Calcium channel α2δ1 proteins mediate trigeminal neuropathic pain states associated with aberrant excitatory synaptogenesis.

To investigate a potential mechanism underlying trigeminal nerve injury-induced orofacial hypersensitivity, we used a rat model of chronic constriction injury to the infraorbital nerve (CCI-ION) to study whether CCI-ION caused calcium channel α2δ1 (Cavα2δ1) protein dysregulation in trigeminal ganglia and associated spinal subnucleus caudalis and C1/C2 cervical dorsal spinal cord (Vc/C2). Furthermore, we studied whether this neuroplasticity contributed to spinal neuron sensitization and neuropathic pain states. CCI-ION caused orofacial hypersensitivity that correlated with Cavα2δ1 up-regulation in trigeminal ganglion neurons and Vc/C2. Blocking Cavα2δ1 with gabapentin, a ligand for the Cavα2δ1 proteins, or Cavα2δ1 antisense oligodeoxynucleotides led to a reversal of orofacial hypersensitivity, supporting an important role of Cavα2δ1 in orofacial pain processing. Importantly, increased Cavα2δ1 in Vc/C2 superficial dorsal horn was associated with increased excitatory synaptogenesis and increased frequency, but not the amplitude, of miniature excitatory postsynaptic currents in dorsal horn neurons that could be blocked by gabapentin. Thus, CCI-ION-induced Cavα2δ1 up-regulation may contribute to orofacial neuropathic pain states through abnormal excitatory synapse formation and enhanced presynaptic excitatory neurotransmitter release in Vc/C2

The role of CFTR in bicarbonate secretion by pancreatic duct and airway epithelia

The secretory epithelia of the pancreatic duct and airway share the ability to generate HCO3--rich fluids. They both express CFTR (cystic fibrosis transmembrane conductance regulator) at the apical membrane and both are adversely affected by cystic fibrosis. CFTR is predominantly a Cl- channel, and it is widely believed that HCO3- secretion in the pancreatic duct is mediated mainly by a Cl-/HCO3- exchanger at the apical membrane. Studies on airway epithelia, however, have suggested that CFTR, despite its low permeability to HCO3-, may nonetheless be directly responsible for HCO3- secretion across the apical membrane. This article reviews recent work that has re-examined both of these hypotheses

Sex differences in efficacy and safety of PCSK9 monoclonal antibodies:A real-world registry

Background and aims: Proprotein convertase subtilisin/kexin 9 monoclonal antibodies (PCSK9 mAbs) reduce low-density lipoprotein (LDL-c) with a favourable safety profile. Available data from PCSK9 antibody trials suggest LDL-c reduction is lower in women compared to men. Data in real-world setting is scarce. The aim of this study was to assess sex differences in efficacy and safety of PCSK9 antibodies in clinical care. Methods: All patients starting with evolocumab or alirocumab in our lipid clinic were included in a prospective registry. We collected clinical information, including baseline and follow-up mean LDL-C levels after initiation of PCSK9 mAbs treatment. In addition, side effects and PCSK9 mAbs discontinuation were recorded. Results: We analysed 436 patients (209 women), mean age 58 ± 11 years. Women had higher baseline LDL-c levels compared to men (4.7 ± 1.6 mmol/L vs 4.1 ± 1.4 mmol/L, p &lt; 0.01). PCSK9 mAbs resulted in less relative LDL-c reduction in women compared to men (50% vs 61% p&lt;0.01), but equal absolute LDL-c reduction (respectively 2.3 ± 1.3 mmol/L vs 2.5 ± 1.1 mmol/L, p = 0.087). Women less often reached LDL-c target levels than men (50% vs 72%). No sex differences were observed in reporting of side effects (women 32% vs men 27% p = 0.26) or PCSK9 mAbs discontinuation (women 13% vs men 10%, p = 0.46). Conclusions: In clinical practice, PCSK9 mAbs are less effective in reducing LDL-c levels in women compared to men and equally safe, implying the importance of sex differences in PCSK9 metabolism.</p

Role of anion exchangers in Cl- and HCO3- secretion by the human airway epithelial cell line Calu-3

Despite the importance of airway surface liquid pH in the lung's defenses against infection, the mechanism of airway HCO3- secretion remains unclear. Our aim was to assess the contribution of apical and basolateral Cl-/HCO3- exchangers to Cl- and HCO3- transport in the Calu-3 cell line, derived from human airway submucosal glands. Changes in intracellular pH (pH(i)) were measured following substitution of Cl- with gluconate. Apical Cl- substitution led to an alkalinization in forskolin-stimulated cells, indicative of Cl-/HCO3- exchange. This was unaffected by the anion exchange inhibitor DIDS but inhibited by the CFTR blocker CFTRinh-172, suggesting that the HCO3- influx might occur via CFTR, rather than a solute carrier family 26 (SLC26) exchanger, as recently proposed. The anion selectivity of the recovery process more closely resembled that of CFTR than an SLC26 exchanger, and quantitative RT-PCR showed only low levels of SLC26 exchanger transcripts relative to CFTR and anion exchanger 2 (AE2). For pHi to rise to observed values (similar to 7.8) through HCO3- entry via CFTR, the apical membrane potential must reverse to at least + 20 mV following Cl- substitution; this was confirmed by perforated-patch recordings. Substitution of basolateral Cl- evoked a DIDS-sensitive alkalinization, attributed to Cl-/HCO3- exchange via AE2. This appeared to be abolished in forskolin-stimulated cells but was unmasked by blocking apical efflux of HCO3- via CFTR. We conclude that Calu-3 cells secrete HCO3- predominantly via CFTR, and, contrary to previous reports, the basolateral anion exchanger AE2 remains active during stimulation, providing an important pathway for basolateral Cl- uptake

