How can Rorty help nursing science in the development of a philosophical ‘foundation’?

What can nurse scientists learn from Rorty in the development of a philosophical foundation? Indeed, Rorty in his 1989 text entitled Contingency, Irony, and Solidarity tantalizes the reader with debates of reason ‘against’ philosophizing. Forget truth seeking; move on to what matters. Rorty would rather the ‘high brow’ thinking go to those that do the work in order to make the effort useful. Nursing as an applied science, has something real that is worth looking at, and that nurse researchers need to think about. And as a profession built upon relationships, we should be thinking of the exchanges we have with those around us, of the contrasts in vocabularies used and of the contingencies involved, letting this launch us into our imaginings and areas of enquiry. The business of nurse researchers is to study what nurses do – how we care; Rorty would have us care. But, not to dismiss the reflective thinker as Rorty advocates for the self‐doubting ironist to continue to seek the final vocabulary, the ideal of what ‘this’ means, accepting this as the best to be offered at the time. As a science struggling to find foundation, we need only to look at what we do and value – as antifoundational as Rorty portrays himself, Rorty ‘ironically’ may have revealed a foundation for nursing science that is consistent with its path.     

Capsaicin affects brain function in a model of hepatic encephalopathy associated with fulminant hepatic failure in mice

Background and purpose:

Hepatic encephalopathy is a neuropsychiatric syndrome caused by liver failure. In view of the effects of cannabinoids in a thioacetamide-induced model of hepatic encephalopathy and liver disease and the beneficial effect of capsaicin (a TRPV1 agonist) in liver disease, we assumed that capsaicin may also affect hepatic encephalopathy.

Experimental approach:

Fulminant hepatic failure was induced in mice by thioacetamide and 24 h later, the animals were injected with one of the following compound(s): 2-arachidonoylglycerol (CB₁, CB₂ and TRPV1 receptor agonist); HU308 (CB₂ receptor agonist), SR141716A (CB₁ receptor antagonist); SR141716A+2-arachidonoylglycerol; SR144528 (CB₂ receptor antagonist); capsaicin; and capsazepine (TRPV1 receptor agonist and antagonist respectively). Their neurological effects were evaluated on the basis of activity in the open field, cognitive function in an eight-arm maze and a neurological severity score. The mice were killed 3 or 14 days after thioacetamide administration. 2-arachidonoylglycerol and 5-hydroxytryptamine (5-HT) levels were determined by gas chromatography-mass spectrometry and high-performance liquid chromatography with electrochemical detection, respectively.

Results:

Capsaicin had a neuroprotective effect in this animal model as shown by the neurological score, activity and cognitive function. The effect of capsaicin was blocked by capsazepine. Thioacetamide induced astrogliosis in the hippocampus and the cerebellum and raised brain 5-hydroxytryptamine levels, which were decreased by capsaicin, SR141716A and HU-308. Thioacetamide lowered brain 2-arachidonoylglycerol levels, an effect reversed by capsaicin.

Conclusions:

Capsaicin improved both liver and brain dysfunction caused by thioacetamide, suggesting that both the endocannabinoid and the vanilloid systems play important roles in hepatic encephalopathy. Modulation of these systems may have therapeutic value.     

Continuous inertial focusing, ordering, and separation of particles in microchannels

Under laminar flow conditions, when no external forces are applied, particles are generally thought to follow fluid streamlines. Contrary to this perspective, we observe that flowing particles migrate across streamlines in a continuous, predictable, and accurate manner in microchannels experiencing laminar flows. The migration is attributed to lift forces on particles that are observed when inertial aspects of the flow become significant. We identified symmetric and asymmetric channel geometries that provide additional inertial forces that bias particular equilibrium positions to create continuous streams of ordered particles precisely positioned in three spatial dimensions. We were able to order particles laterally, within the transverse plane of the channel, with >80-nm accuracy, and longitudinally, in regular chains along the direction of flow. A fourth dimension of rotational alignment was observed for discoidal red blood cells. Unexpectedly, ordering appears to be independent of particle buoyant direction, suggesting only minor centrifugal contributions. Theoretical analysis indicates the physical principles are operational over a range of channel and particle length scales. The ability to differentially order particles of different sizes, continuously, at high rates, and without external forces in microchannels is expected to have a broad range of applications in continuous bioparticle separation, high-throughput cytometry, and large-scale filtration systems.     

