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Journal of Visualized Experiments : JoVE Jun 2024Right ventricular (RV) failure caused by pressure overload is strongly associated with morbidity and mortality in a number of cardiovascular and pulmonary diseases. The...
Right ventricular (RV) failure caused by pressure overload is strongly associated with morbidity and mortality in a number of cardiovascular and pulmonary diseases. The pathogenesis of RV failure is complex and remains inadequately understood. To identify new therapeutic strategies for the treatment of RV failure, robust and reproducible animal models are essential. Models of pulmonary trunk banding (PTB) have gained popularity, as RV function can be assessed independently of changes in the pulmonary vasculature. In this paper, we present a murine model of RV pressure overload induced by PTB in 5-week-old mice. The model can be used to induce different degrees of RV pathology, ranging from mild RV hypertrophy to decompensated RV failure. Detailed protocols for intubation, PTB surgery, and phenotyping by echocardiography are included in the paper. Furthermore, instructions for customizing instruments for intubation and PTB surgery are given, enabling fast and inexpensive reproduction of the PTB model. Titanium ligating clips were used to constrict the pulmonary trunk, ensuring a highly reproducible and operator-independent degree of pulmonary trunk constriction. The severity of PTB was graded by using different inner ligating clip diameters (mild: 450 µm and severe: 250 µm). This resulted in RV pathology ranging from hypertrophy with preserved RV function to decompensated RV failure with reduced cardiac output and extracardiac manifestations. RV function was assessed by echocardiography at 1 week and 3 weeks after surgery. Examples of echocardiographic images and results are presented here. Furthermore, results from right heart catheterization and histological analyses of cardiac tissue are shown.
Topics: Animals; Mice; Disease Models, Animal; Hypertrophy, Right Ventricular; Pulmonary Artery; Heart Failure; Ventricular Dysfunction, Right; Male; Echocardiography; Mice, Inbred C57BL
PubMed: 38949319
DOI: 10.3791/66851 -
BioRxiv : the Preprint Server For... Jun 2024We take a unique approach to understanding the causes of podocyte injury in collagen IV nephropathies, a crucial step in developing targeted therapies for conditions...
RATIONALE
We take a unique approach to understanding the causes of podocyte injury in collagen IV nephropathies, a crucial step in developing targeted therapies for conditions like Alport Syndrome.
OBJECTIVES
We characterize the structural, functional, and biophysical properties of glomerular capillaries and podocytes in mice and analyze kidney cortex transcriptional profiles at various disease stages. We investigate the effects of the ER stress mitigator TUDCA on these parameters. Furthermore, we used human FSGS associated podocyte enriched genes to identify molecular pathways rescued by TUDCA thereby offering potential therapeutic targets for Alport Syndrome.
FINDINGS
We find a clear disease progression timeline in mice. Podocyte injury develops by 3 months, with glomeruli reaching maximum deformability at 4 months, associated with a 40% loss of podocytes. This is followed by progressive stiffening of glomerular capillaries, increasing proteinuria, reduced renal function, inflammatory infiltrates, and fibrosis from months 4 to 8. Bulk RNA sequencing at 2, 4, and 7 months reveals a progressive increase in expression of genes related to cytokine and chemokine signaling, matrix and cell injury, and activation of the TNF pathway, similar to observations in a NEPTUNE FSGS cohort. Podocyte-enriched genes from FSGS patients mapped to mice found that TUDCA, which mitigated glomerular and renal injury suppressed molecular pathways associated with extracellular matrix and basement membrane synthesis, podocyte stress and hypertrophy.
CONCLUSIONS
We uncover two distinct phases of nephropathy progression. The first is characterized by podocytopathy, increased glomerular capillary deformability and accelerated podocyte loss, and the second by increased capillary wall stiffening and renal inflammatory and profibrotic pathway activation. The response of podocytes to TUDCA treatment provides novel insights into downstream signaling pathways, offering potential therapeutic targets for treating Alport and related nephropathies.
PubMed: 38948788
DOI: 10.1101/2024.02.26.582201 -
BioRxiv : the Preprint Server For... Oct 2023Low nephron endowment at birth is a risk factor for chronic kidney disease. The prevalence of this condition is increasing due to higher survival rates of preterm...