MASS DISPERSAL OF TERRESTRIAL ORGANISMS DURING FIRST FLUSH EVENTS IN A TEMPORARY STREAM

Temporary streams expand and contract seasonally, forming a complex mosaic of aquatic, amphibic and terrestrial habitats. We studied the terrestrial arthropod fauna at the surface of the dry river bed as well as the fauna of Coarse Particulate Organic Matter (CPOM) deposits 0, 5 and 10 days after first flush events (years 2004–2006) along the Pardiela stream (SE Portugal). During the dry period, large amounts of organic material accumulated at the surface of the dry bed, colonized by abundant terrestrial arthropods (mean density: 13.3 ± 15.29 Ind gDM (Dry Mass of CPOM)). Arthropod density peaked in fresh flood deposits (mean density: 35.8 ± 33.4 Ind g DM), and subsequently decreased within time. Concurrently, the relative composition of the arthropod community changed from Day 0 to Day 10. The present results demonstrated that the dry bed of temporary streams served as a major habitat for terrestrial arthropods. During the first flush events, a mass dispersal of terrestrial arthropods, rafting on floating CPOM, occurred, subsequently forming distinct deposits along the channel margin. These deposits may constitute critical habitats, refugia and food resources for local and regional terrestrial arthropod assemblage

Mathematical models of morphogen gradients and their effects on gene expression

not applicabl

Experience of primary care among homeless individuals with mental health conditions

The delivery of primary care to homeless individuals with mental health conditions presents unique challenges. To inform healthcare improvement, we studied predictors of favorable primary care experience among homeless persons with mental health conditions treated at sites that varied in degree of homeless-specific service tailoring. This was a multi-site, survey-based comparison of primary care experiences at three mainstream primary care clinics of the Veterans Administration (VA), one homeless-tailored VA clinic, and one tailored non-VA healthcare program. Persons who accessed primary care service two or more times from July 2008 through June 2010 (N = 366) were randomly sampled. Predictor variables included patient and organization characteristics suggested by the patient perception model developed by Sofaer and Firminger (2005), with an emphasis on mental health. The primary care experience was assessed with the Primary Care Quality-Homeless (PCQ-H) questionnaire, a validated survey instrument. Multiple regression identified predictors of positive experiences (i.e. higher PCQ-H total score). Significant predictors of a positive experience included a site offering tailored service design, perceived choice among providers, and currently domiciled status. There was an interaction effect between site and severe psychiatric symptoms. For persons with severe psychiatric symptoms, a homeless-tailored service design was significantly associated with a more favorable primary care experience. For persons without severe psychiatric symptoms, this difference was not significant. This study supports the importance of tailored healthcare delivery designed for homeless persons' needs, with such services potentially holding special relevance for persons with mental health conditions. To improve patient experience among the homeless, organizations may want to deliver services that are tailored to homelessness and offer a choice of providers

Dynamical Instabilities of the Randall-Sundrum Model

We derive dynamical equations to describe a single 3-brane containing fluid matter and a scalar field coupling to the dilaton and the gravitational field in a five dimensional bulk. First, we show that a scalar field or an arbitrary fluid on the brane cannot evolve to cancel the cosmological constant in the bulk. Then we show that the Randall-Sundrum model is unstable under small deviations from the fine-tuning between the brane tension and the bulk cosmological constant and even under homogeneous gravitational perturbations. Implications for brane world cosmologies are discussed.Comment: 12 pages, 2 figure

Plant responses to photoperiod

Photoperiod controls many developmental responses in animals, plants and even fungi. The response to photoperiod has evolved because daylength is a reliable indicator of the time of year, enabling developmental events to be scheduled to coincide with particular environmental conditions. Much progress has been made towards understanding the molecular mechanisms involved in the response to photoperiod in plants. These mechanisms include the detection of the light signal in the leaves, the entrainment of circadian rhythms, and the production of a mobile signal which is transmitted throughout the plant. Flowering, tuberization and bud set are just a few of the many different responses in plants that are under photoperiodic control. Comparison of what is known of the molecular mechanisms controlling these responses shows that, whilst common components exist, significant differences in the regulatory mechanisms have evolved between these responses