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1.  Transmission of Stress-Induced Learning Impairment and Associated Brain Gene Expression from Parents to Offspring in Chickens 
PLoS ONE  2007;2(4):e364.
Stress influences many aspects of animal behaviour and is a major factor driving populations to adapt to changing living conditions, such as during domestication. Stress can affect offspring through non-genetic mechanisms, but recent research indicates that inherited epigenetic modifications of the genome could possibly also be involved.
Methodology/Principal Findings
Red junglefowl (RJF, ancestors of modern chickens) and domesticated White Leghorn (WL) chickens were raised in a stressful environment (unpredictable light-dark rhythm) and control animals in similar pens, but on a 12/12 h light-dark rhythm. WL in both treatments had poorer spatial learning ability than RJF, and in both populations, stress caused a reduced ability to solve a spatial learning task. Offspring of stressed WL, but not RJF, raised without parental contact, had a reduced spatial learning ability compared to offspring of non-stressed animals in a similar test as that used for their parents. Offspring of stressed WL were also more competitive and grew faster than offspring of non-stressed parents. Using a whole-genome cDNA microarray, we found that in WL, the same changes in hypothalamic gene expression profile caused by stress in the parents were also found in the offspring. In offspring of stressed WL, at least 31 genes were up- or down-regulated in the hypothalamus and pituitary compared to offspring of non-stressed parents.
Our results suggest that, in WL the gene expression response to stress, as well as some behavioural stress responses, were transmitted across generations. The ability to transmit epigenetic information and behaviour modifications between generations may therefore have been favoured by domestication. The mechanisms involved remain to be investigated; epigenetic modifications could either have been inherited or acquired de novo in the specific egg environment. In both cases, this would offer a novel explanation to rapid evolutionary adaptation of a population.
PMCID: PMC1838921  PMID: 17426812
2.  Polar Bears Exhibit Genome-Wide Signatures of Bioenergetic Adaptation to Life in the Arctic Environment 
Genome Biology and Evolution  2014;6(2):433-450.
Polar bears (Ursus maritimus) face extremely cold temperatures and periods of fasting, which might result in more severe energetic challenges than those experienced by their sister species, the brown bear (U. arctos). We have examined the mitochondrial and nuclear genomes of polar and brown bears to investigate whether polar bears demonstrate lineage-specific signals of molecular adaptation in genes associated with cellular respiration/energy production. We observed increased evolutionary rates in the mitochondrial cytochrome c oxidase I gene in polar but not brown bears. An amino acid substitution occurred near the interaction site with a nuclear-encoded subunit of the cytochrome c oxidase complex and was predicted to lead to a functional change, although the significance of this remains unclear. The nuclear genomes of brown and polar bears demonstrate different adaptations related to cellular respiration. Analyses of the genomes of brown bears exhibited substitutions that may alter the function of proteins that regulate glucose uptake, which could be beneficial when feeding on carbohydrate-dominated diets during hyperphagia, followed by fasting during hibernation. In polar bears, genes demonstrating signatures of functional divergence and those potentially under positive selection were enriched in functions related to production of nitric oxide (NO), which can regulate energy production in several different ways. This suggests that polar bears may be able to fine-tune intracellular levels of NO as an adaptive response to control trade-offs between energy production in the form of adenosine triphosphate versus generation of heat (thermogenesis).
PMCID: PMC3942037  PMID: 24504087
cellular respiration; mitochondrial genome; nitric oxide; nuclear genome; oxidative phosphorylation
3.  Incidence and risk factors for suicide and attempted suicide following a diagnosis of hematological malignancy 
Cancer Medicine  2014;4(1):147-154.
Solid tumors are associated with an increased risk of suicide, however, there is limited detailed information on the risk of suicide in patients with hematological malignancies. Therefore, we conducted a population-based study including 47,220 patients with hematological malignancies (diagnosed 1992–2006) and their 235,868 matched controls to define the incidence and risk factors for suicide and suicide attempt. Information on suicides, suicide attempts, and preexisting psychiatric disorders was obtained from Swedish registers and individual medical records. There was a twofold increased (hazard ratio [HR] = 1.9, 95% confidence interval 1.5–2.3, P < 0.0001) risk of suicide/suicide attempt during the first 3 years after diagnosis in patients with hematological malignancies compared to matched controls. Of all hematological malignancies, multiple myeloma was associated with the highest risk (HR = 3.4; 2.3–5.0, P < 0.0001). Patients with a preexisting psychiatric disorder were at a very high risk of suicide and suicide attempt (HR = 23.3; 16.6–32.6, P < 0.0001), regardless of type of hematological malignancy. Among patients who committed suicide, 19% were in a palliative phase and 44% were in remission with no active treatment. In conclusion, the risk of suicide and suicide attempt is elevated in patients with hematological malignancies. Certain high-risk patients may benefit from early detection and preventive measures.
PMCID: PMC4312128  PMID: 25155101
Multiple myeloma; population based; psychiatric disorder; suicide; suicide attempt
4.  Duration of residence and psychotropic drug use in recently settled refugees in Sweden - a register-based study 
Recently settled refugee populations have consistently been reported to have high rates of mental health problems, particularly Post-traumatic stress disorder, depression, and anxiety disorders. The aim of this study was to investigate psychotropic drug use among young adult refugees according to duration of residence during the first 10 years in Sweden.
