ABSTRACT
The Shoc2 scaffold protein is crucial in transmitting signals within the Epidermal Growth Factor Receptor (EGFR)-mediated Extracellular signal-Regulated Kinase (ERK1/2) pathway. While the significance of Shoc2 in this pathway is well-established, the precise mechanisms through which Shoc2 governs signal transmission remain to be fully elucidated. Hereditary variants in Shoc2 are responsible for Noonan Syndrome with Loose anagen Hair (NSLH). However, due to the absence of known enzymatic activity in Shoc2, directly assessing how these variants affect its function is challenging. ERK1/2 phosphorylation is used as a primary parameter of Shoc2 function, but the impact of Shoc2 mutants on the pathway activation is unclear. This study investigates how the NSLH-associated Shoc2 variants influence EGFR signals in the context of the ERK1/2 and AKT downstream signaling pathways. We show that when the ERK1/2 pathway is a primary signaling pathway activated downstream of EGFR, Shoc2 variants cannot upregulate ERK1/2 phosphorylation to the level of the WT Shoc2. Yet, when the AKT and ERK1/2 pathways were activated, in cells expressing Shoc2 variants, ERK1/2 phosphorylation was higher than in cells expressing WT Shoc2. In cells expressing the Shoc2 NSLH mutants, we found that the AKT signaling pathway triggers the PAK activation, followed by phosphorylation of Raf-1/MEK1/2 and activation of the ERK1/2 signaling axis. Hence, our studies reveal a previously unrecognized feedback regulation downstream of the EGFR and provide additional evidence for the role of Shoc2 as a "gatekeeper" in controlling the selection of downstream effectors within the EGFR signaling network.
ABSTRACT
BACKGROUND: Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure. METHODS: People aged 0-96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan-Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 m2 (the therapeutic trial window). FINDINGS: Between Jan 18, 2010, and July 25, 2022, 27â285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9-16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<0·0001), but better survival rates (standardised mortality ratio 0·42 [95% CI 0·32-0·52]; p<0·0001). Median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window all varied substantially between rare diseases. INTERPRETATION: Patients with rare kidney diseases differ from the general population of individuals with chronic kidney disease: they have higher 5-year rates of kidney failure but higher survival than other patients with chronic kidney disease stages 3-5, and so are over-represented in the cohort of patients requiring kidney replacement therapy. Addressing unmet therapeutic need for patients with rare kidney diseases could have a large beneficial effect on long-term kidney replacement therapy demand. FUNDING: RaDaR is funded by the Medical Research Council, Kidney Research UK, Kidney Care UK, and the Polycystic Kidney Disease Charity.
Subject(s)
Kidney Failure, Chronic , Renal Insufficiency, Chronic , Renal Insufficiency , Humans , Glomerular Filtration Rate , Kidney , Kidney Failure, Chronic/epidemiology , Kidney Failure, Chronic/therapy , Kidney Failure, Chronic/etiology , Radar , Rare Diseases , Registries , Renal Insufficiency/epidemiology , Renal Insufficiency, Chronic/epidemiology , Renal Insufficiency, Chronic/therapy , Renal Insufficiency, Chronic/complications , United Kingdom/epidemiology , Infant, Newborn , Infant , Child, Preschool , Child , Adolescent , Young Adult , Adult , Middle Aged , Aged , Aged, 80 and overABSTRACT
The ERK1/2 (also known as MAPK3 and MAPK1, respectively) signaling pathway is critical in organismal development and tissue morphogenesis. Deregulation of this pathway leads to congenital abnormalities with severe developmental dysmorphisms. The core ERK1/2 cascade relies on scaffold proteins, such as Shoc2 to guide and fine-tune its signals. Mutations in SHOC2 lead to the development of the pathology termed Noonan-like Syndrome with Loose Anagen Hair (NSLAH). However, the mechanisms underlying the functions of Shoc2 and its contributions to disease progression remain unclear. Here, we show that ERK1/2 pathway activation triggers the interaction of Shoc2 with the ubiquitin-specific protease USP7. We reveal that, in the Shoc2 module, USP7 functions as a molecular 'switch' that controls the E3 ligase HUWE1 and the HUWE1-induced regulatory feedback loop. We also demonstrate that disruption of Shoc2-USP7 binding leads to aberrant activation of the Shoc2-ERK1/2 axis. Importantly, our studies reveal a possible role for USP7 in the pathogenic mechanisms underlying NSLAH, thereby extending our understanding of how ubiquitin-specific proteases regulate intracellular signaling.
