Gut microbiota-derived propionate reduces cancer cell proliferation in the liver

Peer reviewedPublisher PD

Feasibility and findings of electrocardiogram recording in older adults with intellectual disabilities:results of the Healthy Ageing and Intellectual Disabilities study

Background: Older adults with intellectual disabilities (ID) have a high risk of cardiovascular diseases (CVD). At the same time, challenging diagnostic work-up increases the likelihood of underdiagnosis of CVD in this population. To limit this underdiagnosis, it would be beneficial to use objective measures such as the electrocardiogram (ECG). However, little is known about the feasibility of ECG recording and the prevalence of ECG abnormalities in this population. Therefore, the aims of this study were to investigate the feasibility of resting ECG recording, to study the prevalence of ECG abnormalities, and to compare the frequency of ECG abnormalities with medical records in older adults with ID. Method: A cross-sectional study was performed within a cohort of older adults (≥60 years) with ID as part of the Healthy Ageing and Intellectual Disabilities (HA-ID) study. A resting 12-lead ECG was attempted, and the ECG recording was considered feasible if the recording could be made and if the ECG could be interpreted by a cardiologist and the Modular ECG Analysis System (MEANS). ECGs were assessed for the presence of ECG abnormalities and medical record review was performed. If the cardiologist or MEANS concluded that there was evidence of myocardial infarction, atrial fibrillation or QTc prolongation on the ECG in the absence of this ECG diagnosis in the participant's medical record, this was classified as a previously undiagnosed ECG diagnosis. Results: ECG recording was feasible in 134 of the 200 participants (67.0%). Of these 134 participants (70.6 ± 5.8 years; 52.2% female), 103 (76.9%) had one or more ECG abnormality, with the most prevalent being prolonged P-wave duration (27.6%), QTc prolongation (18.7%), minor T-wave abnormalities (17.9%), first degree atrioventricular block (12.7%) and myocardial infarction (6.7%). Eight out of 9 (88.9%) myocardial infarctions and all cases of (significant) QTc prolongation (100%) were previously undiagnosed. Conclusions: This study showed that ECG recording is feasible in the majority of older adults with ID and revealed a substantial underdiagnosis of ECG abnormalities. These results stress the importance of ECG recording and warrant further research into the yield of opportunistic ECG screening in older adults with ID.</p

Asthma beliefs among mothers and children from different ethnic origins living in Amsterdam, the Netherlands

<p>Abstract</p> <p>Background</p> <p>Doctors and patients hold varying beliefs concerning illness and treatment. Patients' and families' explanatory models (EMs) vary according to personality and sociocultural factors. In a multi-ethnic society, it is becoming increasingly significant that doctors understand the different beliefs of their patients in order to improve patient/doctor communication as well as patient adherence to treatment.</p> <p>Methods</p> <p>Twelve focus groups were formed, consisting of 40 children diagnosed with asthma, as well as 28 mothers of these children. These groups included mothers and children of different ethnicities who were living in Amsterdam, the Netherlands. In order to understand the beliefs that both mothers and children hold regarding asthma and its treatment, the explanatory models were analysed and compared.</p> <p>Results</p> <p>Study findings show that mothers and children, regardless of ethnicity and age, have their own EMs. Overall, there is a great deal of uncertainty related to the causes, consequences, problems, and symptoms of asthma and its treatment. It also seems that many concerns and feelings of discomfort are the result of lack of knowledge. For instance, the fact that asthma is not seen as a chronic disease requiring daily intake of an inhaled corticosteroid, but rather as an acute phenomenon triggered by various factors, may be very relevant for clinical practice. This particular belief might suggest an explanation for non-adherent behaviour.</p> <p>Conclusion</p> <p>A thorough understanding of the mothers' and children's beliefs regarding the illness and its treatment is an important aspect in the management of asthma. Gaining an understanding of these beliefs will provide a foundation for a solid clinician-patient/family partnership in asthma care. Although ethnic differences were observed, the similarities between the mothers' and children's beliefs in this multi-ethnic population were striking. In particular, a common belief is that asthma is considered an acute rather than a chronic condition. In addition, there is a lack of knowledge about the course and the self-management of asthma. Health care providers should be aware of these commonly held beliefs, and this information could be shared in educational programs.</p

