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1.
J Am Soc Nephrol ; 2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38913441

ABSTRACT

BACKGROUND: Losing or donating a kidney is associated with risks of developing hypertension and albuminuria. Few studies address mechanisms or interventions. We investigate potential benefits of a K+- alkali-enriched diet and the mechanisms underlying proteinuria. METHODS: Male Sprague Dawley rats were fed either a 2% NaCl + 0.95% KCl diet (HNa-LK) or a 0.74% NaCl + 3% K+-alkali diet (HK-alk) for 3 wk prior to uninephrectomy then maintained on respective diets for 12 wk. Blood pressure (by tail-cuff), urine, blood and kidney proteins were analyzed Pre- and Post-uninephrectomy. RESULTS: Pre-uninephrectomy, HK-alk vs. HNa-LK fed rats exhibited similar blood pressures and plasma [K+], [Na+], but lower proximal (NHE3, NBCe1, NaPi2) and higher distal (NCC, ENaC, pendrin) transporter abundance, a pattern facilitating K+ and HCO3- secretion. Post-uninephrectomy, single nephron GFR rose 50% and Li+ clearance doubled with both diets; in HK-alk vs HNa-LK: the rise in blood pressure was less and ammoniagenesis was lower, abundance of proximal tubule transporters remained lower, ENaC-α fell and NCCp rose consistent with K+ conservation. Post-uninephrectomy, independent of diet, albuminuria increased 8-fold and abundance of endocytic receptors was reduced (megalin by 44%, dab2 by 25-35%) and KIM-1 was increased. CONCLUSIONS: The K-alkali-enriched diet blunted post-uninephrectomy hypertension and facilitated acid clearance by suppressing proximal Na+ transporters and increasing K+ -alkali secretion. Further, uninephrectomy associated proteinuria could be attributed, at least in part, to elevated SNGFR coupled to downregulation of megalin which reduced fractional protein endocytosis and Vmax.

2.
Cell Stem Cell ; 31(6): 921-939.e17, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38692273

ABSTRACT

Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional units of the kidney. Here, manipulation of p38 and YAP activity allowed for long-term clonal expansion of primary mouse and human NPCs and induced NPCs (iNPCs) from human pluripotent stem cells (hPSCs). Molecular analyses demonstrated that cultured iNPCs closely resemble primary human NPCs. iNPCs generated nephron organoids with minimal off-target cell types and enhanced maturation of podocytes relative to published human kidney organoid protocols. Surprisingly, the NPC culture medium uncovered plasticity in human podocyte programs, enabling podocyte reprogramming to an NPC-like state. Scalability and ease of genome editing facilitated genome-wide CRISPR screening in NPC culture, uncovering genes associated with kidney development and disease. Further, NPC-directed modeling of autosomal-dominant polycystic kidney disease (ADPKD) identified a small-molecule inhibitor of cystogenesis. These findings highlight a broad application for the reported iNPC platform in the study of kidney development, disease, plasticity, and regeneration.


Subject(s)
Nephrons , Organoids , Animals , Organoids/cytology , Organoids/metabolism , Humans , Nephrons/cytology , Mice , Cell Differentiation , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/cytology , Podocytes/metabolism , Podocytes/cytology , Kidney/pathology , Polycystic Kidney, Autosomal Dominant/pathology , Polycystic Kidney, Autosomal Dominant/metabolism , Polycystic Kidney, Autosomal Dominant/genetics , Models, Biological , Gene Editing
3.
Biomacromolecules ; 25(5): 2749-2761, 2024 May 13.
Article in English | MEDLINE | ID: mdl-38652072

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD) is a complex disorder characterized by uncontrolled renal cyst growth, leading to kidney function decline. The multifaceted nature of ADPKD suggests that single-pathway interventions using individual small molecule drugs may not be optimally effective. As such, a strategy encompassing combination therapy that addresses multiple ADPKD-associated signaling pathways could offer synergistic therapeutic results. However, severe off-targeting side effects of small molecule drugs pose a major hurdle to their clinical transition. To address this, we identified four drug candidates from ADPKD clinical trials, bardoxolone methyl (Bar), octreotide (Oct), salsalate (Sal), and pravastatin (Pra), and incorporated them into peptide amphiphile micelles containing the RGD peptide (GRGDSP), which binds to the basolateral surface of renal tubules via integrin receptors on the extracellular matrix. We hypothesized that encapsulating drug combinations into RGD micelles would enable targeting to the basolateral side of renal tubules, which is the site of disease, via renal secretion, leading to superior therapeutic benefits compared to free drugs. To test this, we first evaluated the synergistic effect of drug combinations using the 20% inhibitory concentration for each drug (IC20) on renal proximal tubule cells derived from Pkd1flox/-:TSLargeT mice. Next, we synthesized and characterized the RGD micelles encapsulated with drug combinations and measured their in vitro therapeutic effects via a 3D PKD growth model. Upon both IV and IP injections in vivo, RGD micelles showed a significantly higher accumulation in the kidneys compared to NT micelles, and the renal access of RGD micelles was significantly reduced after the inhibition of renal secretion. Specifically, both Bar+Oct and Bar+Sal in the RGD micelle treatment showed enhanced therapeutic efficacy in ADPKD mice (Pkd1fl/fl;Pax8-rtTA;Tet-O-Cre) with a significantly lower KW/BW ratio and cyst index as compared to PBS and free drug-treated controls, while other combinations did not show a significant difference. Hence, we demonstrate that renal targeting through basolateral targeting micelles enhances the therapeutic potential of combination therapy in genetic kidney disease.