Subject(s)
Loose Anagen Hair Syndrome , MAP Kinase Signaling System , Noonan Syndrome , Ubiquitin-Specific Peptidase 7 , Humans , Intracellular Signaling Peptides and Proteins , MAP Kinase Signaling System/genetics , Noonan Syndrome/genetics , Signal Transduction , Tumor Suppressor Proteins , Ubiquitin-Protein Ligases , Ubiquitin-Specific Peptidase 7/geneticsABSTRACT
BACKGROUND: Hospice-at-home aims to enable patients approaching end-of-life to die at home and support their carers. A wide range of different service models exists but synthesised evidence on how best to support family carers to provide sustainable end-of-life care at home is limited. AIM: To explore what works best to promote family carers' experiences of hospice-at-home. DESIGN: Realist evaluation with mixed methods. This paper focuses on qualitative interviews with carers (to gain their perspective and as proxy for patients) and service providers from 12 case study sites in England. Interviews were coded and programme theories were refined by the research team including two public members. SETTING/PARTICIPANTS: Interviews with carers (involved daily) of patients admitted to hospice-at-home services (n = 58) and hospice-at-home staff (n = 78). RESULTS: Post bereavement, 76.4% of carers thought that they had received as much help and support as they needed and most carers (75.8%) rated the help and support as excellent or outstanding. Of six final programme theories capturing key factors relevant to providing optimum services, those directly relevant to carer experiences were: integration and co-ordination of services; knowledge, skills and ethos of hospice staff; volunteer roles; support directed at the patient-carer dyad. CONCLUSIONS: Carers in hospice-at-home services identified care to be of a higher quality than generic community services. Hospice staff were perceived as having 'time to care', communicated well and were comfortable with dying and death. Hands-on care was particularly valued in the period close to death.
Subject(s)
Home Care Services , Hospice Care , Terminal Care , Humans , Caregivers , Palliative Care/methodsABSTRACT
Health Promoting Universities (HPUs) are more likely to perform actions intended to change habits and increase personal empowerment, than they are to develop community actions. The objective of this research is to create an asset map to visualize collective actions in a Chilean HPU. A qualitative study, based on the ABCD model was conducted. There were 149 people, distributed into 48 semi-structured interviews and 14 focus groups, who participated in this study (students, employees, ex-students and retirees). An asset map was elaborated, identifying the contributions of residents, associations and organizations, local institutions, physical resources, economic assets and local culture and with a new category, 'connecting assets'. These categories show the range of resources in a university. According to the participants, the questions on asset identification were a tool for reflection, and by giving their opinions and discovering or drawing attention to new resources, they gained a better understanding of the assets in the university. Several participants stated that these talks could generate a positive emotional environment, which boosted their wellbeing. There were gender- and group-based differences in how the assets were valued. Students stressed assets related to services and benefits from the institution, green areas, and collective spaces. Employees, retirees and ex-students emphasized assets related to belonging, identity and traditions. Men appreciated openness and privacy in physical spaces. Women highlighted assets related to the institution. The resulting map, displays a range of resources that can help the university develop new possibilities for comprehensive and collective actions that would revitalize the HPU strategy.
