Unilateral spinal anaesthesia can be used for inguinal hernia surgery. The advantage is that it provides a stronger block on the side of surgery and accelerated recovery of the nerve block, with ...better maintenance of cardiovascular stability. Hence it can be a valuable technique for high-risk patients.
The aim: This randomized controlled trial was designed to evaluate the onset and duration of Sensory and motor block in both unilateral and bilateral spinal anaesthesia and the adverse effects of buprenorphine given intrathecally with 0.5 % bupivacaine for Spinal anaesthesia in patients scheduled for unilateral inguinal hernia surgery.
Materials and methods: it is a сomparative two group randomized clinical study with 60 patients with 30 patients in Group U (UNILATERAL) and 30 patients in Group B (BILATERAL) is undertaken to study the changes in haemodynamics and side effects. Whereas, within the group (for the unilateral group) comparison of the time taken to reach L1, T12, T10 and the Bromage time between the surgical side and non-surgical side sides of surgery was done.
Results: T10 -T12 spinal anaesthesia was achieved in both groups; the average time to anaesthetic onset in the unilateral group was 5.27±1.2 min, and in the bilateral, it was 5.90±1.02 min (p-value=0.32). Sensory and motor block lasted longer in the bilateral group when compared to the unilateral group; the incidence of side effects was limited to the occurrence of hypotension and bradycardia in the unilateral group than in the bilateral group. The success rate of unilateral spinal anaesthesia in our study was 100 %.
Conclusion: Because of haemodynamic stability and faster recovery characteristics of unilateral spinal block, it can be used as a suitable technique in patients with a limited cardiovascular reserve and for outpatient anaesthesia.
Protein synthesis and autophagy are regulated by cellular ATP content. We tested the hypothesis that mitochondrial dysfunction, including generation of reactive oxygen species (ROS), contributes to ...impaired protein synthesis and increased proteolysis resulting in tissue atrophy in a comprehensive array of models. In myotubes treated with ethanol, using unbiased approaches, we identified defects in mitochondrial electron transport chain components, endogenous antioxidants, and enzymes regulating the tricarboxylic acid (TCA) cycle. Using high sensitivity respirometry, we observed impaired cellular respiration, decreased function of complexes I, II, and IV, and a reduction in oxidative phosphorylation in ethanol-treated myotubes and muscle from ethanol-fed mice. These perturbations resulted in lower skeletal muscle ATP content and redox ratio (NAD+/NADH). Ethanol also caused a leak of electrons, primarily from complex III, with generation of mitochondrial ROS and reverse electron transport. Oxidant stress with lipid peroxidation (thiobarbituric acid reactive substances) and protein oxidation (carbonylated proteins) were increased in myotubes and skeletal muscle from mice and humans with alcoholic liver disease. Ethanol also impaired succinate oxidation in the TCA cycle with decreased metabolic intermediates. MitoTEMPO, a mitochondrial specific antioxidant, reversed ethanol-induced mitochondrial perturbations (including reduced oxygen consumption, generation of ROS and oxidative stress), increased TCA cycle intermediates, and reversed impaired protein synthesis and the sarcopenic phenotype. We show that ethanol causes skeletal muscle mitochondrial dysfunction, decreased protein synthesis, and increased autophagy, and that these perturbations are reversed by targeting mitochondrial ROS.
