Which positive factors give general practitioners job satisfaction and make general practice a rewarding career? A European multicentric qualitative research by the European general practice research network.

BACKGROUND: General Practice (GP) seems to be perceived as less attractive throughout Europe. Most of the policies on the subject focused on negative factors. An EGPRN research team from eight participating countries was created in order to clarify the positive factors involved in appeals and retention in GP throughout Europe. The objective was to explore the positive factors supporting the satisfaction of General Practitioners (GPs) in clinical practice throughout Europe. METHOD: Qualitative study, employing face-to-face interviews and focus groups using a phenomenological approach. The setting was primary care in eight European countries: France, Belgium, Germany, Slovenia, Bulgaria, Finland, Poland and Israel. A thematic qualitative analysis was performed following the process described by Braun and Clarke. Codebooks were generated in each country. After translation and back translation of these codebooks, the team clarified and compared the codes and constructed one international codebook used for further coding. RESULTS: A purposive sample of 183 GPs, providing primary care to patients in their daily clinical practice, was interviewed across eight countries. The international codebook included 31 interpretative codes and six themes. Five positive themes were common among all the countries involved across Europe: the GP as a person, special skills needed in practice, doctor-patient relationship, freedom in the practice and supportive factors for work-life balance. One theme was not found in Poland or Slovenia: teaching and learning. CONCLUSION: This study identified positive factors which give GPs job satisfaction in their clinical practice. This description focused on the human needs of a GP. They need to have freedom to choose their working environment and to organize their practice to suit themselves. In addition, they need to have access to professional education so they can develop specific skills for General Practice, and also strengthen doctor-patient relationships. Stakeholders should consider these factors when seeking to increase the GP workforce.

One consensual depression diagnosis tool to serve many countries: a challenge! A RAND/UCLA methodology.

OBJECTIVE: From a systematic literature review (SLR), it became clear that a consensually validated tool was needed by European General Practitioner (GP) researchers in order to allow multi-centred collaborative research, in daily practice, throughout Europe. Which diagnostic tool for depression, validated against psychiatric examination according to the DSM, would GPs select as the best for use in clinical research, taking into account the combination of effectiveness, reliability and ergonomics? A RAND/UCLA, which combines the qualities of the Delphi process and of the nominal group, was used. GP researchers from different European countries were selected. The SLR extracted tools were validated against the DSM. The Youden index was used as an effectiveness criterion and Cronbach's alpha as a reliability criterion. Ergonomics data were extracted from the literature. Ergonomics were tested face-to-face. RESULTS: The SLR extracted 7 tools. Two instruments were considered sufficiently effective and reliable for use: the Hospital Anxiety and Depression Scale and the Hopkins Symptoms Checklist-25 (HSCL-25). After testing face-to-face, HSCL-25 was selected. A multicultural consensus on one diagnostic tool for depression was obtained for the HSCL-25. This tool will provide the opportunity to select homogeneous populations for European collaborative research in daily practice.

Circadian rhythms of melatonin and cortisol in manifest Huntington's disease and in acute cortical ischemic stroke.

Recent studies indicate disruptions to the circadian system in brain injury and neurodegeneration. The results, however, are often not consistent and limited by measurement of only one circadian marker and by infrequent sampling rates. In this study, we examined diurnal rhythmicity in different stages of Huntington (HD) disease and in patients with acute moderate ischemic stroke (AIS) outside the retinohypothalamic pathway by evaluating serum concentrations of melatonin and cortisol at twelve timepoints. All study participants were subjected to the same study protocol of 12-hour light/dark cycle and controlled room conditions. Using cosinor analysis of data and comparing the results with the controls we found melatonin phase delay with lowered amplitude and mesor in stage III HD patients. These changes coexisted with phase advanced rhythm and elevated values of mesor and amplitude for cortisol. Early and mid-stages of HD showed only a phase advance in cortisol secretion. In AIS the circadian rhythm of serum melatonin was sustained without any phase shift and exhibited more flattened profile (lowered mesor and amplitude values), while advanced rhythm with higher mesor for cortisol was present. In conclusion, 1) abnormal pattern of melatonin release in the late stages of HD and in moderate AIS occurs in conjunction with phase-advanced rhythm of cortisol; 2) changes observed in late stages of HD are similar to those that occur with ageing; 3) brain regions other than the presumptive retinopineal neural pathway may play an important role in the pineal production of melatonin in humans; 4) lesion in extrahypothalamic region is related to the strong adrenal stimulation in response to AIS.