Subject(s)
Students , Universities , Chile , Female , Health Promotion/methods , Humans , Male , Qualitative ResearchABSTRACT
Physical activity (PA) contributes to health throughout life. In particular, young people can benefit from this. Schools can play a key role in providing learning conditions to experience meaningful PAs aimed at inspiring students to lifelong PA. In this article, we argue the need for a salutogenic approach in schools focussing on respecting and enhancing adolescents' agency with regard to their PA. This approach entails listening to adolescents' perspectives and inviting them to participate in actively designing and carrying out PA as a prerequisite for their inclusive engagement. We unpack the concept of agency by drawing on insights from the Capability Approach. This provides input for the integration of agency in health promoting schools and salutogenic approaches, to enhance PA-related agency. Finally, we outline a research agenda to, eventually, create opportunities for students in schools to expand their PA-related agency. Lay Summary Physical activity (PA) contributes to health throughout life. Schools can play a key role in fostering meaningful PA experiences to inspire students to lifelong PA. This requires schools to focus on students' personal aspirations, providing them with the space to develop their autonomy and find opportunities to decide and act upon expanding their agency with respect to the physically active lifestyles they deem meaningful.
Subject(s)
Adolescent Behavior , Sense of Coherence , Adolescent , Exercise , Humans , Schools , StudentsABSTRACT
Different models of care in context of chronicity and multimorbidity include community, health system, clinical practice, health policies, prevention, and health promotion. Among these, the role of the health team as a facilitator of self-management is pointed out, being people the protagonists of their process. Multimorbidity approach is mostly carried out from a risk and disease focused point of view, which limits the exploration of resources of people and their environment. Incorporating a positive health approach can contribute to a greater comprehensiveness. The purpose of this article is to propose an approach from the synergy model of health, integrating salutogenesis and health assets model, to help facilitate self-management promoting people's agency capacity. Potential areas of application of these models are presented to work in the context of multimorbidity, promoting health and well-being conditions in people and their families.
Subject(s)
Self-Management , Sense of Coherence , Health Policy , Health Promotion , Humans , MultimorbidityABSTRACT
AMP-activated protein kinase (AMPK) plays a key role in the cellular response to low energy stress and has emerged as an attractive therapeutic target for tackling metabolic diseases. Whilst significant progress has been made regarding the physiological role of AMPK, its function in the kidney remains only partially understood. We use a mouse model expressing a constitutively active mutant of AMPK to investigate the effect of AMPK activation on kidney function in vivo. Kidney morphology and changes in gene and protein expression were monitored and serum and urine markers were measured to assess kidney function in vivo. Global AMPK activation resulted in an early-onset polycystic kidney phenotype, featuring collecting duct cysts and compromised renal function in adult mice. Mechanistically, the cystic kidneys had increased cAMP levels and ERK activation, increased hexokinase I (Hk I) expression, glycogen accumulation and altered expression of proteins associated with autophagy. Kidney tubule-specific activation of AMPK also resulted in a polycystic phenotype, demonstrating that renal tubular AMPK activation caused the cystogenesis. Importantly, human autosomal dominant polycystic kidney disease (ADPKD) kidney sections revealed similar protein localisation patterns to that observed in the murine cystic kidneys. Our findings show that early-onset chronic AMPK activation leads to a polycystic kidney phenotype, suggesting dysregulated AMPK signalling is a contributing factor in cystogenesis.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Kidney/enzymology , Polycystic Kidney Diseases/enzymology , AMP-Activated Protein Kinases/genetics , Adult , Age Factors , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Cyclic AMP/metabolism , Energy Metabolism , Enzyme Activation , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Genetic Predisposition to Disease , Hexokinase/metabolism , Humans , Kidney/pathology , Male , Mice, Transgenic , Phenotype , Polycystic Kidney Diseases/genetics , Polycystic Kidney Diseases/pathology , Polycystic Kidney, Autosomal Dominant/enzymology , Polycystic Kidney, Autosomal Dominant/genetics , Polycystic Kidney, Autosomal Dominant/pathology , Signal TransductionABSTRACT