Cross-sectional register study of a national cohort of 43 403 refugees and their families (23–35 years old) from Iraq, Iran, Eritrea, Ethiopia, Somalia and Afghanistan and a comparison population of 1.1 million Swedish-born residents. Logistic regression was used to assess the association between duration of residence in Sweden and the dispensing of at least one psychotropic medication during 2009 in four categories (any drug, neuroleptics, antidepressants and anxiolytics/hypnotics), adjusting for age, gender and domicile.
Rates of dispensed psychotropic drugs among recently settled refugees were low, compared to the Swedish-born, with an increase with duration of residence. For refugee men and women from Iraq/Iran who had resided for 0–3 years the adjusted ORs compared to Swedish natives, were 0.83 (95% CI 0.77-0.90) and 0.48 (0.44-0.53) respectively; for men and women from the Horn of Africa the ORs were 0.50 (0.42-0.61) and 0.36 (0.30-0.41) respectively. After 7–10 years of residence, the ORs in these refugee groups approached the Swedish comparison population. Refugees from Afghanistan presented ORs similar to the Swedish-born, with no consistent trend by duration of residence. Women from the Horn of Africa and Iraq/Iran consumed less psychotropic drugs compared with men from these regions of origin, relative to the Swedish-born (p < 0.01). The ORs for dispensed neuroleptics were similar between the different refugee study groups, while the ORs for dispensed antidepressants differed fourfold between the group with the lowest (Horn of Africa) and the highest (Afghanistan).
The rates of dispensed psychotropic drugs in the newly settled refugee populations in this study were low, with an increase with longer duration of residence. This pattern suggests barriers to access mental health care. Interventions that can lower these barriers are needed to enable newly settled refugees to access mental health care on equal terms with the native population.
PMCID: PMC4297375  PMID: 25526935
Refugee; Migration; Mental health; Psychotropic drugs; Acculturation; Access
5.  Predicting the Concentration of Verotoxin-Producing Escherichia coli Bacteria during Processing and Storage of Fermented Raw-Meat Sausages 
A model to predict the population density of verotoxigenic Escherichia coli (VTEC) throughout the elaboration and storage of fermented raw-meat sausages (FRMS) was developed. Probabilistic and kinetic measurement data sets collected from publicly available resources were completed with new measurements when required and used to quantify the dependence of VTEC growth and inactivation on the temperature, pH, water activity (aw), and concentration of lactic acid. Predictions were compared with observations in VTEC-contaminated FRMS manufactured in a pilot plant. Slight differences in the reduction of VTEC were predicted according to the fermentation temperature, 24 or 34°C, with greater inactivation at the highest temperature. The greatest reduction was observed during storage at high temperatures. A population decrease greater than 6 decimal logarithmic units was observed after 66 days of storage at 25°C, while a reduction of only ca. 1 logarithmic unit was detected at 12°C. The performance of our model and other modeling approaches was evaluated throughout the processing of dry and semidry FRMS. The greatest inactivation of VTEC was predicted in dry FRMS with long drying periods, while the smallest reduction was predicted in semidry FMRS with short drying periods. The model is implemented in a computing tool, E. coli SafeFerment (EcSF), freely available from EcSF integrates growth, probability of growth, and thermal and nonthermal inactivation models to predict the VTEC concentration throughout FRMS manufacturing and storage under constant or fluctuating environmental conditions.
PMCID: PMC3993284  PMID: 24561587
6.  The Chromosomal Association of the Smc5/6 Complex Depends on Cohesion and Predicts the Level of Sister Chromatid Entanglement 
PLoS Genetics  2014;10(10):e1004680.
The cohesin complex, which is essential for sister chromatid cohesion and chromosome segregation, also inhibits resolution of sister chromatid intertwinings (SCIs) by the topoisomerase Top2. The cohesin-related Smc5/6 complex (Smc5/6) instead accumulates on chromosomes after Top2 inactivation, known to lead to a buildup of unresolved SCIs. This suggests that cohesin can influence the chromosomal association of Smc5/6 via its role in SCI protection. Using high-resolution ChIP-sequencing, we show that the localization of budding yeast Smc5/6 to duplicated chromosomes indeed depends on sister chromatid cohesion in wild-type and top2-4 cells. Smc5/6 is found to be enriched at cohesin binding sites in the centromere-proximal regions in both cell types, but also along chromosome arms when replication has occurred under Top2-inhibiting conditions. Reactivation of Top2 after replication causes Smc5/6 to dissociate from chromosome arms, supporting the assumption that Smc5/6 associates with a Top2 substrate. It is also demonstrated that the amount of Smc5/6 on chromosomes positively correlates with the level of missegregation in top2-4, and that Smc5/6 promotes segregation of short chromosomes in the mutant. Altogether, this shows that the chromosomal localization of Smc5/6 predicts the presence of the chromatid segregation-inhibiting entities which accumulate in top2-4 mutated cells. These are most likely SCIs, and our results thus indicate that, at least when Top2 is inhibited, Smc5/6 facilitates their resolution.
