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Heart failure accounts for about one third of all deaths worldwide. With lower birth-rates and changing demographics, it is crucial to understand the principals of heart failure with age and which physiological systems affect it.
GDF11 has been identified as a possible candidate to help understand the cardiac ageing system. It is a member of the TGF-beta superfamily and is a circulating protein that decreases with age. Old animals exposed to youthful levels of this circulating protein showed regression in age-related cardiac hypertrophy.
As GDF11 -/- knockout embryos are not feasible with life, we utilised the tamoxifen-inducible Cre lox system to generate knockdown models of GDF11 that could be initiated later in life. Mice with the suitable “Cre/+; GDF11 flox/flox” genotype were injected with hydroxytamoxifen, inducing partial recombination and knockdown of GDF11. We evaluated two different knockdown models: a total inducible knockdown and a cardiac specific knockdown of GDF11.
Through our (5-7 month old) total inducible knockdown model, we showed that the spleen had the highest relative expression of GDF11 when compared to other organs, suggesting that it might play a role in the regulation of GDF11. Through qPCR analysis, we showed that the total knockdown animals had 40% less expression of GDF11 in the spleen after 10 days of hydroxytamoxifen injections. These same animals showed a trend with increased heart weight to tibia length ratios (p=0.11) after the knockdown of the protein. In our aged (18-22 month old) total inducible knockdown model, no significant reduction of GDF11 expression could be noted in any organ after hydroxytamoxifen injections. As opposed to the younger cohort, statistical testing could not be conducted between treatment groups as a high mortality rate affected the sample sizes. Calculations using echocardiographic parameters, did however, show a significant increase in left ventricular mass to tibia length ratios in GDF11 knockdown animals. This significant increase was found when comparing post-treatment to baseline values.
In the cardiac specific knockdown model, no significant reduction could be noted in the relative expression of GDF11 in the harvested organs. This was probably the result of the low sample numbers in certain groups, but may also suggest that the heart is a less prominent regulator of total circulating GDF11 levels in vivo.
All in all, these have been important steps towards fully understanding GDF11’s function in vivo, as well as how it affects cardiac ageing. Even though the results were not always as comprehensible – the supporting trends were – and future experiments with larger sample numbers could indeed shed more light on GDF11’s full potential.
Background and purpose: Cerebral ischemia causes a complex immunological cascade. Inflammation plays an important role in this cascade, both in the central nervous system and in the periphery. Closely linked events are the activation of the hypothalamic-pituitary-adrenal axis, sympathetic nervous system and parasympathetic nervous system, probably leading to stroke-induced immunodepression (SIID). The purpose of the study was to assess whether there is a relation between an increased neuro-inflammatory response and an increased pituitary activity and the occurrence of infections.
Methods: This is a prospective cohort study. Fifteen patients were analysed with a first ever ischemic stroke within a week after the onset of the symptoms. We compared patients who developed signs of inflammation after stroke with those who did not. Further, it was examined whether patients with increased pituitary activity often are associated with infections.
Results: The group with signs of inflammation consisted of six patients (40%) and the group without inflammation of nine patients (60%). Between the groups no significant difference was found when considering the average of the cortisol (P=0.46), TSH (P=0.96) and FT4 values (P=0.61). In addition an increased pituitary activity was not associated with an increased incidence of infections (cortisol (P=0.53), TSH (P=0.67) and FT4 (P=0.80)).
Conclusion: No relationship was found between an increased inflammatory response and increased pituitary activity as well as the occurrence of infections. However, this research has a view limitations, in order to actually exclude a relationship a study with a larger population need to be carried out.
Background: The growth of the elderly population is a rising problem in the Netherlands. This group often has chronic illnesses and comorbidities which frequently lead to polypharmacy. As a result these patients have a higher risk of inappropriate medication use, which in turn can lead to a higher risk of adverse events, increased fall risk, decreased quality of life and cognitive decline. This is particularly the case for nursing home residents. Additionally many of these residents are suffering from dementia, which is often associated with neuropsychiatric symptoms and use of psychopharmaca. This study was part of the the DIM-NHR Study which examines the efficacy and cost-effectiveness of the multidisciplinary multistep medication review in order to optimize drug prescribing and successfully stop inappropriate medication in the nursing home setting.