This article proposes to advance the connections between salutogenic theory and assets models for health improvement. There is a need to integrate their use in public health and health promotion so that their respective potentials can be fully developed. This requires their synergies to be made more explicit so that a more coherent approach can be taken to their utilization. A mechanism is therefore needed that helps to raise awareness of them and their value as a resource together. Bronfenbrenner's bioecological theory provides one framework that can support better integration of salutogenesis with the applied nature of assets-based models. This paper proposes a new 'synergy model for health' that integrates key concepts associated with salutogenic theory-generalized and specific resistance resources (GRRs/SRRs) and generalized and specific resistance deficits and the sense of coherence (SOC). In doing so, it highlights those GRRs and SRRs which are assets that, either individually or collectively, help to develop a stronger SOC. Higher levels of SOC can then support the transformations of potential resources into available assets (that people can understand, manage and make sense of), capable of producing positive health development. The proposed 'Synergy model of health' aims to contribute to a deeper theoretical understanding of health and development through the integration of the key elements of both salutogenesis and assets models. This can facilitate a better contextualization of the ideas into public health policy and practice by making the salutogenic theory more action-oriented and the assets model more theoretical.
Subject(s)
Sense of Coherence , Health Promotion , Humans , Public HealthABSTRACT
Background: Amidst this global pandemic, the impact on accessing care and support for cancer survivors in Australia is uncertain and unknown. The purpose of the current study is to explore the impact that COVID-19 had on Australian rural/regional cancer survivors and their ability to access health services, treatment, and supportive care during this pandemic.Methods: Cancer survivors (n = 66) completed an online survey regarding the impact of COVID-19 on their access to medical and support services.Results: Findings indicated that COVID-19 had a significant impact on the lives of cancer survivors with the biggest challenges being reduced social support and the inability to see their health care providers. Findings also revealed that older participants reported greater impact and distress due to COVID-19.Conclusions: In order to ensure that the health and support needs of cancer survivors are not negatively impacted, providers of psychosocial support may need to make strategic changes in the provision of access to health and support services.
Subject(s)
COVID-19 , Cancer Survivors/psychology , Health Services Accessibility , Neoplasms/psychology , Neoplasms/therapy , Psychological Distress , Social Support , Adult , Aged , Australia , Female , Humans , Male , Middle Aged , Rural PopulationABSTRACT
BACKGROUND: We have undertaken a systematically searched literature review using a realist logic of analysis to help synthesise the diverse range of literature available on hospice at home services. AIM: To find out in the existing literature what features of hospice at home models work best, for whom and under what circumstances. DESIGN: A realist logic of analysis was applied to synthesise the evidence focusing on mechanisms by which an intervention worked (or did not work). An initial programme theory was developed using the National Association for Hospice at Home standards, Normalisation Process Theory and through refinement using stakeholder engagement. DATA SOURCES: PubMed, Science Direct, AMED, BNI, CINAHL, EMBASE, Health Business Elite, HMIC, Medline, PsychINFO, SCOPUS, Web of Science, DARE, Google Scholar, NHS Evidence, NIHR CRN portfolio database, NIHR journal library of funded studies, including searches on websites of relevant professional bodies (August 2014, June 2017, June 2019). RESULTS: Forty-nine papers were reviewed, of which 34 contributed evidence to at least one of the eight theory areas: marketing and referral, sustainable funding model, service responsiveness and availability, criteria for service admission, knowledge and skills of care providers, integration and coordination, anticipatory care, support directed at carers. CONCLUSIONS: Our literature review showed how it was possible to develop a coherent framework and test it against 34 published papers and abstracts. Central to this review was theory building, and as further evidence emerges, our programme theories can be refined and tested against any new empirical evidence.