Overall schema of ethanol-induced mitochondrial function in skeletal muscle. Ethanol impairs ETC function with leak of electrons to generate superoxide (O2-) that causes oxidative injury to tissue and decreases TCA cycle intermediates. Display omitted
•Unbiased approaches showed that ethanol altered muscle mitochondrial regulatory proteins.•Mitochondrial functional studies in situ showed defects in electron transport chain components.•Ethanol increased mitochondrial ROS and oxidative stress in myotubes, human and mouse muscle.•Tricarboxylic acid cycle intermediates were reduced by ethanol in muscle and myotubes.•MitoTempo reversed ethanol induced perturbations in myotubes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Introduction: Hypoxia-mediated damage resulting from vaso-occlusion in sickle cell disease (SCD) leads to abnormal angiogenesis, such as occurs with moyamoya disease and proliferative retinopathy. ...Abnormal angiogenesis in mouse models of SCD has been observed to impact the bone marrow niche, resulting in a structurally abnormal vascular network. A dysfunctional bone marrow environment results in ineffective erythropoiesis and can damage hematopoietic stem cells (HSCs). Healthy HSCs are essential to the maintenance of hemoglobin (Hb) levels regardless of the rapid turnover of red cells and because of their potential as material for gene therapy. Recently, red cell transfusions were shown to reverse pathogenic angiogenesis in a sickle cell mouse model. However, chronic red cell transfusions are difficult to sustain in individuals with SCD due to complications including iron overload, risk of alloimmunization, and the time and cost involved. GBT021601 is a potent sickle Hb polymerization inhibitor that improves the rheology of red blood cells (RBCs) and has been shown to increase total Hb by as much as 3 g/dL. Here, we explore the effectiveness of GBT021601 for restoring bone marrow health and decreasing proangiogenic factors while maintaining the stemness of marrow cells to preserve erythrocyte maturation. Understanding the impact of GBT021601 on aberrant angiogenesis and the function of HSCs will indicate if it has a role in improving the bone marrow niche and HSC fitness in an era of expanded cell-based therapies for SCD. Methods: Nine-week-old, humanized Townes HbSS SCD mice were split into 3 cohorts (n=8 per group: 4 male, 4 female) and for 12 weeks were fed either standard chow (control) or chow containing 0.1% or 0.2% of GBT021601. After 12 weeks, the mice were phlebotomized and euthanized. Spleens were collected and weighed. Whole bone marrow was collected via centrifugation from both tibias and one femur; the other femur was saved for subsequent 3D confocal microscopy. Bone marrow was analyzed using flow cytometry to measure erythroid cell maturation (Annexin V, TER119, and CD44) and HSC markers (Lin, Sca-1, c-kit). Immunoblot analysis was performed on peripheral plasma to measure hypoxia-induced signaling and markers of angiogenesis (VCAM-1, VEGF-A, ANG-1, and -2). Results: Hb increased by 3 g/dL on average with administration of GBT021601, and spleen weights were significantly reduced ( P=0.0023 and P=0.0015 for control vs 0.1% and 0.2%, respectively). Flow cytometry of the extracted bone marrow revealed a significant increase in mature RBCs and a decrease in erythroid progenitors at all stages ( P<0.001 for RBCs and basophils; P=0.04, P=0.002, and P=0.001 for pro-, poly-, and ortho-chromatic erythroblasts, respectively) (Figure 1). HSCs, defined as Lin-Sca-1 +c-kit +, were not significantly different between groups (control vs 0.1%, control vs 0.2%, and for 0.1% vs 0.2%). Immunoblot analysis revealed a reduction in VCAM-1 and ANG-1 markers with administration of GBT021601 relative to control. However, no difference between ANG-2 and VEGF-A markers was observed between treated and control mice (Figure 2). Conclusions: Treatment with GBT021601 was effective at reducing extramedullary hematopoiesis as determined by the reduction in spleen size compared with control mice. VCAM-1 and ANG-1 are increased in HbSS compared with HbAA mice; treatment with GBT021601 reduced factors that contribute to pathogenic angiogenesis. Treatment with GBT021601 did not change ANG-2 and VEGF-A expression; notably, VEGF-A levels are similar between HbSS and HbAA mice. Our findings support GBT021601 as a sustainable treatment to reduce ineffective erythropoiesis and abnormal angiogenesis-which can otherwise damage the bone marrow niche-thereby suggesting a potential benefit for individuals with SCD participating in future cell-based therapies with curative intent and improved outcomes. More work is planned to examine the ability of GBT021601 to normalize the bone marrow environment and reduce the risk of deleterious effects on allogenic or autologous edited HSCs.