Author Summary
When cells divide, sister chromatids have to be segregated away from each other for the daughter cells to obtain a correct set of chromosomes. Using yeast as model organism, we have analyzed the function of the cohesin and the Smc5/6 complexes, which are essential for chromosome segregation. Cohesin is known to hold sister chromatid together until segregation occurs, and our results show that cohesin also controls Smc5/6, which is found to associate to linked chromatids specifically. In line with this, our analysis points to that the chromosomal localization of Smc5/6 is an indicator of the level of entanglement between sister chromatids. When Smc5/6 is non-functional, the resolution of these entanglements is shown to be inhibited, thereby preventing segregation of chromatids. Our results also indicate that DNA entanglements are maintained on chromosomes at specific sites until segregation. In summary, we uncover new functions for cohesin, in regulating when and where Smc5/6 binds to chromosomes, and for the Smc5/6 complex in facilitating the resolution of sister chromatid entanglements.
PMCID: PMC4199498  PMID: 25329383
7.  Organization of nursing care in three Nordic countries: relationships between nurses’ workload, level of involvement in direct patient care, job satisfaction, and intention to leave 
BMC Nursing  2014;13:27.
Health care systems in Finland, Norway and Sweden share many similarities, e.g. full-coverage and tax-financed, with predominately public sector hospitals. Despite similarities, there are differences in the working situations for RNs within these Nordic countries. The aim of this study was to analyze associations between RNs’ patient workload and level of involvement in direct patient care, their job satisfaction and intention to leave in these countries.
A workforce survey was conducted through RN4CAST, an EU 7th framework project. The survey included 118 items derived from validated instruments or tested in prior research. Responses from 1133 RNs at 32 Finnish hospitals, 3752 RNs at 35 Norwegian hospitals, and 11 015 RNs at 71 Swedish hospitals comprise the database, which was analyzed using logistic and odds ratio regressions analyses.
We found statistically significant differences in RNs’ level of involvement in direct patient care (p < 0.001, Sweden compared to Norway and Finland), in patient workload and in number of patients needing ADL assistance and surveillance. A U-formed relationship was found between level of involvement in direct patient care and intention to leave in Sweden, and more satisfaction among RNs in roles with more direct patient care (OR = 1.16, 1.02 ≤ CI95% ≤ 1.32). Nearly half the Finnish sample report intention to leave, with significantly lower levels in Norway and Sweden (p < 0.001). Patient workload is associated with job satisfaction and intention to leave to some degree in all countries, i.e. greater patient workload, less job satisfaction and greater intention to leave.
This study suggests that more attention paid to patient mix, workload and role of RNs in patient care might potentially diminish intention to leave and increase job satisfaction in these Nordic countries.
PMCID: PMC4193956  PMID: 25309127
Health services research; Job satisfaction; Nursing; Organization and administration; Workload
8.  “An on-going individual adjustment”: a qualitative study of midwives’ experiences counselling pregnant women on physical activity in Sweden 
In Sweden, midwives play prominent supportive role in antenatal care by counselling and promoting healthy lifestyles. This study aimed to explore how Swedish midwives experience the counselling of pregnant women on physical activity, specifically focusing on facilitators and barriers during pregnancy. Also, addressing whether the midwives perceive that their own lifestyle and body shape may influence the content of the counselling they provide.
Eight focus group discussions (FGD) were conducted with 41 midwives working in antenatal care clinics in different parts of Sweden between September 2013 and January 2014. Purposive sampling was applied to ensure a variation in age, work experience, and geographical location. The FGD were digitally recorded, transcribed verbatim, and analyzed using manifest and latent content analysis.
The main theme– “An on-going individual adjustment” was built on three categories: “Counselling as a challenge”; “Counselling as walking the thin ice” and “Counselling as an opportunity” reflecting the midwives on-going need to adjust their counselling depending on each woman’s specific situation. Furthermore, counselling pregnant women on physical activity was experienced as complex and ambiguous, presenting challenges as well as opportunities. When midwives challenged barriers to physical activity, they risked being rejected by the pregnant women. Despite risking rejection, the midwives tried to promote increased physical activity based on their assessment of individual needs of the pregnant woman. Some participants felt that their own lifestyle and body shape might negatively influence the counselling; however, the majority of participants did not agree with this perspective.
Counselling on physical activity during pregnancy may be a challenging task for midwives, characterized by on-going adjustments based on a pregnant woman’s individual needs. Midwives strive to find individual solutions to encourage physical activity. However, to improve their counselling, midwives may benefit from further training, also organizational and financial barriers need to be addressed. Such efforts might result in improved opportunities to further support pregnant women’s motivation for performance of physical activity.
PMCID: PMC4190373  PMID: 25269457
9.  Rapidly growing and ulcerating metastatic renal cell carcinoma of the lower lip: A case report and review of the literature 
Oncology Letters  2014;8(5):2175-2178.
Renal cell carcinomas (RCCs) have a tendency to metastasize at an early stage, therefore, the patients frequently exhibit metastatic disease at the time of diagnosis. Common locations for the metastases are adjacent organs and abdominal lymph nodes; however, occasionally metastasis to the peripheral organs may be the initial clinical symptom. The 71-year-old male patient in the current case suffered from radioresistant and aggressively behaving RCC metastasis in the mandible and lower lip, which was successfully managed by surgical resection. RCC metastasis to the facial area is considered to be uncommon based on a review of the existing literature. RCC are somewhat radioresistant and therefore, palliative surgery must be considered when treating patients with this metastatic disease.