Subject(s)
Drug Delivery Systems , Micelles , Animals , Mice , Drug Delivery Systems/methods , Humans , Polycystic Kidney, Autosomal Dominant/drug therapy , Polycystic Kidney, Autosomal Dominant/pathology , Oligopeptides/chemistry , Polycystic Kidney Diseases/drug therapy , Polycystic Kidney Diseases/pathology
4.
Hematol Rep ; 16(1): 140-150, 2024 Mar 12.
Article in English | MEDLINE | ID: mdl-38534885

ABSTRACT

BACKGROUND: Second- and third-generation tyrosine kinase inhibitors (TKIs) are now available to treat chronic-phase chronic myeloid leukemia (CP-CML) in the first and second line. However, vascular adverse events (VAEs) have been reported for patients with CML treated with some TKIs. METHODS: We retrospectively evaluated the cumulative incidence (CI) and cardiovascular risk for 210 patients included in the Canarian Registry of CML. RESULT: With a mean follow up of 6 years, 19/210 (9.1%) patients developed VAEs, all of whom presented at least one cardiovascular risk factor at diagnosis. The mean time to VAE presentation was 54 months from the start of TKI treatment. We found a statistically significant difference between the CI for nilotinib-naïve vs. nilotinib-treated patients (p = 0.005), between dasatinib-naïve and dasatinib-treated patients (p = 0.039), and for patients who received three lines of treatment with first-line imatinib vs. first-line imatinib (p < 0.001). From the multivariable logistic regression analyses, the Framingham risk score (FRS) and patients with three lines of TKI with first-line imatinib were the only variables with statistically significant hazard ratios for VAE development. Significant increases in HDL-C and total cholesterol may also be predictive for VAE. CONCLUSIONS: In conclusion, it is important to estimate the cardiovascular risk at the diagnosis of CML as it can help determine whether a patient is likely to develop a VAE during TKI treatment.

5.
Aten. prim. (Barc., Ed. impr.) ; 56(2): [102807], Feb. 2024. ilus, tab, graf
Article in English | IBECS | ID: ibc-230391

ABSTRACT

Aims:The aim of this study is to analyse the effect of pharmacological and non-pharmacological treatment on weight control in patients with diabetes and obesity. Design: Epidemiological, descriptive, cross-sectional study. Site: Primary care. In 11 health centres in Málaga and Cádiz during April and October 2022. Participants: 281 patients over 18 years old with type 2 diabetes and obesity are included. Main measurements: Socio-demographics, clinical, treatment and lifestyle habits variables were obtained from medical records and personal interview. Descriptive statistics were obtained for continuous variables. Statistical tests were performed based on the nature of the variables. Results: Variables like marital status, level of education and occupation, and smoking habit, shows differences regarding the sex (p<0.05). 82.3% of those who received education lost weight, compared to 67.5% of lost weight who received no health education (p=0.004). GLP1 and SGLT2 were more commonly prescribed for women (p=0.048), and SGLT2 more commonly prescribed for men (p=0.047). Patients taking GLP1, SGLT2 or both, regardless of sex, weight loss during the study period was −3.1kg (SE: 0.60), while the loss of those who took other medications was −1.33kg (SE: 0.62). The mean difference was 1.75kg (p=0.046). Conclusions: In terms of weight loss, obese diabetics who took GLP1, SGLT2 or both were 2.5 times more likely to lose weight than those who did not. Healthy lifestyle choices are key to weight loss in obese diabetic patients.(AU)