Which DSM validated tools for diagnosing depression are usable in primary care research? A systematic literature review.

INTRODUCTION: Depression occurs frequently in primary care. Its broad clinical variability makes it difficult to diagnose. This makes it essential that family practitioner (FP) researchers have validated tools to minimize bias in studies of everyday practice. Which tools validated against psychiatric examination, according to the major depression criteria of DSM-IV or 5, can be used for research purposes? METHOD: An international FP team conducted a systematic review using the following databases: Pubmed, Cochrane and Embase, from 2000/01/01 to 2015/10/01. RESULTS: The three databases search identified 770 abstracts: 546 abstracts were analyzed after duplicates had been removed (224 duplicates); 50 of the validity studies were eligible and 4 studies were included. In 4 studies, the following tools were found: GDS-5, GDS-15, GDS-30, CESD-R, HADS, PSC-51 and HSCL-25. Sensitivity, Specificity, Positive Predictive Value, Negative Predictive Value were collected. The Youden index was calculated. DISCUSSION: Using efficiency data alone to compare these studies could be misleading. Additional reliability, reproducibility and ergonomic data will be essential for making comparisons. CONCLUSION: This study selected seven tools, usable in primary care research, for the diagnosis of depression. In order to define the best tools in terms of efficiency, reproducibility, reliability and ergonomics for research in primary care, and for care itself, further research will be essential.

IL-12B Gene Polymorphisms and IL-12 p70 Serum Levels Among Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is one of the autoimmune diseases, where different polymorphisms in cytokine genes play a pathogenic role. IL-12 is now recognized as a critical cytokine in terms of regulating the balance between Th1 and Th2 cells. We investigated the role of single nucleotide polymorphisms (SNPs) (rs3212227 (A/C) and rs17860508 (CTCTAA/GC)) of the IL-12B gene in the genetic susceptibility to RA and in the severity of the disease. Six hundred and thirty-four Caucasian RA patients and 341 healthy matched controls were studied using PCR-RFLP method and high-resolution melting analysis. Concentration of IL-12 cytokine level in serum was evaluated using ELISA. The genotype frequency did not deviate from HWE in each examined group. Frequencies of the rs3212227 CC genotype were statistically higher in patients with RA compared with the healthy control group in both codominant and recessive models (P = 0.037; P = 0.04, respectively). The frequency of rs3212227 C allele also showed similar tendency (P = 0.07). IL-12 level in serum was significantly higher in RA group compared with control (P < 0.0001). We observed that increased IL-12 serum level was correlated with higher number of tender and swollen joints, ExRA presence and higher levels of haemoglobin, CRP and PLT. Also higher IL-12 level in serum was observed within RA patients with hypertension. Present findings indicated that IL-12p40 + 1188A/C polymorphism as well as IL-12p70 protein levels may be associated with RA in the Polish population.

Which positive factors determine the GP satisfaction in clinical practice? A systematic literature review.

BACKGROUND: Looking at what makes General Practitioners (GPs) happy in their profession, may be important in increasing the GP workforce in the future. The European General Practice Research Network (EGPRN) created a research team (eight national groups) in order to clarify the factors involved in GP job satisfaction throughout Europe. The first step of this study was a literature review to explore how the satisfaction of GPs had been studied before. The research question was "Which factors are related to GP satisfaction in Clinical Practice?" METHODS: Systematic literature review according to the PRISMA statement. The databases searched were Pubmed, Embase and Cochrane. All articles were identified, screened and included by two separate research teams, according to inclusion or exclusion criteria. Then, a qualitative appraisal was undertaken. Next, a thematic analysis process was undertaken to capture any issue relevant to the research question. RESULTS: The number of records screened was 458. One hundred four were eligible. Finally, 17 articles were included. The data revealed 13 subthemes, which were grouped into three major themes for GP satisfaction. First there were general profession-related themes, applicable to many professions. A second group of issues related specifically to a GP setting. Finally, a third group was related to professional life and personal issues. CONCLUSIONS: A number of factors leading to GP job satisfaction, exist in literature They should be used by policy makers within Europe to increase the GP workforce. The research team needs to undertake qualitative studies to confirm or enhance those results.