Low nephron endowment at birth is a risk factor for chronic kidney disease. The prevalence of this condition is increasing due to higher survival rates of preterm infants and children with multi- organ birth defect syndromes that affect the kidney and urinary tract. We created a mouse model of congenital low nephron number due to deletion of in nephron progenitor cells. is a core component of the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex. These mice developed albuminuria at 4 weeks of age followed by focal segmental glomerulosclerosis (FSGS) at 8 weeks, with progressive kidney injury and fibrosis. Our studies reveal that altered mitochondrial metabolism in the post-natal period leads to accumulation of neutral lipids in glomeruli at 4 weeks of age followed by reduced mitochondrial oxygen consumption. We found that NuRD cooperated with Zbtb7a/7b to regulate a large number of metabolic genes required for fatty acid oxidation and oxidative phosphorylation. Analysis of human kidney tissue also supported a role for reduced mitochondrial lipid metabolism and ZBTB7A/7B in FSGS and CKD. We propose that an inability to meet the physiological and metabolic demands of post-natal somatic growth of the kidney promotes the transition to CKD in the setting of glomerular hypertrophy due to low nephron endowment.
PubMed: 38948707
DOI: 10.1101/2023.10.18.562984 -
Frontiers in Endocrinology 2024Obesity impairs bone marrow (BM) glucose metabolism. Adult BM constitutes mostly of adipocytes that respond to changes in energy metabolism by modulating their...
OBJECTIVES
Obesity impairs bone marrow (BM) glucose metabolism. Adult BM constitutes mostly of adipocytes that respond to changes in energy metabolism by modulating their morphology and number. Here we evaluated whether diet or exercise intervention could improve the high-fat diet (HFD) associated impairment in BM glucose uptake (BMGU) and whether this associates with the morphology of BM adipocytes (BMAds) in rats.
METHODS
Eight-week-old male Sprague-Dawley rats were fed either HFD or chow diet for 24 weeks. Additionally after 12 weeks, HFD-fed rats switched either to chow diet, voluntary intermittent running exercise, or both for another 12 weeks. BMAd morphology was assessed by perilipin-1 immunofluorescence staining in formalin-fixed paraffin-embedded tibial sections. Insulin-stimulated sternal and humeral BMGU were measured using [F]FDG-PET/CT. Tibial microarchitecture and mineral density were measured with microCT.
RESULTS
HFD rats had significantly higher whole-body fat percentage compared to the chow group (17% vs 13%, respectively; = 0.004) and larger median size of BMAds in the proximal tibia (815 µm vs 592 µm, respectively; = 0.03) but not in the distal tibia. Switch to chow diet combined with running exercise normalized whole-body fat percentage ( < 0.001) but not the BMAd size. At 32 weeks of age, there was no significant difference in insulin-stimulated BMGU between the study groups. However, BMGU was significantly higher in sternum compared to humerus ( < 0.001) and higher in 8-week-old compared to 32-week-old rats ( < 0.001). BMAd size in proximal tibia correlated positively with whole-body fat percentage (r = 0.48, = 0.005) and negatively with humeral BMGU (r = -0.63, = 0.02). HFD significantly reduced trabecular number ( < 0.001) compared to the chow group. Switch to chow diet reversed this as the trabecular number was significantly higher ( = 0.008) than in the HFD group.
CONCLUSION
In this study we showed that insulin-stimulated BMGU is age- and site-dependent. BMGU was not affected by the study interventions. HFD increased whole-body fat percentage and the size of BMAds in proximal tibia. Switching from HFD to a chow diet and running exercise improved glucose homeostasis and normalized the HFD-induced increase in body fat but not the hypertrophy of BMAds.
Topics: Animals; Male; Rats, Sprague-Dawley; Rats; Adiposity; Diet, High-Fat; Physical Conditioning, Animal; Bone Marrow; Glucose; Obesity; Adipocytes
PubMed: 38948514
DOI: 10.3389/fendo.2024.1422869 -
Cancer Innovation Jun 2024Histone deacetylase 6 (HDAC6) belongs to a class of epigenetic targets that have been found to be a key protein in the association between tumors and cardiovascular... (Review)
Review
Histone deacetylase 6 (HDAC6) belongs to a class of epigenetic targets that have been found to be a key protein in the association between tumors and cardiovascular disease. Recent studies have focused on the crucial role of HDAC6 in regulating cardiovascular diseases such as atherosclerosis, myocardial infarction, myocardial hypertrophy, myocardial fibrosis, hypertension, pulmonary hypertension, and arrhythmia. Here, we review the association between HDAC6 and cardiovascular disease, the research progress of HDAC6 inhibitors in the treatment of cardiovascular disease, and discuss the feasibility of combining HDAC6 inhibitors with other therapeutic agents to treat cardiovascular disease.