Objetivo: Analizar el efecto del tratamiento farmacológico y no farmacológico en el control del peso en pacientes diabéticos obesos. Diseño: Estudio epidemiológico, descriptivo y transversal. Emplazamiento: Atención primaria: 11 centros de salud en Málaga y Cádiz durante abril y octubre de 2022. Participantes: Fueron incluidos 281 pacientes mayores de 18 años con diabetes tipo 2 y obesidad. Mediciones principales: Se obtuvieron variables sociodemográficas, clínicas, de tratamiento y de hábitos de vida a partir de registros médicos de entrevistas personales. Se obtuvieron estadísticos descriptivos para variables continuas. Se realizaron pruebas estadísticas en función de la naturaleza de las variables. Resultados: Variables como el estado civil, el nivel educativo, la ocupación y el hábito de fumar mostraron diferencias dependiendo del sexo (p<0,05). El 82,3% de los que recibieron educación sobre salud perdieron peso en comparación con el 67,5% de los que perdieron peso y no la recibieron (p=0,004). Los medicamentos GLP1 y SGLT2 se recetaron con mayor frecuencia a las mujeres (p=0,048), mientras que los SGLT2 se prescribieron más en hombres (p=0,047). Los pacientes que tomaron GLP1, SGLT2 o ambos, independientemente del sexo, perdieron 3,1kg durante el estudio (EE: 0,60), mientras que aquellos que tomaron otros medicamentos perdieron 1,33kg (EE: 0,62). La diferencia media fue de 1,75kg (p=0,046). Conclusiones: Los diabéticos obesos que tomaron GLP1, SGLT2 o ambos tenían 2,5 veces más probabilidades de perder peso que aquellos que no los tomaron. Un estilo de vida saludable es fundamental para la pérdida de peso en pacientes diabéticos obesos.(AU)


Subject(s)
Humans , Male , Female , Obesity/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Sodium-Glucose Transporter 2 Inhibitors , Life Style , Quality of Life , Primary Health Care , Epidemiology, Descriptive , Cross-Sectional Studies , Diabetes Mellitus/diagnosis
6.
Aten Primaria ; 56(2): 102807, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37972467

ABSTRACT

AIMS: The aim of this study is to analyse the effect of pharmacological and non-pharmacological treatment on weight control in patients with diabetes and obesity. DESIGN: Epidemiological, descriptive, cross-sectional study. SITE: Primary care. In 11 health centres in Málaga and Cádiz during April and October 2022. PARTICIPANTS: 281 patients over 18 years old with type 2 diabetes and obesity are included. MAIN MEASUREMENTS: Socio-demographics, clinical, treatment and lifestyle habits variables were obtained from medical records and personal interview. Descriptive statistics were obtained for continuous variables. Statistical tests were performed based on the nature of the variables. RESULTS: Variables like marital status, level of education and occupation, and smoking habit, shows differences regarding the sex (p<0.05). 82.3% of those who received education lost weight, compared to 67.5% of lost weight who received no health education (p=0.004). GLP1 and SGLT2 were more commonly prescribed for women (p=0.048), and SGLT2 more commonly prescribed for men (p=0.047). Patients taking GLP1, SGLT2 or both, regardless of sex, weight loss during the study period was -3.1kg (SE: 0.60), while the loss of those who took other medications was -1.33kg (SE: 0.62). The mean difference was 1.75kg (p=0.046). CONCLUSIONS: In terms of weight loss, obese diabetics who took GLP1, SGLT2 or both were 2.5 times more likely to lose weight than those who did not. Healthy lifestyle choices are key to weight loss in obese diabetic patients.


Subject(s)
Diabetes Mellitus, Type 2 , Male , Humans , Female , Adolescent , Diabetes Mellitus, Type 2/therapy , Diabetes Mellitus, Type 2/drug therapy , Sodium-Glucose Transporter 2/therapeutic use , Cross-Sectional Studies , Obesity/complications , Obesity/therapy , Weight Loss , Primary Health Care
7.
Am J Physiol Cell Physiol ; 326(1): C229-C251, 2024 Jan 01.
Article in English | MEDLINE | ID: mdl-37899748

ABSTRACT

This review summarizes methods to study kidney intercalated cell (IC) function ex vivo. While important for acid-base homeostasis, IC dysfunction is often not recognized clinically until it becomes severe. The advantage of using ex vivo techniques is that they allow for the differential evaluation of IC function in controlled environments. Although in vitro kidney tubular perfusion is a classical ex vivo technique to study IC, here we concentrate on primary cell cultures, immortalized cell lines, and ex vivo kidney slices. Ex vivo techniques are useful in evaluating IC signaling pathways that allow rapid responses to extracellular changes in pH, CO2, and bicarbonate (HCO3-). However, these methods for IC work can also be challenging, as cell lines that recapitulate IC do not proliferate easily in culture. Moreover, a "pure" IC population in culture does not necessarily replicate its collecting duct (CD) environment, where ICs are surrounded by the more abundant principal cells (PCs). It is reassuring that many findings obtained in ex vivo IC systems signaling have been largely confirmed in vivo. Some of these newly identified signaling pathways reveal that ICs are important for regulating NaCl reabsorption, thus suggesting new frontiers to target antihypertensive treatments. Moreover, recent single-cell characterization studies of kidney epithelial cells revealed a dual developmental origin of IC, as well as the presence of novel CD cell types with certain IC characteristics. These exciting findings present new opportunities for the study of IC ex vivo and will likely rediscover the importance of available tools in this field.NEW & NOTEWORTHY The study of kidney intercalated cells has been limited by current cell culture and kidney tissue isolation techniques. This review is to be used as a reference to select ex vivo techniques to study intercalated cells. We focused on the use of cell lines and kidney slices as potential useful models to study membrane transport proteins. We also review how novel collecting duct organoids may help better elucidate the role of these intriguing cells.


