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American Journal of Physiology. Renal... May 2024In the aftermath of acute kidney injury (AKI), surviving proximal tubule epithelia repopulate injured tubules to promote repair. However, a portion of cells fail to...
In the aftermath of acute kidney injury (AKI), surviving proximal tubule epithelia repopulate injured tubules to promote repair. However, a portion of cells fail to repair [termed failed-repair proximal tubule cells (FR-PTCs)] and exert ongoing proinflammatory and profibrotic effects. To better understand the molecular drivers of the FR-PTC state, we reanalyzed a mouse ischemia-reperfusion injury single-nucleus RNA-sequencing (snRNA-seq) atlas to identify Traf2 and Nck interacting kinase () to be exclusively expressed in FR-PTCs but not in healthy or acutely injured proximal tubules after AKI (2 and 6 wk) in mice. We confirmed expression of Tnik protein in injured mouse and human tissues by immunofluorescence. Then, to determine the functional role of Tnik in FR-PTCs, we depleted with siRNA in two human renal proximal tubule epithelial cell lines (primary and immortalized hRPTECs) and analyzed each by bulk RNA-sequencing. Pathway analysis revealed significant upregulation of inflammatory signaling pathways, whereas pathways associated with differentiated proximal tubules such as organic acid transport were significantly downregulated. gene knockdown drove reduced cell viability and increased apoptosis, including differentially expressed poly(ADP-ribose) polymerase () family members, cleaved PARP-1 fragments, and increased annexin V binding to phosphatidylserine. Together, these results indicate that Tnik upregulation in FR-PTCs acts in a compensatory fashion to suppress inflammation and promote proximal tubule epithelial cell survival after injury. Modulating TNIK activity may represent a prorepair therapeutic strategy after AKI. The molecular drivers of successful and failed repair in the proximal tubule after acute kidney injury (AKI) are incompletely understood. We identified Traf2 and Nck interacting kinase () to be exclusively expressed in failed-repair proximal tubule cells after AKI. We tested the effect of si depletion in two proximal tubule cell lines followed by bulk RNA-sequencing analysis. Our results indicate that TNIK acts to suppress inflammatory signaling and apoptosis in injured renal proximal tubule epithelial cells to promote cell survival.
Topics: Kidney Tubules, Proximal; Animals; Apoptosis; Acute Kidney Injury; Epithelial Cells; Humans; Protein Serine-Threonine Kinases; TNF Receptor-Associated Factor 2; Reperfusion Injury; Signal Transduction; Disease Models, Animal; Mice; Mice, Inbred C57BL; Cell Line; Inflammation; Male
PubMed: 38482555
DOI: 10.1152/ajprenal.00262.2023 -
Clinical and Experimental Nephrology Jul 2024The time for diabetic nephropathy (DN) to progress from mild to severe is long. Thus, methods to continuously repress DN are required to exert long-lasting effects... (Review)
Review
The time for diabetic nephropathy (DN) to progress from mild to severe is long. Thus, methods to continuously repress DN are required to exert long-lasting effects mediated through epigenetic regulation. In this study, we demonstrated the ability of nicotinamide adenine dinucleotide (NAD) and its metabolites to reduce albuminuria through Sirt1- or Nampt-dependent epigenetic regulation. We previously reported that proximal tubular Sirt1 was lowered before glomerular Sirt1. Repressed glomerular Sirt1 was found to epigenetically elevate Claudin-1. In addition, we reported that proximal tubular Nampt deficiency epigenetically augmented TIMP-1 levels in Sirt6-mediated pathways, leading to type-IV collagen deposition and diabetic fibrosis. Altogether, we propose that the Sirt1/Claudin-1 axis may be crucial in the onset of albuminuria at the early stages of DN and that the Nampt/Sirt6/TIMP-1 axis promotes diabetic fibrosis in the middle to late stages of DN. Finally, administration of NMN, an NAD precursor, epigenetically potentiates the regression of the onset of DN to maintain Sirt1 and repress Claudin-1 in podocytes, suggesting the potential use of NAD metabolites as epigenetic medications for DN.