PubMed: 38947757
DOI: 10.1002/cai2.114 -
IDCases 2024Kaposi sarcoma is an indolent angio-proliferative spindle- cell tumor derived from endothelial and immune cells infected with Human herpes virus type 8(HHV-8). In the...
Kaposi sarcoma is an indolent angio-proliferative spindle- cell tumor derived from endothelial and immune cells infected with Human herpes virus type 8(HHV-8). In the era of highly active antiretroviral (HAART), Kaposi sarcoma is a rare form of initial presentation of HIV infection [1]. The author presents a case of diffuse gingival hypertrophied Kaposi sarcoma in 18-year-old male newly diagnosed RVI patient. After confirming the diagnosis patient started on HAART and mouth care. Surgical excision is the first line of treatment with HAART, since this patient has low CD4 count of 30 cells/mm3 which will complicate the surgery. So, we are waiting for CD4 count to increase above 200 cells/mm3 to undergo surgical excision. The case is representative of HIV complexity and aimed to bring awareness of unusual presentation of HIV.This case also reminds us how important early initiation of HAART is.
PubMed: 38947560
DOI: 10.1016/j.idcr.2024.e02003 -
European Review For Medical and... Jun 2024A condition known as ligamentum flavum (LF) hypertrophy occurs when the ligamentum flavum (LF) swells as a result of pressures applied to the spine. Among the elderly... (Observational Study)
Observational Study
OBJECTIVE
A condition known as ligamentum flavum (LF) hypertrophy occurs when the ligamentum flavum (LF) swells as a result of pressures applied to the spine. Among the elderly population, lumbar spinal stenosis is a major cause of pain and disabilities. Numerous studies indicate that lumbar spinal stenosis etiology involves the ligamentum flavum in a major way. This study looks into the relationship between low back pain and ligamentum flavum thickening.
PATIENTS AND METHODS
The imaging tests and case histories of all patients with low back pain who had consecutive magnetic resonance imaging exams performed at the Prince Sattam University and King Khalid hospitals in Al Kharj City will serve as the basis for this retrospective observational study. A radiologist utilized the Pfirrmann grading system, which is based on spinal levels starting from the first lumbar to the first sacral vertebrae, to measure the thickness of the ligamentum flavum in all cases who underwent magnetic resonance imaging (MRI). A correlation between age, hypertrophy of LF, and low back pain was investigated.
RESULTS
There were 79 participants in the study, ages ranging from 21 to 82, 49 of which were men. The patients' average age was 54 years, and 62% of them were men. We found no appreciable variations in LF thickness according to gender. At the L4-L5 and L5-S1 levels, the left LF was noticeably thicker than the right. Moreover, there was a significant difference (p < 0.05) in the bilateral LF thicknesses at L5-S1 compared to the comparable sides at L4-L5.
CONCLUSIONS
By evaluating the thickness of LF on magnetic resonance images, we discovered that it may be closely associated with the etiology of pain processes in the spine.
Topics: Humans; Ligamentum Flavum; Low Back Pain; Hypertrophy; Male; Middle Aged; Female; Aged; Magnetic Resonance Imaging; Retrospective Studies; Adult; Aged, 80 and over; Young Adult; Lumbar Vertebrae; Spinal Stenosis
PubMed: 38946379
DOI: 10.26355/eurrev_202406_36458 -
Clinical Hypertension Jul 2024This study explores the impact of intensive blood pressure (BP) control on left ventricular hypertrophy (LVH) incidence and evaluates the prognostic implications of LVH...
BACKGROUND
This study explores the impact of intensive blood pressure (BP) control on left ventricular hypertrophy (LVH) incidence and evaluates the prognostic implications of LVH status (pre-existing/new-onset/persistent/regression) using Systolic Blood Pressure Intervention Trial (SPRINT) Electrocardiogram Data.
METHODS
Poisson regression was used to assess new-onset LVH and LVH regression rates. Multivariable-adjusted Cox proportional hazard models determined the risk of adverse cardiovascular events (ACE), a composite of myocardial infarction (MI), non-MI acute coronary syndrome, stroke, heart failure, or cardiovascular death, alongside safety adverse events.
RESULTS
In 8,016 participants, intensive BP control significantly reduced new-onset LVH (8.27 vs. 14.79 per 1000-person years; adjusted p<0.001) and increased LVH regression (14.89 vs. 11.89 per 1000-person years; adjusted p<0.001). Elevated ACE risk was notable in participants with pre-existing LVH [adjusted HR: 1.94 (95% CI: 1.25-2.99); p = 0.003], new-onset LVH [adjusted 1.74 (95% CI: 1.16-2.60); p = 0.007], and persistent LVH[adjusted HR: 1.96 (95% CI: 1.11-3.46); p = 0.020], compared to those without LVH. Intriguingly, LVH regression attenuated this risk increment [adjusted HR: 1.57 (95% CI: 0.98-2.53); p = 0.062]. Achieving a BP target of < 120/80 mmHg nullified the increased ACE risk in those with pre-existing LVH.
