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Cellular and Molecular Life Sciences :... Jun 2024Blood ultrafiltration in nephrons critically depends on specialized intercellular junctions between podocytes, named slit diaphragms (SDs). Here, by studying a...
Blood ultrafiltration in nephrons critically depends on specialized intercellular junctions between podocytes, named slit diaphragms (SDs). Here, by studying a homologous structure found in Drosophila nephrocytes, we identify the phospholipid scramblase Scramb1 as an essential component of the SD, uncovering a novel link between membrane dynamics and SD formation. In scramb1 mutants, SDs fail to form. Instead, the SD components Sticks and stones/nephrin, Polychaetoid/ZO-1, and the Src-kinase Src64B/Fyn associate in cortical foci lacking the key SD protein Dumbfounded/NEPH1. Scramb1 interaction with Polychaetoid/ZO-1 and Flotillin2, the presence of essential putative palmitoylation sites and its capacity to oligomerize, suggest a function in promoting SD assembly within lipid raft microdomains. Furthermore, Scramb1 interactors as well as its functional sensitivity to temperature, suggest an active involvement in membrane remodeling processes during SD assembly. Remarkably, putative Ca-binding sites in Scramb1 are essential for its activity raising the possibility that Ca signaling may control the assembly of SDs by impacting on Scramb1 activity.
Topics: Animals; Podocytes; Drosophila Proteins; Phospholipid Transfer Proteins; Membrane Proteins; Drosophila melanogaster; Membrane Microdomains; Intercellular Junctions
PubMed: 38878170
DOI: 10.1007/s00018-024-05287-z -
Scientific Reports Jun 2024Congenital diaphragmatic hernia (CDH) is a birth defect characterized by incomplete closure of the diaphragm, herniation of abdominal organs into the chest, and...
Congenital diaphragmatic hernia (CDH) is a birth defect characterized by incomplete closure of the diaphragm, herniation of abdominal organs into the chest, and compression of the lungs and the heart. Besides complications related to pulmonary hypoplasia, 1 in 4 survivors develop neurodevelopmental impairment, whose etiology remains unclear. Using a fetal rat model of CDH, we demonstrated that the compression exerted by herniated organs on the mediastinal structures results in decreased brain perfusion on ultrafast ultrasound, cerebral hypoxia with compensatory angiogenesis, mature neuron and oligodendrocyte loss, and activated microglia. In CDH fetuses, apoptosis was prominent in the subventricular and subgranular zones, areas that are key for neurogenesis. We validated these findings in the autopsy samples of four human fetuses with CDH compared to age- and sex-matched controls. This study reveals the molecular mechanisms and cellular changes that occur in the brain of fetuses with CDH and creates opportunities for therapeutic targets.
Topics: Animals; Hernias, Diaphragmatic, Congenital; Neurons; Oligodendroglia; Rats; Humans; Brain; Female; Stem Cells; Fetus; Disease Models, Animal; Pregnancy; Male
PubMed: 38871804
DOI: 10.1038/s41598-024-64412-x -
BMJ Sexual & Reproductive Health Jun 2024
PubMed: 38871443
DOI: 10.1136/bmjsrh-2024-202279 -
Journal of Gastrointestinal Surgery :... Jun 2024Small bowel obstruction is a major source of morbidity and mortality that carries a significant economic burden. Recurrent small bowel obstruction may be secondary to...
BACKGROUND
Small bowel obstruction is a major source of morbidity and mortality that carries a significant economic burden. Recurrent small bowel obstruction may be secondary to circumferential strictures (small bowel diaphragm disease), an under-recognized entity secondary to long-term nonsteroidal anti-inflammatory drug (NSAID) use. We aimed to describe the sensitivity of preoperative computed tomography (CT) enterography in patients with surgically treated small bowel diaphragm disease.
METHODS
We retrospectively reviewed adult patients who underwent elective small bowel resection for small bowel obstruction performed by a single minimally invasive surgeon between 2010 and 2023. Patient history, radiographic, endoscopic, operative, and pathology reports were reviewed for reference to NSAID use, small bowel strictures, diaphragms, and enteropathy. Exclusion criteria were prior radiation, inflammatory bowel disease, malignancy, adhesive disease, and anastomotic strictures.
RESULTS
A total of 225 patients were identified, 22 (10%) of whom met the inclusion criteria. The mean age was 60.7 years (range 29-78), with 15 women (68%). All patients underwent minimally invasive small bowel resection for obstruction with histopathologic evidence of stricture without evidence of transmural inflammation, granuloma, or dysplasia and confirmed NSAID use (n = 22, 100%). Anemia was present in 36% (n = 8). Preoperative CT or magnetic resonance (MR) enterography was performed in 18 patients (82%), of which stricturing was reported in 13 (72%). Intraoperatively, palpation identified strictures in all patients.
CONCLUSION
NSAID-induced small bowel injury is an under-recognized condition that, in severe cases, can present as small bowel obstruction. Surgeons should consider diaphragm disease in patients with obstruction and NSAID use, in which preoperative CT or MR enterography may be useful but cannot rule out disease.