Subject(s)
Home Care Services , Hospice Care , Terminal Care , Humans , Logistic Models , Palliative CareABSTRACT
Objective- SAA (serum amyloid A) is a family of acute-phase reactants that have proinflammatory and proatherogenic activities. SAA is more lipophilic than apoA-I (apolipoprotein A-I), and during an acute-phase response, <10% of plasma SAA is found lipid-free. In most reports, SAA is found exclusively associated with high-density lipoprotein; however, we and others have reported SAA on apoB (apolipoprotein B)-containing lipoproteins in both mice and humans. The goal of this study was to determine whether SAA is an exchangeable apolipoprotein. Approach and Results- Delipidated human SAA was incubated with SAA-free human lipoproteins; then, samples were reisolated by fast protein liquid chromatography, and SAA analyzed by ELISA and immunoblot. Both in vitro and in vivo, we show that SAA associates with any lipoprotein and does not remain in a lipid-free form. Although SAA is preferentially found on high-density lipoprotein, it can exchange between lipoproteins. In the presence of CETP (cholesterol ester transfer protein), there is greater exchange of SAA between lipoproteins. Subjects with diabetes mellitus, but not those with metabolic syndrome, showed altered SAA lipoprotein distribution postprandially. Proteoglycan-mediated lipoprotein retention is thought to be an underlying mechanism for atherosclerosis development. SAA has a proteoglycan-binding domain. Lipoproteins containing SAA had increased proteoglycan binding compared with SAA-free lipoproteins. Conclusions- Thus, SAA is an exchangeable apolipoprotein and increases apoB-containing lipoproteins' proteoglycan binding. We and others have previously reported the presence of SAA on low-density lipoprotein in individuals with obesity, diabetes mellitus, and metabolic syndrome. We propose that the presence of SAA on apoB-containing lipoproteins may contribute to cardiovascular disease development in these populations.
Subject(s)
Apolipoproteins/metabolism , Serum Amyloid A Protein/metabolism , Aged , Animals , Apolipoprotein B-100/metabolism , Apolipoproteins/blood , Cholesterol Ester Transfer Proteins/genetics , Cholesterol Ester Transfer Proteins/metabolism , Diabetes Mellitus/blood , Female , Humans , Lipoproteins, HDL/metabolism , Male , Metabolic Syndrome/blood , Mice, Inbred C57BL , Mice, Knockout, ApoE , Middle Aged , Obesity/blood , Postprandial Period , Protein Binding , Protein Interaction Domains and Motifs , Proteoglycans/metabolism , Serum Amyloid A Protein/deficiency , Serum Amyloid A Protein/geneticsABSTRACT
BACKGROUND: Stroke is the fourth largest cause of death in the UK and a leading cause of death and disability worldwide. Policy recommends reviewing patients at six-months post-stroke to identify unmet needs but lacks evidence of effectiveness. This study explored needs identified by patients, how they were addressed by the six-month review (6MR) and whether or not policy aspirations for the review were substantiated by the data. METHODS: A multiple case study design underpinned by critical realism. Data sources included interviews with 46 patients and 28 professionals across three sites in the South East Coast of England. Patients' interviews coincided with their reviews of which twenty-nine were observed. Thematic analysis of interviews, observations and policy documents was carried out within and across sites. RESULTS: There were 'hotspots' in the care pathway where patients and carers felt particularly unsupported. Whilst these gaps exacerbated anxiety, they were neither universal nor ameliorated by review. Patients consistently identified unmet needs related to rehabilitation, information/education and support. Stroke nurse specialists focused on investigations, medication and liaising with general practitioners or consultants while the Stroke Association co-ordinator focused on sign-posting to other services and provision of generic information which not all respondents found helpful. The remit of review was more modest than that of policy aspirations. CONCLUSIONS: The review rests on two causal assumptions: that identifying unmet need will lead to its amelioration; and that provision of information will lead to behaviour change and self-management. While there was some evidence to support the former, there was almost none for the latter. The 6MR would benefit from a patient-led approach to its timing and format; a consistent and individualised approach to stroke education and self-management that is embedded across the care pathway; and targeting reviews should be considered.
