Citations

Abstract Colloidal dispersion of single-walled carbon nanotubes (SWCNTs) is often the first processing step to many of their unique applications. However, dispersed SWCNTs often exist in kinetically trapped states where aggregation can be of concern. Recent work revealed prominent DNA–SWCNT aggregation following intravascular injection. In this study, we performed detailed analysis of DNA–SWCNT aggregate formation, structure, and composition in the context of endothelial cell condition media. Interestingly, we found that aggregates formed within condition media from cells that have undergone a stress response differ in size and organization from that of the control. We also found that temperature increases also promote DNA–SWCNT associations. A mathematical model was developed to describe the kinetics of SWCNT extraction from solution. Through orthogonal optical analysis and imaging modalities, we verified that proteins form the bulk of the aggregate structure and dictate aggregate assembly at multiple levels of organization. Finally, physiochemical analysis indicated preferential extraction of low-abundance hydrophobic and charged proteins. The formed aggregates also remain relatively stable in solution, making them potential macroscopic indicators of solution content.

Purpose TH-302, a prodrug of the cytotoxic alkylating agent bromo-isophosphoramide mustard, is preferentially activated in hypoxic conditions. This phase II study investigated TH-302 in combination with doxorubicin, followed by single-agent TH-302 maintenance therapy in patients with first-line advanced soft tissue sarcoma (STS) to assess progression-free survival (PFS), response rate, overall survival, safety, and tolerability. Patients and Methods In this open-label phase II study, TH-302 300 mg/m 2 was administered intravenously on days 1 and 8 with doxorubicin 75 mg/m 2 on day 1 of each 21-day cycle. After six cycles, patients with stable and/or responding disease could receive maintenance monotherapy with TH-302. Results Ninety-one patients initiated TH-302 plus doxorubicin induction treatment. The PFS rate at 6 months (primary efficacy measure) was 58% (95% CI, 46% to 68%). Median PFS was 6.5 months (95% CI, 5.8 to 7.7 months); median overall survival was 21.5 months (95% CI, 16.0 to 26.2 months). Best tumor responses were complete response (n = 2 [2%]) and partial response (n = 30 [34%]). During TH-302 maintenance (n = 48), five patients improved from stable disease to partial response, and one patient improved from partial to complete response. The most common adverse events during induction were fatigue, nausea, and skin and/or mucosal toxicities as well as anemia, thrombocytopenia, and neutropenia. These were less severe and less frequent during maintenance. There was no evidence of TH-302–related hepatic, renal, or cardiac toxicity. Conclusion PFS, overall survival, and tumor response compared favorably with historical outcomes achieved with other first-line chemotherapies for advanced STS. A phase III study of TH-302 is ongoing (NCT01440088).

ABSTRACTIntroduction: Numerous methods for motor unit number estimation (MUNE) have been developed. The objective of this article is to summarize and compare the major methods and the available data regarding their reproducibility, validity, application, refinement, and utility.Methods: Using specified search criteria, a systematic review of the literature was performed. Reproducibility, normative data, application to specific diseases and conditions, technical refinements, and practicality were compiled into a comprehensive database and analyzed.Results: The most commonly reported MUNE methods are the incremental, multiple‐point stimulation, spike‐triggered averaging, and statistical methods. All have established normative data sets and high reproducibility. MUNE provides quantitative assessments of motor neuron loss and has been applied successfully to the study of many clinical conditions, including amyotrophic lateral sclerosis and normal aging.Conclusions: MUNE is an important research technique in human subjects, providing important data regarding motor unit populations and motor unit loss over time.Muscle Nerve50: 884–893, 2014