Subject(s)
Kidney Tubules, Collecting , Kidney Tubules, Collecting/metabolism , Primary Cell Culture , Kidney/metabolism , Cell Line , Epithelial Cells/metabolism , Organoids
8.
J Appl Gerontol ; : 7334648231218095, 2023 Dec 01.
Article in English | MEDLINE | ID: mdl-38038169

ABSTRACT

This study investigated the relationship between physical activity, inactivity, physical function, and sleep in older adults with a frailty phenotype. A total of 184 pre-frail/frail older adults were included. Physical activity, inactive behavior, and sleep parameters were assessed using a wrist-worn accelerometer. Participants were categorized into four groups based on their levels of inactivity and physical activity. The results showed that individuals with lower levels of inactivity had better lower body mean velocity and sleep regularity than those with higher levels of inactivity. Physically active older adults exhibited faster gait speed and performed better in lower body strength tests than physically inactive participants. Further analysis revealed that specific combinations of inactivity and physical activity were associated with varying levels of physical function. The findings highlight the importance of physical activity and the negative impact of inactivity on physical function and sleep in older adults with a frailty phenotype.

9.
Healthcare (Basel) ; 11(14)2023 Jul 09.
Article in English | MEDLINE | ID: mdl-37510427

ABSTRACT

The aim of this study was to investigate the effects of listening to self-chosen music on the quality of life of family caregivers of cancer patients receiving palliative home care. A total of 82 family caregivers were assigned either to the intervention group (n = 41) or to the control group (n = 41) in this double-blind, multicentre, randomised controlled clinical trial. The recruitment period was between July 2020 and September 2021. The intervention group received individualised pre-recorded music in daily 30 min sessions for 7 consecutive days. The control group was given a recorded repetition of the basic therapeutic training education also in 30 min sessions for 7 consecutive days. The primary endpoint assessed was the caregivers' quality of life (Quality of Life Family Version and European Quality of Life visual analogue scale) before and after the intervention. The secondary endpoint was their perceived satisfaction with the intervention (Client Satisfaction Questionnaire). The music intervention was successful, producing a tangible improvement in the caregivers' quality of life (p < 0.01) and satisfaction with the care provided (p = 0.002). The intervention was not only effective but produced no adverse effects. This study encourages the use of self-chosen music as a complementary intervention in nursing care for family caregivers of palliative cancer patients.

10.
Curr Psychol ; : 1-9, 2023 Apr 21.
Article in English | MEDLINE | ID: mdl-37359685

ABSTRACT

This study aims to characterize the strategies researchers used to cope with Covid-19 impact and to explore the relationship between those strategies, researchers' characteristics and the pandemic impact in their lives. 721 researchers, proportionally distributed among three Spanish regions, answered an online survey on the pandemic impact on their activity. Scales referred to social support, productivity, research tasks, working conditions, and work and personal life balance. An open-ended section was included to collect the strategies they used to cope with the pandemic consequences. 1528 strategies were content analysed and categorised based on their purposes and related to the rest of the impact variables. Results show the predominance of some strategies for the whole sample both at the work level, such as organizing work duties and plans, and at the personal level, such as maintaining life-work balance and improving personal well-being. Results stress to what extent a strategic approach contributed to minimize contextual issues or constraints even in an extreme situation as the Covid-19 pandemic and lockdown. A non-strategic approach, consisting of just reacting emotionally or dropping research, was the less effective way to maintain interest in research, sustained work and productivity and to warrant work-life balance. Developing a strategic approach was easier for those without caring responsibilities and for men. Women in our study, especially with caring responsibilities, had reduced opportunities to continue with their careers during the pandemic. No evidence of institutional strategies supporting researchers to cope with the situation was found.

