Thermal ablation of tumor cells with antibody-functionalized single-walled carbon nanotubes

Single-walled carbon nanotubes (CNTs) emit heat when they absorb energy from near-infrared (NIR) light. Tissue is relatively transparent to NIR, which suggests that targeting CNTs to tumor cells, followed by noninvasive exposure to NIR light, will ablate tumors within the range of NIR. In this study, we demonstrate the specific binding of antibody-coupled CNTs to tumor cells in vitro, followed by their highly specific ablation with NIR light. Biotinylated polar lipids were used to prepare stable, biocompatible, noncytotoxic CNT dispersions that were then attached to one of two different neutralite avidin-derivatized mAbs directed against either human CD22 or CD25. CD22(+)CD25(-) Daudi cells bound only CNTs coupled to the anti-CD22 mAb; CD22(-)CD25(+) activated peripheral blood mononuclear cells bound only to the CNTs coupled to the anti-CD25 mAb. Most importantly, only the specifically targeted cells were killed after exposure to NIR light.     

Burst analysis spectroscopy: a versatile single-particle approach for studying distributions of protein aggregates and fluorescent assemblies

Many essential cellular functions depend on the assembly and disassembly of macromolecular complexes. The size, form, and distribution of these assemblies can be heterogeneous and complex, rendering their detailed characterization difficult. Here we describe a simple non-correlation-based method capable of directly measuring population distributions at very low sample concentrations. Specifically, we exploit the highest signal-to-noise light bursts from single fluorescent particles transiting a confocal excitation spot to recursively determine the brightness and size distribution of complex mixtures of fluorescent objects. We refer to this method as burst analysis spectroscopy (BAS) and demonstrate the sensitivity of this technique by examining the free-solution, time-resolved distribution of assembled protein aggregates by using two fluorescently labeled proteins: the aggregation-prone, chaperonin-dependent, folding model protein ribulose-bisphosphate carboxylase/oxygenase (RuBisCO), and an amyloidogenic fragment of the yeast prion protein Sup35. We find that the assembly kinetics of both proteins display complex multimodal behavior not readily quantifiable with other methods.     

Relation of adult-onset asthma to coronary heart disease and stroke

Asthma was associated with atherosclerotic disease in several studies, with evidence that this association may be limited to women. However, most previous studies failed to account for the heterogeneity of asthma subtypes. We previously reported increased carotid intima-medial thickness in women with adult-onset asthma. In this study, the association of adult- and child-onset asthma with incident coronary heart disease (CHD) and stroke were examined. Subjects were classified according to self-report of physician-diagnosed asthma and age of asthma onset. Cox proportional hazards models were used to test the association of adult- and child-onset asthma with incident CHD and stroke, testing for gender interaction. Subanalysis was also performed using only never smokers. Women with adult-onset asthma experienced a 2-fold increase in incident CHD and stroke that was independent of other risk factors, including smoking, body mass index, and physical activity, and persisted when analysis was restricted to never smokers. No significant association was found in women with child-onset asthma or in men. In conclusion, adult-onset asthma may be a significant risk factor for CHD and stroke in women, but not men.     

Vasopressin in liver disease--should we turn on or off?

Arginine vasopressin is a naturally occurring peptide with established physiological functions acting as a vasoconstrictor through V1 receptors or an aquagenic agent allowing free water retention through V2 receptors in the kidney. Portal haemodynamic changes of chronic liver disease are responsible for the lethal consequences of cirrhosis--bleeding oesophageal varices and hepatorenal syndrome. Increasing hepatic vascular resistance to blood flow coupled with central hypovolaemia and a hyperdynamic circulation driven by changes in nitric oxide responsiveness disturbs the normal circulatory physiology raising portal pressure. Vasopressin and its analogues are potent vasoconstrictors and can be utilised in the management of the complications of cirrhosis. Hyponatraemia is common in end stage liver disease due in part to sodium retention and a decreased free water clearance. Diuretic therapy often leads to a worsening of the sodium status and have little true effect on improving free water clearance. Recently a new class of drugs, V2 receptor antagonists, have been evaluated in chronic liver disease whereby increasing free water clearance they may reduce ascitic fluid development. This review addresses the pharmacology of both vasopressin agonists and antagonists, their clinical application and future potential roles in managing patients with acute on chronic liver failure.     