PMCID: PMC4186528  PMID: 25289097
renal cell carcinoma; head and neck; metastasis; lip
10.  MitoPark mice mirror the slow progression of key symptoms and L-DOPA response in Parkinson’s disease 
Genes, brain, and behavior  2009;9(2):173-181.
The MitoPark mouse, in which the mitochondrial transcription factor Tfam is selectively removed in midbrain dopamine (DA) neurons, is a genetic model for Parkinson’s disease (PD) that replicates the slow and progressive development of key symptoms. To further validate this model, we have extended both behavioral and biochemical analyses in these animals. We found that vertical movements decline earlier and faster than horizontal movements, possibly modeling the early occurrence of axial, postural instability in PD. L-DOPA induces different locomotor responses depending on the age: in young MitoPark mice the L-DOPA-induced motor activation is small; middle-aged MitoPark mice respond in a dose-dependent manner to L-DOPA, whereas aged MitoPark mice display a double-peaked locomotor response to a high dose of L-DOPA that includes an intermittent period of very low motor activity, similar to the ‘on–off’ phenomenon in PD. To correlate behavior with biochemical data, we analyzed monoamine levels in three different brain areas that are highly innervated by the DA system: striatum, anterior cortex and olfactory bulb. DA levels declined earlier and faster in striatum than in cortex; only at the latest time-point analyzed, DA levels were found to be significantly lower than control levels in the olfactory bulb. Interestingly, the ratio between homovanillic acid (HVA) and DA differed between regions over time. In striatum and olfactory bulb, the ratio increased steeply indicating increased DA turnover. In contrast, the ratio decreased over time in cortex, revealing important differences between DA cells in substantia nigra and the ventral tegmental area.
PMCID: PMC4154513  PMID: 20002202
Cre-loxP system; HPLC; mitochondria; striatum; substantia nigra; tissue-specific knock-out mice
11.  Picropodophyllin causes mitotic arrest and catastrophe by depolymerizing microtubules via Insulin-like growth factor-1 receptor-independent mechanism 
Oncotarget  2014;5(18):8379-8392.
Picropodophyllin (PPP) is an anticancer drug undergoing clinical development in NSCLC. PPP has been shown to suppress IGF-1R signaling and to induce a G2/M cell cycle phase arrest but the exact mechanisms remain to be elucidated.
The present study identified an IGF-1-independent mechanism of PPP leading to pro-metaphase arrest. The mitotic block was induced in human cancer cell lines and in an A549 xenograft mouse but did not occur in normal hepatocytes/mouse tissues.
Cell cycle arrest by PPP occurred in vitro and in vivo accompanied by prominent CDK1 activation, and was IGF-1R-independent since it occurred also in IGF-1R-depleted and null cells. The tumor cells were not arrested in G2/M but in mitosis. Centrosome separation was prevented during mitotic entry, resulting in a monopolar mitotic spindle with subsequent prometaphase-arrest, independent of Plk1/Aurora A or Eg5, and leading to cell features of mitotic catastrophe. PPP also increased soluble tubulin and decreased spindle-associated tubulin within minutes, indicating that it interfered with microtubule dynamics.
These results provide a novel IGF-1R-independent mechanism of antitumor effects of PPP.
PMCID: PMC4226690  PMID: 25268741
Picropodophyllin; mitotic arrest; CDK1; IGF-1R; mitotic catastrophe
12.  Autologous adipose stem cells and polylactide discs in the replacement of the rabbit temporomandibular joint disc 
The temporomandibular joint (TMJ) disc lacks functional replacement after discectomy. We investigated tissue-engineered bilayer polylactide (PLA) discs and autologous adipose stem cells (ASCs) as a potential replacement for the TMJ disc. These ASC discs were pre-cultured either in control or in differentiation medium, including transforming growth factor (TGF)-β1 for one week. Prior to implantation, expression of fibrocartilaginous genes was measured by qRT-PCR. The control and differentiated ASC discs were implanted, respectively, in the right and left TMJs of rabbits for six (n = 5) and 12 months (n = 5). Thereafter, the excised TMJ areas were examined with cone beam computed tomography (CBCT) and histology. No signs of infection, inflammation or foreign body reactions were detected at histology, whereas chronic arthrosis and considerable condylar hypertrophy were observed in all operated joints at CBCT. The left condyle treated with the differentiated ASC discs appeared consistently smoother and more sclerotic than the right condyle. The ASC disc replacement resulted in dislocation and morphological changes in the rabbit TMJ. The ASC discs pre-treated with TGF-β1 enhanced the condylar integrity. While adverse tissue reactions were not shown, the authors suggest that with improved attachment and design, the PLA disc and biomaterial itself would hold potential for TMJ disc replacement.
PMCID: PMC4043160  PMID: 23720535
temporomandibular joint disc; biodegradable replacement; discectomy; tissue engineering; polylactide; adipose stem cell
13.  Tick-Borne Encephalitis Virus Sequenced Directly from Questing and Blood-Feeding Ticks Reveals Quasispecies Variance 
PLoS ONE  2014;9(7):e103264.