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KISLJ, NUK, OILJ, PNG, SAZU, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
The loss of integrity of the glomerular filtration barrier results in proteinuria that is often attributed to podocyte loss. Yet how damaged podocytes are lost remains unknown. Germline loss of ...murine podocyte-associated Hdac1 and Hdac2 ( Hdac1/2 ) results in proteinuria and collapsing glomerulopathy due to sustained double-stranded DNA damage. Hdac1/2 deletion induces loss of podocyte quiescence, cell cycle entry, arrest in G1, and podocyte senescence, observed both in vivo and in vitro . Through the senescence secretory associated phenotype, podocytes secrete proteins that contribute to their detachment. These results solidify the role of HDACs in cell cycle regulation and senescence, providing important clues in our understanding of how podocytes are lost following injury.
Intact expression of podocyte histone deacetylases (HDAC) during development is essential for maintaining a normal glomerular filtration barrier because of its role in modulating DNA damage and preventing premature senescence.
Germline podocyte-specific Hdac1 and 2 ( Hdac1 / 2 ) double-knockout mice were generated to examine the importance of these enzymes during development.
Podocyte-specific loss of Hdac1 / 2 in mice resulted in severe proteinuria, kidney failure, and collapsing glomerulopathy. Hdac1 / 2 -deprived podocytes exhibited classic characteristics of senescence, such as senescence-associated β-galactosidase activity and lipofuscin aggregates. In addition, DNA damage, likely caused by epigenetic alterations such as open chromatin conformation, not only resulted in podocyte cell-cycle entry as shown in vivo by Ki67 expression and by FUCCI-2aR mice, but also in p21-mediated cell-cycle arrest. Through the senescence secretory associated phenotype, the damaged podocytes secreted proinflammatory cytokines, growth factors, and matrix metalloproteinases, resulting in subsequent podocyte detachment and loss, evidenced by senescent podocytes in urine.
Hdac1 / 2 plays an essential role during development. Loss of these genes in double knockout mice leads to sustained DNA damage and podocyte senescence and loss.
The progression of proteinuric kidney diseases is associated with podocyte loss, but the mechanisms underlying this process remain unclear. Podocytes reenter the cell cycle to repair double-stranded ...DNA breaks. However, unsuccessful repair can result in podocytes crossing the G1/S checkpoint and undergoing abortive cytokinesis. In this study, we identified Pfn1 as indispensable in maintaining glomerular integrity - its tissue-specific loss in mouse podocytes resulted in severe proteinuria and kidney failure. Our results suggest that this phenotype is due to podocyte mitotic catastrophe (MC), characterized histologically and ultrastructurally by abundant multinucleated cells, irregular nuclei, and mitotic spindles. Podocyte cell cycle reentry was identified using FUCCI2aR mice, and we observed altered expression of cell-cycle associated proteins, such as p21, p53, cyclin B1, and cyclin D1. Podocyte-specific translating ribosome affinity purification and RNA-Seq revealed the downregulation of ribosomal RNA-processing 8 (Rrp8). Overexpression of Rrp8 in Pfn1-KO podocytes partially rescued the phenotype in vitro. Clinical and ultrastructural tomographic analysis of patients with diverse proteinuric kidney diseases further validated the presence of MC podocytes and reduction in podocyte PFN1 expression within kidney tissues. These results suggest that profilin1 is essential in regulating the podocyte cell cycle and its disruption leads to MC and subsequent podocyte loss.