CONCLUSIONS
Intensive BP control is instrumental in both reducing the emergence of LVH and fostering its regression. Pre-existing, new-onset LVH and persistent LV remain a predictor of adverse cardiovascular prognosis, whereas LVH regression and achieving on-treatment BP < 120/80 mmHg in pre-existing LVH individuals may further mitigate residual cardiovascular risk.
CLINICAL TRIAL REGISTRATION
URL: ClinicalTrials.gov Unique Identifier: NCT01206062.
PubMed: 38946010
DOI: 10.1186/s40885-024-00275-8 -
Journal of Nutritional Science and... 2024Alaska pollack protein (APP), has been reported as a protein source that can enhance muscle hypertrophy more than other protein sources in animal studies. This study... (Randomized Controlled Trial)
Randomized Controlled Trial
Alaska pollack protein (APP), has been reported as a protein source that can enhance muscle hypertrophy more than other protein sources in animal studies. This study aimed to examine the effects of APP ingestion on muscle quantity and quality in young adults. Fifty-five young college students were assigned to two groups: APP and placebo (whey protein: WP) groups, and instructed to ingest 4.5 g of each protein in addition to daily meals, and to maintain their usual daily physical activities for 3 mo. Twenty-one and 23 students completed the intervention and were analyzed in APP and WP groups, respectively. The maximum knee extension torque significantly increased in both groups during the intervention. The motor unit discharge rate, which is an indicator of activation, for a given force level significantly decreased in both groups during the intervention, but its decrease in the APP group was significantly greater than in the WP group. Echo intensity of the vastus lateralis evaluated by ultrasound images significantly decreased in both groups. The muscle thickness and skeletal muscle mass did not change. Small amount of additional APP intake induces greater effects on neural activation than WP, suggesting the greater neural economy of generation of force.
Topics: Humans; Young Adult; Male; Female; Muscle, Skeletal; Dietary Proteins; Adult; Adaptation, Physiological; Gadiformes; Torque; Quadriceps Muscle; Muscle Strength; Double-Blind Method
PubMed: 38945888
DOI: 10.3177/jnsv.70.228 -
Mymensingh Medical Journal : MMJ Jul 2024Soft tissue injuries of the hand or forearm often results in exposure of tendon or bone which needs coverage with a suitable flap. This prospective observational study... (Observational Study)
Observational Study
Soft tissue injuries of the hand or forearm often results in exposure of tendon or bone which needs coverage with a suitable flap. This prospective observational study was carried out in National Institute of Traumatology and Orthopaedic Rehabilitation (NITOR), Dhaka, Bangladesh from February 2019 to January 2020, to evaluate the use of the pedicled paraumbilical perforator flaps as a reliable flap to cover such defects. Total 34 patients having soft tissue defects in the hand and forearm with exposed tendons, bones or implant were included in this study. All the defects were covered by paraumbilical perforator flap. The defects were caused by road traffic accident (n=22), machinery injury (n=10) and burn injury (n=2). Sixteen patients had defects involving the forearm, six over dorsum of hand, another two over first web space and the rest had defects over two or more areas of forearm, hand and wrist. Lateral extent of flaps was upto anterior axillary line in 41.18% cases and upto mid-axillary line in 55.88% cases. Flap division and final inset was done in second stage after 3 weeks. Donor site closed primarily in all cases, except in two cases where it was covered by skin graft. All the flaps survived with no incidence of flap necrosis, dehiscence or infection after first stage. However, after the division of the flap, two patients developed marginal necrosis of the proximal margin which healed spontaneously by conservative treatment. The mean flap surface area utilized was 108 cm2. Donor area healed well without any major complications. Three patients developing scar hypertrophy were treated with intra-lesional triamcinolone injections. The paraumbilical perforator flap is a reliable option to cover soft tissue defects of hand and forearm due to easier planning and harvesting of the flap, adequate skin paddle and minimum donor site morbidity.
Topics: Humans; Perforator Flap; Male; Soft Tissue Injuries; Female; Adult; Prospective Studies; Hand Injuries; Middle Aged; Forearm; Adolescent; Forearm Injuries; Young Adult; Plastic Surgery Procedures; Child
PubMed: 38944720
DOI: No ID Found