AbstractBackgroundFamilies of Dutch‐German‐Russian Mennonite descent with multi‐incident parkinsonism have been identified as harboring a pathogenic DNAJC13 p.N855S mutation and are awaiting clinical and pathophysiological characterization.MethodsFamily members were examined clinically longitudinally, and 5 underwent dopaminergic PET imaging. Four family members came to autopsy.ResultsOf the 16 symptomatic DNAJC13 mutation carriers, 12 had clinically definite, 3 probable, and 1 possible Parkinson's disease (PD). Symptoms included bradykinesia, tremor, rigidity, and postural instability, with a mean onset of 63 years (range, 40‐85) and slow progression. Eight of ten subjects who required treatment had a good levodopa response; motor complications and nonmotor symptoms were observed. Dopaminergic PET imaging revealed rostrocaudal striatal deficits typical for idiopathic PD in established disease and subtle abnormalities in incipient disease. Pathological examinations revealed Lewy body pathology.ConclusionPD associated with a DNAJC13 p.N855S mutation presents as late‐onset, often slowly progressive, usually dopamine‐responsive typical PD. © 2014 International Parkinson and Movement Disorder Society

Gene therapy with adeno-associated virus (AAV) has advanced in the last few years from promising results in animal models to >100 clinical trials (reported or under way). While vector availability was a substantial hurdle a decade ago, innovative new production methods now routinely match the scale of AAV doses required for clinical testing. These advances may become relevant to translational research in the chronic pain field. AAV for pain targeting the peripheral nervous system was proven to be efficacious in rodent models several years ago, but has not yet been tested in humans. The present review addresses the steps needed for translation of AAV for pain from the bench to the bedside focusing on pre-clinical toxicology. We break the potential toxicities into three conceptual categories of risk: First, risks related to the delivery procedure used to administer the vector. Second, risks related to AAV biology, i.e., effects of the vector itself that may occur independently of the transgene. Third, risks related to the effects of the therapeutic transgene. To identify potential toxicities, we consulted the existing evidence from AAV gene therapy for other nervous system disorders (animal toxicology and human studies) and from the clinical pharmacology of conventional analgesic drugs. Thereby, we identified required preclinical studies and charted a hypothetical path towards a future phase I/II clinical trial in the oncology-palliative care setting.

Abstract IL-17 is known to play important roles in immune and inflammatory disease, such as in asthma, but its functions in allergic airway inflammation are still controversial, and the molecular mechanisms mediating these functions remain unclear. Increased production of eosinophils in bone marrow and their emergence in the airway have been linked to the onset and progression of allergic asthma. In this study, we investigated the effects of exogenous IL-17 on allergic airway inflammation and explored the underlying molecular mechanisms through eosinophil generation. Exogenous IL-17 significantly attenuated the features of allergic inflammation induced by ovalbumin in mice. It inhibited eosinophil differentiation both in vivo and in vitro, accompanied by down-regulated expression of CC chemokine receptor 3, GATA binding protein 1 (GATA-1), and GATA binding protein 2 (GATA-2), as well as reduced formation of common myeloid progenitors and eosinophil progenitors, but without influencing eosinophil apoptosis. IL-17 also significantly decreased the number of eosinophils in IL-5–transgenic mice, although it notably increased the levels of IL-3, IL-5, and granulocyte/macrophage colony–stimulating factor. In addition, IL-17 had little effect on secretion of the inflammatory cytokines by eosinophils. Neutralization of endogenous IL-17 significantly augmented eosinophil recruitment in the airways. Together, these findings suggest that exogenous IL-17 protects against allergic airway inflammation, most likely through inhibition of the eosinophil differentiation in bone marrow.

The history of postpartum thyroid dysfunction (PPTD) dates back almost two millennia, when Soranus of Ephesus, who practiced obstetrics and neonatology, observed swelling in the necks (presumably goiters) of women after pregnancy. The next reference to PPTD appeared in artwork more than 1000 years later, with many portraits illustrating women with goiter while holding infants. In the early to mid-19th century, Caleb Hillier Parry and Armand Trousseau described postpartum hyperthyroidism, while in the late 1800s, Sir Horatio Bryan Donkin reported the first patient with postpartum hypothyroidism. The modern era of PPTD began with the description in the late 1940s by H.E.W. Roberton of women after delivery reporting hypothyroid symptoms and responding to thyroid extract. The immunologic influence on PPTD was recognized initially by Parker and Beierwaltes in the early 1960s, and the clinical variability and natural history were carefully documented by numerous investigators in the 1970s–1980s. The past two decades have seen further refinements in understanding the prevalence, etiology, and treatment of PPTD. Yet to be determined is the role of screening as a cost-effective measure.