Patterns of knee osteoarthritis management in general practice:a retrospective cohort study using electronic health records

Objective: This study determined patterns of knee osteoarthritis (OA) management by general practitioners (GPs) using routine healthcare data from Dutch general practices from 2011 to 2019. Design: A retrospective cohort study was conducted using the Integrated Primary Care Information database between 2011 and 2019. Electronic health records (EHRs) of n = 750 randomly selected knee OA patients (with either codified or narrative diagnosis) were reviewed against eligibility criteria and n = 503 patients were included. Recorded information was extracted on GPs’ management from six months before to three years after diagnosis and patterns of management were analysed.Results: An X-ray referral was the most widely recorded management modality (63.2%). The next most widely recorded management modalities were a referral to secondary care (56.1%) and medication prescription or advice (48.3%). Records of recommendation of/referral to other primary care practitioners (e.g. physiotherapists) were found in only one third of the patients. Advice to lose weight was least common (1.2%). Records of medication prescriptions or recommendation of/referral to other primary care practitioners were found more frequently in patients with an X-ray referral compared to patients without, while records of secondary care referrals were found less frequently. Records of an X-ray referral were often found in narratively diagnosed knee OA patients before GPs recorded a code for knee OA in their EHR. Conclusion: These findings emphasize the importance of better implementing non-surgical management of knee OA in general practice and on initiatives for reducing the overuse of X-rays for diagnosing knee OA in general practice.</p

Patterns of knee osteoarthritis management in general practice:a retrospective cohort study using electronic health records

Objective: This study determined patterns of knee osteoarthritis (OA) management by general practitioners (GPs) using routine healthcare data from Dutch general practices from 2011 to 2019. Design: A retrospective cohort study was conducted using the Integrated Primary Care Information database between 2011 and 2019. Electronic health records (EHRs) of n = 750 randomly selected knee OA patients (with either codified or narrative diagnosis) were reviewed against eligibility criteria and n = 503 patients were included. Recorded information was extracted on GPs’ management from six months before to three years after diagnosis and patterns of management were analysed.Results: An X-ray referral was the most widely recorded management modality (63.2%). The next most widely recorded management modalities were a referral to secondary care (56.1%) and medication prescription or advice (48.3%). Records of recommendation of/referral to other primary care practitioners (e.g. physiotherapists) were found in only one third of the patients. Advice to lose weight was least common (1.2%). Records of medication prescriptions or recommendation of/referral to other primary care practitioners were found more frequently in patients with an X-ray referral compared to patients without, while records of secondary care referrals were found less frequently. Records of an X-ray referral were often found in narratively diagnosed knee OA patients before GPs recorded a code for knee OA in their EHR. Conclusion: These findings emphasize the importance of better implementing non-surgical management of knee OA in general practice and on initiatives for reducing the overuse of X-rays for diagnosing knee OA in general practice.</p

Functional tests to guide management in an adult with loss of function of type-1 angiotensin II receptor

BACKGROUND: Genetic loss of function of AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), or AGTR1 (type-1 angiotensin II receptor) leads to renal tubular dysgenesis (RTD). This syndrome is almost invariably lethal. Most surviving patients reach stage 5 chronic kidney disease at a young age. METHODS: Here, we report a 28-year-old male with a homozygous truncating mutation in AGTR1 (p.Arg216*), who survived the perinatal period with a mildly impaired kidney function. In contrast to classic RTD, kidney biopsy showed proximal tubules that were mostly normal. During the subsequent three decades, we observed evidence of both tubular dysfunction (hyperkalemia, metabolic acidosis, salt-wasting and a urinary concentrating defect) and glomerular dysfunction (reduced glomerular filtration rate, currently ~30 mL/min/1.73 m(2), accompanied by proteinuria). To investigate the recurrent and severe hyperkalemia, we performed a patient-tailored functional test and showed that high doses of fludrocortisone induced renal potassium excretion by 155%. Furthermore, fludrocortisone lowered renal sodium excretion by 39%, which would have a mitigating effect on salt-wasting. In addition, urinary pH decreased in response to fludrocortisone. Opposite effects on urinary potassium and pH occurred with administration of amiloride, further supporting the notion that a collecting duct is present and able to react to fludrocortisone. CONCLUSIONS: This report provides living proof that even truncating loss-of-function mutations in AGTR1 are compatible with life and relatively good GFR and provides evidence for the prescription of fludrocortisone to treat hyperkalemia and salt-wasting in such patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00467-021-05018-7