Aims of the study: To assess successful discontinuation of medication and its effects on clinical outcomes cognition, quality of life, neuropsychiatric symptoms and adverse events, as well as assessing whether there is a difference between residents with and without dementia. Methods: Data were collected in X nursing homes in the Netherlands. Medication use data were collected for the four month period. The Mini-Mental-State examination (MMSE), Sever impairment Battery short version(SIB-s), Dementia Quality of Life index Dementia (DQI, EuroQol-5D (EQ-5D-3L), EQ-VAS and Neuropsychiatric Inventory (NPI) were taken at baseline and follow- up. Medical record study was done at follow up to look at adverse events. Once the proportion of nursing home residents who successfully discontinued medication had been calculated, the differences in clinical outcomes were analyzed, as well as the differences between the dementia and non-dementia subgroup. Results: Overall, 199 residents were included (mean age 82,3, 67,3% female). For 84 (42,2%) residents at least one drug was successfully discontinued. There were no significant differences in clinical outcomes between residents who did an did not successfully discontinue medication. When successfully discontinued, the EQ-VAS significantly improved in the non-dementia subgroup, but not in the dementia group. In the non-dementia group the number of falls are significantly lower than in the dementia group. The number of paramedical consults and visits by a specialist in geriatric medicine were significant higher in the non-dementia group. Conclusion: In nearly half of the cases one or more medications have been stopped during the study period. Successful discontinuation of medication improves some clinical outcomes in the non-dementia subgroup.
Predicting the outcome on various domains of development can be very important for the course of an infant’s development, especially if the infant is preterm or experienced any complication during early life. Such a prediction is still a challenge. A method with both a high sensitivity and specificity for predicting the infant’s neurological (dys)function is the Prechtl General Movements Assessment (GMA). Together with other movements and patterns, the GMA is referred to as the early motor repertoire.
We retrospectively assessed associations between the early motor repertoire and language development in a prospective cohort study of low-risk term born infants, conducted at the
Institute of Physiology of the Medical University of Graz.
All infants were videoed at the age of 3 and 5 months and were later assessed for language performance at 4;7 and 10;5 (years; months). The assessment of the early motor repertoire was performed using the Motor Optimality Score.
Significant and trending associations between certain aspects of the early motor repertoire and different language tests were found. Fidgety movements at 3 months were positively significant associated with expressive vocabulary at 4;7 years. No associations between fidgety movements at 5 months and language development were found. Negative significant associations between concurrent movements at 3 months and language outcome, namely between the number of normal movement patterns and receptive vocabulary and between the number of abnormal movement patterns and articulation at 4;7 years. Between the overall movement character and language outcome at both ages positive significant associations were found. These were the associations between the infants’ movement character at 3 months and expressive vocabulary at 10;5 years (e.g. r = 0.597) and between movement character at 5 months and receptive vocabulary at 4;7 years (e.g. r = 0.586). No significant associations were found between the subscales repertoire of co-existent other movements and posture of the early motor repertoire and language performance.
In conclusion, language development is associated with the early motor repertoire and therefore GMA might be a valuable tool for the prediction of language outcome.
Structure and elevator mechanism of the Na(+)-citrate transporter CitS.
Curr Opin Struct Biol. 2016 Oct 21;45:1-9
Authors: Lolkema JS, Slotboom DJ
The recently determined crystal structure of the bacterial Na(+)-citrate symporter CitS provides unexpected structural and mechanistic insights. The protein has a fold that has not been seen in other proteins, but the oligomeric state, domain organization and proposed transport mechanism strongly resemble those of the sodium-dicarboxylate symporter vcINDY, and the putative exporters YdaH and MtrF, thus hinting at convergence in structure and function. CitS and the related proteins are predicted to translocate their substrates by an elevator-like mechanism, in which a compact transport domain slides up and down through the membrane while the dimerization domain is stably anchored. Here we review the large body of available biochemical data on CitS in the light of the new crystal structure. We show that the biochemical data are fully consistent with the proposed elevator mechanism, but also demonstrate that the current structural data cannot explain how strict coupling of citrate and Na(+) transport is achieved. We propose a testable model for the coupling mechanism.