PubMed: 38871074
DOI: 10.1016/j.gassur.2024.06.004 -
Cureus Jun 2024A patient with multiple comorbidities and an eight-year history of tracheostomy was being treated for tracheitis. At this point, she became incapable of using regular...
A patient with multiple comorbidities and an eight-year history of tracheostomy was being treated for tracheitis. At this point, she became incapable of using regular speaking valves, and multiple attempts to reintroduce the speaking valve failed. A Ferrer adjustable speaking valve (FASV) was designed with gradations of outflow closure, allowing air to go through the vocal cords for phonation. The FASV was offered to her through the compassionate use program at the FDA. At 20% initial closure, the patient was able to tolerate the valve and was advanced to 50% closure, at which point she could phonate partially. The use of the valve was terminated at the time of her transfer, 23 days after the initiation of use. This suggests the safety and possible efficacy of using an adjustable speaking valve earlier than regular valves, allowing patients to communicate earlier and further exercise their diaphragms.
PubMed: 38868548
DOI: 10.7759/cureus.62081 -
Journal of Applied Physiology... Jun 2024Respiratory deficits after C2 hemisection (C2Hx) have been well documented through single sex investigations. Although ovarian sex hormones enable enhanced respiratory...
Respiratory deficits after C2 hemisection (C2Hx) have been well documented through single sex investigations. Although ovarian sex hormones enable enhanced respiratory recovery observed in females two weeks post-C2Hx, it remains unknown if sex impacts spontaneous respiratory recovery at chronic time points. We conducted a longitudinal study to provide a comprehensive sex-based characterization of respiratory neuromuscular recovery for 8 weeks after C2Hx. We recorded ventilation and chronic diaphragm electromyography (EMG) output in awake behaving animals, phrenic motor output in anesthetized animals, and performed diaphragm muscle histology in chronically injured male and female rodents. Our results show that females expressed a greater recovery of tidal volume and minute ventilation compared to males during sub-acute and chronic time points. Eupneic diaphragm EMG amplitude during wakefulness and phrenic motor amplitude are similar between sexes at all time points after injury. Our data also suggests that females have a greater reduction in ipsilateral diaphragm EMG amplitude during spontaneous deep breaths (e.g., sighs) compared to males. Finally, we show evidence for atrophy and remodeling of the fast, fatigable fibers ipsilateral to injury in females, but not males. To our knowledge, the data presented here represent the first study to report sex-dependent differences in spontaneous respiratory recovery and diaphragm muscle morphology following chronic C2Hx. These data highlight the need to study both sexes to inform evidence-based therapeutic interventions in respiratory recovery post-SCI.
PubMed: 38867665
DOI: 10.1152/japplphysiol.00040.2024 -
Experimental Physiology Jun 2024Duchenne muscular dystrophy (DMD) is characterised by respiratory muscle injury, inflammation, fibrosis and weakness, ultimately culminating in respiratory failure. The...
Duchenne muscular dystrophy (DMD) is characterised by respiratory muscle injury, inflammation, fibrosis and weakness, ultimately culminating in respiratory failure. The dystrophin-deficient mouse model of DMD (mdx) shows evidence of respiratory muscle remodelling and dysfunction contributing to impaired respiratory system performance. The antioxidant N-acetylcysteine (NAC) has been shown to exert anti-inflammatory and anti-fibrotic effects leading to improved respiratory muscle performance in a range of animal models of muscle dysfunction, including mdx mice, following short-term administration (2 weeks). We sought to build on previous work by exploring the effects of chronic NAC administration (3 months) on respiratory system performance in mdx mice. One-month-old male mdx mice were randomised to receive normal drinking water (n = 30) or 1% NAC in the drinking water (n = 30) for 3 months. At 4 months of age, we assessed breathing in conscious mice by plethysmography followed by ex vivo assessment of diaphragm force-generating capacity. Additionally, diaphragm histology was performed. In separate studies, in anaesthetised mice, respiratory electromyogram (EMG) activity and inspiratory pressure across a range of behaviours were determined, including assessment of peak inspiratory pressure-generating capacity. NAC treatment did not affect force-generating capacity of the mdx diaphragm. Collagen content and immune cell infiltration were unchanged in mdx + NAC compared with mdx diaphragms. Additionally, there was no significant effect of NAC on breathing, ventilatory responsiveness, inspiratory EMG activity or inspiratory pressure across the range of behaviours from basal conditions to peak system performance. We conclude that chronic NAC treatment has no apparent beneficial effects on respiratory system performance in the mdx mouse model of DMD suggesting limited potential of NAC treatment alone for human DMD.
PubMed: 38867461
DOI: 10.1113/EP091862 -
Biophysical Journal Jun 2024Exchange of material across two membranes, as in the case of synaptic neurotransmitter release from a vesicle, involves the formation and poration of a hemifusion...