11.
bioRxiv ; 2023 May 25.
Article in English | MEDLINE | ID: mdl-37293038

ABSTRACT

Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional units of the kidney. Here we report manipulation of p38 and YAP activity creates a synthetic niche that allows the long-term clonal expansion of primary mouse and human NPCs, and induced NPCs (iNPCs) from human pluripotent stem cells. Cultured iNPCs resemble closely primary human NPCs, generating nephron organoids with abundant distal convoluted tubule cells, which are not observed in published kidney organoids. The synthetic niche reprograms differentiated nephron cells into NPC state, recapitulating the plasticity of developing nephron in vivo. Scalability and ease of genome-editing in the cultured NPCs allow for genome-wide CRISPR screening, identifying novel genes associated with kidney development and disease. A rapid, efficient, and scalable organoid model for polycystic kidney disease was derived directly from genome-edited NPCs, and validated in drug screen. These technological platforms have broad applications to kidney development, disease, plasticity, and regeneration.

12.
Rev. esp. med. legal ; 49(2): 71-78, Abril - Junio 2023. graf
Article in Spanish | IBECS | ID: ibc-224050

ABSTRACT

La identificación de cadáveres en sucesos con múltiples víctimas es un reto y una de las actividades principales de la patología forense. De la correcta identificación y gestión de identificación se derivan repercusiones legales, humanitarias y sociales generando un gran impacto.El objetivo del presente trabajo es presentar el proceso de gestión e identificación de las 13 víctimas mortales del accidente de autobús ocurrido en la autopista AP7 en marzo de 2016, en Freginals (Tarragona, España). Se analizan las rápidas identificaciones de las víctimas mortales, los diferentes mecanismos de control de calidad empleados, la atención a los familiares, así como la gestión propia de la catástrofe con los recursos humanos y materiales disponibles.A pesar de la nacionalidad extranjera de todas las víctimas, que determinó el método de identificación, todas ellas fueron identificadas rápidamente mediante odontología, huellas dactilares o ADN y fueron rápidamente retornadas a sus familias y países de origen. Italia fue el país de donde procedían un mayor número de víctimas. Se destaca la participación de los médicos forenses en la recuperación de datos antemortem. (AU)


Corpses identification in events with multiple victims is a challenge and one of the main activities of Forensic Pathology. Legal, humanitarian and social repercussions are derived from the correct identification and also its management, generating a great impact.The objective of this paper is to present the management and identification process of the 13 deaths that occurred in the bus accident on the AP7 motorway in March 2016 in Freginals (Tarragona, Spain). The rapid identification of fatalities, the different quality control mechanisms used, attention to family members, as well as the proper management of the catastrophe with the human and material resources available are analysed.Despite the foreign nationality of all the victims, which determined the method of identification, all of them were quickly identified by dentistry, fingerprinting or DNA and were quickly returned to their families and countries of origin. Italy was the country where the largest number of victims came from. The participation of forensic doctors in ante mortem data recovery is highlighted. (AU)


Subject(s)
Humans , Forensic Dentistry , Forensic Medicine , Autopsy , DNA , Victims Identification , Disaster Victims , Disaster Medicine , Surge Capacity , Spain
13.
Healthcare (Basel) ; 11(6)2023 Mar 10.
Article in English | MEDLINE | ID: mdl-36981482

ABSTRACT

In Andalusia, the right to maximum waiting times for healthcare clashes with the available supply, leading to an increase in demand in the form of waiting lists. To address this situation, the activity of private centers has been created for certain diagnostic tests. The Social Return on Investment (SROI) model evaluates an intervention from an economic and stakeholder perspective. However, there are no studies on the suitability of waiting lists using SROI, which is why it is intended to be studied as a decision-making tool for the clinical and healthcare management of waiting lists. This research protocol is designed to determine the quality of life gained, with the EuroQol-5D-5L questionnaire, and its social assessment, with the specific survey of the SROI method, and, thus, analyze the social return on investment and determine the suitability of the intervention (diagnostic endoscopy activity arranged in a contracted center). After the study, we will know the economic (cost in public health centers and the incremental cost of extraordinary health resources), social (quality of life with health), and environmental scenarios of the concerted activity intervention in order to adjust waiting list times.

14.
Article in English | MEDLINE | ID: mdl-36901671

ABSTRACT

The experience of caregiver burden among family members of patients with advanced cancer is a common problem. The aim of this study was to determine whether the burden may be alleviated by means of a therapeutic approach based on self-chosen music. This randomised controlled trial (ClinicalTrials.gov, NCT04052074. Registered 9 August 2019) included 82 family caregivers of patients receiving home palliative care for advanced cancer. The intervention group (n = 41) listened to pre-recorded, self-chosen music for 30 min/day for seven consecutive days, while the control group (n = 41) listened to a recording of basic therapeutic education at the same frequency. The degree of burden was assessed by the Caregiver Strain Index (CSI), calculated before and after the seven-day intervention. According to this measure, caregiver burden fell significantly in the intervention group (CSI change: -0.56, SD 2.16) but increased in the control group (CSI change: +0.68, SD 1.47), with a significant group x moment interaction F(1, 80) = 9.30, p = 0.003, η2p = 0.11. These results suggest that, in the short term at least, the use of therapy based on self-chosen music alleviates the burden on family caregivers of palliative cancer patients. Moreover, this therapy is easy to administer at home and does not present any problems in practice.