The increased distribution of the tick-borne encephalitis virus (TBEV) in Scandinavia highlights the importance of characterizing novel sequences within the natural foci. In this study, two TBEV strains: the Norwegian Mandal 2009 (questing nymphs pool) and the Swedish Saringe 2009 (blood-fed nymph) were sequenced and phylogenetically characterized. Interestingly, the sequence of Mandal 2009 revealed the shorter form of the TBEV genome, similar to the highly virulent Hypr strain, within the 3′ non-coding region (3′NCR). A different genomic structure was found in the 3′NCR of Saringe 2009, as in-depth analysis demonstrated TBEV variants with different lengths within the poly(A) tract. This shows that TBEV quasispecies exists in nature and indicates a putative shift in the quasispecies pool when the virus switches between invertebrate and vertebrate environments. This prompted us to further sequence and analyze the 3′NCRs of additional Scandinavian TBEV strains and control strains, Hypr and Neudoerfl. Toro 2003 and Habo 2011 contained mainly a short (A)3C(A)6 poly(A) tract. A similar pattern was observed for the human TBEV isolates 1993/783 and 1991/4944; however, one clone of 1991/4944 contained an (A)3C(A)11 poly(A) sequence, demonstrating that quasispecies with longer poly(A) could be present in human isolates. Neudoerfl has previously been reported to contain a poly(A) region, but to our surprise the re-sequenced genome contained two major quasispecies variants, both lacking the poly(A) tract. We speculate that the observed differences are important factors for the understanding of virulence, spread, and control of the TBEV.
PMCID: PMC4110009  PMID: 25058476
14.  Long-term smoking increases the need for acute care among asthma patients: a case control study 
BMC Pulmonary Medicine  2014;14:119.
To examine risk factors for asthma patients’ emergency room (ER) visits in a well organized asthma care setting.
A random sample of 344 asthma patients from a Pulmonary Clinic of a University Hospital were followed through medical records from 1995 to 2006. All the ER visits due to dyspnea, respiratory infections, chest pain, and discomfort were evaluated.
The mean age of the study population was 56 years (SD 13 years), 72% being women. 117 (34%) of the patients had had at least one ER visit during the follow-up (mean 0.5 emergency visits per patient year, range 0–7). Asthma exacerbation, lower and upper respiratory infections accounted for the 71% of the ER visits and 77% of the hospitalizations. The patients with ER visits were older, had suffered longer from asthma and more frequently from chronic sinusitis, were more often ex- or current smokers, and had lower lung function parameters compared to the patients without emergency visits. Previous (HR 1.9, CI 1.3-3.1) and current smoking (HR 3.6, CI 1.6-8.2), poor self-reported health related quality of life (HRQoL) (HR 2.5, CI 1.5-4), and poor lung function (FEV1 < 65%, HR 2.2, CI 1.3-3.7) remained independent risk factors for ER visits after adjustment for age and gender.
Asthma patients who are or have been long-term smokers are more likely to require ER care compared to never smokers.
PMCID: PMC4108236  PMID: 25030656
Obstructive lung disease; Emergency visits; Hospitalizations; Smoking cessation
15.  Specific Growth Rate Determines the Sensitivity of Escherichia coli to Lactic Acid Stress: Implications for Predictive Microbiology 
BioMed Research International  2014;2014:471317.
This study tested the hypothesis that sensitivity of Escherichia coli to lactic acid at concentrations relevant for fermented sausages (pH 4.6, 150 mM lactic acid, aw = 0.92, temperature = 20 or 27°C) increases with increasing growth rate. For E. coli strain 683 cultured in TSB in chemostat or batch, subsequent inactivation rates when exposed to lactic acid stress increased with increasing growth rate at harvest. A linear relationship between growth rate at harvest and inactivation rate was found to describe both batch and chemostat cultures. The maximum difference in T90, the estimated times for a one-log reduction, was 10 hours between bacteria harvested during the first 3 hours of batch culture, that is, at different growth rates. A 10-hour difference in T90 would correspond to measuring inactivation at 33°C or 45°C instead of 37°C based on relationships between temperature and inactivation. At similar harvest growth rates, inactivation rates were lower for bacteria cultured at 37°C than at 15–20°C. As demonstrated for E. coli 683, culture conditions leading to variable growth rates may contribute to variable lactic acid inactivation rates. Findings emphasize the use and reporting of standardised culture conditions and can have implications for the interpretation of data when developing inactivation models.
PMCID: PMC4109666  PMID: 25110680
16.  Co-morbidities are the key nominators of the health related quality of life in mild and moderate COPD 
BMC Pulmonary Medicine  2014;14:102.
Co-morbidities are common in chronic obstructive pulmonary disease (COPD). We assessed the contribution of common co-morbidities on health related quality of life (HRQoL) among COPD patients.
Using both generic (15D) and respiratory-specific (AQ20) instruments, HRQoL was assessed in a hospital based COPD population (N = 739, 64% males, mean age 64 years, SD 7 years) in this observational study with inferential analysis. The prevalence of their co-morbidities was compared with those of 5000 population controls. The patients represented all severity stages of COPD and the patterns of common concomitant disorders differed between patients.
