Variable sensitivity to noxious heat is mediated by differential expression of the CGRP gene

Heat sensitivity shows considerable functional variability in humans and laboratory animals, and is fundamental to inflammatory and possibly neuropathic pain. In the mouse, at least, much of this variability is genetic because inbred strains differ robustly in their behavioral sensitivity to noxious heat. These strain differences are shown here to reflect differential responsiveness of primary afferent thermal nociceptors to heat stimuli. We further present convergent behavioral and electrophysiological evidence that the variable responses to noxious heat are due to strain-dependence of CGRP expression and sensitivity. Strain differences in behavioral response to noxious heat could be abolished by peripheral injection of CGRP, blockade of cutaneous and spinal CGRP receptors, or long-term inactivation of CGRP with a CGRP-binding Spiegelmer. Linkage mapping supports the contention that the genetic variant determining variable heat pain sensitivity across mouse strains affects the expression of the Calca gene that codes for CGRPalpha.     

Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1

Glucocorticoids (GCs), which are used in the treatment of immune-mediated inflammatory diseases, inhibit the expression of many inflammatory mediators. They can also induce the expression of dual specificity phosphatase 1 (DUSP1; otherwise known as mitogen-activated protein kinase [MAPK] phosphatase 1), which dephosphorylates and inactivates MAPKs. We investigated the role of DUSP1 in the antiinflammatory action of the GC dexamethasone (Dex). Dex-mediated inhibition of c-Jun N-terminal kinase and p38 MAPK was abrogated in DUSP1-/- mouse macrophages. Dex-mediated suppression of several proinflammatory genes (including tumor necrosis factor, cyclooxygenase 2, and interleukin 1alpha and 1beta) was impaired in DUSP1-/- mouse macrophages, whereas other proinflammatory genes were inhibited by Dex in a DUSP1-independent manner. In vivo antiinflammatory effects of Dex on zymosan-induced inflammation were impaired in DUSP1-/- mice. Therefore, the expression of DUSP1 is required for the inhibition of proinflammatory signaling pathways by Dex in mouse macrophages. Furthermore, DUSP1 contributes to the antiinflammatory effects of Dex in vitro and in vivo.     

The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans

Sex specificity of neural mechanisms modulating nociceptive information has been demonstrated in rodents, and these qualitative sex differences appear to be relevant to analgesia from kappa-opioid receptor agonists, a drug class reported to be clinically effective only in women. Via quantitative trait locus mapping followed by a candidate gene strategy using both mutant mice and pharmacological tools, we now demonstrate that the melanocortin-1 receptor (Mc1r) gene mediates kappa-opioid analgesia in female mice only. This finding suggested that individuals with variants of the human MC1R gene, associated in our species with red hair and fair skin, might also display altered kappa-opioid analgesia. We found that women with two variant MC1R alleles displayed significantly greater analgesia from the kappa-opioid, pentazocine, than all other groups. This study demonstrates an unexpected role for the MC1R gene, verifies that pain modulation in the two sexes involves neurochemically distinct substrates, and represents an example of a direct translation of a pharmacogenetic finding from mouse to human.     

Nursing shortages: let's be flexible

The following paper is a report outlining a significant work pattern change in an acute cardiac ward at a large Brisbane-based private hospital. The nursing staff expressed the desire for more flexible rostering and the opportunity to work 12-hour shifts. After agreement was reached between the hospital, the union and the Industrial Relations Board, guidelines were put in place and a Flexible Rostering System was proposed and trialed. An 80% consensus of staff was required both to proceed with the trial and to implement any permanent changes. Initially, the trial was conducted for three months and extended to six months. The shifts trialed were between four and 12 hours in length with varied starting and finishing times. The Flexible Rostering System was evaluated using feedback from staff surveys and the results of a staff vote. In addition, patient feedback, incident reports, financial and managerial evaluation of staff costs, hours per patient day utilised, sick leave, and the use of permanent staff for voluntary extra shifts were also monitored. The outcome of the trial was positive with over 80% of staff voting to implement the Flexible Rostering System permanently. A significant reduction in sick leave of 41% and improved retention of skilled registered nursing staff was noted. There was no increase in the number of incident reports or patient complaints. Both patients and nurses commented on the improved continuity of care. Salaries and wages were within budget. Staff surveys showed positive feedback such as increased morale, increased flexibility with rosters, decreased fatigue levels, improved patient assessment on night duty and an increase in number of days off. In conclusion, the Flexible Rostering System has been accepted as a positive change for staff and is cost effective for the hospital. In light of nursing shortages, the outcome of this trial cannot be ignored.     