Role for Msh5 in the regulation of Ig class switch recombination

Ig class switch recombination (CSR) and somatic hypermutation serve to diversify antibody responses and are orchestrated by the activity of activation-induced cytidine deaminase and many proteins involved in DNA repair and genome surveillance. Msh5, a gene encoded in the central MHC class III region, and its obligate heterodimerization partner Msh4 have a critical role in regulating meiotic homologous recombination and have not been implicated in CSR. Here, we show that MRL/lpr mice carrying a congenic H-2(b/b) MHC interval exhibit several abnormalities regarding CSR, including a profound deficiency of IgG3 in most mice and long microhomologies at Ig switch (S) joints. We found that Msh5 is expressed at low levels on the H-2(b) haplotype and, importantly, a similar long S joint microhomology phenotype was observed in both Msh5 and Msh4-null mice. We also present evidence that genetic variation in MSH5 is associated with IgA deficiency and common variable immune deficiency (CVID) in humans. One of the human MSH5 alleles identified contains two nonsynonymous polymorphisms, and the variant protein encoded by this allele shows impaired binding to MSH4. Similar to the mice, Ig S joints from CVID and IgA deficiency patients carrying disease-associated MSH5 alleles show increased donor/acceptor microhomology, involving pentameric DNA repeat sequences and lower mutation rates than controls. Our findings suggest that Msh4/5 heterodimers contribute to CSR and support a model whereby Msh4/5 promotes the resolution of DNA breaks with low or no terminal microhomology by a classical nonhomologous end-joining mechanism while possibly suppressing an alternative microhomology-mediated pathway.     

Pharmacological characterization of the first potent and selective antagonist at the cysteinyl leukotriene 2 (CysLT2) receptor

Background and purpose:

Cysteinyl leukotrienes (CysLTs) have been implicated in the pathophysiology of inflammatory and cardiovascular disorders. Their actions are mediated by CysLT₁ and CysLT₂ receptors. Here we report the discovery of 3-({[(1S,3S)-3-carboxycyclohexyl]amino}carbonyl)-4-(3-{4-[4-(cyclo-hexyloxy)butoxy]phenyl}propoxy) benzoic acid (HAMI3379), the first potent and selective CysLT₂ receptor antagonist.

Experimental approach:

Pharmacological characterization of HAMI3379 was performed using stably transfected CysLT₁ and CysLT₂ receptor cell lines, and isolated, Langendorff-perfused, guinea pig hearts.

Key results:

In a CysLT₂ receptor reporter cell line, HAMI3379 antagonized leukotriene D₄- (LTD₄-) and leukotriene C₄- (LTC₄-) induced intracellular calcium mobilization with IC₅₀ values of 3.8 nM and 4.4 nM respectively. In contrast, HAMI3379 exhibited very low potency on a recombinant CysLT₁ receptor cell line (IC₅₀ > 10 000 nM). In addition, HAMI3379 did not exhibit any agonistic activity on both CysLT receptor cell lines. In binding studies using membranes from the CysLT₂ and CysLT₁ receptor cell lines, HAMI3379 inhibited [³H]-LTD₄ binding with IC₅₀ values of 38 nM and >10 000 nM respectively. In isolated Langendorff-perfused guinea pig hearts HAMI3379 concentration-dependently inhibited and reversed the LTC₄-induced perfusion pressure increase and contractility decrease. The selective CysLT₁ receptor antagonist zafirlukast was found to be inactive in this experimental setting.

Conclusions and implications:

HAMI3379 was identified as a potent and selective CysLT₂ receptor antagonist, which was devoid of CysLT receptor agonism. Using this compound, we showed that the cardiac effects of CysLTs are predominantly mediated by the CysLT₂ receptor.     

Incidence of catheter-associated bloodstream infection after introduction of minocycline and rifampin antimicrobial-coated catheters in a pediatric burn population

The Centers for Disease Control and Prevention guidelines for prevention of intravascular catheter-related infections suggest that antimicrobial-coated catheters can decrease the risk of developing catheter-related bloodstream infection in a variety of adult patient populations. There are limited data on their efficacy in the pediatric population, particularly among children with burn injuries. A study was conducted at Shriners Hospitals for Children?, Boston, to determine whether minocycline/rifampin (MR)-coated catheters could decrease the incidence of catheter-associated bloodstream infection (CABSI) in a pediatric burn population. A historical control group included all patients with double- or triple-lumen catheters inserted in the 18-month period from January 2006 to June 2007. The study group included all patients with MR antimicrobial double- or triple-lumen catheters inserted in the subsequent 18-month period, July 2007 to December 2008. Data collected included name, age, date of burn/injury, date of admission, percent TBSA area burn injury or other diagnosis, catheter site (subclavian, internal jugular, or femoral), method of insertion (new percutaneous stick or guidewire), type of catheter (double or triple lumen), date inserted, duration of catheter placement (days), and positive blood cultures recovered while the central venous catheter was in place. CABSI was defined using the Centers for Disease Control and Prevention definition of laboratory-confirmed bloodstream infection. There were a total of 66 patients with 252 catheters (1780 catheter days) in the control group and 75 patients with 263 catheters (1633 catheter days) in the study group. Age, percent burn injury, catheter site, and method of insertion were not statistically different between the two groups. The percentage of infected catheters and the rate of infection were significantly different for the two groups, with the MR antimicrobial catheters only half as likely to become infected. In a subset of these patients with catheters in place for more than 4 days, the percentage of infected catheters and rate of infection were also significantly different with results similar to those in the entire group. MR antimicrobial-coated catheters significantly reduced the incidence of CABSI in this pediatric burn population compared with noncoated catheters.