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BioRxiv : the Preprint Server For... Jun 2024Kidney tubular cells are submitted to two distinct mechanical forces generated by the urine flow: shear stress and hydrostatic pressure. In addition, the mechanical...
Kidney tubular cells are submitted to two distinct mechanical forces generated by the urine flow: shear stress and hydrostatic pressure. In addition, the mechanical properties of the surrounding extracellular matrix modulate tubule deformation under constraints. These mechanical factors likely play a role in the pathophysiology of kidney diseases as exemplified by autosomal dominant polycystic kidney disease, in which pressure, flow and matrix stiffness have been proposed to modulate the cystic dilation of tubules with mutations. The lack of systems recapitulating the mechanical environment of kidney tubules impedes our ability to dissect the role of these mechanical factors. Here we describe a perfused kidney-on-chip with tunable extracellular matrix mechanical properties and hydrodynamic constraints, that allows a decoupling of shear stress and flow. We used this system to dissect how these mechanical cues affect tubule dilation. Our results show two distinct mechanisms leading to tubular dilation. For PCT cells (proximal tubule), overproliferation mechanically leads to tubular dilation, regardless of the mechanical context. For mIMCD-3 cells (collecting duct), tube dilation is associated with a squamous cell morphology but not with overproliferation and is highly sensitive to extracellular matrix properties and hydrodynamic constraints. Surprisingly, flow alone suppressed mIMCD-3 tubule dilation observed in static conditions, while the addition of luminal pressure restored it. Our model emulating nephron geometrical and mechanical organization sheds light on the roles of mechanical constraints in ADPKD and demonstrates the importance of controlling intraluminal pressure in kidney tubule models.
PubMed: 38948811
DOI: 10.1101/2024.06.18.599137 -
World Journal of Hepatology Jun 2024The standard approach to organ preservation in liver transplantation is by static cold storage and the time between the cross-clamping of a graft in a donor and its...
The standard approach to organ preservation in liver transplantation is by static cold storage and the time between the cross-clamping of a graft in a donor and its reperfusion in the recipient is defined as cold ischemia time (CIT). This simple definition reveals a multifactorial time frame that depends on donor hepatectomy time, transit time, and recipient surgery time, and is one of the most important donor-related risk factors which may influence the graft and recipient's survival. Recently, the growing demand for the use of marginal liver grafts has prompted scientific exploration to analyze ischemia time factors and develop different organ preservation strategies. This review details the CIT definition and analyzes its different factors. It also explores the most recent strategies developed to implement each timestamp of CIT and to protect the graft from ischemic injury.
PubMed: 38948435
DOI: 10.4254/wjh.v16.i6.883 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024To investigate the effects of intrauterine perfusion with granulocyte colony-stimulating factor (G-CSF) on the endometrial thickness, volume, and blood flow parameters...
[Effect of Intrauterine Perfusion of Granulocyte Colony-Stimulating Factor on Endometrium and Blood Flow Parameters in Patients With Thin Endometrium: A Prospective Controlled Clinical Trial].
OBJECTIVE
To investigate the effects of intrauterine perfusion with granulocyte colony-stimulating factor (G-CSF) on the endometrial thickness, volume, and blood flow parameters of patients with thin endometrium and their clinical outcomes.
METHODS
We designed a prospective non-randomized synchronous controlled trial and recruited patients with thin endometrium who underwent frozen-thawed embryo transfer (FET) at Mianyang Central Hospital between September 1, 2021 and September 1, 2023. They were divided into two groups, an experimental group of patients who received the experimental treatment of intrauterine perfusion with G-CSF and a control group of patients who did not receive the experimental treatment. The general data and the clinical outcomes of the two groups were analyzed and compared. The endometrial thickness, volume and blood flow parameters of patients in the experimental group before and after intrauterine perfusion with G-CSF were analyzed.
RESULTS
The clinical data of 83 patients were included in the study. The experimental group included 51 cases, while the control group included 31 cases. There were no significant differences in the baseline data between the two groups. The clinical pregnancy rate of the experimental group (56.86%) was higher than that of the control group (50.00%) and the rate of spontaneous abortion in the experimental group (27.59%) was lower than that in the control group (37.50%), but the differences were not statistically significant (>0.05). In the experimental group, the postperfusion endometrial thickness ([0.67±0.1] cm) was greater than the preperfusion endometrial thickness ([0.59±0.09] cm), the postperfusion ([1.84±0.81] cm) was greater than the preperfusion endometrial volume ([1.54±0.69] cm), and the postperfusion vascularization flow index (VFI) (1.97±2.82) was greater than the preperfusion VFI (0.99±1.04), with all the differences being statistically significant (<0.05).