Co-morbidities such as psychiatric conditions, alcohol abuse, cardiovascular diseases, and diabetes were more common among COPD patients than in age and gender matched controls. Psychiatric conditions and alcohol abuse were the strongest determinants of HRQoL in COPD and could be detected by both 15D (Odds Ratio 4.7 and 2.3 respectively) and AQ20 (OR 2.0 and 3.0) instruments. Compared to respiratory specific AQ20, generic 15D was more sensitive to the effects of comorbidities while AQ20 was slightly more sensitive for the low FEV1. FEV1 was a strong determinant of HRQoL only at more severe stages of disease (FEV1 < 40% of predicted). Poor HRQoL also predicted death during the next five years.
The results suggest that co-morbidities may impair HRQoL at an early stage of the disease, while bronchial obstruction becomes a significant determinant of HRQoL only in severe COPD.
PMCID: PMC4229911  PMID: 24946786
Generic HRQoL; Respiratory specific HRQoL; HRQoL; COPD; 15D; AQ20; Co-morbidities; Mortality
17.  No consensus on gestational diabetes mellitus screening regimes in Sweden: pregnancy outcomes in relation to different screening regimes 2011 to 2012, a cross-sectional study 
Although associated adverse pregnancy outcomes, no international or Swedish consensus exists that identifies a cut-off value or what screening method to use for definition of gestational diabetes mellitus. This study investigates the following: i) guidelines for screening of GDM; ii) background and risk factors for GDM and selection to OGTT; and iii) pregnancy outcomes in relation to GDM, screening regimes and levels of OGTT 2 hour glucose values.
This cross-sectional and population-based study uses data from the Swedish Maternal Health Care Register (MHCR) (2011 and 2012) combined with guidelines for GDM screening (2011–2012) from each Maternal Health Care Area (MHCA) in Sweden. The sample consisted of 184,183 women: 88,140 in 2011 and 96,043 in 2012. Chi-square and two independent samples t-tests were used. Univariate and multivariate logistic regression analyses were performed.
Four screening regimes of oral glucose tolerance test (OGTT) (75 g of glucose) were used: A) universal screening with a 2-hour cut-off value of 10.0 mmol/L; B) selective screening with a 2-hour cut-off value of 8.9 mmol/L; C) selective screening with a 2-hour cut-off value of 10.0 mmol/L; and D) selective screening with a 2-hour cut-off value of 12.2 mmol/L. The highest prevalence of GDM (2.9%) was found with a 2-hour cut-off value of 8.9 mmol/L when selective screening was applied. Unemployment and low educational level were associated with an increased risk of GDM. The OR was 4.14 (CI 95%: 3.81-4.50) for GDM in obese women compared to women with BMI <30 kg/m2. Women with non-Nordic origin presented a more than doubled risk for GDM compared to women with Nordic origin (OR = 2.24; CI 95%: 2.06-2.43). Increasing OGTT values were associated with increasing risks of adverse pregnancy outcomes.
There was no consensus regarding screening regimes for GDM from 2011 through 2012 when four different regimes were applied in Sweden. Increasing levels of OGTT 2-hour glucose values were strongly associated with adverse pregnancy outcomes. Based on these findings, we suggest that Sweden adopts the recent recommendations of the International Association of Diabetes and Pregnancy Study Group (IADPSG) concerning the performance of OGTT and the diagnostic criteria for GDM.
PMCID: PMC4055242  PMID: 24884711
18.  Nurses' Practice Environment and Work-Family Conflict in Relation to Burn Out: A Multilevel Modelling Approach 
PLoS ONE  2014;9(5):e96991.
To investigate associations between nurse work practice environment measured at department level and individual level work-family conflict on burnout, measured as emotional exhaustion, depersonalization and personal accomplishment among Swedish RNs.
A multilevel model was fit with the individual RN at the 1st, and the hospital department at the 2nd level using cross-sectional RN survey data from the Swedish part of RN4CAST, an EU 7th framework project. The data analysed here is based on a national sample of 8,620 RNs from 369 departments in 53 hospitals.
Generally, RNs reported high values of personal accomplishment and lower values of emotional exhaustion and depersonalization. High work-family conflict increased the risk for emotional exhaustion, but for neither depersonalization nor personal accomplishment. On department level adequate staffing and good leadership and support for nurses reduced the risk for emotional exhaustion and depersonalization. Personal accomplishment was statistically significantly related to staff adequacy.
The findings suggest that adequate staffing, good leadership, and support for nurses are crucial for RNs' mental health. Our findings also highlight the importance of hospital managers developing policies and practices to facilitate the successful combination of work with private life for employees.
PMCID: PMC4018443  PMID: 24820972
19.  A genetic variant in osteoprotegerin is associated with progression of joint destruction in rheumatoid arthritis 
Arthritis Research & Therapy  2014;16(3):R108.
Progression of joint destruction in rheumatoid arthritis (RA) is partly heritably; 45 to 58% of the variance in joint destruction is estimated to be explained by genetic factors. The binding of RANKL (Receptor Activator for Nuclear Factor κ B Ligand) to RANK results in the activation of TRAF6 (tumor necrosis factor (TNF) receptor associated factor-6), and osteoclast formation ultimately leading to enhanced bone resorption. This bone resorption is inhibited by osteoprotegerin (OPG) which prevents RANKL-RANK interactions. The OPG/RANK/RANKL/TRAF6 pathway plays an important role in bone remodeling. Therefore, we investigated whether genetic variants in OPG, RANK, RANKL and TRAF6 are associated with the rate of joint destruction in RA.