PMID: 27776291 [PubMed – as supplied by publisher]
Hiv-incidence on Curaçao is still increasing with an average of 100 new hiv-infections in
recent years. Patients are often diagnosed in a late stage with much delay between diagnosis,
entry into care and start of antiretroviral therapy (ART). The ‘test and treat’ strategy is based
on both tracing hiv-infected persons and immediate start of ART. Theoretically this will lead
to a lower viral load in the community and eventually to a lower hiv-incidence. This is the
first study where provider initiated testing and counseling (PITC) is introduced in a primary
healthcare setting in a middle-prevalent area as the basis of the ‘test and treat’ strategy. Four
general practicioner (GP) practices on Curaçao introduced PITC, all presenting patients aged
16 and older were invited for an oral hiv rapidtest. The aim of this pilotstudy is to evaluate
the feasibility and effectivity of PITC in the GP practice. After 1.5 year of testing PITC was
succesfully implemented in half of the practices and acceptability was high among patients.
Motivation and involvement of all GP’s working in one practice are major factors affecting
feasibility. Almost 3000 patients were tested of which 8 persons had a positive result.
Without PITC 7 of them would not have been tested during the same consultation.
Extrapolation of these results to the population of Curaçao shows an hiv-incidence 3 to 5
times higher than the current official numbers. PITC in the GP practice is a feasible and
effective strategy to diagnose more hiv-patients and is a good point of entry for the test and
treat strategy. We recommend to expand PITC to a larger number of motivated GP practices
PURPOSE: To assess the diagnostic value of low dose Cone Beam Computed Tomography (CBCT) and Multislice Computed Tomography (MSCT) for zygomaticomaxillary fracture diagnosis.
MATERIAL AND METHODS: Unilateral zygomaticomaxillary fractures were inflicted on four out of six fresh frozen human cadaver head specimen. All specimen were scanned using two CBCT and four MSCT protocols where the radiation exposure was systematically reduced. A blinded diagnostic routine was recreated where 16 radiologists and 8 oral and maxillofacial surgeons performed 144 randomized image assessments. As a gold standard, the presence of fractures of the zygomatic region was verified by an open operative approach.
RESULTS: Zygomaticomaxillary fractures were correctly diagnosed in 90.3% (n=130) of the image assessments. The zygomatic arch was most often correctly diagnosed (91.0%). The zygomatic alveolar crest showed the lowest degree of correct diagnosis (65.3%). No significant decrease of correctly diagnosed fracture sites was found between the baseline and low dose CBCT and MSCT protocols. Dose reduction did not significant decrease the ability to assess dislocation, comminution, orbital volume, volume rendering and soft tissues. OMF surgeons considered the low dose protocols sufficient for treatment planning. The effective dose of MSCT (129.9 to 51.0 μSv) remained well in range of CBCT (122 to 28 μSv).
CONCLUSION: Dose reduction seems not to decrease the diagnostic value of CBCT and MSCT protocols for the diagnosis of zygomaticomaxillary fractures.
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Pharmacogenetics of asthma: toward precision medicine.
Curr Opin Pulm Med. 2016 Oct 18;
Authors: Kersten ET, Koppelman GH
PURPOSE OF REVIEW: Although currently available drugs to treat asthma are effective in most patients, a proportion of patients do not respond or experience side-effects; which is partly genetically determined. Pharmacogenetics is the study of how genetic variations influence drug response. In this review, we summarize prior results and recent studies in pharmacogenetics to determine if we can use genetic profiles for personalized treatment of asthma.
RECENT FINDINGS: The field of pharmacogenetics has moved from candidate gene studies in single populations toward genome-wide association studies and meta-analysis of multiple studies. New technologies have been used to enrich results, and an expanding number of genetic loci have been associated with therapeutic responses to asthma drugs. Prospective, genotype-stratified treatment studies have been conducted for β2-agonists, showing attenuated response in children carrying the Arg16 variant in the β2-adrenoreceptor gene.
SUMMARY: Although there has been much progress, many findings have not been replicated and currently known genetic loci only account for a fraction of variability in drug response. More research is necessary to translate into clinical practice. A polygenic predictive approach integrated in complex networks with other ‘omics’ technologies could aid to achieve this goal. Finally, to change clinical practice, studies that compare precision medicine with traditional medicine are needed.