CONCLUSION
Intrauterine perfusion with G-CSF can enhance the endometrial thickness, volume, and some blood flow parameters in patients with thin endometrium.
Topics: Humans; Female; Endometrium; Granulocyte Colony-Stimulating Factor; Prospective Studies; Pregnancy; Embryo Transfer; Pregnancy Rate; Adult; Perfusion
PubMed: 38948297
DOI: 10.12182/20240560504 -
JPRAS Open Sep 2024Flap necrosis continues to occur in skin free flap autologous breast reconstruction. Therefore, we investigated the benefits of indocyanine green angiography (ICGA)...
Flap necrosis continues to occur in skin free flap autologous breast reconstruction. Therefore, we investigated the benefits of indocyanine green angiography (ICGA) using quantitative parameters for the objective, perioperative evaluation of flap perfusion. In addition, we investigated the feasibility of hyperspectral (HSI) and thermal imaging (TI) for postoperative flap monitoring. A single-center, prospective observational study was performed on 15 patients who underwent deep inferior epigastric perforator (DIEP) flap breast reconstruction (n=21). DIEP-flap perfusion was evaluated using ICGA, HSI, and TI using a standardized imaging protocol. The ICGA perfusion curves and derived parameters, HSI extracted oxyhemoglobin (oxyHb) and deoxyhemoglobin (deoxyHb) values, and flap temperatures from TI were analyzed and correlated to the clinical outcomes. Post-hoc quantitative analysis of intraoperatively collected data of ICGA application accurately distinguished between adequately and insufficiently perfused DIEP flaps. ICG perfusion curves identified the lack of arterial inflow (n=2) and occlusion of the venous outflow (n=1). In addition, a postoperatively detected partial flap epidermolysis could have been predicted based on intraoperative quantitative ICGA data. During postoperative monitoring, HSI was used to identify impaired perfusion areas within the DIEP flap based on deoxyHb levels. The results of this study showed a limited added value of TI. Quantitative, post-hoc analysis of ICGA data produced objective and reproducible parameters that enabled the intraoperative detection of arterial and venous congested DIEP flaps. HSI appeared to be a promising technique for postoperative flap perfusion assessment. A diagnostic accuracy study is needed to investigate ICGA and HSI parameters in real-time and demonstrate their clinical benefit.
PubMed: 38948075
DOI: 10.1016/j.jpra.2024.04.007 -
World Journal of Transplantation Jun 2024Portal vein arterialization (PVA) has been used in liver transplantation (LT) to maximize oxygen delivery when arterial circulation is compromised or has been used as an...
BACKGROUND
Portal vein arterialization (PVA) has been used in liver transplantation (LT) to maximize oxygen delivery when arterial circulation is compromised or has been used as an alternative reperfusion technique for complex portal vein thrombosis (PVT). The effect of PVA on portal perfusion and primary graft dysfunction (PGD) has not been assessed.
AIM
To examine the outcomes of patients who required PVA in correlation with their LT procedure.
METHODS
All patients receiving PVA and LT at the Fundacion Santa Fe de Bogota between 2011 and 2022 were analyzed. To account for the time-sensitive effects of graft perfusion, patients were classified into two groups: prereperfusion (pre-PVA), if the arterioportal anastomosis was performed before graft revascularization, and postreperfusion (post-PVA), if PVA was performed afterward. The pre-PVA rationale contemplated poor portal hemodynamics, severe vascular steal, or PVT. Post-PVA was considered if graft hypoperfusion became evident. Conservative interventions were attempted before PVA.
RESULTS
A total of 25 cases were identified: 15 before and 10 after graft reperfusion. Pre-PVA patients were more affected by diabetes, decompensated cirrhosis, impaired portal vein (PV) hemodynamics, and PVT. PGD was less common after pre-PVA (20.0% 60.0%) ( = 0.041). Those who developed PGD had a smaller increase in PV velocity (25.00 cm/s 73.42 cm/s) ( = 0.036) and flow (1.31 L/min 3.34 L/min) ( = 0.136) after arterialization. Nine patients required PVA closure (median time: 62 d). Pre-PVA and non-PGD cases had better survival rates than their counterparts (56.09 months 22.77 months and 54.15 months 31.91 months, respectively).
CONCLUSION
This is the largest report presenting PVA in LT. Results suggest that pre-PVA provides better graft perfusion than post-PVA. Graft hyperperfusion could play a protective role against PGD.
PubMed: 38947972
DOI: 10.5500/wjt.v14.i2.92528 -
Cureus May 2024Platypnea-orthodeoxia syndrome (POS) is a rare condition characterized by dyspnea and oxygen desaturation that worsens in the upright position and improves when lying...