1,418 patients with 4,885 X-rays of hands and feet derived from four independent data-sets were studied. In each data-set the relative increase of the progression rate per year in the presence of a genotype was assessed. First, explorative analyses were performed on 600 RA-patients from Leiden. 109 SNPs, tagging OPG, RANK, RANKL and TRAF6, were tested. Single nucleotide polymorphisms (SNPs) significantly associated in phase-1 were genotyped in data-sets from Groningen (Netherlands), Sheffield (United Kingdom) and Lund (Switzerland). Data were summarized in an inverse weighted variance meta-analysis. Bonferonni correction for multiple testing was applied.
We found that 33 SNPs were significantly associated with the rate of joint destruction in phase-1. In phase-2, six SNPs in OPG and four SNPs in RANK were associated with progression of joint destruction with P-value <0.05. In the meta-analyses of all four data-sets, RA-patients with the minor allele of OPG-rs1485305 expressed higher rates of joint destruction compared to patients without these risk variants (P = 2.35x10−4). This variant was also significant after Bonferroni correction.
These results indicate that a genetic variant in OPG is associated with a more severe rate of joint destruction in RA.
PMCID: PMC4060386  PMID: 24886600
20.  Sec-containing TrxR1 is essential for self-sufficiency of cells by control of glucose-derived H2O2 
Cell Death & Disease  2014;5(5):e1235-.
It is commonly recognized that diabetic complications involve increased oxidative stress directly triggered by hyperglycemia. The most important cellular protective systems against such oxidative stress have yet remained unclear. Here we show that the selenoprotein thioredoxin reductase 1 (TrxR1), encoded by the Txnrd1 gene, is an essential enzyme for such protection. Individually grown Txnrd1 knockout (Txnrd1−/−) mouse embryonic fibroblasts (MEFs) underwent massive cell death directly linked to glucose-induced H2O2 production. This death and excessive H2O2 levels could be reverted by reconstituted expression of selenocysteine (Sec)-containing TrxR1, but not by expression of Sec-devoid variants of the enzyme. Our results show that Sec-containing TrxR1 is absolutely required for self-sufficient growth of MEFs under high-glucose conditions, owing to an essential importance of this enzyme for elimination of glucose-derived H2O2. To our knowledge, this is the first time a strict Sec-dependent function of TrxR1 has been identified as being essential for mammalian cells.
PMCID: PMC4047868  PMID: 24853413
glucose; mouse embryonic fibroblasts (MEFs); reactive oxygen species (ROS); selenocysteine; thioredoxin reductase 1 (TrxR1)
21.  Association of HLA-DRB1-restricted CD4+ T cell responses with HIV immune control 
Nature medicine  2013;19(7):930-933.
The contribution of HLA class II-restricted CD4+ T cell responses to HIV immune control is poorly defined. Here, we delineated novel peptide-DRB1 restrictions in functional assays and analyzed the host genetic effects of HLA-DRB1 alleles on HIV viremia in a large cohort of HIV controllers and progressors (n=1085). We found distinct stratifications in the effect of HLA-DRB1 alleles on HIV viremia, with DRB1*15:02 significantly associated with low viremia (P=0.003, q=0.04) and DRB1*03:01 significantly associated with high viremia (P=0.004, q=0.04). Interestingly, a sub-group of HLA-DRB1 alleles linked with low viremia showed the ability to promiscuously present a larger breadth of peptides with lower functional avidity when compared to HLA-DRB1 alleles linked with high viremia (p=0.018). Our data provide systematic evidence that HLA-DRB1 allele expression significantly impacts the durable control of HIV replication, an effect that appears to be mediated primarily by the protein-specificity of HIV-specific CD4+ T cell responses to Gag and Nef.
PMCID: PMC3974408  PMID: 23793098
22.  Staffing and resource adequacy strongly related to RNs’ assessment of patient safety: a national study of RNs working in acute-care hospitals in Sweden 
BMJ Quality & Safety  2013;23(3):242-249.
Although registered nurses (RNs) are central in patient care, we have not found prior research that specifically addresses how RNs assess the safety of patient care at their workplace and how factors in RNs’ work environment are related to their assessments. This study aims to address these issues.
9236 RNs working with inpatient care in 79 acute-care hospitals in Sweden completed a national population-based survey, including Practice Environment Scale of the Nursing Work Index—Revised and items from Agency for Healthcare Research and Quality's Hospital Survey on Patient Safety Culture. Correlation coefficients (Pearson and Spearman) and proportional odds regression were used for analysis.
Nursing work environment factors were strongly related to RNs’ assessments of patient safety. RNs’ perception of having adequate staffing and resources improved their assessment of patient safety by at least two and a half times (OR 2.74 CI 2.52 to 2.97). RNs with a higher level of involvement in direct patient care gave a better patient safety grade than RNs with a more supervisory role. Most, but not all, patient safety culture items were related to RNs’ assessed patient safety grade. We found that work experience seemed to have no influence on RNs’ patient safety assessment.
While previous research emphasises patient-to-nurse ratios in strengthening patient safety practices, this study complements this by emphasising RNs’ own perception of having enough staff and resources to provide quality nursing care, as well as having good collegial nurse–physician relations and the presence of visible and competent nursing leadership—all factors highly related to RNs’ assessment of the safety of patient care at their workplace.
