CDKN2A/p16INK4a expression is associated with vascular progeria in chronic kidney disease

Patients with chronic kidney disease (CKD) display a progeric vascular phenotype linked to apoptosis, cellular senescence and osteogenic transformation. This has proven intractable to modelling appropriately in model organisms. We have therefore investigated this directly in man, using for the first time validated cellular biomarkers of ageing (CDKN2A/p16INK4a, SA-β-Gal) in arterial biopsies from 61 CKD patients undergoing living donor renal transplantation. We demonstrate that in the uremic milieu, increased arterial expression of CDKN2A/p16INK4a associated with vascular progeria in CKD, independently of chronological age. The arterial expression of CDKN2A/p16INK4a was significantly higher in patients with coronary calcification (p=0.01) and associated cardiovascular disease (CVD) (p=0.004). The correlation between CDKN2A/p16INK4a and media calcification was statistically significant (p=0.0003) after correction for chronological age. We further employed correlate expression of matrix Gla protein (MGP) and runt-related transcription factor 2 (RUNX2) as additional pathognomonic markers. Higher expression of CDKN2A/p16INK4a, RUNX2 and MGP were observed in arteries with severe media calcification. The number of p16INK4a and SA-β-Gal positive cells was higher in biopsies with severe media calcification. A strong inverse correlation was observed between CDKN2A/p16INK4a expression and carboxylated osteocalcin levels. Thus, impaired vitamin K mediated carboxylation may contribute to premature vascular senescence

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Renal Morphology, Clinical Findings, and Progression Rate in Mesoamerican Nephropathy.

BACKGROUND: Mesoamerican nephropathy (MeN) is a chronic kidney disease affecting rural inhabitants in Central America. We have previously described the renal morphology in 8 patients from El Salvador. To confirm the renal pathology, we have studied kidney biopsies from patients with MeN in Nicaragua. Follow-up urine and blood samples from both biopsy studies were collected to investigate the natural history. STUDY DESIGN: Case series. SETTINGS & PARTICIPANTS: In the kidney biopsy study, 19 male sugarcane workers in Nicaragua with suspected MeN were investigated with questionnaires, kidney biopsies, and blood and urine analysis. Inclusion criteria were age 20 to 65 years and plasma creatinine level of 1.13 to 2.49mg/dL or estimated glomerular filtration rate (eGFR) of 30 to 80mL/min/1.73m2. Exclusion criteria were proteinuria with protein excretion > 3g/24 h, uncontrolled hypertension, diabetes mellitus, or other known kidney disease. In the follow up-study, blood and urine from the kidney biopsy study in Nicaragua (n=18) and our previous biopsy study of MeN cases in El Salvador (n=7) were collected 1 to 1.5 and 2 to 2.5 years after biopsy, respectively. OUTCOMES: Renal morphology, clinical, and biochemical characteristics, change in eGFR per year. MEASUREMENTS: eGFR was calculated using the CKD-EPI creatinine (eGFRcr), cystatin C (eGFRcys), and creatinine-cystatin C (eGFRcr-cys) equations. RESULTS: In the kidney biopsy study, participants had a mean eGFRcr of 57 (range, 33-96) mL/min/1.73m2. 47% had low plasma sodium and 21% had low plasma potassium levels. 16 kidney biopsies were representative and showed glomerulosclerosis (mean, 38%), glomerular hypertrophy, and signs of chronic glomerular ischemia. Mild to moderate tubulointerstitial damage and mostly mild vascular changes were seen. In the follow up-study, median duration of follow-up was 13 (range, 13-27) months. Mean change in eGFRcr was -4.4±8.4 (range, -27.7 to 10.2) mL/min/1.73m2 per year. Most patients had stopped working with sugarcane cultivation. LIMITATIONS: 3 biopsy specimens had 4 or fewer glomeruli. CONCLUSIONS: This study confirms the renal morphology of MeN: chronic glomerular and tubulointerstitial damage with glomerulosclerosis and chronic glomerular ischemia. Follow-up data show that eGFRs, on average, deteriorated

CDKN2A/p16INK4a expression is associated with vascular progeria in chronic kidney disease

Patients with chronic kidney disease (CKD) display a progeric vascular phenotype linked to apoptosis, cellular senescence and osteogenic transformation. This has proven intractable to modelling appropriately in model organisms. We have therefore investigated this directly in man, using for the first time validated cellular biomarkers of ageing (CDKN2A/p16INK4a, SA-β-Gal) in arterial biopsies from 61 CKD patients undergoing living donor renal transplantation. We demonstrate that in the uremic milieu, increased arterial expression of CDKN2A/p16INK4a associated with vascular progeria in CKD, independently of chronological age. The arterial expression of CDKN2A/p16INK4a was significantly higher in patients with coronary calcification (p=0.01) and associated cardiovascular disease (CVD) (p=0.004). The correlation between CDKN2A/p16INK4a and media calcification was statistically significant (p=0.0003) after correction for chronological age. We further employed correlate expression of matrix Gla protein (MGP) and runt-related transcription factor 2 (RUNX2) as additional pathognomonic markers. Higher expression of CDKN2A/p16INK4a, RUNX2 and MGP were observed in arteries with severe media calcification. The number of p16INK4a and SA-β-Gal positive cells was higher in biopsies with severe media calcification. A strong inverse correlation was observed between CDKN2A/p16INK4a expression and carboxylated osteocalcin levels. Thus, impaired vitamin K mediated carboxylation may contribute to premature vascular senescence