Topics: Animals; Humans; Albuminuria; Claudin-1; Cytokines; Diabetic Nephropathies; Epigenesis, Genetic; Fibrosis; Kidney Tubules, Proximal; Mice, Inbred C57BL; Mice, Knockout; NAD; Nicotinamide Mononucleotide; Nicotinamide Phosphoribosyltransferase; Podocytes; Sirtuin 1; Sirtuins; Tissue Inhibitor of Metalloproteinase-1
PubMed: 38587753
DOI: 10.1007/s10157-024-02502-w -
Medicina (Kaunas, Lithuania) Dec 2023The incidence of proximal femoral fractures is escalating rapidly, generating a significant challenge for healthcare systems globally and, carrying serious social and... (Review)
Review
The incidence of proximal femoral fractures is escalating rapidly, generating a significant challenge for healthcare systems globally and, carrying serious social and economic implications. The primarily object of this study was to discover potential distinguishing factors between fractures occurring in the femoral neck and trochanteric region. We performed a prospective cohort study of the radiographic images of 70 people over 65 years of age who were admitted to the orthopedic department with hip fracture and who fulfilled our eligibility criteria. Neck Length (NL), Offset Lenth (OL), Hip Axis Length (HAL), Neck Shaft Angle (NSA), Wiberg Angle (WA), Acetabular Angle (AA), Femoral Neck Diameter (FND), Femoral Head Diameter (FHD), Femoral Shaft Diameter (FSD), Femoral Canal Diameter (FCD) and Tonnis classification were recorded. For the comparison of the categorical variables, Pearson's χ2 criterion was used, while Student's -test was applied for the comparison of means of quantitative variables across fracture types. There were no statistically significant variances observed while comparing the selected geometric parameters of the proximal femur with the type of fracture. This finding was reaffirmed in relation to age, gender, and Tonnis classification. However, a moderate correlation was noted, revealing comparatively reduced values of HAL, FHD, and FND in women as opposed to men. The inability of our research to establish the differentiative geometric factors between femoral neck and trochanteric fractures underscores the need for further investigations, which would take into consideration the intrinsic characteristics of the proximal femur.
Topics: Male; Humans; Female; Femoral Neck Fractures; Proximal Femoral Fractures; Prospective Studies; Bone Density; Hip Fractures; Femur
PubMed: 38138234
DOI: 10.3390/medicina59122131 -
Journal of Maxillofacial and Oral... Dec 2023This retrospective study aimed to determine the angulation changes of the proximal segment following bilateral sagittal split osteotomy (BSSO) setback and its...
OBJECTIVES
This retrospective study aimed to determine the angulation changes of the proximal segment following bilateral sagittal split osteotomy (BSSO) setback and its correlation with the amount of immediate postoperative surgical movement. The correlation between postoperative relapse of the distal and proximal segment at six months postoperatively was also evaluated.
MATERIALS AND METHODS
The CBCT-generated lateral cephalometric images of 39 patients who underwent BSSO setback with or without Le Fort I osteotomy were evaluated preoperatively (0), immediately postoperative (1), and six months postoperatively (2).
RESULTS
The mean surgical setback was 7.28 ± 4.45 mm at B point. The proximal segment's immediate postoperative mean posterior rotation was 2.13 ± 3.59 degrees. Six months after the operation, the mean distal segment relapse was 0.89 ± 3.03 mm at B point. The proximal segment relapse was 0.81 ± 1.63 degrees. A significant moderate correlation was found ( < 0.05) between the surgical movement and the immediate postoperative proximal segment rotation and between the surgical movement and the distal segment relapse. A significant correlation was found between the distal segment relapse and the average and left proximal segment relapse. There was no significant correlation between immediate postoperative proximal segment rotation and distal segment relapse.
CONCLUSION
The immediate postoperative posterior rotation of the proximal segment had a negligible effect on mandibular relapse. The amount of surgical movement, on the other hand, was more related to distal segment relapse. The intraoperative proximal segment rotation should thus be minimized in cases with a significant surgical setback.
