Genetic Modifiers of Mendelian Monogenic Collagen IV Nephropathies in Humans and Mice

Familial hematuria is a clinical sign of a genetically heterogeneous group of conditions, accompanied by broad inter- and intrafamilial variable expressivity. The most frequent condition is caused by pathogenic (or likely pathogenic) variants in the collagen-IV genes, COL4A3/A4/A5. Pathogenic variants in COL4A5 are responsible for the severe X-linked glomerulopathy, Alport syndrome (AS), while homozygous or compound heterozygous variants in the COL4A3 or the COL4A4 gene cause autosomal recessive AS. AS usually leads to progressive kidney failure before the age of 40-years when left untreated. People who inherit heterozygous COL4A3/A4 variants are at-risk of a slowly progressive form of the disease, starting with microscopic hematuria in early childhood, developing Alport spectrum nephropathy. Sometimes, they are diagnosed with benign familial hematuria, and sometimes with autosomal dominant AS. At diagnosis, they often show thin basement membrane nephropathy, reflecting the uniform thin glomerular basement membrane lesion, inherited as an autosomal dominant condition. On a long follow-up, most patients will retain normal or mildly affected kidney function, while a substantial proportion will develop chronic kidney disease (CKD), even kidney failure at an average age of 55-years. A question that remains unanswered is how to distinguish those patients with AS or with heterozygous COL4A3/A4 variants who will manifest a more aggressive kidney function decline, requiring prompt medical intervention. The hypothesis that a subgroup of patients coinherit additional genetic modifiers that exacerbate their clinical course has been investigated by several researchers. Here, we review all publications that describe the potential role of candidate genetic modifiers in patients and include a summary of studies in AS mouse models

Positive and negative well-being and objectively measured sedentary behaviour in older adults: evidence from three cohorts

Background: Sedentary behaviour is related to poorer health independently of time spent in moderate to vigorous physical activity. The aim of this study was to investigate whether wellbeing or symptoms of anxiety or depression predict sedentary behaviour in older adults. Method: Participants were drawn from the Lothian Birth Cohort 1936 (LBC1936) (n = 271), and the West of Scotland Twenty-07 1950s (n = 309) and 1930s (n = 118) cohorts. Sedentary outcomes, sedentary time, and number of sit-to-stand transitions, were measured with a three-dimensional accelerometer (activPAL activity monitor) worn for 7 days. In the Twenty-07 cohorts, symptoms of anxiety and depression were assessed in 2008 and sedentary outcomes were assessed ~ 8 years later in 2015 and 2016. In the LBC1936 cohort, wellbeing and symptoms of anxiety and depression were assessed concurrently with sedentary behaviour in 2015 and 2016. We tested for an association between wellbeing, anxiety or depression and the sedentary outcomes using multivariate regression analysis. Results: We observed no association between wellbeing or symptoms of anxiety and the sedentary outcomes. Symptoms of depression were positively associated with sedentary time in the LBC1936 and Twenty-07 1950s cohort, and negatively associated with number of sit-to-stand transitions in the LBC1936. Meta-analytic estimates of the association between depressive symptoms and sedentary time or number of sit-to-stand transitions, adjusted for age, sex, BMI, long-standing illness, and education, were β = 0.11 (95% CI = 0.03, 0.18) and β = − 0.11 (95% CI = − 0.19, −0.03) respectively. Conclusion: Our findings indicate that depressive symptoms are positively associated with sedentary behavior. Future studies should investigate the causal direction of this association

Maximum (prior) brain size, not atrophy, correlates with cognition in community-dwelling older people: a cross-sectional neuroimaging study

<p>Abstract</p> <p>Background</p> <p>Brain size is associated with cognitive ability in adulthood (correlation ~ .3), but few studies have investigated the relationship in normal ageing, particularly beyond age 75 years. With age both brain size and fluid-type intelligence decline, and regional atrophy is often suggested as causing decline in specific cognitive abilities. However, an association between brain size and intelligence may be due to the persistence of this relationship from earlier life.</p> <p>Methods</p> <p>We recruited 107 community-dwelling volunteers (29% male) aged 75–81 years for cognitive testing and neuroimaging. We used principal components analysis to derived a 'general cognitive factor' (g) from tests of fluid-type ability. Using semi-automated analysis, we measured whole brain volume, intracranial area (ICA) (an estimate of maximal brain volume), and volume of frontal and temporal lobes, amygdalo-hippocampal complex, and ventricles. Brain atrophy was estimated by correcting WBV for ICA.</p> <p>Results</p> <p>Whole brain volume (WBV) correlated with general cognitive ability (g) (r = .21, P < .05). Statistically significant associations between brain areas and specific cognitive abilities became non-significant when corrected for maximal brain volume (estimated using ICA), i.e. there were no statistically significant associations between atrophy and cognitive ability. The association between WBV and g was largely attenuated (from .21 to .03: i.e. attenuating the variance by 98%) by correcting for ICA. ICA accounted for 6.2% of the variance in g in old age, whereas atrophy accounted for < 1%.</p> <p>Conclusion</p> <p>The association between brain regions and specific cognitive abilities in community dwelling people of older age is due to the life-long association between whole brain size and general cognitive ability, rather than atrophy of specific regions. Researchers and clinicians should therefore be cautious of interpreting global or regional brain atrophy on neuroimaging as contributing to cognitive status in older age without taking into account prior mental ability and brain size.</p