PMID: 27764000 [PubMed – as supplied by publisher]
My Body Looks Like That Girl’s: Body Mass Index Modulates Brain Activity during Body Image Self-Reflection among Young Women.
PLoS One. 2016;11(10):e0164450
Authors: Gao X, Deng X, Wen X, She Y, Vinke PC, Chen H
Body image distress or body dissatisfaction is one of the most common consequences of obesity and overweight. We investigated the neural bases of body image processing in overweight and average weight young women to understand whether brain regions that were previously found to be involved in processing self-reflective, perspective and affective components of body image would show different activation between two groups. Thirteen overweight (O-W group, age = 20.31±1.70 years) and thirteen average weight (A-W group, age = 20.15±1.62 years) young women underwent functional magnetic resonance imaging while performing a body image self-reflection task. Among both groups, whole-brain analysis revealed activations of a brain network related to perceptive and affective components of body image processing. ROI analysis showed a main effect of group in ACC as well as a group by condition interaction within bilateral EBA, bilateral FBA, right IPL, bilateral DLPFC, left amygdala and left MPFC. For the A-W group, simple effect analysis revealed stronger activations in Thin-Control compared to Fat-Control condition within regions related to perceptive (including bilateral EBA, bilateral FBA, right IPL) and affective components of body image processing (including bilateral DLPFC, left amygdala), as well as self-reference (left MPFC). The O-W group only showed stronger activations in Fat-Control than in Thin-Control condition within regions related to the perceptive component of body image processing (including left EBA and left FBA). Path analysis showed that in the Fat-Thin contrast, body dissatisfaction completely mediated the group difference in brain response in left amygdala across the whole sample. Our data are the first to demonstrate differences in brain response to body pictures between average weight and overweight young females involved in a body image self-reflection task. These results provide insights for understanding the vulnerability to body image distress among overweight or obese young females.
PMID: 27764116 [PubMed – in process]
Posted in PLoS One
Introduction: Infants who underwent an surgery under general anesthesia show cognitive and/or motoric development problems as they grow older. These development problems are thought to be caused by perioperatieve cerebral hypoxia. To analyse the incidence and risk factors for this hypoxia, this study monitored the perioperatieve cerebral oxygensaturation (cSO2) noninvasively with near infrared spectroscopy (NIRS). Material en methods: Infants undergoing surgery at the age of 0-6 months under general anesthesia were included in this observational study. Cerebral desaturation is defined as cSO2<55%. Patient characteristics, perioperative conduct and events were analysed. Results: 123 infants were included, 25 of them showed cerebral desaturations. The groups with or without desaturations differed significantly in age, weight and ASA-classification. Laparo/thoracotomies were more frequent in the group with desaturations. This group also received more RBC-transfusions, although the Hb-value was above the transfusiontrigger. Conclusion: Lower (birth)weights, higher ASA-classifications, (ex)prematurity, laparo/thoractomies and and lower Hb-values are possible risk factors for cerebral desaturation. More patients are to be included in this study to indentify a good preoperative risk prediction for these infants.
Background: Myofascial pelvic pain syndrome is a common condition with a major negative
impact on the quality of life. As aetiology is multifactorial, a biopsychosocial model and central
sensitivity model can be applied. A multidisciplinary approach is advised by current guidelines.
So far, the outcomes of this approach have not been well explored.
Objective: The aim of this study is to evaluate the results of the multidisciplinary approach of
patients with myofasical pelvic pain syndrome in the pelvic floor centre at the academic medical
centre Groningen and to explore the influence of age and follow-up duration on the results.
Study design: A paired t-test was used to test the change of health and psychosocial items after
a follow-up period with an average of 54 months. The items were quantified with the pelvic
floor questionnaire of the Dutch Society of Obstetrics and Gynaecology. The influence of age
and follow-up duration on score change was estimated with a linear regression analysis. In
addition, patients were asked to give feedback about different aspects of the given care.
Results and conclusions: An improvement was assessed in urogenital symptoms and
urogenital pain, defaecation symptoms and incontinence impact. Sexual symptoms did not
change. There appears to be little or no influence of age and follow-up time on the results.