Time to flowering in the winter growth habit bread wheat is dependent on vernalization (exposure to cold conditions) and exposure to long days (photoperiod). Dominant Vrn-1 (Vrn-A1, Vrn-B1 and ...Vrn-D1) alleles are associated with vernalization-independent spring growth habit. The semidominant Ppd-D1a mutation confers photoperiod-insensitivity or rapid flowering in wheat under short day and long day conditions. The objective of this study was to reveal the nature of interaction between Vrn-1 and Ppd-D1a mutations (active alleles of the respective genes vrn-1 and Ppd-D1b). Twelve Indian spring wheat cultivars and the spring wheat landrace Chinese Spring were characterized for their flowering times by seeding them every month for five years under natural field conditions in New Delhi. Near isogenic Vrn-1 Ppd-D1 and Vrn-1 Ppd-D1a lines constructed in two genetic backgrounds were also phenotyped for flowering time by seeding in two different seasons. The wheat lines of Vrn-A1a Vrn-B1 Vrn-D1 Ppd-D1a, Vrn-A1a Vrn-B1 Ppd-D1a and Vrn-A1a Vrn-D1 Ppd-D1a (or Vrn-1 Ppd-D1a) genotypes flowered several weeks earlier than that of Vrn-A1a Vrn-B1 Vrn-D1 Ppd-D1b, Vrn-A1b Ppd-D1b and Vrn-D1 Ppd-D1b (or Vrn-1 Ppd-D1b) genotypes. The flowering time phenotypes of the isogenic vernalization-insensitive lines confirmed that Ppd-D1a hastened flowering by several weeks. It was concluded that complementary interaction between Vrn-1 and Ppd-D1a active alleles imparted super/very-early flowering habit to spring wheats. The early and late flowering wheat varieties showed differences in flowering time between short day and long day conditions. The flowering time in Vrn-1 Ppd-D1a genotypes was hastened by higher temperatures under long day conditions. The ambient air temperature and photoperiod parameters for flowering in spring wheat were estimated at 25°C and 12 h, respectively.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In an attempt to find the genes involved in salt tolerance of the highly adaptable chickpea rhizobium strain, Mesorhizobium ciceri Ca181, a Tn5 transposon insertion library was generated and screened ...to identify five mutants with inability to survive in the presence of 0.1 M NaCl. The genes disrupted in these mutants due to insertion of the transposon were identified by sequencing of Tn5 flanking sequences after inverse PCR. One of the mutants had a disruption in diguanylate cyclase gene which is involved in bacterial biofilm formation and persistence. The second mutant had a disruption in an ABC transporter membrane protein gene, which is involved in the uptake of nutrients and cellular osmoprotection. The third mutant had a disruption in a gene showing homology with rhamnulose 1-phosphate aldolase which has an important role in the central metabolism of L-rhamnulose. The fourth mutant had a disruption in a capsule synthesis gene and the fifth mutant had an insertion in an oxidoreductase gene. When these mutants were inoculated into the host chickpea plant under normal non-saline conditions, they formed symbiotic nodules but with severely reduced nitrogenase activity. Hence, it appears that bacterial ability to adapt to hyper-osmotic salt stress conditions is also important for its nitrogen fixing ability in the chickpea root nodules. Allele mining for variant forms of the identified genes in the germplasm resources of M. ciceri may help in the development of highly adaptive and efficient nitrogen fixing strains of the chickpea rhizobium.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To understand the role of INSECATUS (INS) gene in pea, the leaf blades of wild-type, ins mutant and seven other genotypes, constructed by recombining ins with uni-tac, af, tl and mfp gene mutations, ...were quantitatively compared. The ins was inherited as a recessive mutant allele and expressed its phenotype in proximal leaflets of full size leaf blades. In ins leaflets, the midvein development was arrested in distal domain and a cleft was formed in lamina above this point. There was change in the identity of ins leaflets such that the intercalary interrupted midvein bore a leaf blade. Such adventitious blades in ins, ins tl and ins tl mfp were like the distal segment of respective main leaf blade. The ins phenotype was not seen in ins af and ins af uni-tac genotypes. There was epistasis of uni-tac over ins. The ins, tl and mfp mutations interacted synergistically to produce highly pronounced ins phenotype in the ins tl mfp triple mutant. The role(s) of INS in leaf-blade organogenesis are: positive regulation of vascular patterning in leaflets, repression of UNI activity in leaflet primordia for ectopic growth and in leaf-blade primordium for indeterminate growth of rachis, delimitation of proximal leaflet domain and together with TL and MFP homeostasis for meristematic activity in leaflet primordia. The variant apically bifid shape of the affected ins leaflets demonstrated that the leaflet shape is dependent on the venation pattern.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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