Subject(s)
Health Services Needs and Demand , Stroke Rehabilitation , England , Humans , Policy MakingABSTRACT
BACKGROUND: Health care systems are increasingly moving towards more integrated approaches. Shared decision making (SDM) is central to these models but may be complicated by the need to negotiate and communicate decisions between multiple providers, as well as patients and their family carers; particularly for older people with complex needs. The aim of this review was to provide a context relevant understanding of how interventions to facilitate SDM might work for older people with multiple health and care needs, and how they might be applied in integrated care models. METHODS: Iterative, stakeholder driven, realist synthesis following RAMESES publication standards. It involved: 1) scoping literature and stakeholder interviews (n = 13) to develop initial programme theory/ies, 2) systematic searches for evidence to test and develop the theories, and 3) validation of programme theory/ies with stakeholders (n = 11). We searched PubMed, The Cochrane Library, Scopus, Google, Google Scholar, and undertook lateral searches. All types of evidence were included. RESULTS: We included 88 papers; 29 focused on older people or people with complex needs. We identified four context-mechanism-outcome configurations that together provide an account of what needs to be in place for SDM to work for older people with complex needs. This includes: understanding and assessing patient and carer values and capacity to access and use care, organising systems to support and prioritise SDM, supporting and preparing patients and family carers to engage in SDM and a person-centred culture of which SDM is a part. Programmes likely to be successful in promoting SDM are those that allow older people to feel that they are respected and understood, and that engender confidence to engage in SDM. CONCLUSIONS: To embed SDM in practice requires a radical shift from a biomedical focus to a more person-centred ethos. Service providers will need support to change their professional behaviour and to better organise and deliver services. Face to face interactions, permission and space to discuss options, and continuity of patient-professional relationships are key in supporting older people with complex needs to engage in SDM. Future research needs to focus on inter-professional approaches to SDM and how families and carers are involved.
Subject(s)
Caregivers/trends , Decision Making , Health Status , Needs Assessment/trends , Professional-Patient Relations , Social Support , Caregivers/psychology , HumansABSTRACT
Hyperinsulinemic hypoglycemia (HI) and congenital polycystic kidney disease (PKD) are rare, genetically heterogeneous disorders. The co-occurrence of these disorders (HIPKD) in 17 children from 11 unrelated families suggested an unrecognized genetic disorder. Whole-genome linkage analysis in five informative families identified a single significant locus on chromosome 16p13.2 (logarithm of odds score 6.5). Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, we found in all patients a promoter mutation (c.-167G>T) in the phosphomannomutase 2 gene (PMM2), either homozygous or in trans with PMM2 coding mutations. PMM2 encodes a key enzyme in N-glycosylation. Abnormal glycosylation has been associated with PKD, and we found that deglycosylation in cultured pancreatic ß cells altered insulin secretion. Recessive coding mutations in PMM2 cause congenital disorder of glycosylation type 1a (CDG1A), a devastating multisystem disorder with prominent neurologic involvement. Yet our patients did not exhibit the typical clinical or diagnostic features of CDG1A. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2 We propose that the PMM2 promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.