Platypnea-orthodeoxia syndrome (POS) is a rare condition characterized by dyspnea and oxygen desaturation that worsens in the upright position and improves when lying down. We report the case of a 67-year-old male who presented with a 14-month history of dyspnea in the sitting/standing position. Despite treatment for suspected asthma, his symptoms persisted, and he was referred to our hospital for further evaluation. Physical examination and arterial blood gas analysis confirmed the presence of POS, with a significant decrease in PaO and SpO when moving from a supine to an upright position. Contrast-enhanced CT showed no obvious embolism nor arteriovenous fistula, and ventilation-perfusion scintigraphy demonstrated ventilation-perfusion mismatch with a right-to-left shunt fraction of 9.4%, without any focal defect. Transthoracic echocardiography with a microbubble test demonstrated a right-to-left shunt that increased in the upright position. Transesophageal echocardiography revealed an atrial septal defect (ASD) with an atrial septal aneurysm and the presence of an inferior vena cava valve, causing a bidirectional shunt. The patient was diagnosed with POS secondary to ASD and was referred for percutaneous closure of the defect. Following the procedure, the shunt resolved, and the patient's orthostatic oxygen desaturation improved. This case highlights the importance of considering POS in patients with positional dyspnea and the value of performing diagnostic tests, such as echocardiography, in different positions to identify the underlying cause. Early recognition and appropriate management of POS can significantly improve patients' quality of life and prevent complications associated with chronic hypoxemia.
PubMed: 38947622
DOI: 10.7759/cureus.61260 -
Journal of Cancer 2024Tumor hypoxia has been frequently detected in nasopharyngeal carcinoma (NPC) and is intently associated with therapeutic resistance. The aim of the study is to...
Establishment and Application of Novel Hypoxia-driven Dual-reporter Model to Investigate Hypoxic Impact on Radiation Sensitivity in Human Nasopharyngeal Carcinoma Xenografts.
Tumor hypoxia has been frequently detected in nasopharyngeal carcinoma (NPC) and is intently associated with therapeutic resistance. The aim of the study is to establish a clonogenically stable hypoxia-inducible dual reporter model and apply it to investigate the effect of tumor hypoxia on DNA double strand break (DSB) and synergistic effect of irradiation in combination with chemotherapy or targeted therapy. The plasmid vector consisting of hypoxia response elements to regulate HSV1-TK and GFP genes, was constructed and stably transfected into human NPC cells. The expected clone was identified and validated by and assay. DSB repair was measured by γH2AX foci formation. Tumor growth delay assay and spatial biodistribution of various biomarkers was designed to investigate the anti-tumor effect. The system has the propensity of high expression of reporter genes under hypoxia and low to no expression under normoxia. Intratumoral biodistributions of GFP and classic hypoxic biomarkers were identical in poor-perfused region. Upon equilibration with 10% O, the xenografts showed higher expression of hypoxic biomarkers. Cisplatin radiosensitized SUNE-1/HRE cells under hypoxia by suppressing DSB repair while the addition of PI3K/mTOR inhibitor further enhanced the anti-tumoral therapeutic efficacy. Combination of IR, DDP and NVP-BEZ235 exhibited most effective anti-tumor response . These observations underline the importance of dual reporter model for imaging tumor hypoxia in therapeutic study. Our preclinical model enables the investigation of heterogeneous tumor hypoxic regions in xenograft tissues and explores the treatment efficacy of combinations of various therapeutic approaches to overcome hypoxia.
PubMed: 38947402
DOI: 10.7150/jca.96378 -
Frontiers in Molecular Neuroscience 2024It is generally accepted that hydrocephalus is a consequence of the disbalance between cerebrospinal fluid (CSF) secretion and absorption which should in turn lead to...
Changes of cerebrospinal fluid pressure gradient in different body positions under experimental impairment of cerebrospinal fluid pathway: new insight into hydrocephalus development.