Genetic Variants in IL-12B and IL-27 in the Polish Patients with Systemic Lupus Erythematosus.

To investigate the potential association between IL-12B and IL-27 gene polymorphisms and systemic lupus erythematosus (SLE), we performed a case-control study based on the Polish population. Patients with SLE and healthy individuals were examined for -6415 CTCTAA/GC (rs17860508) and +1188A/C (rs3212227) in IL-12B and -924A/G (rs153109) and 4730T/C (rs181206) in IL-27 gene polymorphisms using the high-resolution melting method, PCR-RFLP method and TaqMan SNP genotyping assay, respectively. An increased frequency of GC/GC genotype as well as GC allele of the IL-12B rs17860508 was found in patients with SLE, as compared with healthy subjects (P < 0.001). We did not find differences in genotype and allele frequencies of the IL-12B rs3212227 and IL-27 rs153109 and rs181206 variants between patients with SLE and controls. IL-27 haplotype rs181206C/rs153109G indicated higher risk for SLE (P = 0.002), whereas haplotype rs181206T/rs153109G indicated reduced risk for SLE (P = 0.005). The IL-12B rs3212227 A/C polymorphism was associated with the mean value of the platelets (PLT), urea and complement C3 level. Furthermore, IL-12B rs17860508 genetic variant showed correlation with PLT, prothrombin time, international normalized ratio and alkaline phosphatase. Our results revealed that IL-12B rs17860508 and IL-27 haplotype CG are genetic risk factors for SLE and that both IL-12B rs17860508 and rs3212227 predict disease phenotype.

The Correlation of PPARα Activity and Cardiomyocyte Metabolism and Structure in Idiopathic Dilated Cardiomyopathy during Heart Failure Progression.

This study aimed to define relationship between PPARα expression and metabolic-structural characteristics during HF progression in hearts with DCM phenotype. Tissue endomyocardial biopsy samples divided into three groups according to LVEF ((I) 45-50%, n = 10; (II) 30-40%, n = 15; (III) <30%, n = 15; and control (donor hearts, >60%, n = 6)) were investigated. The PPARα mRNA expression in the failing hearts was low in Group (I), high in Group (II), and comparable to that of the control in Group (III). There were analogous changes in the expression of FAT/CD36 and CPT-1 mRNA in contrast to continuous overexpression of GLUT-4 mRNA and significant increase of PDK-4 mRNA in Group (II). In addition, significant structural changes of cardiomyocytes with glycogen accumulation were accompanied by increased expression of PPARα. For the entire study population with HF levels of FAT/CD36 mRNA showed a strong tendency of negative correlation with LVEF. In conclusion, PPARα elevated levels may be a direct cause of adverse remodeling, both metabolic and structural. Thus, there is limited time window for therapy modulating cardiac metabolism and protecting cardiomyocyte structure in failing heart.

What research agenda could be generated from the European General Practice Research Network concept of Multimorbidity in Family Practice?

BACKGROUND: Multimorbidity is an intuitively appealing, yet challenging, concept for Family Medicine (FM). An EGPRN working group has published a comprehensive definition of the concept based on a systematic review of the literature which is closely linked to patient complexity and to the biopsychosocial model. This concept was identified by European Family Physicians (FPs) throughout Europe using 13 qualitative surveys. To further our understanding of the issues around multimorbidity, we needed to do innovative research to clarify this concept. The research question for this survey was: what research agenda could be generated for Family Medicine from the EGPRN concept of Multimorbidity? METHODS: Nominal group design with a purposive panel of experts in the field of multimorbidity. The nominal group worked through four phases: ideas generation phase, ideas recording phase, evaluation and analysis phase and a prioritization phase. RESULTS: Fifteen international experts participated. A research agenda was established, featuring 6 topics and 11 themes with their corresponding study designs. The highest priorities were given to the following topics: measuring multimorbidity and the impact of multimorbidity. In addition the experts stressed that the concept should be simplified. This would be best achieved by working in reverse: starting with the outcomes and working back to find the useful variables within the concept. CONCLUSION: The highest priority for future research on multimorbidity should be given to measuring multimorbidity and to simplifying the EGPRN model, using a pragmatic approach to determine the useful variables within the concept from its outcomes.

Microstructure and biocompatibility of titanium oxides produced on nitrided surface layer under glow discharge conditions.