Association of hypoxia inducible factor-1 alpha gene polymorphism with both type 1 and type 2 diabetes in a Caucasian (Hungarian) sample

BACKGROUND: Hypoxia inducible factor-1 alpha (HIF-1alpha) is a transcription factor that plays an important role in neo-vascularisation, embryonic pancreas beta-cell mass development, and beta cell protection. Recently a non synonymous single nucleotide polymorphism (g.C45035T SNP, rs11549465) of HIF-1alpha gene, resulting in the p.P582S amino acid change has been shown to be associated with type 2 diabetes (T2DM) in a Japanese population. Our aim was to replicate these findings on a Caucasian (Hungarian) population, as well as to study whether this genetic effect is restricted to T2DM or can be expanded to diabetes in general. METHODS: A large Caucasian sample (N = 890) was recruited including 370 T2DM, 166 T1DM and 354 healthy subjects. Genotyping was validated by two independent methods: a restriction fragment analysis (RFLP) and a real time PCR using TaqMan probes. An overestimation of heterozygotes by RFLP was observed as a consequence of a nearby SNP (rs34005929). Therefore genotyping results of the justified TaqMan system were accepted. The measured genotype distribution corresponded to Hardy-Weinberg equilibrium (P = 0.740) RESULTS: As the TT genotype was extremely rare in the population (0.6% in clinical sample and 2.5% in controls), the genotypes were grouped as T absent (CC) and T present (CT and TT). Genotype-wise analysis showed a significant increase of T present group in controls (24.0%) as compared to patients (16.8%, P = 0.008). This genetic effect was demonstrated in the separated samples of type 1 (15.1%, P = 0.020), and also in type 2 (17.6%, P = 0.032) diabetes. Allele-wise analysis gave identical results showing a higher frequency of the T allele in the control sample (13.3%) than in the clinical sample (8.7%, P = 0.002) with similar results in type 1 (7.8%, P = 0.010) and type 2 (9.1%, P = 0.011) diabetes. The odds ratio for diabetes (either type 1 or 2) was 1.56 in the presence of the C allele. CONCLUSION: We confirmed the protective effect of a rare genetic variant of HIF-1alpha gene against type 2 diabetes in a Caucasian sample. Moreover we demonstrated a genetic contribution of the same polymorphism in type 1 diabetes as well, supporting a possible overlap in pathomechanism for T2DM and a T1DM

Effectiveness and cost-effectiveness of 'BeweegKuur', a combined lifestyle intervention in the Netherlands: Rationale, design and methods of a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Improving the lifestyle of overweight and obese adults is of increasing interest in view of its role in several chronic diseases. Interventions aiming at overweight or weight-related chronic diseases suffer from high drop-out rates. It has been suggested that Motivational Interviewing and more frequent and more patient-specific coaching could decrease the drop-out rate. 'BeweegKuur' is a multidisciplinary lifestyle intervention which offers three programmes for overweight persons. The effectiveness and the cost-effectiveness of intensively guided programmes, such as the 'supervised exercise programme' of 'BeweegKuur', for patients with high weight-related health risk, remain to be assessed. Our randomized controlled trial compares the expenses and effects of the 'supervised exercise programme' with those of the less intensively supervised 'start-up exercise programme'.</p> <p>Methods/Design</p> <p>The one-year intervention period involves coaching by a lifestyle advisor, a physiotherapist and a dietician, coordinated by general practitioners (GPs). The participating GP practices have been allocated to the interventions, which differ only in terms of the amount of coaching offered by the physiotherapist. Whereas the 'start-up exercise programme' includes several consultations with physiotherapists to identify barriers hampering independent exercising, the 'supervised exercise programme' includes more sessions with a physiotherapist, involving exercise under supervision. The main goal is transfer to local exercise facilities. The main outcome of the study will be the participants' physical activity at the end of the one-year intervention period and after one year of follow-up. Secondary outcomes are dietary habits, health risk, physical fitness and functional capacity. The economic evaluation will consist of a cost-effectiveness analysis and a cost-utility analysis. The primary outcome measures for the economic evaluation will be the physical activity and the number of quality-adjusted life years. Costs will be assessed from a societal perspective with a time horizon of two years. Additionally, a process evaluation will be used to evaluate the performance of the intervention and the participants' evaluation of the intervention.</p> <p>Discussion</p> <p>This study is expected to provide information regarding the additional costs and effects of the 'supervised exercise programme' in adults with very high weight-related health risk.</p> <p>Trial registration number</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN46574304">ISRCTN46574304</a></p

