The perceived meaning of a (w)holistic view among general practitioners and district nurses in Swedish primary care: a qualitative study

BACKGROUND: The definition of primary care varies between countries. Swedish primary care has developed from a philosophic viewpoint based on quality, accessibility, continuity, co-operation and a holistic view. The meaning of holism in international literature differs between medicine and nursing. The question is, if the difference is due to different educational traditions. Due to the uncertainties in defining holism and a holistic view we wished to study, in depth, how holism is perceived by doctors and nurses in their clinical work. Thus, the aim was to explore the perceived meaning of a holistic view among general practitioners (GPs) and district nurses (DNs). METHODS: Seven focus group interviews with a purposive sample of 22 GPs and 20 nurses working in primary care in two Swedish county councils were conducted. The interviews were transcribed verbatim and analysed using qualitative content analysis. RESULTS: The analysis resulted in three categories, attitude, knowledge, and circumstances, with two, two and four subcategories respectively. A professional attitude involves recognising the whole person; not only fragments of a person with a disease. Factual knowledge is acquired through special training and long professional experience. Tacit knowledge is about feelings and social competence. Circumstances can either be barriers or facilitators. A holistic view is a strong motivator and as such it is a facilitator. The way primary care is organised can be either a barrier or a facilitator and could influence the use of a holistic approach. Defined geographical districts and care teams facilitate a holistic view with house calls being essential, particularly for nurses. In preventive work and palliative care, a holistic view was stated to be specifically important. Consultations and communication with the patient were seen as important tools. CONCLUSION: 'Holistic view' is multidimensional, well implemented and very much alive among both GPs and DNs. The word holistic should really be spelt 'wholistic' to avoid confusion with complementary and alternative medicine. It was obvious that our participants were able to verbalise the meaning of a 'wholistic' view through narratives about their clinical, every day work. The possibility to implement a 'wholistic' perspective in their work with patients offers a strong motivation for GPs and DNs

Target enzyme mutations are the molecular basis for resistance towards pharmacological inhibition of nicotinamide phosphoribosyltransferase

<p>Abstract</p> <p>Background</p> <p>Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) are promising cancer drugs currently in clinical trials in oncology, including APO866, CHS-828 and the CHS-828 prodrug EB1627/GMX1777, but cancer cell resistance to these drugs has not been studied in detail.</p> <p>Methods</p> <p>Here, we introduce an analogue of CHS-828 called TP201565 with increased potency in cellular assays. Further, we describe and characterize a panel of cell lines with acquired stable resistance towards several NAMPT inhibitors of 18 to 20,000 fold compared to their parental cell lines.</p> <p>Results</p> <p>We find that 4 out of 5 of the resistant sublines display mutations of NAMPT located in the vicinity of the active site or in the dimer interface of NAMPT. Furthermore, we show that these mutations are responsible for the resistance observed. All the resistant cell lines formed xenograft tumours <it>in vivo</it>. Also, we confirm CHS-828 and TP201565 as competitive inhibitors of NAMPT through docking studies and by NAMPT precipitation from cellular lysate by an analogue of TP201565 linked to sepharose. The NAMPT precipitation could be inhibited by addition of APO866.</p> <p>Conclusion</p> <p>We found that CHS-828 and TP201565 are competitive inhibitors of NAMPT and that acquired resistance towards NAMPT inhibitors can be expected primarily to be caused by mutations in NAMPT.</p

A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration.

NAD metabolism regulates diverse biological processes, including ageing, circadian rhythm and axon survival. Axons depend on the activity of the central enzyme in NAD biosynthesis, nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), for their maintenance and degenerate rapidly when this activity is lost. However, whether axon survival is regulated by the supply of NAD or by another action of this enzyme remains unclear. Here we show that the nucleotide precursor of NAD, nicotinamide mononucleotide (NMN), accumulates after nerve injury and promotes axon degeneration. Inhibitors of NMN-synthesising enzyme NAMPT confer robust morphological and functional protection of injured axons and synapses despite lowering NAD. Exogenous NMN abolishes this protection, suggesting that NMN accumulation within axons after NMNAT2 degradation could promote degeneration. Ectopic expression of NMN deamidase, a bacterial NMN-scavenging enzyme, prolongs survival of injured axons, providing genetic evidence to support such a mechanism. NMN rises prior to degeneration and both the NAMPT inhibitor FK866 and the axon protective protein Wld(S) prevent this rise. These data indicate that the mechanism by which NMNAT and the related Wld(S) protein promote axon survival is by limiting NMN accumulation. They indicate a novel physiological function for NMN in mammals and reveal an unexpected link between new strategies for cancer chemotherapy and the treatment of axonopathies

Electronic Pneumatic Injection-Assisted Dermal Drug Delivery Visualized by Ex Vivo Confocal Microscopy

Background and Objectives: Electronic pneumatic injection (EPI) is a technique for dermal drug delivery, which is increasingly being used in clinical practice. However, only few studies have been reported on cutaneous drug distribution and related clinical endpoints. We aimed to visualize the immediate cutaneous drug distribution, changes in skin architecture, and related clinical endpoint of EPI. Study Design/Materials and Methods: Acridine orange (AO) solution was administered to ex vivo porcine skin by EPI at pressure levels from 4 to 6 bar with a fixed injection volume of 50 µl and nozzle size of 200 µm. Immediate cutaneous distribution was visualized using ex vivo confocal microscopy (EVCM). Changes in skin architecture were visualized using both EVCM and hematoxylin and eosin-stained cryosections. Results: The defined immediate endpoint was a clinically visible papule formation on the skin. The pressure threshold to consistently induce a papule was 4 bar, achieving delivery of AO to the deep dermis (2319 µm axial and 5944 µm lateral distribution). Increasing the pressure level to 6 bar did not lead to significant differences in axial and lateral dispersion (P = 0.842, P = 0.905; respectively). A distinctively hemispherical distribution pattern was identified. Disruption of skin architecture occurred independently of pressure level, and consisted of subepidermal clefts, dermal vacuoles, and fragmented collagen. Conclusions: This is the first study to relate a reproducible clinical endpoint to EPI-assisted immediate drug delivery using EVCM. An EPI-induced skin papule indicates dermal drug delivery throughout all layers of the dermis, independent of pressure level settings. Lasers Surg. Med