The disadvantages of titanium implants are their low wear resistance and the release of titanium elements into surrounding tissue. These can be eliminated by modifying the surface by surface engineering methods, among them nitriding under glow discharge conditions which allow to produce diffusive surface layers. Their combining with an oxide layer might be valuable for biological events occurring at the bone implant interface. The aim of this study was to enhance the titanium biomaterial performance via combining nitriding and oxidizing treatments in one process under glow discharge conditions. The oxynitrided surface layers were produced at 680 degrees C. The obtained layer was TiO + TiN + Ti2N + alphaTi(N) type and about 4-microm thick and was of diffusive character. This layer significantly increased wear resistance and slightly corrosion resistance compared to that of the reference titanium alloy. The produced titanium oxide was about 400-nm thick and built from fine crystallites. This oxide exhibits bioactivity in SBF (simulated body fluid). Osteoblasts of Saos-2 line incubated on this surface exhibited good adhesion and proliferation and ALP release comparable with cells cultured on the reference titanium alloy and TiN + Ti2N + alphaTi(N) surface layers. A quantitative analysis of blood platelets adhering to this layer revealed their highest amount in comparison to that on both the nitrided surface layer and titanium alloy. The presented study provided a simple and reproducible method of combining oxidizing and nitriding under glow discharge in one process. Experimental data in vitro suggests that titanium alloy oxynitriding under low temperatures at glow discharge conditions improves titanium alloy properties and biocompatibility and tissue healing. Therefore, the layer of TiO + TiN +Ti2N + alphaTi(N) type could be valuable for long-term bone implants.

A novel nonsense mutation in CUL4B gene in three brothers with X-linked mental retardation syndrome.

Cabezas syndrome (MIM 300354) is a recently identified syndromic form of X-linked mental retardation (XLMR) caused by mutations in the CUL4B gene. In total, nine XLMR families carrying mutations in the CUL4B gene have been described to date. Here, we present a detailed clinical phenotype of three affected brothers of Polish descent. Based on the symptoms, we made a clinical diagnosis of Cabezas syndrome, which was subsequently confirmed by identification of a novel nonsense mutation (c.2107A-->T, p.703K-->X) in exon 18 of the CUL4B gene. The mutation was inherited from an asymptomatic mother and was present in all three affected brothers. The patients presented with typical features of Cabezas syndrome, such as severe mental retardation, speech impairment, hyperactivity, seizures, intention tremor, inguinal hernia, small feet, and craniofacial dysmorphism. In addition to previously described symptoms, syndactyly of the second and third toes and skin manifestations (hyperhydrosis and keratosis pilaris) were present in our cases. Our report provides further support that Cabezas syndrome is a recognizable syndromic form of XLMR. We conclude that the CUL4B gene should be screened in males with severe speech impairment and primary intention tremor, especially if characteristic facial dysmorphism is also present.

RNA interference-mediated knockdown of DNMT1 and DNMT3B induces CXCL12 expression in MCF-7 breast cancer and AsPC1 pancreatic carcinoma cell lines.

It has been recently demonstrated that in colonic carcinoma, CXCL12 expression undergoes epigenetic regulation by methylation of cytosine in cytosine-guanosine (CpG) dinucleotides of the promoter sequence. Using lentiviral vectors, we generated stable RNA interference-mediated knockdown of DNMT1 and DNMT3B in MCF-7 breast cancer and AsPC1 pancreatic carcinoma cell lines. Employing reverse transcription real-time quantitative PCR and immunofluorescence analysis, we determined re-expression levels of CXCL12 transcript and protein in these cells. Bisulfite sequencing revealed that the level of promoter demethylation appeared more effective in cells expressing DNMT1 siRNA than in those expressing DNMT3B siRNA, and this correlated with higher expression of CXCL12. Moreover, the combined expression of DNMT1 and DNMT3B siRNAs enhanced promoter demethylation that was associated only with a slight increase of CXCL12 expression. However, the demethylating agent 5-Aza-2'-deoxycytidine exhibited the strongest effect on promoter demethylation, which correlated with the highest expression level of CXCL12 transcript and protein in MCF-7 and AsPC1 cells. Our findings suggest that DNMT1 plays a key role in maintenance of methylation, and DNMT3B may act as an accessory DNA methyltransferase to epigenetically silence CXCL12 expression in MCF-7 and AsPC1 cells.