Subject(s)
Congenital Hyperinsulinism/complications , Congenital Hyperinsulinism/genetics , Mutation , Phosphotransferases (Phosphomutases)/genetics , Polycystic Kidney Diseases/complications , Polycystic Kidney Diseases/genetics , Promoter Regions, Genetic/genetics , Child, Preschool , Female , Humans , Infant , Infant, Newborn , MaleABSTRACT
Animal studies demonstrate that hyperlipidemia and renal lipid accumulation contribute to the pathogenesis of diabetic nephropathy (DN). We previously demonstrated that renal lipoproteins colocalize with biglycan, a renal proteoglycan. The purpose of this study was to determine whether prevention of renal lipid (apoB) accumulation attenuates DN. Biglycan-deficient and biglycan wild-type Ldlr-/- mice were made diabetic via streptozotocin and fed a high cholesterol diet. As biglycan deficiency is associated with elevated transforming growth factor-ß (TGF-ß), in some experiments mice were injected with either the TGF-ß-neutralizing antibody, 1D11, or with 13C4, an irrelevant control antibody. Biglycan deficiency had no significant effect on renal apoB accumulation, but led to modest attenuation of DN with â¼30% reduction in albuminuria; however, biglycan deficiency caused a striking elevation in TGF-ß. Use of 1D11 led to sustained suppression of TGF-ß for approximately 8 weeks at a time. The 1D11 treatment caused decreased renal apoB accumulation, decreased albuminuria, decreased renal hypertrophy, and improved survival, compared with the 13C4 treatment. Thus, prevention of renal apoB accumulation is protective against development of DN. Furthermore, this study demonstrates that prevention of renal apoB accumulation is a mechanism by which TGF-ß inhibition is nephroprotective.
Subject(s)
Albuminuria/drug therapy , Apolipoproteins B/genetics , Diabetes Mellitus, Experimental/drug therapy , Diabetic Nephropathies/drug therapy , Transforming Growth Factor beta/genetics , Albuminuria/genetics , Albuminuria/metabolism , Albuminuria/pathology , Animals , Antibodies, Neutralizing/pharmacology , Apolipoprotein B-100 , Apolipoproteins B/metabolism , Biglycan/deficiency , Biglycan/genetics , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/metabolism , Diabetic Nephropathies/genetics , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Diet, High-Fat/adverse effects , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, LDL/deficiency , Receptors, LDL/genetics , Streptozocin , Survival Analysis , Transforming Growth Factor beta/antagonists & inhibitors , Transforming Growth Factor beta/metabolismABSTRACT
BACKGROUND: Accurate determination of causes of stillbirth is critical to effective prevention. Autopsy remains the gold standard investigation for stillbirth; however, with low autopsy rates many stillbirths are likely to be 'unexplored' rather than 'unexplained'. AIM: To determine factors associated with autopsy following stillbirth. MATERIALS AND METHODS: Routinely collected population-based data on all singleton stillbirths of at least 400 g birthweight or 20 weeks gestation in Queensland between July 2000 and December 2011 were examined. Adjusted odds ratios (aOR, 99% CI) were calculated accounting for sociodemographic, pregnancy and medical factors. Of interest was initially unexplained stillbirth on the death certificate; analysis was stratified by gestational age group (<24, 24-27, 28-36 and ≥37 weeks). RESULTS: Of 3842 singleton stillbirths included in these analyses, 1356 (35.3%) had an autopsy performed. Initially unexplained stillbirth was associated with decreased odds of autopsy at late gestation (28-36 weeks, aOR 0.63 (99% CI 0.42-0.93); ≥37 weeks, aOR 0.53 (99% CI 0.35-0.81)) as was intrapartum stillbirth (<24 weeks, aOR 0.63 (99% CI 0.43-0.94); 28-36 weeks, aOR 0.37 (99% CI 0.14-0.98)). Congenital abnormality (<24 weeks, ≥37 weeks), small-for-gestational age (<24 weeks), and primigravidity (≥37 weeks) were associated with increased odds of autopsy following stillbirth. CONCLUSIONS: Pregnancy factors are associated with stillbirth autopsy. These findings have implications for development of appropriate information for parents and education of clinical staff. Further research is needed into factors influencing autopsy following stillbirth.
