformly and finds the local spectrum instantaneously and accurately. It is useful for real‐time applications such as monitoring, control and filtering. In addition, the FTFT‐1D is memory efficient, robust and adaptive in nature.

Context: Articular cartilage injuries are common in patients presenting to surgeons with primary complaints of knee pain or mechanical symptoms. Treatment options include comprehensive nonoperative management, palliative surgery, joint preservation operations, and arthroplasty. Evidence Acquisition: A MEDLINE search on articular cartilage restoration techniques of the knee was conducted to identify outcome studies published from 1993 to 2013. Special emphasis was given to Level 1 and 2 published studies. Study Design: Clinical review. Level of Evidence: Level 3. Results: Current surgical options with documented outcomes in treating chondral injuries in the knee include the following: microfracture, osteochondral autograft transfer, osteochondral allograft transplant, and autologous chondrocyte transplantation. Generally, results are favorable regarding patient satisfaction and return to sport when proper treatment algorithms and surgical techniques are followed, with 52% to 96% of patients demonstrating good to excellent clinical outcomes and 66% to 91% returning to sport at preinjury levels. Conclusion: Clinical, functional, and radiographic outcomes may be improved in the majority of patients with articular cartilage restoration surgery; however, some patients may not fully return to their preinjury activity levels postoperatively. In active and athletic patient populations, biological techniques that restore the articular surface may be options that provide symptom relief and return patients to their prior levels of function.

The use of contrast agents is becoming a routine practice in diagnostic ultrasound imaging. Microbubble contrast agents are proving to be a safe and practical way of enhancing conventional ultrasound images. This paper discusses the concept of using microbubble contrast agents in the vibro-acoustography (VA) technique. A brief background of microbubbles and their clinical applications is given as well as a summary of the different attempts at modeling microbubble contrast agents in ultrasound fields. A general Keller–Herring equation is modified to mathematically model the interaction of encapsulated microbubbles in blood with VA ultrasound. The frequency response and scattered pressure of microbubbles with initial radius of 1 and 3 m are presented. This method is accurate for pressure amplitudes up to 500 kPa. Understanding this interaction is important for the correct interpretation of clinical investigations when using VA.

Vibro-acoustography is a technique that images the vibro-acoustic response of an object to the harmonic ultrasound radiation force. The system point-spread function is associated to the radiation force exerted on a point-target by a dual-frequency ultrasound beam. So far the radiation force was calculated by assuming a dual-frequency beam composed by two plane waves. This reduces the radiation force to a one-dimensional quantity neglecting transverse components. Here, we model the radiation force as a three-dimensional vector. In this model, the scattering of a dual-frequency beam with any spatial distribution by a point-target is solved. The incident and scattered fields are used to calculate the radiation force on a sphere whose radius approaches to zero. The force is proportional to the gradient of the product of the incident wave amplitudes. Evaluation of the radiation force produced by a two-element co-focused transducer shows that the transverse component of the force is about −20 dB smaller than the corresponding axial component. Effects of the transverse force on image formation are still under investigation. In conclusion, the presented model describes vibro-acoustography systems with dual-frequency beams of any spatial distribution. [Work partially supported by Grant No. DCR2003.013-FAPEAL/CNPq.]

Primary sclerosing cholangitis (PSC) is an idiopathic, progressive, cholestatic liver disease with considerable morbidity and mortality and no established pharmacotherapy. In addition to the long-recognized association between PSC and inflammatory bowel disease, several lines of preclinical and clinical evidence implicate the microbiota in the etiopathogenesis of PSC. Here we provide a concise review of these data which, taken together, support further investigation of the role of the microbiota and antibiotics in PSC as potential avenues toward elucidating safe and effective pharmacotherapy for patients afflicted by this illness.