Characterization of diversity in toxicity mechanism using in vitro cytotoxicity assays in quantitative high throughput screening

Assessing the potential health risks of environmental chemical compounds is an expensive undertaking that has motivated the development of new alternatives to traditional in vivo toxicological testing. One approach is to stage the evaluation, beginning with less expensive and higher throughput in vitro testing before progressing to more definitive trials. In vitro testing can be used to generate a hypothesis about a compound's mechanism of action, which can then be used to design an appropriate in vivo experiment. Here we begin to address the question of how to design such a battery of in vitro cell-based assays by combining data from two different types of assays, cell viability and caspase activation, with the aim of elucidating the mechanism of action. Because caspase activation is a transient event during apoptosis, it is not possible to design a single end-point assay protocol that would identify all instances of compound-induced caspase activation. Nevertheless, useful information about compound mechanism of action can be obtained from these assays in combination with cell viability data. Unsupervised clustering in combination with Dunn's cluster validity index is a robust method for identifying mechanisms of action without requiring any a priori knowledge about mechanisms of toxicity. The performance of this clustering method is evaluated by comparing the clustering results against literature annotations of compound mechanisms.     

Drinking for negative reinforcement: the semantic priming of alcohol concepts

Cognitive models of alcohol abuse posit that the context typically associated with alcohol use, such as negative affect, implicitly activates alcohol use cognitions, which in turn leads to alcohol consumption. We selected 40 undergraduate women based upon their alcohol use and reported anxiety sensitivity, and proposed that drinking for the purpose of negative reinforcement would predict increased semantic priming between anxiety and alcohol concepts. A lexical decision task compared the response latencies of alcohol targets preceded by anxiety words to those same targets preceded by neutral words (anxiety–alcohol priming). Level of anxiety sensitivity did not relate to anxiety–alcohol priming, but drinking following social conflict was associated with increased anxiety–alcohol priming. This study specifically suggests that the contextual antecedents to drinking behavior relate to the organization of semantic information about alcohol, and more generally supports cognitive models of substance abuse.     

Variation in the Developmental and Morphological Interaction Between the Nasal Septum and Facial Skeleton

While the nasal septum exerts a morphogenetic influence on the facial skeleton, there is evidence that this relationship is highly variable. To better appreciate the precise role of the septum, it is important understand the variable interaction between the septum and surrounding skeleton during ontogeny. Here we analyzed nasal septal and facial skeletal postnatal phenotypic variation using cross‐sectional samples of C3H/HeJ and C57BL/6J mice. Initial observations indicated between‐strain variation in the magnitude of septal deviation, suggesting differences in septal and facial skeletal interaction. We examined whether variation in septal deviation is due to ontogenetic differences in septal size, or whether variation in facial skeletal growth imposes spatial constraints on the septum. Using microCT we quantified septal size and deviation, and collected coordinate landmark data, which we analyzed using geometric morphometrics. C3H/HeJ mice were significantly more deviated than C57BL/6J during development. We found no differences in septal size between the two strains. However, while both strains exhibited an ontogenetic increase in snout length, C3H/HeJ mice exhibited a non‐allometric reduction in nasal bone length. This appears to be influenced by between‐strain variation in the spatial relationship between the nasal septum and nasofrontal suture. Unlike C57BL/6J mice, the C3H/HeJ nasal septum is positioned anterior to the nasofrontal suture potentially limiting an early direct influence of septal growth (e.g., through interstitial expansion) on sutural growth. Ultimately, our results underscore that while the septum is a key facial growth center, its precise influence on facial growth varies even in narrow morphological and taxonomic ranges. Anat Rec, 299:730–740, 2016. © 2016 Wiley Periodicals, Inc.     

Incident opioid drug use among older adults with chronic obstructive pulmonary disease: a population‐based cohort study

Aims

The purpose of the present study was to describe the scope, pattern and patient characteristics associated with incident opioid use among older adults with chronic obstructive pulmonary disease (COPD).

Methods

This was a retrospective population‐based cohort study using Ontario, Canada, healthcare administrative data. Study participants were individuals aged 66 years and older with physician‐diagnosed COPD, identified using a validated algorithm, who were not receiving palliative care. We examined the incidence of oral opioid receipt between 1 April 2003 and 31 March 2012, as well as several patterns of incident opioid drug use.

Results

Among 107 109 community‐dwelling and 16 207 long‐term care resident older adults with COPD, 72 962 (68.1%) and 8811 (54.4%), respectively, received an incident opioid drug during the observation period. Among long‐term care residents, multiple opioid dispensings (8.8%), dispensings for >30 days'' duration (up to 19.8%), second dispensings (35–43%) and early refills (24.2%) were observed. Incident opioid dispensing was also observed to occur during COPD exacerbations (6.9% among all long‐term care residents; 18.1% among long‐term care residents with frequent exacerbations). These same patterns of incident opioid use occurred among community‐dwelling individuals, but with relatively lower frequencies.

Conclusions

New opioid use was high among older adults with COPD. Potential safety concerns are raised by the degree and pattern of new opioid use, but further studies are needed to evaluate if adverse events are associated with opioid drug use in this older and respiratory‐vulnerable population.