Subject(s)
Home Care Services , Music , Neoplasms , Humans , Caregivers , Quality of Life , Neoplasms/therapy
15.
J Clin Nurs ; 32(11-12): 2339-2360, 2023 Jun.
Article in English | MEDLINE | ID: mdl-35293058

ABSTRACT

AIM AND OBJECTIVES: The aim of this study is to identify preoperative indicators and/or predictors of complications or inefficiencies in the surgical process that can be modified within nursing practice. BACKGROUND: Due to rapid sociodemographic and technological change, the global demand for surgical attention is rising exponentially, requiring new strategies for optimisation and sustainability in perioperative care. DESIGN: We conduced the scoping review using the methodology recommended by the Joanna Briggs Institute supported with The PAGER framework and guided by the PRISMA-ScR Checklist. METHODS: Four databases (CINAHL, MEDLINE, SCOPUS and PUBMED) were examined to extract relevant published results for elective surgery on adult patients during the period 2011-2021. This process identified 609 records. Exclusion criteria were applied, and the sample was then evaluated with the Quality Assessment Tool for Studies with Diverse Designs (QATSDD), after which 15 studies remained. RESULTS: The following preoperative indicators and/or predictors were considered: (1) Anxiety; (2) Pain; (3) Health education, knowledge and training; (4) Satisfaction; (5) Management/organisation (including costs, resources used/available, organisational issues, hospital stay (preoperative), standardisation and protocolisation. CONCLUSION: The identification of five indicators and/or predictors of complications or inefficiencies in the surgical process, which can be modified by nursing, allows the effective application of interventions in the preoperative phase, optimising care and improving health outcomes. RELEVANCE TO CLINICAL PRACTICE: The development and implementation of specific nursing skills in the preoperative phase are essential to optimise the surgical process.


Subject(s)
Elective Surgical Procedures , Perioperative Care , Adult , Humans , Length of Stay
16.
Front Mol Biosci ; 9: 1001941, 2022.
Article in English | MEDLINE | ID: mdl-36504724

ABSTRACT

ADPKD has few therapeutic options. Tolvaptan slows disease but has side effects limiting its tolerability. Bempedoic acid (BA), an ATP citrate-lyase (ACLY) inhibitor FDA-approved for hypercholesterolemia, catalyzes a key step in fatty acid/sterol synthesis important for cell proliferation. BA is activated by very long-chain acyl-CoA synthetase (FATP2) expressed primarily in kidney and liver. BA also activates AMPK. We hypothesized that BA could be a novel ADPKD therapy by inhibiting cyst growth, proliferation, injury, and metabolic dysregulation via ACLY inhibition and AMPK activation. Pkd1-null kidney cell lines derived from mouse proximal tubule (PT) and collecting duct (IMCD) were grown in 2D or 3D Matrigel cultures and treated ± BA, ± SB-204990 (another ACLY inhibitor) or with Acly shRNA before cyst analysis, immunoblotting or mitochondrial assays using MitoSox and MitoTracker staining. Pkd1 fl/fl ; Pax8-rtTA; Tet-O-Cre C57BL/6J mice were induced with doxycycline injection on postnatal days 10 and 11 (P10-P11) and then treated ± BA (30 mg/kg/d) ± tolvaptan (30-100 mg/kg/d) by gavage from P12-21. Disease severity was determined by % total-kidney-weight-to-bodyweight (%TKW/BW) and BUN levels at euthanasia (P22). Kidney and liver homogenates were immunoblotted for expression of key biomarkers. ACLY expression and activity were upregulated in Pkd1-null PT and IMCD-derived cells vs. controls. Relative to controls, both BA and SB-204990 inhibited cystic growth in Pkd1-null kidney cells, as did Acly knockdown. BA inhibited mitochondrial superoxide production and promoted mitochondrial elongation, suggesting improved mitochondrial function. In ADPKD mice, BA reduced %TKW/BW and BUN to a similar extent as tolvaptan vs. untreated controls. Addition of BA to tolvaptan caused a further reduction in %TKW/BW and BUN vs. tolvaptan alone. BA generally reduced ACLY and stimulated AMPK activity in kidneys and livers vs. controls. BA also inhibited mTOR and ERK signaling and reduced kidney injury markers. In liver, BA treatment, both alone and together with tolvaptan, increased mitochondrial biogenesis while inhibiting apoptosis. We conclude that BA and ACLY inhibition inhibited cyst growth in vitro, and BA decreased ADPKD severity in vivo. Combining BA with tolvaptan further improved various ADPKD disease parameters. Repurposing BA may be a promising new ADPKD therapy, having beneficial effects alone and along with tolvaptan.