Exchange of material across two membranes, as in the case of synaptic neurotransmitter release from a vesicle, involves the formation and poration of a hemifusion diaphragm (HD). The nontrivial geometry of the HD leads to environment-dependent control, regarding the stability and dynamics of the pores required for this kind of exocytosis. This work combines particle simulations, field-based calculations, and phenomenological modeling to explore the factors influencing the stability, dynamics, and possible control mechanisms of pores in HDs. We find that pores preferentially form at the HD rim, and that their stability is sensitive to a number of factors, including the three line tensions, membrane tension, HD size, and the ability of lipids to "flip-flop" across leaflets. Along with a detailed analysis of these factors, we discuss ways that vesicles or cells may use them to open and close pores and thereby quickly and efficiently transport material.
PubMed: 38867448
DOI: 10.1016/j.bpj.2024.06.009 -
Journal of Cardiovascular Computed... Jun 2024Pre-eclampsia is a pregnancy related disorder associated with hypertension and vascular inflammation, factors that are also involved in the pathological pathway of...
BACKGROUND
Pre-eclampsia is a pregnancy related disorder associated with hypertension and vascular inflammation, factors that are also involved in the pathological pathway of aortic dilatation and aneurysm development. It is, however, unknown if younger women with previous pre-eclampsia have increased aortic dimensions. We tested the hypothesis that previous pre-eclampsia is associated with increased aortic dimensions in younger women.
METHODS
The study was a cross-sectional cohort study of women with previous pre-eclampsia, aged 40-55, from the PRECIOUS population matched by age and parity with women from the general population. Using contrast-enhanced CT, aortic diameters were measured in the aortic root, ascending aorta, descending aorta, at the level of the diaphragm, suprarenal aorta, and infrarenal aorta.
RESULTS
1355 women (684 with previous pre-eclampsia and 671 from the general population), with a mean (standard deviation) age of 46.9 (4.4) were included. The pre-eclampsia group had larger mean (standard deviation) aortic diameters (mm) in all measured segments from the ascending to the infrarenal aorta (ascending: 33.4 (4.0) vs. 31.4 (3.7), descending: 23.9 (2.1) vs. 23.3 (2.0), diaphragm: 20.8 (1.8) vs. 20.4 (1.8), suprarenal: 22.9 (1.9) vs. 22.0 (2.0), infrarenal: 19.3 (1.6) vs. 18.6 (1.7), p < 0.001 for all, also after adjustment for age, height, parity, menopause, dyslipidemia, smoking and chronic hypertension. Guideline-defined ascending aortic aneurysms were found in 8 vs 2 women (p = 0.12).
CONCLUSIONS
Women with previous pre-eclampsia have larger aortic dimensions compared with women from the general population. Pre-eclampsia was found to be an independent risk factor associated with a larger aortic diameter.
PubMed: 38866633
DOI: 10.1016/j.jcct.2024.06.001 -
Respiratory Care Jun 2024Patients with a tracheostomy and difficult weaning from invasive mechanical ventilation constitute a challenging problem in critical care. An increased duration of...
BACKGROUND
Patients with a tracheostomy and difficult weaning from invasive mechanical ventilation constitute a challenging problem in critical care. An increased duration of ventilation may lead to diaphragmatic dysfunction and a noninvasive assessment of the diaphragm, such as ultrasound, attracts interest in the clinical practice. We evaluated the relationship of ultrasound-derived indices with weaning outcome and with established indices of respiratory strength and load in subjects who are tracheostomized and undergoing weaning.
METHODS
This prospective study was conducted at an academic ICU in Greece. Twenty subjects with tracheostomy and difficult weaning, during a spontaneous breathing trial, underwent time synchronous diaphragmatic sonography and esophageal manometry, to assess diaphragmatic excursion and thickening fraction, esophageal and transdiaphragmatic pressures, pressure-time product of the esophageal pressure, and maximum inspiratory pressure. The primary outcome was liberation from mechanical ventilation at 48 h. The relationship of diaphragmatic ultrasound with esophageal pressure-derived indices was also evaluated.
RESULTS
Weaning from invasive ventilation failed in 10 subjects. Diaphragmatic excursion exhibited a significant difference between weaning success and failure (1.34 ± 0.56 versus 0.79 ± 0.44; = .044), a strong correlation with transdiaphragmatic pressure (r = 0.7, = .02), and a moderate correlation with the pressure-time product of the esophageal pressure (r = 0.65, = .02) and the maximum inspiratory pressure (r = 0.66, = .02). Transdiaphragmatic pressure presented the highest area under the curve (0.97). However, when transdiaphragmatic pressure was compared with diaphragmatic excursion (area under the curve, 0.84) for predictive accuracy, no significant difference was found.
CONCLUSIONS
Diaphragmatic excursion is a valuable tool for the assessment of diaphragmatic strength, respiratory load, and weaning prediction.
PubMed: 38866417
DOI: 10.4187/respcare.11782