Patients are generally positive about the care and appreciate the clarity of the explanations, time
and attention they received. They requested to be more involved in decision making, to receive
more information and to have access to an improved follow-up.
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To assess prevalence and predictors of frailty in elderly patients in a tertiary cardiac outpatient clinic.
Outpatients in a tertiary cardiology centre.
Three hundred and eight consecutive outpatients aged 65 and older, visiting a cardiology outpatient clinic.
The Groningen Frailty Indicator was used to identify frailty.
Prevalence of frailty was 41.2%. Predictors of frailty were age, female gender, recent fall, malignancy and aspirin use.
Prevalence of frailty in an outpatient cardiac clinic is high, and especially increased in older age, females, those with recent fall and patients with cancer. Since frailty has been associated with increased risk of morbidity and mortality after (invasive) treatment, existence of frailty should be routinely assessed in these patients.
Introduction: Asymmetrical sensorineural hearing loss is the major symptom of vestibular schwannoma (95%). The golden standard with 100% sensitivity and a high specificity is the Magnetic Resonance Imaging. In approximately 1% of the MRI-scans a vestibular schwannoom has been noticed. Aim: This study investigates the association between audiometry and a vestibular schwannoma. Can the principle component analysis be a better predictor in finding a vestibular schwannoma and will this reduce the amount of MRI-scans? Methods: A retrospective chart survey was performed, involving the analysis of 79 patients with vestibular schwannoom (patient group) which were discussed in the schedelbasiswerkgroep in the University Medical Center Groningen during the years 2012-2014 and 141 patients with asymmetrical sensorineural hearing loss (control group) from the University Medical Center Groningen and without tumor in the year 2012. All patients already received audiometry and a MRI-scan. The principle component analysis was performed on the entire patient cohort of 217 patients. Individual principle component scores were compared between tumor and non- tumor patients. The analysis was performed twice: 1) including pure- tone and speech audiometry, and 2) including anamnestic parameters in addition to pure- tone and speech audiometry
Results: The principle component scores of 32 patients without tumor differed substantially frome those in the tumor group. When the anamnestic parameters were included in the principle component analysis, the scores of 13 patients differed from the rest. There were 56 patients with 1 symptom only 9 patients had a vestibular schwannoma. Conclusion: This study concluded that when the non- suspected ear has a huge hearing loss at the non- suspected ear a MRI-scan is unnecessary. Using the principle component scores on new patients could be useful as a selection criterion. This would reduce the amount of MRI scans.
Objectives: Donor kidneys of inferior quality are increasingly being accepted to decrease waiting time for a kidney transplant. Normothermic machine perfusion (NMP) of an isolated donor kidney could enable active organ conditioning and gives the opportunity for an intervention prior to transplantation. There is increasing evidence that mesenchymal stromal cells (MSCs) could have a positive effect on ischaemia-reperfusion injury. Main objective of this study was to determine if and in which quantity MSCs reach the kidney and to which structures they home when added during NMP.
Methods: Porcine kidneys and autologous whole blood were obtained from two slaughterhouses in the vicinity of Groningen. Time between cardiac arrest and cold flush of kidneys was standardised at 30 min. Kidneys were cold stored for 3.5-5 hrs. Next, kidneys were perfused during 6 hours in a recirculating circuit with 350 ml washed autologous red blood cells and 500 ml Williams’ Medium E at 37°C. After 1 hour of perfusion either 0, 105, 106 or 107 cultured human adipose tissue derived MSCs were added (n=3 per group). Vital parameters were monitored and perfusate and urine samples were taken regularly. Biopsies were taken to assess renal histology and to locate and quantify the MSCs using immunohistochemistry and FACS analysis.
Results: A stable NMP system and culturing routine for human MSCs was established. There was no difference in renal function during NMP between groups. MSCs were detected in the lumen of the capillaires in the glomeruli in biopsies in the 107 MSC group but not in the other groups. Quantifying the number of vital MSCs with a FACS analysis did not succeed.
Conclusion: MSCs treatment did not significantly change very early renal function during NMP. After 6h of NMP, MSCs home to the lumen of the capillaires in the glomeruli. Further research is required to determine dose-dependency of the addition of MSCs.