17.
Drugs Context ; 112022.
Article in English | MEDLINE | ID: mdl-35912002

ABSTRACT

Background: Sonidegib and vismodegib are Hedgehog pathway inhibitors (HhIs) that play a relevant role in the management of locally advanced basal cell carcinoma (laBCC). This study compared the efficacy and safety of both HhIs based on their available data using effect size measures such as number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH). Methods: We reviewed data from pivotal trials of sonidegib (BOLT) and vismodegib (ERIVANCE). The NNT for sonidegib and vismodegib was calculated from objective response rate (ORR) values. The NNH was calculated from data relating to treatment discontinuation due to adverse events (AEs) and incidence of AEs. The LHH was calculated as the ratio between the corresponding NNH and NNT. Results: For sonidegib (200 mg), the NNT for ORR at 18 months was 1.65 (95% CI 1.35-2.01) whilst that for vismodegib (150 mg) at 21 months was 2.10 (95% CI 1.65-2.82). The NNH related to treatment discontinuation due to AEs was 1.9 (95% CI 1.6-2.5) for sonidegib and 1.8 (95% CI 1.4-2.2) for vismodegib. The LHH for sonidegib and vismodegib related to treatment discontinuation due to AEs was 1.14 and 0.84, respectively, whilst the LHH according to AEs of grade ≥3 was 1.41 for sonidegib and 0.85 for vismodegib. Conclusions: Sonidegib showed a better benefit-risk ratio compared to vismodegib, being more likely to achieve therapeutic response than to AEs leading to discontinuation. These results should be confirmed in clinical practice and/or in a direct comparison study.

18.
Am J Physiol Renal Physiol ; 322(1): F27-F41, 2022 01 01.
Article in English | MEDLINE | ID: mdl-34806449

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in the polycystin 1 (PKD1) or polycystin 2 genes, presents with progressive development of kidney cysts and eventual end-stage kidney disease with limited treatment options. Previous work has shown that metformin reduces cyst growth in rapid ADPKD mouse models via inhibition of cystic fibrosis transmembrane conductance regulator-mediated fluid secretion, mammalian target of rapamycin, and cAMP pathways. The present study importantly tested the effectiveness of metformin as a therapy for ADPKD in a more clinically relevant Pkd1RC/RC mouse model, homozygous for the R3277C knockin point mutation in the Pkd1 gene. This mutation causes ADPKD in humans. Pkd1RC/RC male and female mice, which have a slow progression to end-stage kidney disease, received metformin (300 mg/kg/day in drinking water vs. water alone) from 3 to 9 or 12 mo of age. As previously reported, Pkd1RC/RC females had a more severe disease phenotype as compared with males. Metformin treatment reduced the ratio of total kidney weight-to-body weight relative to age-matched and sex-matched untreated controls at both 9 and 12 mo and reduced the cystic index in females at 9 mo. Metformin also increased glomerular filtration rate, lowered systolic blood pressure, improved anemia, and lowered blood urea nitrogen levels relative to controls in both sexes. Moreover, metformin reduced gene expression of key inflammatory markers and both gene and protein expression of kidney injury marker-1 and cyclin-dependent kinase-1 versus untreated controls. Altogether, these findings suggest several beneficial effects of metformin in this highly relevant slowly progressive ADPKD mouse model, which may help inform new ADPKD therapies in patients.NEW & NOTEWORTHY Metformin treatment improved ADPKD disease severity in a relevant, slowly progressive ADPKD mouse model that recapitulates a PKD-associated PKD1 mutation. Relative to controls, metformin reduced kidney weight/body weight, cystic index and BUN levels, while improving GFR, blood pressure and anemia. Metformin also reduced key inflammatory and injury markers, along with cell proliferation markers. These findings suggest several beneficial effects of metformin in this ADPKD mouse model, which may help inform new ADPKD therapies in patients.