It is generally accepted that hydrocephalus is a consequence of the disbalance between cerebrospinal fluid (CSF) secretion and absorption which should in turn lead to CSF pressure gradient development and ventricular enlargement. To test CSF pressure gradient role in hydrocephalus development, we experimentally caused CSF system impairment at two sites in cats. In the first group of animals, we caused Sylvian aqueduct obstruction and recorded CSF pressure changes pre and post obstruction at three measuring sites (lateral ventricle -LV, cortical-CSS and lumbar subarachnoid space -LSS) during 15 min periods and in different body positions over 360 degrees. In the second group of experiments, we caused cervical stenosis by epidural plastic semiring implantation and monitored CSF pressure changes pre and post stenosis implantation at two measuring sites (lateral ventricle and lumbar subarachnoid space) during 15 min periods in different body positions over 360 degrees. Both groups of experimental animals had similar CSF pressures before stenosis or obstruction at all measuring points in the horizontal position. During head-up verticalization, CSF pressures inside the cranium gradually became more subatmospheric with no significant difference between LV and CSS, as they are measured at the same hydrostatic level, while CSF pressure inside LSS became more positive, causing the development of a large hydrostatic gradient between the cranial and the spinal space. With cervical stenosis, CSF pressure inside the cranium is positive during head-up verticalization, while in cats with aqueductal obstruction CSF pressure inside the CSS remains negative, as it was during control period. Concomitantly, CSF pressure inside LV becomes less negative, thus creating a small hydrostatic gradient between LV and CSS. Since CSF pressure and gradient changes occur only by shifting body position from the horizontal plane, our results indicate that cervical stenosis in a head-up vertical position reduces blood perfusion of the whole brain, while aqueductal obstruction impairs only the perfusion of the local periventricular brain tissue. It seems that, for evolutionary important bipedal activity, free craniospinal communication and good spinal space compliance represent crucial biophysical parameters for adequate cerebral blood perfusion and prevention of pathophysiological changes leading to the development of hydrocephalus.
PubMed: 38947218
DOI: 10.3389/fnmol.2024.1397808 -
Research Square Jun 2024Static cold storage of donor livers at 4°C incompletely arrests metabolism, ultimately leading to decreases in ATP levels, oxidative stress, cell death, and organ...
Static cold storage of donor livers at 4°C incompletely arrests metabolism, ultimately leading to decreases in ATP levels, oxidative stress, cell death, and organ failure. Hydrogen Sulfide (H S) is an endogenously produced gas, previously demonstrated to reduce oxidative stress, reduce ATP depletion, and protect from ischemia and reperfusion injury. H S is difficult to administer due to its rapid release curve, resulting in cellular death at high concentrations. AP39, a mitochondrially targeted, slow-release H S donor, has been shown to reduce ischemia-reperfusion injury in hearts and kidneys. Thus, we investigated whether the addition of AP39 during 3-day static cold storage can improve liver graft viability. At the end of storage, livers underwent six hours of acellular normothermic machine perfusion, a model of transplantation. During simulated transplantation, livers stored with AP39 showed reduced resistance, reduced cellular damage (ALT and AST), and reduced apoptosis. Additionally, bile production and glucose, as well as energy charge were improved by the addition of AP39. These results indicate that AP39 supplementation improves liver viability during static cold storage.
PubMed: 38947096
DOI: 10.21203/rs.3.rs-4487319/v1 -
Research Square Jun 2024Background and Purpose Impaired cerebral circulation, induced by blood vessel constrictions and microthrombi, leads to delayed cerebral ischemia after subarachnoid...
Background and Purpose Impaired cerebral circulation, induced by blood vessel constrictions and microthrombi, leads to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). 12/15-Lipooxygenase (12/15-LOX) overexpression has been implicated in worsening early brain injury outcomes following SAH. However, it is unknown if 12/15-LOX is important in delayed pathophysiological events after SAH. Since 12/15-LOX produces metabolites that induce inflammation and vasoconstriction, we hypothesized that 12/15-LOX leads to microvessel constriction and microthrombi formation after SAH, and thus 12/15-LOX is an important target to prevent delayed cerebral ischemia. Methods SAH was induced in C57BL/6 and 12/15-LOX mice of both sexes by endovascular perforation. Expression of 12/15-LOX was assessed in brain tissue slices and . C57BL/6 mice were administered either ML351 (12/15-LOX inhibitor) or vehicle. Mice were evaluated for daily neuroscore and euthanized on day five to assess cerebral 12/15-LOX expression, vessel constrictions, platelet activation, microthrombi, neurodegeneration, infarction, cortical perfusion, and for development of delayed deficits. Finally, the effect of 12/15-LOX inhibition on platelet activation was assessed in SAH patient samples using a platelet spreading assay. Results In SAH mice, 12/15-LOX was upregulated in brain vascular cells and there was an increase in 12-S-HETE. Inhibition of 12/15-LOX improved brain perfusion on days 4-5 and attenuated delayed pathophysiological events, including microvessel constrictions, microthrombi, neuronal degeneration, and infarction. Additionally, 12/15-LOX inhibition reduced platelet activation in human and mouse blood samples. Conclusions Cerebrovascular 12/15-LOX overexpression plays a major role in brain dysfunction after SAH by triggering microvessel constrictions and microthrombi formation, which reduces brain perfusion. Inhibiting 12/15-LOX may be a therapeutic target to improve outcomes after SAH.
PubMed: 38947083
DOI: 10.21203/rs.3.rs-4468292/v1