The cAMP-dependent protein kinase pathway as therapeutic target: possibilities and pitfalls

The prototype second messenger cAMP and its major mediator, the cAMP-dependent protein kinase (PKA), is able to control simultaneously multiple processes within the same cell. This appears to be achieved through its unique dissociative regulation and the spatiotemporal regulation of both cAMP and PKA. The widespread tissue distribution and physiological function of this pathway makes it an attractive, but challenging pharmacological target. We will discuss current progress in manipulating the fine-tuning of PKA, and outline so far underexploited possibilities for therapy, such as novel ways to target specific substrates and catalytic cycle intermediates of PKA. An attractive strategy to achieve a more focused pharmacological treatment is to combine more traditional targeting of extracellular receptors or ligands with that of intracellular signaling pathway components. The cAMP signaling pathway provides a variety of possibilities for such an approach.     

Effects of a conductive education course in young children with cerebral palsy:A randomized controlled trial

Purpose: To evaluate the effects of a conductive education (CE) course followed by conventional practice, on gross motor function, other functional skills, quality of life, and parents’ experiences of family-centered services in young children with cerebral palsy (CP). Methods: Twenty-one children with CP, 3–6 years old, were randomized to one 3-week CE course followed by conventional practice or conventional practice on a waiting list. Outcomes were measured 4 months after baseline. A web-based log collected data on the conventional practice. Results: No additional improvements in the children’s outcome were found. However, parents in the CE group reported that they received more information than parents in the waiting list group (p = 0.01). Children in both groups performed high amount of conventional practice at home. Conclusions: A 3-week CE course did not add any improvements in the children’s functioning, possibly explained by the large amount of conventional practice reported of both groups.     

Role of neutrophil to lymphocyte and monocyte to lymphocyte ratios in the diagnosis of bacterial infection in patients with fever

Purpose

To study the role of the neutrophil:lymphocyte ratio (NLR) and monocyte:lymphocyte ratio (MLR) in discriminating between different patient groups hospitalized for fever due to infection and those without infection.

Methods

For 299 patients admitted to hospital for fever with unknown cause, a number of characteristics including NLR and MLR were recorded. These characteristics were used in a multiple multinomial regression analysis to estimate the probability of a final diagnostic group of bacterial, viral, clinically confirmed, or no infection.

Results

Both NLR and MLR significantly predicted final diagnostic group. Being highly correlated, however, both variables could not be retained in the same model. Both variables also interacted significantly with duration of fever. Generally, higher values of NLR and MLR indicated larger probabilities for bacterial infection and low probabilities for viral infection. Patients with septicemia had significantly higher NLR compared to patients with other bacterial infections with fever for less than one week. White blood cell counts, neutrophil counts, and C-reactive proteins did not differ significantly between septicemia and the other bacterial infection groups.

Conclusions

NLR is a more useful diagnostic tool to identify patients with septicemia than other more commonly used diagnostic blood tests. NLR and MLR may be useful in the diagnosis of bacterial infection among patients hospitalized for fever.

     

Group supervision to strengthen nurses in their preceptor role in the bachelor nursing education – Perceptions before and after participation

BackgroundA collaborative project was carried out at four bachelor nursing colleges in Sweden and Norway, to support preceptors in the clinical fields by means of group supervision.The aim of this study was to investigate the preceptors' views on their own ability and satisfaction in the role before and after taking part in group supervision during one year and to describe their perception of the supervision model used.MethodForty-five preceptors participated in the study. Baseline and endpoint questionnaires were used for data collection.ResultsBefore taking part in group supervision most preceptors expressed that they were content with their ability and knowledge with regards to the preceptor role. Despite this most of them considered that the participation had increased their ability to supervise students, and more than half of them considered that it also had promoted to their personal development. At the end of the project a majority of them had positive experiences of group supervision. Most of the structure and climate factors in the supervision model were considered important and almost all were highly realised. Conclusion: The study showed that group supervision could be a valuable tool to provide support to clinical preceptors in bachelor nursing education.     

Effects of WIN 64338, a nonpeptide bradykinin B2 receptor antagonist, on guinea-pig trachea.