PMCID: PMC3932760  PMID: 24125740
Nurses; Patient Safety; Management; Health Services Research; Healthcare Quality Improvement
23.  HIV-specific cytolytic CD4 T cell responses during acute HIV infection predict disease outcome 
Science translational medicine  2012;4(123):123ra25.
Early immunological events during acute HIV infection are thought to fundamentally influence long-term disease outcome. Whereas the contribution of HIV-specific CD8 T cell responses to early viral control is well established, the role of HIV-specific CD4 T cell responses in the control of viral replication following acute infection is unknown. A growing body of evidence suggests that CD4 T cells - besides their helper function - have the capacity to directly recognize and kill virally infected cells. In a longitudinal study of a cohort of individuals acutely infected with HIV, we observed that subjects able to spontaneously control HIV replication in the absence of antiretroviral therapy showed a significant expansion of HIV-specific CD4 T cell responses—but not CD8 T cell responses–compared to subjects who progressed to a high viral set point (p=0.038). Strikingly, this expansion occurred prior to differences in viral load or CD4 T cell count and was characterized by robust cytolytic activity and expression of a distinct profile of perforin and granzymes at the earliest time point. Kaplan-Meier analysis revealed that the emergence of Granzyme A+ HIV-specific CD4 T cell responses at baseline was highly predictive of slower disease progression and clinical outcome (average days to CD4 T cell count <350/μl was 575 versus 306, p=0.001). These data demonstrate that HIV-specific CD4 T cell responses can be used during the earliest phase of HIV infection as an immunological predictor of subsequent viral set point and disease outcome. Moreover, these data suggest that expansion of Granzyme A+ HIV-specific cytolytic CD4 T cell responses early during acute HIV infection contributes substantially to the control of viral replication.
PMCID: PMC3918726  PMID: 22378925
24.  A Systematic Survey Instrument Translation Process for Multi-Country, Comparative Health Workforce Studies 
As health services research (HSR) expands across the globe, researchers will adopt health services and health worker evaluation instruments developed in one country for use in another. This paper explores the cross-cultural methodological challenges involved in translating HSR in the language and context of different health systems.
To describe the pre-data collection systematic translation process used in a twelve country, eleven language nursing workforce survey.
Design & Settings
We illustrate the potential advantages of Content Validity Indexing (CVI) techniques to validate a nursing workforce survey developed for RN4CAST, a twelve country (Belgium, England, Finland, Germany, Greece, Ireland, Netherlands, Norway, Poland, Spain, Sweden, and Switzerland), eleven language (with modifications for regional dialects, including Dutch, English, Finnish, French, German, Greek, Italian, Norwegian, Polish, Spanish, and Swedish), comparative nursing workforce study in Europe.
Expert review panels comprised of practicing nurses from twelve European countries who evaluated cross-cultural relevance, including translation, of a nursing workforce survey instrument developed by experts in the field.
The method described in this paper used Content Validity Indexing (CVI) techniques with chance correction and provides researchers with a systematic approach for standardizing language translation processes while simultaneously evaluating the cross-cultural applicability of a survey instrument in the new context.
The cross-cultural evaluation process produced CVI scores for the instrument ranging from .61 to .95. The process successfully identified potentially problematic survey items and errors with translation.
The translation approach described here may help researchers reduce threats to data validity and improve instrument reliability in multinational health services research studies involving comparisons across health systems and language translation.
PMCID: PMC3395768  PMID: 22445444
25.  Downregulation of Wip1 phosphatase modulates the cellular threshold of DNA damage signaling in mitosis 
Cell Cycle  2013;12(2):251-262.
Cells are constantly challenged by DNA damage and protect their genome integrity by activation of an evolutionary conserved DNA damage response pathway (DDR). A central core of DDR is composed of a spatiotemporally ordered net of post-translational modifications, among which protein phosphorylation plays a major role. Activation of checkpoint kinases ATM/ATR and Chk1/2 leads to a temporal arrest in cell cycle progression (checkpoint) and allows time for DNA repair. Following DNA repair, cells re-enter the cell cycle by checkpoint recovery. Wip1 phosphatase (also called PPM1D) dephosphorylates multiple proteins involved in DDR and is essential for timely termination of the DDR. Here we have investigated how Wip1 is regulated in the context of the cell cycle. We found that Wip1 activity is downregulated by several mechanisms during mitosis. Wip1 protein abundance increases from G1 phase to G2 and declines in mitosis. Decreased abundance of Wip1 during mitosis is caused by proteasomal degradation. In addition, Wip1 is phosphorylated at multiple residues during mitosis, and this leads to inhibition of its enzymatic activity. Importantly, ectopic expression of Wip1 reduced γH2AX staining in mitotic cells and decreased the number of 53BP1 nuclear bodies in G1 cells. We propose that the combined decrease and inhibition of Wip1 in mitosis decreases the threshold necessary for DDR activation and enables cells to react adequately even to modest levels of DNA damage encountered during unperturbed mitotic progression.
PMCID: PMC3575454  PMID: 23255129
DNA damage response; Wip1 phosphatase; cell cycle; mitotic progression; γH2AX

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