The pancreatic ductal epithelium serves as a potential pool of progenitor cells

Abstract:  With the increasing success of islet transplantation, β-cell replacement therapy has had renewed interest. To make such a therapy available to more than a few of the thousands of patients with diabetes, new sources of insulin-producing cells must become readily available. The most promising sources are stem cells, whether embryonic or adult stem cells. Clearly identifiable adult pancreatic stem cells have yet to be characterized. Although considerable evidence suggests their possibility, recent lineage-tracing experiments challenge their existence. Even in light of these lineage-tracing experiments, we suggest that evidence for neogenesis or new islet formation after birth remains strong. Our work has suggested that the pancreatic duct epithelium itself serves as a pool for progenitors for both islet and acinar tissues after birth and into adulthood and, thus, that the duct epithelium can be considered 'facultative stem cells'. We will develop our case for this hypothesis in this perspective.     

Characterization of esophageal body and lower esophageal sphincter motor function in the very premature neonate.

OBJECTIVES: To characterize esophageal body and lower esophageal sphincter (LES) motor function in very premature infants. STUDY DESIGN: Esophageal manometry was performed in 12 very premature infants of 26 to 33 weeks' postmenstrual age (PMA) (body weights of 610-1360 g). Esophageal motor patterns were recorded for 30 minutes with a perfused micromanometric sleeve assembly (outer diameter, 2.0 mm). RESULTS: Esophageal pressure waves triggered by dry swallows were predominantly (84%) peristaltic in propagation sequence. All infants showed tonic LES contraction; the mean resting LES pressure (LESP) for individual infants ranged from 5.0 +/- 4.1 mm Hg to 20.0 +/- 4.8 mm Hg. In all infants the LES relaxed (duration, 5.8 +/- 3.0 seconds; nadir pressure, 1.8 +/- 2.6 mm Hg) in response to pharyngeal swallows. Transient LES relaxations (TLESRs) (duration, 21.7 +/- 8.7 seconds; nadir pressure, 0.1 +/- 1.8 mm Hg) occurred on average 2.6 +/- 1.6 times per study; 86% of these relaxations triggered esophageal body common cavity events known to be associated with gastroesophageal reflux. CONCLUSIONS: Esophageal motor function is well developed in very premature infants. Our data also suggest that TLESR is the predominant mechanism of reflux in these babies.     

Patient-Centered Contraceptive Counseling: Evidence to Inform Practice

Patient centeredness is an increasingly recognized aspect of quality health care. The application of this framework to contraceptive counseling and care has not been well described. We propose a definition of patient-centered contraceptive counseling that focuses on and prioritizes each patient’s individual needs and preferences regarding contraceptive methods and the counseling experience. Guided by this definition, we review recent research that has advanced our understanding of how patient-centered contraceptive counseling can be delivered in practice, focusing on how women decide on a contraceptive method, their preferences for counseling, and their experiences with counseling. This research provides evidence that women have diverse preferences around attributes of their contraceptive methods and value personal, supportive relationships with their family planning providers that focus on their individual preferences. We discuss the implications of this research for practice and review recent interventions that incorporate patient centeredness to varying degrees.     

Shiga toxin is transported from the endoplasmic reticulum following interaction with the luminal chaperone HEDJ/ERdj3

Shiga toxin (Stx) follows a complex intracellular pathway in order to kill susceptible cells. After binding to cell surface glycolipids, the toxin is internalized and trafficked in retrograde fashion to the endoplasmic reticulum (ER). From the ER lumen, the toxin must gain access to the cytoplasm, where it enzymatically inactivates the 28S rRNA, inhibiting protein synthesis. The host molecules involved in this pathway and the mechanisms utilized by the toxin to access the cytoplasm from the ER are largely unknown. We found that Stx is capable of energy-dependent transport across the ER lumen, as has recently been demonstrated for the cholera and ricin toxins. Genetic screening for molecules involved in Shiga toxin trafficking yielded a cDNA encoding a prematurely truncated protein. Characterization of this cDNA revealed that it encodes a novel Hsp40 chaperone, designated HEDJ or ERdj3, localized to the ER lumen, where it interacts with BiP, a molecule known to be involved in protein retrotranslocation out of the ER. We demonstrated that within the ER lumen Stx interacts with HEDJ and other chaperones known to be involved in retrotranslocation of proteins across the ER membrane. Moreover, sequential immunoprecipitation revealed that Shiga toxin was present in a complex that included HEDJ and Sec61, the translocon through which proteins are retrotranslocated to the cytoplasm. These findings suggest that HEDJ is a component of the ER quality control system and that Stx utilizes HEDJ and other ER-localized chaperones for transport from the ER lumen to the cytosol.     

Comparison of user groups' perspectives of barriers and facilitators to implementing electronic health records: a systematic review

Background  

Electronic health record (EHR) implementation is currently underway in Canada, as in many other countries. These ambitious projects involve many stakeholders with unique perceptions of the implementation process. EHR users have an important role to play as they must integrate the EHR system into their work environments and use it in their everyday activities. Users hold valuable, first-hand knowledge of what can limit or contribute to the success of EHR implementation projects. A comprehensive synthesis of EHR users' perceptions is key to successful future implementation. This systematic literature review was aimed to synthesize current knowledge of the barriers and facilitators influencing shared EHR implementation among its various users.