Gender specific effects of the calcium channel TRPV4 on osteoporotic fracture risk and osteoblast-osteoclast coupling

TRPV4 is a member of the transient receptor potential (TRP) superfamily and responds to an array of stimuli, including osmolarity, pH and pressure. Recent findings showing that TRPV4 deficiency leads to reduced sensing of mechanical stimuli led us to explore the role of TRPV4 in bone. TRPV4 mRNA was abundantly expressed in both osteoblasts and osteoclasts as assessed by qPCR. Femoral cortical and trabecular bone mass as assessed by microcomputed tomography was higher in male TRPV4 knockout mice compared to wild type mice. Despite thicker bone structures, cortical porosity was increased in the male TRPV4 knockout mice leading to reduced bone strength as assessed by 3-point bending. Osteoclast and osteoblast differentiation and function was studied, using bone marrow cultures from wildtype and TRPV4 knockout mice. Osteoclast numbers as well as the formation of resorption pits were significantly reduced in cultures of TRPV4 knockout mice compared to wildtype littermates. In contrast, osteoblast differentiation and matrix mineralization was significantly increased in TRPV4 knockout bone marrow cultures. None of these parameters were significantly different in bones and bone marrow cultures of female knock out mice. These data implicate a gender-specific osteoblast–osteoclast uncoupling and support the observed increase in bone mass in male TRPV4 deficient mice. To assess the possible impact of TRPV4 on osteoporotic outcome in humans, we extracted data from the genome-wide association study within the Rotterdam Study. Two single nucleotide polymorphisms (SNPs) in the TRPV4 gene showed strong associations with osteoporotic fracture risk fragility fracture risk and hip fracture risk in men, but not in women. This was not affected after adjusting for height, weight, age and bone mineral density (BMD). In conclusion, TRPV4 plays an important role in male but not female bone biology. Apparently, the increased periosteal bone apposition fails to overcome the increased cortical porosity, leading to reduced bone strength in TRPV4 deficient male mice. In line with the gender-specific findings in mice, variations in the TRPV4 gene are predicting fracture risk in men but not in women

GATA2 heterozygosity causes an epigenetic feedback mechanism resulting in myeloid and erythroid dysplasia

The transcription factor GATA2 has a pivotal role in haematopoiesis. Heterozygous germline GATA2 mutations result in a syndrome characterized by immunodeficiency, bone marrow failure and predispositions to myelodysplastic syndrome (MDS) and acute myeloid leukaemia. Clinical symptoms in these patients are diverse and mechanisms driving GATA2-related phenotypes are largely unknown. To explore the impact of GATA2 haploinsufficiency on haematopoiesis, we generated a zebrafish model carrying a heterozygous mutation of gata2b (gata2b+/−), an orthologue of GATA2. Morphological analysis revealed myeloid and erythroid dysplasia in gata2b+/− kidney marrow. Because Gata2b could affect both transcription and chromatin accessibility during lineage differentiation, this was assessed by single-cell (sc) RNA-seq and single-nucleus (sn) ATAC-seq. Sn-ATAC-seq showed that the co-accessibility between the transcription start site (TSS) and a −3.5–4.1 kb putative enhancer was more robust in gata2b+/− zebrafish HSPCs compared to wild type, increasing gata2b expression and resulting in higher genome-wide Gata2b motif use in HSPCs. As a result of increased accessibility of the gata2b locus, gata2b+/− chromatin was also more accessible during lineage differentiation. scRNA-seq data revealed myeloid differentiation defects, that is, impaired cell cycle progression, reduced expression of cebpa and cebpb and increased signatures of ribosome biogenesis. These data also revealed a differentiation delay in erythroid progenitors, aberrant proliferative signatures and down-regulation of Gata1a, a master regulator of erythropoiesis, which worsened with age. These findings suggest that cell-intrinsic compensatory mechanisms, needed to obtain normal levels of Gata2b in heterozygous HSPCs to maintain their integrity, result in aberrant lineage differentiation, thereby representing a critical step in the predisposition to MDS.</p