PubMed: 38105835
DOI: 10.1007/s12663-022-01760-z -
European Journal of Trauma and... Apr 2024In the past, preinjury direct oral anticoagulant (DOAC) intake has led to delays in time to surgery (TTS) in patients with proximal femur fractures and delays in surgery... (Review)
Review
PURPOSE
In the past, preinjury direct oral anticoagulant (DOAC) intake has led to delays in time to surgery (TTS) in patients with proximal femur fractures and delays in surgery have been associated with impaired outcomes. Although healthcare institutions/federal committees have set rules for treatment within 24 h of injury, comprehensive guidelines for the perioperative management of these patients, in particular when on preinjury DOACs, are still lacking. This contribution aims to summarize the current evidence on the safe time window for surgery in patients with proximal femur fractures on preinjury DOACs and to outline therapeutic options if emergency DOAC reversal becomes necessary.
METHODS
Narrative review based upon selective review of the pertinent literature.
RESULTS
For the majority of patients with proximal femur fractures and on preinjury DOACs, early surgery appears safe as soon as medical clearance has been obtained. There may be an increase in the need for blood products but with data not yet conclusive. Work-up including assessment of remaining anticoagulant activity and potential reversal should be restricted to patients at risk for bleeding complications, in particular in the presence of renal/hepatic impairment. Methodology for rapid assessment of DOACs including quantitative/qualitative concentration levels is work in progress. In the case of bleeding, rapidly acting reversal agents are available.
CONCLUSION
Preinjury DOAC use should not routinely delay surgery in patients with proximal femur fractures.
Topics: Humans; Anticoagulants; Time-to-Treatment; Administration, Oral; Femoral Fractures; Hemorrhage; Hip Fractures; Factor Xa Inhibitors; Proximal Femoral Fractures
PubMed: 38400927
DOI: 10.1007/s00068-024-02472-4 -
Journal of Clinical Orthopaedics and... Sep 2023Humeral shaft fractures are common injuries treated by orthopaedic surgeons. The purpose of this study is to evaluate displaced diaphyseal humerus fractures and describe...
INTRODUCTION
Humeral shaft fractures are common injuries treated by orthopaedic surgeons. The purpose of this study is to evaluate displaced diaphyseal humerus fractures and describe the incidence and characteristics associated with non or minimally displaced fracture line extension into the proximal metadiaphyseal region of the humerus.
METHODS AND MATERIALS
All adult patients with diaphyseal humeral shaft fractures located within the distal two-thirds of the humeral shaft, treated at a single level I trauma institution between 2007 and 2020, were retrospectively identified. 202 patients with 203 fractures of the humeral shaft were included. Fracture patterns were classified according to AO/OTA classification and fracture line extension into the proximal metadiaphyseal region was evaluated on radiographs. Patient demographics, management details, and radiographic outcomes were obtained from review of the electronic medical record.
RESULTS
Of 203 diaphyseal humerus fractures, 11.8 % (n = 24) had non or minimally displaced proximal extension of their main fracture line. This included 43.7 % (n = 7) of all proximal third junction diaphyseal fractures, 10.7 % (n = 16) of all middle third diaphyseal fractures, and 2.6 % (n = 1) of all distal third diaphyseal fractures. Patients with proximal fracture extension were, on average, older (61.7 versus 44.4 years, p < 0.001), and a higher percentage were female (75 % versus 45.5 %, p < 0.01) compared to patients without fracture proximal extension. Fractures with proximal extension were all closed fractures (n = 24), were more often sustained from low-energy fall (87.5 % versus 35.2 %, p < 0.001), and were more often spiral type fractures (62.5 % versus 17.2 %). Fractures with proximal extension were more often treated non-operatively (58.3 % versus 42.1 %, p < 0.01), but were found to have a higher rate of nonunion after non-operative treatment (17.6 % versus 8.1 %) compared to fractures without proximal extension. All operatively treated fractures that had proximal metaphyseal extension were secured with a fixation construct to achieve fixation proximal to the extent of the fracture line, most often into the humeral head and neck. Operative management with proximal fixation into the humeral head was also pursued for a patient with nonunion, including persistent lucency of the proximal extension line, after failed non-operative treatment. Mean follow-up was 35.5 weeks (range: 0-607 weeks).
CONCLUSIONS
Proximal fracture line extension in the setting of diaphyseal humerus fractures is not uncommon. Detection and consideration of this sometimes subtle finding is important when planning to treat these injuries operatively.
PubMed: 37860085
DOI: 10.1016/j.jcot.2023.102248 -
Radiologie (Heidelberg, Germany) Nov 2023This study was designed to investigate the use of proximal femoral Hounsfield units (HU) in conventional abdominal and pelvic computed tomography (CT) to predict hip...