The Accumulation of Organic Carbon in Mineral Soils by Afforestation of Abandoned Farmland

The afforestation of abandoned farmland significantly influences soil organic carbon (OC). However, the dynamics between OC inputs after afforestation and the original OC are not well understood. To learn more about soil OC dynamics after afforestation of farmland, we measured the soil OC content in paired forest and farmland plots in Shaanxi Province, China. The forest plots had been established on farmland 18, 24, 48, 100, and 200 yr previously. The natural 13C abundance of soil organic matter was also analyzed to distinguish between crop- and forest-derived C in the afforested soils. We observed a nonlinear accumulation of total OC in the 0–80 cm depth of the mineral soil across time. Total soil OC accumulated more rapidly under forest stands aged 18 to 48 yr than under forest stands aged 100 or 200 yrs. The rate of OC accumulation was also greater in the 0–10 cm depth than in the 10–80 cm depth. Forest-derived OC in afforested soils also accumulated nonlinearly across time, with the greatest increase in the 0–20 cm depth. Forest-derived OC in afforest soils accounted for 52–86% of the total OC in the 0–10 cm depth, 36–61% of the total OC in the 10–20 cm depth, and 11–50% of the total OC in the 20–80 cm depth. Crop-derived OC concentrations in the 0–20 cm depth decreased slightly after afforestation, but there was no change in crop-derived OC concentrations in the 20–80 cm depth. The results of our study support the claim that afforestation of farmland can sequester atmospheric CO2 by increasing soil OC stocks. Changes in the OC stocks of mineral soils after afforestation appear to be influenced mainly by the input of forest-derived C rather than by the loss of original OC

CCL2/MCP-I Genotype-Phenotype Relationship in Latent Tuberculosis Infection

Among the known biomarkers, chemokines, secreted by activated macrophages and T cells, attract groups of immune cells to the site of infection and may determine the clinical outcome. Association studies of CCL-2/MCP-1 -2518 A/G functional SNP linked to high and low phenotypes with tuberculosis disease susceptibility have shown conflicting results in tuberculosis. Some of these differences could be due the variability of latent infection and recent exposure in the control groups. We have therefore carried out a detailed analysis of CCL-2 genotype SNP -2518 (A/G transition) with plasma CCL-2 levels and related these levels to tuberculin skin test positivity in asymptomatic community controls with no known exposure to tuberculosis and in recently exposed household contacts of pulmonary tuberculosis patients. TST positivity was linked to higher concentrations of plasma CCL2 (Mann Whitney U test; p = 0.004) and was more marked when the G allele was present in TST+ asymptomatic controls (A/G; p = 0.01). Recent exposure also had a significant effect on CCL-2 levels and was linked to the G allele (p = 0.007). Therefore association studies for susceptibility or protection from disease should take into consideration the PPD status as well as recent exposure of the controls group used for comparison. Our results also suggest a role for CCL-2 in maintaining the integrity of granuloma in asymptomatic individuals with latent infection in high TB burden settings. Therefore additional studies into the role of CCL-2 in disease reactivation and progression are warranted

Understanding the consumption of folic acid during preconception, among Pakistani, Bangladeshi and white British mothers in Luton, UK: a qualitative study

Background To review the similarities and differences in Pakistani, Bangladeshi and White British mothers health beliefs (attitudes, knowledge and perceptions) and health behaviour regarding their consumption of folic acid pre-conception, to reduce the risk of neural tube defects. Methods Our study used a descriptive qualitative research approach, implementing face-to-face focus group discussions with Pakistani, Bangladeshi or White British mothers (normal birth outcomes and mothers with poor birth outcomes) and semi-structured interviews or focus groups with service providers using semi-structured topic guides. This method is well suited for under researched areas where in-depth information is sought. There were three sample groups: 1. Pakistani, Bangladeshi and White British mothers with normal birth outcomes (delivery after 37 weeks of gestation, in the preceding 6 to 24 months, weighing 2500 g and living within a specified postcode area in Luton, UK). 2. Pakistani Bangladeshi and white British bereaved mothers who had suffered a perinatal mortality (preceding 6 to 24 months, residing within a specificied postcode area). 3. Healthcare professionals working on the local maternity care pathway (i.e. services providing preconception, antenatal, antepartum and postpartum care). Transcribed discussions were analysed using the Framework Analysis approach. Results The majority of mothers in this sample did not understand the benefits or optimal time to take folic acid pre-conception. Conversely, healthcare professionals believed the majority of women did consume folic acid, prior to conception. Conclusions There is a need to increase public health awareness of the optimal time and subsequent benefits for taking folic acid, to prevent neural tube defects.</p