Subject(s)
Kidney Failure, Chronic/prevention & control , Kidney/drug effects , Metformin/pharmacology , Polycystic Kidney, Autosomal Dominant/drug therapy , Renal Agents/pharmacology , Animals , Cell Proliferation/drug effects , Disease Models, Animal , Disease Progression , Female , Genetic Predisposition to Disease , Glomerular Filtration Rate/drug effects , Inflammation Mediators/metabolism , Kidney/metabolism , Kidney/pathology , Kidney/physiopathology , Kidney Failure, Chronic/metabolism , Kidney Failure, Chronic/pathology , Kidney Failure, Chronic/physiopathology , Male , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Transgenic , Mutation , Polycystic Kidney, Autosomal Dominant/metabolism , Polycystic Kidney, Autosomal Dominant/pathology , Polycystic Kidney, Autosomal Dominant/physiopathology , TRPP Cation Channels/genetics , Time Factors
19.
Nat Commun ; 12(1): 3641, 2021 06 15.
Article in English | MEDLINE | ID: mdl-34131121

ABSTRACT

Current kidney organoids model development and diseases of the nephron but not the contiguous epithelial network of the kidney's collecting duct (CD) system. Here, we report the generation of an expandable, 3D branching ureteric bud (UB) organoid culture model that can be derived from primary UB progenitors from mouse and human fetal kidneys, or generated de novo from human pluripotent stem cells. In chemically-defined culture conditions, UB organoids generate CD organoids, with differentiated principal and intercalated cells adopting spatial assemblies reflective of the adult kidney's collecting system. Aggregating 3D-cultured nephron progenitor cells with UB organoids in vitro results in a reiterative process of branching morphogenesis and nephron induction, similar to kidney development. Applying an efficient gene editing strategy to remove RET activity, we demonstrate genetically modified UB organoids can model congenital anomalies of kidney and urinary tract. Taken together, these platforms will facilitate an enhanced understanding of development, regeneration and diseases of the mammalian collecting duct system.


Subject(s)
Kidney Tubules, Collecting/cytology , Kidney/cytology , Kidney/growth & development , Organogenesis/physiology , Organoids/cytology , Organoids/growth & development , Ureter , Urinary Tract/cytology , Adult , Animals , Cell Differentiation , Cells, Cultured , Humans , Kidney/embryology , Kidney Tubules, Collecting/embryology , Male , Mice , Morphogenesis , Nephrons , Organogenesis/genetics , Organoids/embryology , Pluripotent Stem Cells/cytology , Urinary Tract/embryology , Urinary Tract/growth & development
20.
Fertil Steril ; 116(2): 583-596, 2021 08.
Article in English | MEDLINE | ID: mdl-33926715

ABSTRACT

OBJECTIVE: To quantify the percentage of monopronuclear-derived blastocysts (MNBs) that are potentially useful for reproductive purposes using classic and state-of-the-art chromosome analysis approaches, and to study chromosomal distribution in the inner cell mass (ICM) and trophectoderm (TE) for intertissue/intratissue concordance comparison. DESIGN: Prospective experimental study. SETTING: Single-center in vitro fertilization clinic and reproductive genetics laboratory. PATIENT(S): A total of 1,128 monopronuclear zygotes were obtained between June 2016 and December 2018. INTERVENTION(S): MNBs were whole-fixed or biopsied to obtain a portion of ICM and 2 TE portions (TE1 and TE2) and were subsequently analyzed by fluorescence in situ hybridization, new whole-genome sequencing, and fingerprinting by single-nucleotide polymorphism array-based techniques (a-SNP). MAIN OUTCOME MEASURE(S): We assessed MNB rate, ploidy rate, and chromosomal constitution by new whole-genome sequencing, and parental composition by comparative a-SNP, performed in a "trio"-format (embryo/parents). The 24-chromosome distribution was compared between the TE and the ICM and within the TE. RESULT(S): A total of 18.4% of monopronuclear zygotes progressed to blastocysts; 77.6% of MNBs were diploid; 20% of MNBs were male and euploid, which might be reproductively useful. Seventy-five percent of MNBs were biparental and half of them were euploid, indicating that 40% might be reproductively useful. Intratissue concordance (TE1/TE2) was established for 93.3% and 73.3% for chromosome matching. Intertissue concordance (TE/ICM) was established for 78.8%, but 57.6% for chromosome matching. When segmental aneuploidy was not considered, intratissue concordance and chromosome matching increased to 100% and 80%, respectively, and intertissue concordance and chromosome matching increased to 84.8% and 75.8%, respectively. CONCLUSION(S): The a-SNP-trio strategy provides information about ploidy, euploidy, and parental origin in a single biopsy. This approach enabled us to identify 40% of MNBs with reproductive potential, which can have a significant effect in the clinical setting. Additionally, segmental aneuploidy is relevant for mismatched preimplantation genetic testing of aneuploidies, both within and between MNB tissues. Repeat biopsy might clarify whether segmental aneuploidy is a prone genetic character.


Subject(s)
Blastocyst/ultrastructure , Chromosomes/ultrastructure , Ploidies , Polymorphism, Single Nucleotide , Biopsy , Blastocyst/pathology , Blastocyst Inner Cell Mass/ultrastructure , DNA Fingerprinting , Female , High-Throughput Nucleotide Sequencing , Humans , In Situ Hybridization, Fluorescence , Prospective Studies
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