We investigated the effect of the nonpeptide bradykinin receptor antagonist, [[4-[[2-[[bis(cyclohexylamino)methylene] amino]-3-(2-naphthalenyl) 1-oxopropyl]amino]-phenyl]-tributyl, chloride, monohydrochloride (WIN 64338), on [3H]-bradykinin binding and on bradykinin-induced contraction of the guinea-pig trachea. This non peptide bradykinin receptor antagonist inhibited [3H]-bradykinin binding with a nanomolar range of affinity, Ki = 50.9 +/- 19 nM and inhibited bradykinin-induced contraction in a non-competitive manner with a KB value of 6.43 10(-8) +/- 2.34 10(-8) M.     

Junctional epidermolysis bullosa inversa (locus EBR2A) assigned to 1q31 by linkage and association to LAMC1

Junctional epidermolysis bullosa Inversa is an autosomal recessiveblistering skin disease with an ultrastructural hemldesmosomedefect similar to that of the Heriltz disease, yet with a non-lethaland different course of the disease. Its delineation is basedon five geographically associated Norwegian families where allparents are likely to carry a mutant EBR2A allele Identicalin descent. Three informative families show a lod score of +1.65at zero recombination to a trinucleotide repeat marker In Intron20 of the laminin gamma 1 (LAMC1, previously LAMB2) locus on1q31. The four patients of these families are all homozygousfor the 146 bp LAMC1 allele present only on 5% of random Norwegianchromosomes. The daughter of a deceased patient in a fourthfamily carries the same 146 bp allele. This extreme associationconfirms that the disease locus, EBR2A, Is at or closely linkedto LAMC1. Localized and generalized Mitis types as well as themajority of tested families with the Herlitz type of junctionalepidermolysis bullosa appeared not to be similarly linked orassociated to LAMC1. The Msp\ and Alu\ RFLPs of LAMC1 showedabsolute allelic association. Each of the two RFLP haplotypesshowed association to either ‘long’ or ‘short’intron 20 STR alleles.     

Cervicogenic headache. Radiological investigations concerning head/neck

Eleven patients with cervicogenic headache took part in a radiological diagnostic workup related to the head and neck. All the patients were female with a mean age of 43 years (range 25-59) at the onset of the study. Cerebral and cervical computer tomography as well as standard X-ray of the spine were carried out in all patients. Six patients underwent cerebral angiography and six cervical myelography. The different investigations showed no typical characteristic pathology in the group. No indication of a common therapeutic approach in this group of patients could therefore be derived from these investigations.     

Specific allergen immunotherapy: effect on IgE,IgG4 and chemokines in patients with allergic rhinitis

Background: Allergen-specific immunotherapy (SIT) is considered as the most effective treatment for Immunoglobulin E (IgE)-mediated allergies. However, how specific immunotherapy attenuates allergic responses is still not clear, but could potentially involve cytokines as well as IgG4-mediated responses. Based on the role of chemokines in IgE-mediated inflammation, we examined the SIT-induced chemokine response in patients with allergic rhinitis.

Methods: We included 35 patients with allergic rhinitis; 20 patients received SIT and 15 patients were not treated with specific immunotherapy. The patients were followed for 3 years. Blood samples were collected before SIT and 3, 5, 7 and 21 weeks and 1, 2 and 3 years after the start of therapy. Total IgE, specific IgE, IgG4 and chemokine levels were assessed.

Results: Our main findings were: (i) SIT was associated with an early increase in total and specific IgE during the first 7 weeks, with a subsequent decline, accompanied by a marked increase in specific IgG4 when IgE started to decline; (ii) these SIT-induced responses were accompanied by and in some degree correlated with increased plasma concentrations of the chemokines, monocyte chemoattractant protein (MCP)-1, and eotaxin; and (iii) within the SIT group, these correlations with chemokines were restricted to IgE and IgG4 against birch tree pollen.

Conclusion: Our findings further support a role for IgG4-mediated mechanisms in the beneficial effects of SIT in patients with allergic rhinitis (AR) and that increased levels of certain chemokines also could be of importance for the effect of such therapy.     

Unhappy doctors? A longitudinal study of life and job satisfaction among Norwegian doctors 1994 – 2002

Background  

General opinion is that doctors are increasingly dissatisfied with their job, but few longitudinal studies exist. This study has been conducted to investigate a possible decline in professional and personal satisfaction among doctors by the turn of the century.