Subject(s)
Autopsy/statistics & numerical data , Stillbirth , Adolescent , Adult , Congenital Abnormalities/diagnosis , Female , Forecasting , Gestational Age , Humans , Infant, Small for Gestational Age , Parity , Pregnancy , Queensland , Young AdultABSTRACT
AIM: Suicide from depression is the second leading cause of death in young people. To better understand depression, a concept analysis was conducted using the Lorraine Walker and Kay Avant method. SOURCE OF DATA: Three electronic databases searched using keywords such as depress*, stigma, and feeling depressed yielded 40 articles in English from 2006 through 2016. RESULTS: Primary attribute was depressed mood; stress was the primary antecedent found in young people. Consequences included health, emotional, and financial well-being. CONCLUSION: A better understanding of depression by healthcare providers can foster quicker assessment and treatment in young people and impact final outcome-suicide.
Subject(s)
Depression/psychology , Adolescent , Depression/diagnosis , Depression/etiology , Health Status , Humans , Social Stigma , Stress, Psychological/complications , Stress, Psychological/psychology , Young AdultABSTRACT
Biomarkers, the measurable indicators of biological conditions, are fast becoming a popular approach in providing information to track disease processes that could lead to novel therapeutic interventions for chronic conditions. Inherited, chronic kidney disease affects millions of people worldwide and although pharmacological treatments exist for some conditions, there are still patients whose only option is kidney dialysis and kidney transplantation. In the past 10 years, certain chronic kidney diseases have been reclassified as ciliopathies. Cilia in the kidney are antenna-like, sensory organelles that are required for signal transduction. One of the signalling pathways that requires the primary cilium in the kidney is Wnt signalling and it has three components such as canonical Wnt, non-canonical Wnt/planar cell olarity (PCP) and non-canonical Wnt/Ca2+ signalling. Identification of the novel role of ATM INteractor (ATMIN) as an effector molecule in the non-canonical Wnt/PCP pathway has intrigued us to investigate its potential role in chronic kidney disease. ATMIN could thus be an important biomarker in disease prognosis and treatment that might lighten the burden of chronic kidney disease and also affect on its progression.
Subject(s)
Biomarkers/metabolism , Cilia/metabolism , Kidney Diseases/metabolism , Polycystic Kidney Diseases/metabolism , Transcription Factors/metabolism , Wnt Signaling Pathway , Disease Progression , Humans , Kidney Diseases/therapy , Models, Biological , Polycystic Kidney Diseases/therapy , PrognosisABSTRACT
BACKGROUND: Stillbirths and neonatal deaths are devastating events for both parents and clinicians and are global public health concerns. Careful clinical management after these deaths is required, including appropriate investigation and assessment to determine cause (s) to prevent future losses, and to improve bereavement care for families. An educational programme for health care professionals working in maternal and child health has been designed to address these needs according to the Perinatal Society of Australia and New Zealand Guideline for Perinatal Mortality: IMproving Perinatal mortality Review and Outcomes Via Education (IMPROVE). The programme has a major focus on stillbirth and is delivered as six interactive skills-based stations. We aimed to determine participants' pre- and post-programme knowledge of and confidence in the management of perinatal deaths, along with satisfaction with the programme. We also aimed to determine suitability for international use. METHODS: The IMPROVE programme was delivered to health professionals in maternity hospitals in all seven Australian states and territories and modified for use internationally with piloting in Vietnam, Fiji, and the Netherlands (with the assistance of the International Stillbirth Alliance, ISA). Modifications were made to programme materials in consultation with local teams and included translation for the Vietnam programme. Participants completed pre- and post-programme evaluation questionnaires on knowledge and confidence on six key components of perinatal death management as well as a satisfaction questionnaire. RESULTS: Over the period May 2012 to May 2015, 30 IMPROVE workshops were conducted, including 26 with 758 participants in Australia and four with 136 participants internationally. Evaluations showed a significant improvement between pre- and post-programme knowledge and confidence in all six stations and overall, and a high degree of satisfaction in all settings. CONCLUSIONS: The IMPROVE programme has been well received in Australia and in three different international settings and is now being made available through ISA. Future research is required to determine whether the immediate improvements in knowledge are sustained with less causes of death being classified as unknown, changes in clinical practice and improvement in parents' experiences with care. The suitability for this programme in low-income countries also needs to be established.