OBJECTIVE
This study was designed to investigate the use of proximal femoral Hounsfield units (HU) in conventional abdominal and pelvic computed tomography (CT) to predict hip osteoporosis by coupling with data from quantitative CT (QCT).
METHODS
In this study, 315 patients who underwent routine abdominal and pelvic CT with the proximal femur included in the scanning range were also subjected to QCT of the proximal femur. Pearson correlation test was performed to analyze the correlations of the femoral head, femoral neck, proximal femur, and femoral trochanter CT HU with the femoral neck, femoral trochanter, and intertrochanteric femur bone mineral density (BMD) values from QCT. The diagnostic performance of CT HU measurement of the proximal femur for osteoporosis was analyzed using receiver operating characteristic (ROC) curves.
RESULTS
The CT HU of the proximal femur showed the highest correlation with the BMD value of the hip (r = 0.826; p < 0.01). The mean CT HU of the proximal femur differed significantly (all p < 0.01) for the three QCT-defined BMD categories of osteoporosis (192.23 HU vs. 188.71), of osteopenia (247.86 HU vs. 248.36 HU), and of normal individuals (308.13 HU vs. 310.41 HU) in left and right sides, respectively. In the ROC curve analysis, the area under the ROC curve values to predict osteoporosis in the left and right proximal femurs were 0.942 and 0.941, respectively.
CONCLUSION
The CT HU of the proximal femur was significantly associated with the BMD value of the hip measured by QCT. The CT HU of the proximal femur is highly effective in diagnosing osteoporosis and could be used for hip osteoporosis screening.
Topics: Humans; Bone Density; Absorptiometry, Photon; Osteoporosis; Femur; Tomography, X-Ray Computed
PubMed: 37603067
DOI: 10.1007/s00117-023-01190-z -
Journal of the American Veterinary... Dec 2023To determine the proximal diffusion distance of radiopaque contrast medium and mepivacaine/methylene blue solution and incidence of inadvertent intrasynovial and...
Modified abaxial sesamoid nerve block provides enhanced proximal diffusion compared to basisesamoid block and lower proximal diffusion than traditional low plantar nerve block in equine hind limbs: ex vivo and in vivo study.
OBJECTIVE
To determine the proximal diffusion distance of radiopaque contrast medium and mepivacaine/methylene blue solution and incidence of inadvertent intrasynovial and intravascular injections of modified sesamoid nerve block (MASB) when compared with traditional plantar nerve analgesia techniques of the equine distal hind limb.
SAMPLE
Ex vivo model: 18 hind limbs; and in vivo model: 5 horses in a crossover study.
METHODS
In the ex vivo model, a mepivacaine/methylene blue solution was used to compare the diffusion distance between MASB, basisesamoid block (BSB), and traditional low plantar block (TLPB). Ten minutes after injection, skin was dissected and proximal diffusion distance of the dye patch was measured. In the in vivo model, both hind limbs were injected with radiopaque contrast medium with either MASB or TLPB. Ten minutes after injection, a radiograph was acquired and the proximal diffusion of the contrast medium patch was measured.
RESULTS
In the ex vivo model, solution proximal diffusion distance for MASB was significantly longer than BSB (P < .050) and significantly shorter than TLPB (P < .050). Both techniques reached the proximal aspect of DFTS similarly (P = .289), and no difference in the incidence of intrasynovial or intravascular injections was observed (P = .292). In the in vivo model, contrast medium proximal diffusion of MASB was significantly shorter than TLPB (P < .050). The proportion of injections that diffused subcutaneously to the proximal aspect of the proximal pouch of the DFTS was not significantly different between techniques (P = .136). No difference in the incidence of DFTS intrasynovial or intravascular injections was observed (P = .305).
CLINICAL RELEVANCE
MASB presented significantly more proximal diffusion than BSB and less proximal diffusion than TLPB, consistently reached the proximal aspect of DFTS, and presented a very low risk of intrasynovial and intravascular injections.
Topics: Horses; Animals; Mepivacaine; Cross-Over Studies; Methylene Blue; Contrast Media; Nerve Block; Anesthetics, Local
PubMed: 37643724
DOI: 10.2460/javma.23.04.0212