Resolving feelings of professional inadequacy : Student teachers’ coping with distressful situations

Student teachers face various difficult situations during their teacher education. The aim of this study was to examine how student teachers perceive coping with distressful situations during their teacher training. Focus groups and individual interviews were conducted. The results show that student teachers feel professionally inadequate, characterized by powerlessness, limited means of action and uncertainty. In resolving professional inadequacy, they use concepts connected to the social process of becoming teachers: modifying professional ideals, dependence on future colleagues and continuing to build experience. These concepts lead to acceptance and postponing strategies for learning from distressful situations.Funding agencies: Swedish Research Council [2013-2310]</p

Change advocacy as coping strategy : How beginning teachers cope with emotionally challenging situations

Beginning to teach after teacher education is commonly depicted as an emotionally challenging period. Beginning teachers deploy stra- tegies to cope with the emotionally challenging transition from tea- cher education and starting a position as a teacher. One way of coping is trying change the origin of the challenges. The aim of the study was to investigate how teachers in their last year as student teachers and their first year as teachers make meaning of a change advocacy strategy to cope with challenging situations as teachers. A qualitative interview study was performed. Twenty-five participants were inter- viewed while studying in their last year of teacher education, and 20 were interviewed again after having worked as a teacher for a year. In between, 68 self-reports were collected. The material was analysed using constructivist grounded theory tools. The findings show that as student teachers the participants identified two prerequisites to be able to use the change advocacy strategy as beginning teachers: (1) establishing teacher ambiguity and (2) challenging the perceived negative mindset. When utilising a change advocacy strategy as begin- ning teachers, the participants tried to reform teaching practices and attain a position of competence.Funding: VetenskapsradetSwedish Research Council [721-2013-2310]</p

The struggle to understand : Exploring medical students’ experiences of learning and understanding during a university course

The aim of the research reported in this paper was to explore students' ‘journey’ towards conceptual understanding during an undergraduate course. The task that medical students face – to learn a substantial quantity of detailed knowledge and integrate into a coherent whole in a limited time frame – is demanding. Seven students were interviewed in a group, and 17 students gave their reflections in writing. Data was gathered from both groups on five separate occasions. The findings suggest that students seek different kinds of understandings as they get to grips with their studies. The forms of understanding were: understanding as ‘knowing the language’, ‘knowing the map’, ‘knowing the catalogue’ and ‘experiencing an integrated whole’. Students first appeared to focus on the first two forms, and later in the course, as they learned more, they focused on the ‘catalogue’ or the ‘integrated whole’. The findings point to potential pathways students might take towards gaining deeper understanding.QC 20160220</p

Conflicts viewed through the micro-political lens : beginning teachers’ coping strategies for emotionally challenging situations

The aim of the present study was to use the narratives of beginning teachers to investigate the emotionally challenging situations they face, with a focus on how their perspectives and definitions of such situations guided their actions and made coping possible. A short term longitudinal qualitative interview study was adopted. Twenty participants were interviewed at the outset of their last year of teacher education and then followed up with an interview at their first year of teaching. In between self-reports were written in addition to the interviews. The material was analysed using constructivist grounded theory tools. The findings show that new teachers experienced conflicts that were both interpersonal (with students, parents and colleagues) and intrapersonal (being ‘good enough’; establishing boundaries related to time and engagement; suppression of emotions) as they started out in teaching. In order to cope with these challenges, the beginning teachers used various strategies including collaboration, conformity, influencing and autonomy.Funding agencies:  Swedish Research Council [7212013-2310]; Vetenskapsradet [721-2013-2310]</p

Emotionally challenging learning situations : medical students’ experiences of autopsies

Objectives: To explore medical students' experiences of an emotionally challenging learning situation: the autopsy. Methods: Qualitative data were collected by means of written accounts from seventeen students after their first and third autopsies and a group interview with seven students after their first autopsy. Data was interpreted using inductive thematic analysis. Results: Students experienced the autopsy in three ways: as an unnatural situation, as a practical exercise, and as a way to learn how pathologists work. Most students found the situation unpleasant, but some were overwhelmed. Their experiences were characterised by strong unpleasant emotions and closeness to the situation. The body was perceived as a human being, recently alive. Students who experienced the autopsy as a practical exercise saw it mainly as a part of the course and their goal was to learn anatomy and pathology. They seemed to objectify the body and distanced themselves from the situation. Students who approached the autopsy as a way to learn how pathologists work concentrated on professional aspects of the autopsy. The body was perceived as a patient rather than as a biological specimen. Conclusions: Autopsies are emotionally challenging learning situations. If students attend autopsies, they need to participate in several autopsies in order to learn about procedures and manifestations of pathological changes. Students need opportunities to discuss their experiences afterwards, and teachers need to be aware of how different students perceive the autopsies, and guide students through the procedure. Our findings emphasize the importance of investigating emotional aspects of medical education.QC 20160226</p